Thyroid Papillary Carcinoma, Follicular (and Encapsulated) Variant Bruce M. Wenig Beth Israel Medical Center New York City

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Clinical History A 67 year old female presented with a right neck mass. Work-up revealed a "cold" nodule in the right lobe of the thyroid gland. A fine needle aspiration biopsy was performed with a diagnosis of "atypical follicular lesion, highly suspicious for thyroid papillary carcinoma" with the recommendation for surgical resection of the thyroid lobe with intraoperative evaluation. At the time of surgery, frozen section was performed with a diagnosis of "follicular epithelial cell lesion, defer to permanent sections". A right thyroid lobectomy and isthmusectomy was performed. A well-circumscribed nodule measuring 2.1 cm in greatest dimension was identified in the right lobe of the thyroid gland. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 Low magnification showing the presence of a well-circumscribed follicular epithelial cell lesion. Figure 2 Slightly higher magnification showing the well-circumscribed follicular epithelial cell lesion within which are scattered areas of apparent increased cellularity. Figure 3 At higher magnification, areas of this lesion show round and regular appearing nuclei with coarse nuclear chromatin. Figure 4 At higher magnification, areas of this lesion show round and regular appearing nuclei with coarse nuclear chromatin. Figure 5 At higher magnification, areas of this lesion show the presence of enlarged nuclei with irregularities in size and shape, dispersed to optical clear appearing nuclear chromatin, nuclear crowding and overlapping, and nuclear grooves. Figure 6 At higher magnification, areas of this lesion show the presence of enlarged nuclei with irregularities in size and shape, dispersed to optical clear appearing nuclear chromatin, nuclear crowding and overlapping, and nuclear grooves. Thyroid Neoplasms - General Considerations Thyroid cancer is the most common endocrine malignancy but represents less than 2% of all human cancers diagnosed in the United States. The percentage of cancer deaths (mortality rate) due to thyroid cancer is low (0.4%). Clinically apparent thyroid nodules occur in a fairly large percentage of the population (up to 10%); while many of these nodules are probably benign, the differential diagnosis of any thyroid nodule includes a malignant thyroid neoplasm. The vast majority of thyroid tumors are of follicular epithelial cell origin and include follicular adenoma, follicular carcinoma and papillary carcinoma, and variants thereof; less common are the C cell-derived thyroid medullary carcinoma. Nonepithelial neoplasms of the thyroid are uncommon; the most common non-epithelial thyroid neoplasm is malignant lymphoma; rarely, primary mesenchymal tumors as well as metastases to the thyroid gland occur. In general, thyroid tumors are more common in women than in men and occur in all ages ranging from the young (children in the 1st and 2nd decades of life) to elderly adults. Risk factors for the development of thyroid cancer include: radiation exposure; iodine deficiency; pre-existing thyroid disease (e.g., adenomatoid nodules, lymphocytic thyroiditis, Graves' disease); hormonal factors (thyroid neoplasms occur more commonly in women than in men); drugs (lithium and phenobarbitol); genetic predisposition: Familial nonmedullary thyroid cancers occur; Association of follicular-derived thyroid cancers with HLA-DR7; Gardner's syndrome - autosomal dominant inheritance characterized by multiple adenomatous polyps of the large intestine, multiple osteomas of the skull and mandible, cutaneous keratinous cysts and soft tissue tumors (e.g. fibromatosis) is associated with an increase risk of thyroid papillary carcinoma; Cowden's disease (multiple hamartoma syndrome) - autosomal dominant inheritance characterized by multiple hamartomas, mucocutaneous lesions including trichilemomas, acral keratoses and oral mucosal papillomas is associated with an increased risk of follicular epithelial cell tumors (adenomatoid nodules, tumors); 3) Multiple Endocrine Neoplasia syndrome is linked to the development of C cell-related lesions/neoplasms; Cellular oncogene abnormalities including activation, point mutations, somatic rearrangements, decreased expression or increased expression of various proto-oncogenes (e.g., RET, TRK, BRAF, RAS, PAX8/PPARγ, TP53, others). The clinical evaluation of thyroid tumors includes: Age: very young (< 14 years) and older patients (> 65 years) have a higher incidence of malignant thyroid tumors; for the same tumor type, younger patients (less than 40 years) have a better prognosis than older aged patients; better differentiated tumors tend to occur in younger patients while less differentiated tumors tend to occur in older patients; Gender: men are more apt to have malignant thyroid tumors than women; Family history: linked with the development of medullary carcinoma; less often with follicular tumors; History of radiation exposure or Hashimoto's thyroiditis: has been associated with the development of malignant thyroid tumors; Clinical presentation: a rapidly enlarging of the thyroid or of long-standing thyroid nodule(s) is a hallmark presentation for some thyroid malignant tumors, including anaplastic carcinoma and malignant lymphoma; hoarseness and/or vocal cord paralysis in the presence of a thyroid mass may indicate a malignant thyroid tumor. Physical examination: Number of nodules: although not always true, multiple nodules are more likely to be benign while solitary nodules are more likely to be malignant; a hard and fixed thyroid mass is more likely to be malignant; ipsilateral cervical adenopathy may indicate metastasis from an identifiable thyroid malignant tumor or from an occult thyroid malignant tumor. Radiologic findings: Radioactive iodine scan (131I): the incidence of carcinoma is higher for hypofunctioning "cold" nodules than for hyperfunctioning ("hot") nodules; "hot" nodules are almost always benign; ultrasound: a solid tumor is more likely to be malignant than a cystic tumor although papillary carcinoma may present as a partially or predominantly cystic tumor. Laboratory testing: Most patients with thyroid cancer are euthyroid; serum thyroglobulin is of limited value in the diagnosis of follicular epithelial tumors as serum thyroglobulin levels do not assist in the diagnosis of non-neoplastic versus neoplastic lesions of follicular lesions; elevated serum calcitonin, seen in virtually all cases, is a key diagnostic feature in thyroid medullary carcinoma. Fine Needle Aspiration Biopsy (FNAB): Represents an extremely useful initial approach in the diagnosis of a thyroid mass; quick and inexpensive with minimal complications; diagnostic sensitivity and specificity reported to be high on the order of greater than 90%; there are limitations to the use of FNAB in tumor diagnosis such as the inability to differentiate a follicular adenoma from a follicular carcinoma on the basis of their cytologic appearance; the hallmark for follicular carcinoma is the presence of capsular invasion or angioinvasion, these diagnostic features cannot be identified in the FNAB of any mass lesion. On the other hand, FNAB can be diagnostic for many other thyroid tumors such as papillary carcinoma, undifferentiated carcinoma, medullary carcinoma, lymphoma, metastatic tumors to the thyroid and others; FNAB may produce changes that create diagnostic problems in the evaluation of tissue sections such as disruption of the tumor capsule with pseudoinvasion, necrosis, pseudopapillae (particularly in oxyphilic tumors) and cytologic irregularities. Frozen section diagnosis (intraoperative consultation): The utilization of intraoperative frozen sections in the diagnosis of thyroid tumors has decreased with the increasing use of FNAB. Radioactive iodine therapy (131I): Thyroid ablation with 131I is utilized in the treatment of differentiated thyroid carcinoma; 131I destroys residual microscopic (metastatic) thyroid cancer; it facilitates the identification of metastatic foci by radioactive iodine scanning; used in the treatment of distant metastasis with the best results seen in patients who are under 40 years of age at the time of their metastasis and whose metastatic foci concentrate 131I; poorer outcomes are seen in patients over 40 years of age at the time of their metastasis; have extensive metastatic disease, poorly-differentiated tumors and/or tumors that do not uptake 131I; utility of radioactive iodine therapy is negated in the presence of a normally-situated thyroid gland proper as the latter would concentrate the radioactive iodine rather than the intent for this therapy to destroy residual cancer outside the confines of the thyroid gland proper. External irradiation: May be utilized postoperatively in patients with differentiated thyroid carcinoma with or without metastasis. Chemotherapy: Generally has limited role in the treatment of thyroid cancers; most often used in conjunction with other modes of therapy (surgery and radiation) in the treatment of poorly-differentiated or undifferentiated (anaplastic) carcinomas. Thyroid hormone therapy: Differentiated thyroid carcinomas contain functional thyroid stimulating hormone (TSH) receptors which are more abundant in follicular carcinoma than papillary carcinoma; TSH stimulates the growth of differentiated thyroid carcinoma; in theory, suppression of TSH receptors with suppressive doses of thyroxine may result in tumor regression. Prognosis: The prognosis with the more common types of thyroid cancers is good with the best overall survival rates associated with papillary carcinoma; important prognostic factors include: presence or absence of extrathyroidal spread; presence or absence of metastatic disease; age and gender of the patient; pathologic features: histology, tumor size, presence or absence of encapsulation. Follicular Adenoma (FA) Definition: Benign encapsulated tumor with evidence of follicular cell differentiation showing growth pattern and cytomorphology different from the surrounding thyroid parenchyma, but lacking features of thyroid papillary carcinoma. Whether clonality is part of the definition of an adenoma in contrast to adenomatoid nodules is controversial since clonality has been shown to be present in a large percentage (70%) of dominant adenomatoid nodules in the setting of nodular goiter. Clinical Features Affects women more than men; occurs over a wide age range but is most common in the 5th-6th decades of life. The clinical presentation is usually that of a painless neck (thyroid) mass; duration of symptoms varies from months to years. Adenomas are most often solitary and limited to one part of the thyroid lobe but may involve the entire lobe; rarely, multiple adenomas may be present in a single gland. There are no specific etiologic factors associated with the development of an adenoma. Patients are usually euthyroid; serum thyroglobulin may be raised but clinical evidence of hyperthyroidism is rarely seen. Thyroid imaging (I-123 or Technetium-99m) ­- poorly functional or "cold" nodule; adenomas are most often "cold" or hypofunctional nodules. Pathologic Features Fine Needle Aspiration Biopsy:features associated with a follicular neoplasm that contrast with those of a (cellular) adenomatoid nodule or other lesions include: syncytial groups with or without distinct microfollicles; microfollicular or trabecular growth; cellular smears; increased cellularity; scanty colloid which is usually dense and in follicular lumina; uniform cells with round nuclei, inconspicuous nucleoli and ill-defined cell borders; chromatin is opaque to coarsely granular, and is usually evenly distributed;cytoplasmic features vary from scant to oxyphilic; absence of features diagnostic for thyroid papillary carcinoma. Gross Solitary encapsulated mass; the capsule varies in thickness but usually it is thin; if a thick capsule is present, suspicion for a carcinoma should be maintained. Adenomas vary in size but generally measure < 3 cm.; larger tumors measuring more than 10 cm can be seen. Solid with a rubbery to firm consistency and a homogeneous appearance (except in the presence of secondary [degenerative] changes); pale tan to brown to orange (oxyphilic) in color. Secondary changes including hemorrhage, fibrosis, cyst formation, calcification, and infarction may alter the appearance. Histology FAs are encapsulated tumors without evidence of capsular or vascular invasion. The capsule is composed of fibrous tissue within which small to medium sized vascular spaces and smooth muscle bundles may be seen. The capsule is generally thin and clearly demarcated from the neoplasm on one side and the uninvolved thyroid tissue on the other side which is usually compressed and may be atrophic. The capsule may vary in thickness from thin and regular to thick and irregular. A thickened capsule may be a cause of concern for the possible presence of a carcinoma and should engender ample sampling of the lesion to include the tumor-to-capsule-to-parenchymal interface. The tumor is composed of relatively uniform appearing colloid-filled follicles; growth patterns may vary and include normofollicular (simple), macrofollicular (colloid), microfollicular (fetal), solid, trabecular and organoid. In general, follicular adenomas usually have a single architectural pattern but may show an admixture of patterns; a neoplasm with a variety of growth patterns should raise the suspicion for a thyroid papillary carcinoma. The cellularity and cytologic appearance of follicular adenoma varies from tumor to tumor and even within the same tumor; the neoplastic cells are generally uniform with defined cell borders. As compared to nonneoplastic follicular cells, the nuclei in adenomas are enlarged, regularly-shaped, often align along the basal aspect of the cell and are small to medium in size, hyperchromatic with absent to inconspicuous nucleoli and a variable amount of cytoplasm; the cytoplasm may be amphophilic, eosinophilic, oxyphilic (oncocyte) or clear. In the presence of oxyphilic cytoplasmic changes, the nuclei may be further enlarged but they retain their uniformity in shape and their hyperchromatic appearance. Colloid filled follicles are generally readily apparent but in some instances may be difficult to identify. Periodic acid Schiff (PAS) stains will be of assistance in identifying the presence of colloid. Follicular adenomas are well-vascularized and the stromal component includes small to large sized vascular spaces; neoplastic cells can be seen within the stromal vascular spaces but any neoplastic foci in vascular spaces within the tumor itself does not qualify the tumor as a carcinoma. Rare mitotic figures can be seen; the presence of increased mitotic activity and necrosis should be of concern and raises the suspicion for a carcinoma. Degenerative stromal changes may uncommonly be seen and are not as frequently found as in adenomatoid nodules. Papillary or pseudopapillary architecture may be present but the cytomorphologic (i.e., nuclear) findings associated with thyroid papillary carcinoma are not present; the term "papillary adenoma" has been used for such lesions but the use of this designation should be avoided. In FAs, there is an absence of capsular or vascular invasion. Special Studies Immunohistochemistry Thyroglobulin, thyroid transcription factor-1 and cytokeratins (AE1/AE3, CK7, CK8, CK18) positive; CK19 negative; calcitonin, chromogranin and synaptophysin negative. Cytogenetics and Molecular Genetics Clonal cytogenetic abnormalities include trisomy 7 alone or in association with other trisomies. Translocations of long arm of chromosome 19 (19q13) and short arm of chromosome 2 (2p21). Translocations involving chromosomal region 19q13 are a frequent finding in follicular adenomas. A putative candidate gene, ZNF331, formerly referred to as RITA (Rearranged in Thyroid Adenoma) has been identified located close to the breakpoint; Deletions of chromosome 13; RAS gene mutations: H-RAS polymorphism found in high percentage of thyroid follicular neoplasms (adenomas and carcinomas); H-RAS 81 polymorphism is significantly associated with aneuploidy in thyroid follicular tumors; H-RAS polymorphism does not appear to confer a higher propensity for neoplastic transformation as it is also found in hyperplastic lesions, Treatment and Prognosis Conservative surgery (lobectomy) is the treatment of choice. No recurrences or metastases. Histologic Types of Follicular Adenoma (Table 1) Generally, the histologic variants of follicular adenoma do not confer on a given neoplasm any difference in the clinical parameters or biologic behavior as compared to the conventional type of follicular adenoma. Possible exceptions include the atypical follicular adenoma and the hyalinizing trabecular adenoma. The histologic subtypes of follicular adenoma including the oxyphil (oncocytic or so-called Hürthle cell) type, clear cell type and signet ring cell type, include those tumors in which one of these cell types represents the dominant cell (defined roughly as 75% of the tumor). Table 1. Histologic types of Follicular Adenoma Atypical Hyalinizing trabecular adenoma (Paraganglioma?like) Oxyphil (Hürthle) cell Signet ring cell Clear cell Follicular Carcinoma (FC) Definition: Follicular cell differentiated thyroid neoplasm, not belonging to papillary carcinoma, with evidence invasion (i.e., capsular and/or vascular invasion) and/or metastatic disease. Clinical Features FC represents approximately 10-20% of all malignant thyroid tumors. More common in women than in men; occurs over a wide age range, including children and adolescents, but is most common in the 5th-6th decades of life (approximately one decade older than patients with papillary carcinoma). Clinical presentation is usually as a solitary, painless neck mass; pain may occur later in the disease course; the initial presentation may be as a pulmonary metastasis or pathologic fracture secondary to osseous metastasis. Patients are usually euthyroid; uncommonly, patients with follicular carcinoma may present with clinical manifestations of hyperthyroidism. The incidence is greater in iodine-deficient regions of the world and partly for this reason occurs in glands which have been enlarged for long periods; the addition of supplemental iodine to the diet has been associated with a decrease in the incidence of follicular carcinoma in these regions. The development of follicular carcinoma has been linked to irradiation and Cowden's disease. On thyroid scan (123I), follicular carcinomas are most often solitary, "cold" or hypofunctioning nodules. Pathologic Features Fine Needle Aspiration Biopsy The use of FNAB in the diagnosis of a differentiated (non-anaplastic) follicular carcinoma is limited; in a neoplasm where the diagnosis of a carcinoma is based on invasive growth (capsular or vascular) and not the cytomorphology, a needle aspiration cannot supply the cytopathologist with that information; FNAB is an excellent screening tool in the evaluation of a mass lesion of the thyroid; in the case of differentiating a follicular adenoma from a follicular carcinoma, often the FNAB diagnosis is "follicular neoplasm, not further specified" which informs the treating physician that a neoplasm is present requiring additional therapy (i.e., surgical removal). FCs may be cellular with minimal to absent colloid. Cells are often arranged in a microfollicular pattern but trabecular pattern can also be seen; small three-dimensional clusters with syncytial configuration can be seen; isolated cells are often found. In general, the cells are monomorphic and enlarged from non-neoplastic follicular epithelial cells with uniform, round to oval nuclei with evenly distributed, finely granular (coarse) chromatin, small to inconspicuous nucleoli and pale to clear cytoplasm with indistinct cell margins. Nuclei may vary in appearance; anisokaryosis and anisochromatosis can be seen. Histology Similar to their benign counterparts follicular carcinomas are encapsulated tumors; typically, the capsule in follicular carcinomas tends to be thicker than the capsule in follicular adenomas; for the widely invasive follicular carcinomas a distinct, readily identifiable capsule may be absent. The tumor is composed of relatively uniform appearing colloid-filled follicles; growth patterns may vary; there is a tendency for follicular carcinomas to demonstrate greater cellularity, as well as solid and trabecular patterns as compared to adenomas; further, the presence of a thickly encapsulated and cellular follicular neoplasm should raise concern for a possible diagnosis of carcinoma. In general, follicular carcinomas usually have a single architectural pattern but may show an admixture of patterns; a neoplasm with a variety of growth patterns should raise the suspicion for a thyroid papillary carcinoma. The cellularity and cytologic appearance of follicular carcinoma varies from tumor to tumor and even within the same tumor; the neoplastic cells are generally uniform with defined cell borders. The nuclei are regularly-shaped, often aligned along the basal aspect of the cell and are small to medium in size, hyperchromatic with absent to inconspicuous nucleoli and a variable amount of cytoplasm; the cytoplasm may be amphophilic, eosinophilic, oxyphilic (oncocyte) or clear; nuclear pleomorphism may be present. In the presence of oxyphilic cytoplasmic changes, the nuclei may be enlarged, have prominent nucleoli but retain their uniformity in shape and their hyperchromatic appearance. Colloid filled follicles are generally readily apparent but in some instances may be difficult to identify; periodic acid Schiff (PAS) stains will be of assistance in delineating the presence of colloid. Mitotic figures can be seen, but are usually uncommon; increased mitotic activity may be present in the more widely invasive follicular carcinoma. Intratumoral vascularity in the form of delicate capillaries is present but is often inconspicuous by routine light microscopy. Degenerative stromal changes often seen in adenomatoid nodules and in follicular adenomas are not uncommon in follicular carcinomas. Follicular carcinomas lack the architectural and cytomorphologic features of thyroid papillary carcinoma. Criteria for Malignancy Invasion A diagnosis of follicular carcinoma is predicated on the presence of invasive growth (capsular and/or vascular invasion), extension into adjacent thyroid parenchyma and/or on the presence of metastatic tumor. The categorization of follicular carcinoma includes minimally invasive (low-grade) and widely invasive types; this categorization is based on the extent of invasion. The histologic definition of invasion includes capsular invasion and vascular invasion. Capsular Invasion The extent of capsular invasion is a source of contention. Some believe that any degree of invasion into the capsule qualifies categorization as a minimally invasive follicular carcinoma; others feel that the tumor has to penetrate the entire thickness of the capsule to be regarded as unequivocal evidence of capsular invasion. Elastic stains may be helpful in determining whether capsular invasion has occurred. Problematic features relative to diagnostic interpretation include: irregular contours of the tumor; tangential sectioning; a separate nodule lying immediately outside the capsule of the main tumor mass. In this setting, serial sections to determine whether there is a connection present or not are indicated. The presence of continuity between the main mass and the nodule outside the capsule would be indicative of a carcinoma. The absence of any connection does not exclude a diagnosis of carcinoma. The appearance of the entire gland must be considered such that the presence of multiple other nodules may be indicative of multiple adenomatoid nodules. Angioinvasion Represents a more reliable feature of malignancy than capsular invasion; since nodal metastasis is rare in association with follicular carcinoma, the invaded vascular space are not lymphatics. Some authorities have advocated dividing follicular carcinomas with angioinvasion (with or without capsular invasion) as moderately invasive follicular carcinomas as opposed to minimally invasive follicular carcinoma that have capsular invasion without angioinvasion and widely invasive follicular carcinomas with extensive invasion. In the low-grade or minimally invasive follicular carcinoma, the vascular space invasion involves small to medium sized blood vessels but not large caliber sized vascular spaces. The 'violated' vascular space must lie within the capsule or beyond the capsule. Tumor cells must be adherent to a vessel wall which is lined by identifiable endothelial cells. Tumor cells protruding into a vascular space but which have an endothelial layer identified over the bulging tumor nests should be regarded as invasive. Acceptable as angioinvasion in the absence of identifiable endothelium is the presence of tumor adherent to the wall with associated thrombus formation. Special stains such as elastic tissue stains or trichrome may be helpful but because a continuous smooth muscle layer may not be present; these stains usually are of only limited help. Stains for endothelial markers (Factor VIII-related antigen, Ulex europaeus agglutinin I, CD31 and CD34) may only be of limited assistance. Types of Follicular Carcinoma Based on the extent of the invasive component, two types of follicular carcinoma are recognized differing in their biologic behavior and in their treatment; these types of follicular carcinoma include minimally invasive follicular carcinomaand widely invasive follicular carcinoma. Minimally Invasive (Low-Grade) Follicular Carcinoma Definition: An encapsulated follicular epithelial neoplasm histologically showing limited evidence of invasion and lacking features of thyroid papillary carcinoma. Synonymsinclude encapsulated type of follicular carcinoma; angioinvasive grossly encapsulated follicular carcinoma. Many of the histologic features are similar to those of follicular adenoma; however, by definition, capsular and/or vascular invasion must be present to qualify as a low-grade or minimally invasive follicular carcinoma. While an invasive component is present, the extent of invasion in these tumors is limited, including capsular invasion and smaller caliber sized vascular spaces; invasion into the adjacent thyroid parenchyma may be seen but demonstrates surrounding fibroconnective tissue (part of the capsule) but there is an absence of extensive parenchymal invasion. Within this category of follicular carcinoma, tumors may be further subdivided on the basis of whether there is: capsular invasion only, limited angioinvasion (less than 4 vascular spaces) or extensive angioinvasion (4 or more vascular spaces). The latter two categories may or may not have associated capsular invasion. Treatment and Prognosis A contentious issue relative to the minimally invasive follicular carcinomas is the appropriate mode of therapy. Treatment options include conservative treatment versus more radical approaches. Conservative therapy includes limited resection (lobectomy or subtotal thyroidectomy) without radioactive iodine therapy. Radical therapeutic intervention includes total thyroidectomy followed by administration of radioactive iodine. The only caveat to utilizing conservative modalities is the presence of limited invasion and the absence of metastatic tumor. In the presence of metastasis, treatment includes radioactive iodine. The prognosis for minimally invasive or low-grade follicular carcinoma is excellent with 70-100% 10-year survival rates (cure rates reported to be >95%); however, the prognosis may be dependent on whether the tumor demonstrates only capsular invasion or whether there is angioinvasion. For those tumors showing only capsular invasion the long term prognosis is excellent with very low likelihood of metastatic disease (approximately 0.1%); for those tumors with angioinvasion the prognosis is guarded since there is an increase incidence of metastatic disease, albeit approximately 5%. Prognosis for limited angioinvasion is considered excellent; prognosis for extensive angioinvasion is guarded. In the presence of metastatic disease the 10 year survival rate is approximately 50%. Follicular Neoplasm of Uncertain Malignant Potential The interpretation of what constitutes capsular invasion is still controversial with a lack of consensus among experts as to the diagnostic criteria for capsular invasion. The designation of follicular neoplasm of uncertain malignant potential was introduced for those tumors in which there is limited capsular invasion (absence of complete capsular transgression) and absence of angioinvasion. Alternatively, the designation of atypical adenoma can be used in this particular situation. Widely Invasive Follicular Carcinoma Definition: An encapsulated follicular epithelial neoplasm grossly and/or histologically showing evidence of invasion, including complete transgression of an identifiable capsule, angioinvasion into medium and large caliber-sized vascular spaces and/or invasion into the adjacent thyroid parenchyma, and lacking features of thyroid papillary carcinoma. The widely invasive follicular carcinoma is much less common than its minimally invasive counterpart. Less of a diagnostic dilemma with less subjectivity as compared to the minimally invasive follicular carcinoma. Clear cut invasion beyond the capsular delimitation of the tumor with extension into adjacent thyroid parenchyma; not infrequently, there is a mushroom-like protrusion ("atom bomb-like explosion") of the tumor through and beyond its capsular delimitation; further, satellite neoplastic nodules separate from the main mass within thyroid parenchyma is another indicator for a widely invasive follicular carcinoma. Due to extensive invasion a capsule may not be readily identifiable. In addition, angioinvasion, especially into larger sized vascular spaces is evident. These tumors also tend to be less differentiated as well as having a greater percentage of solid or trabecular growth patterns, hypercellularity, increased mitotic activity, nuclear hyperchromasia, and necrosis. Treatment and Prognosis For the widely invasive type of follicular carcinoma, aggressive management is indicated and includes total thyroidectomy and radioactive iodine therapy. Prognosis varies but is generally considered to be poor. These tumors tend to disseminate hematogenously with metastasis to osseous sites, lungs and brain; cutaneous metastasis also occur. Metastatic disease may be identified at the initial presentation. Metastatic tumor is treated with radioactive iodine therapy which may offer long-term palliation but not a cure. The metastatic foci are histologically similar to the primary tumor and may appear bland lacking cytologic atypia. Survival statistics rival those of poorly-differentiated thyroid carcinomas with 25-45% 10-year survival rates. Adverse prognostic factors include: presence of extraglandular spread into adjacent soft tissues; presence of distant metastasis; older age of the patient (over 40 years); male gender may be associated with a worse prognosis; extensive intrathyroidal invasion; presence of intravascular invasion; tumor size: tumors greater than 3.5 to 6 cm have a worse prognosis. Tissue Sectioning In a follicular neoplasm with worrisome features (i.e., thickly encapsulated, high cellularity with increased mitotic figures and necrosis) but in the initial sections lacks definitive evidence for a diagnosis of carcinoma, the most critical issue is adequate and appropriate sectioning of the tumor in order to evaluate the tumor-capsule-thyroid parenchymal interface for evidence of invasive growth. Tangential sectioning should be avoided. There are no set criteria for the number of sections required for adequate histologic evaluation; a guideline to the number of sections considered adequate in order to exclude the presence of invasion is: For a tumor measuring < 6 cm = submit the entire tumor; For a tumor measuring 6 cm = submit at least 10 blocks; For a tumor measuring > 6 cm = submit one additional block per centimeter of tumor. Special Studies Immunohistochemistry In general, immunohistochemical staining is unnecessary in the diagnosis or differential diagnosis of a follicular epithelial-derived tumor, including follicular carcinoma. Thyroglobulin is the most useful stain in the diagnosis and differential diagnosis of thyroid follicular epithelial-derived tumors; cytokeratin reactivity will also be present but unlike thyroglobulin cytokeratin reactivity is not specific for thyroid lesions. Thyroid Transcription Factor 1 (TTF-1) is another useful stain but it is not specific for thyroid follicular epithelial tumors as TTF-1 reactivity can be identified in thyroid based neuroendocrine tumors, as well as in non-thyroid neuroendocrine tumors (e.g., pulmonary neuroendocrine tumors) and non-neuroendocrine tumors (e.g., low-grade nasopharyngeal papillary adenocarcinoma, pulmonary adenocarcinomas). To date, there are no immunomarkers that allow for discrimination between follicular adenoma and follicular carcinoma or that allow for distinguishing thyroid papillary carcinoma from follicular adenoma/carcinoma. Cytogenetics and Molecular Genetics A number of studies have documented the presence of molecular alterations in follicular carcinomas as compared to follicular adenoma and papillary carcinoma, including: loss of heterozygosity (LOH) on chromosomes (in descending order of frequency): 3p, 17p and 10q and 3p; LOH on 17p correlates to mortality suggesting that this finding may represent a late event (as compared to LOH on 3p and 10q) in the development of follicular carcinoma; more frequent activation of point mutations of the ras oncogene (N-ras) is present in follicular carcinomas as compared to follicular adenomas suggesting that ras mutations represent an early event in the development of follicular carcinoma; these findings allow for a better understanding relative to the development and progression of the carcinoma, but at present do not offer a mechanism for diagnosis or differential diagnosis. Clonal chromosomal abnormalities are identified in follicular carcinomas including: t(7;8)(p15;q24) which is associated with more aggressive behavior and widely invasive follicular carcinomas; deletions of chromosome 3p25 is commonly present; loss of chromosome 22 is associated with older age at presentation and more often seen in the widely invasive follicular carcinoma than the minimally invasive follicular carcinoma. Flow cytometric analysis for ploidy has not proven effective in differentiating follicular carcinomas from follicular adenomas, as both tumor types may be diploid or aneuploid. Molecular Profiling: recent reports indicate that molecular (gene) profiling allows for discrimination of benign (nonneoplastic and adenomas) and malignant thyroid follicular tumors with high sensitivity (approximately 92%) and specificity (approximately 96%); cancer gene profiles include known cancer-associated genes (MET, galectin-3), as well as previously unidentified genes; expression levels of TFF3 mRNA significantly decreased in follicular carcinomas, especially in widely invasive types and those with evident metastases, as compared to follicular adenomas. Histologic variants of follicular carcinoma (both minimally and widely invasive) types include: Follicular carcinoma with oxyphilic (Hürthle) cells (see below); Follicular carcinoma with clear cells; Follicular carcinoma with signet ring cells: Follicular carcinoma, mucinous variant; Follicular Carcinoma with Oncocytic (Oxyphilic) Cells represents a follicular epithelial cell-derived neoplasm dominated by the presence of cells rich in mitochondria (i.e., oncocytes, oxyphilic cells) with evidence of invasion (i.e., capsular invasion and/or angioinvasion). Like non-oncocytic follicular carcinomas, classification as low-grade (minimally invasive) and widely invasive is dependant on the extent of invasion. Simply because a tumor has oncocytic cells (i.e., Hürthle cells) does not correlate to a widely invasive (aggressive) neoplasm.Oxyphilia is derived from the Greek word meaning "swollen"; oxyphilia results from an increase in mitochondrial content of a cell; by light microscopy, an oxyphilic cell is one that has a prominent granular eosinophilic appearing cytoplasm. Synonyms includeHürthle cell carcinoma; oncocytic carcinoma; oxyphilic cell carcinoma. The genetic changes associated with follicular carcinomas with oncocytic cells differ from the genetic changes associated with non-oncocytic follicular carcinomas including: higher percentage of ras mutations; increase in allelic alterations; significant differences in the expression of TGF-α, TGF-β, N-myc, and IGF-1. These findings suggest that oncocytic and non-oncocytic follicular carcinomas are different tumor types. The presence of oncocytic (Hürthle) cells does not in and of itself correlate to any one diagnosis nor is it suggestive of a specific biologic behavior for that tumor; non-neoplastic and benign neoplasms of the thyroid may also have oncocytic (Hürthle) cells. As a group follicular carcinomas with oncocytic cells tend to occur in older patients and tend to be larger tumors, features that often are associated with a higher frequency of malignancy in these tumors as compared to non-oncocytic follicular neoplasms. Treatment, prognosis and the biologic course are the same as for 'conventional' type of follicular carcinoma although some authors believe that total or near total thyroidectomy should be performed for all oncocytic follicular carcinomas irrespective of whether they are minimally or widely invasive; the oncocytic follicular carcinomas are more aggressive than those follicular carcinomas without oxyphilia of the same size and extent of invasion. Higher risk of recurrence in follicular carcinomas with oncocytic (Hürthle) cells in the presence of greater than or equal to four foci of (capsular) vascular invasion. The recommendation for documenting in the surgical pathology report the number of involved blood vessels (i.e., less than 4, greater or equal to 4) is gaining wider support and may become part of the standard reporting of thyroid carcinomas in general and thyroid carcinomas with oncocytic cells in specific. The overall mortality rate is 30-70%; the worse prognosis associated with these tumors as compared to non-oncocytic follicular carcinomas may correlate with the facts that: oncocytic follicular carcinomas generally take up radioactive iodine less satisfactorily than non-oncocytic follicular carcinomas; these tumors tend to occur in an older age population which carries a greater risk of aggressive behavior; a higher percentage of these tumors show the presence of extrathyroidal invasion; a higher percentage of these tumors tend to recur more often and more frequently metastasize. In addition, aggressive behavior may also be linked: occurrence in men; larger tumor size (tumors measuring 4cm or more in greatest dimension); aneuploidy (aneuploid tumors behave more aggressively than diploid tumors). Thyroid Papillary Carcinomas (TPC)Usual or Conventional Type Definition: TPC is a malignant epithelial cell-derived neoplasm with evidence of follicular cell differentiation, typically but not uniformly with papillary and/or follicular structures, and characteristic nuclear features. Variations in the architectural patterns of thyroid papillary carcinoma can occur but this neoplasm is defined by its cytomorphologic (i.e., nuclear) changes. Clinical Features TPC represents the most common malignant thyroid neoplasm in countries with iodine-sufficient or iodine-excess diets (i.e., nonendemic comprising up to 80% of all thyroid malignant tumors. TPC tends to occur more frequently in women than in men; occur in all age groups including pediatric and adolescent, but is most common in the 3rd-5th decades of life; TPC is the most common thyroid malignant tumor in the prepubertal age group. Clinically apparent TPC presents as an asymptomatic, palpable thyroid mass with or without enlargement of regional (cervical) lymph nodes; TPC may initially present as a lateral neck mass from an occult primary (ipsilateral) thyroid tumor. Any part of the thyroid gland can be affected. On thyroid scan, (123I), papillary carcinomas are most often "cold" or hypofunctioning nodules. The etiology for TPC includes: 1) Iodine excess: - in areas of endemic goiter, the addition of iodine to the diet of people has been associated with an increase in the incidence of TPC and a decrease in the incidence of follicular carcinoma; 2) External radiation: - radiation exposure to the neck region is a known etiologic factor associated with the development of thyroid cancer in general and TPC in specific; - the development of carcinoma is dose dependent and may arise in a relatively short time period if the exposure is large (e.g., following the Chernobyl exposure or atomic bomb) or decades later if the radiation exposure is less intense; - thyroid cancer risk following external irradiation is highest following radiation at a young age, decreases with increasing age at treatment, and increases with follow-up duration; - the majority of patients who developed TPC after the Chernobyl accident were children with aggressive cancers that were invasive, had a high frequency of RET/PTC gene rearrangement and were often associated with lymphocytic thyroiditis. 3) Genetic predisposition: - Familial non-medullary thyroid carcinoma: papillary carcinoma may occur within families; reported to be inherited as an autosomal dominant disorder; possibly more aggressive than sporadic form; 4) Increased risk of TPC has also been associated wth: familial adenomatous polyposis (FAP); Cowden's disease; pre-existing thyroid lesions, such as chronic lymphocytic thyroiditis. Pathology Fine Needle Aspiration Biopsy In contrast to follicular neoplasms such as follicular adenoma and follicular carcinoma, the cytologic features of papillary carcinoma are diagnostic by FNAB making needle aspiration an excellent diagnostic tool for all variants of thyroid papillary carcinoma. Aspirates and smears are cellular; colloid is scant and may be absent. Cells may be arranged in papillary formations, monolayers, follicles, small or large cell clusters (syncytium-like formations) or are individually dispersed. The papillary formations may be sharply outlined with complex branching and a central vascular core. The most diagnostic component of papillary carcinoma are the nuclear features which include: enlargement with irregularities in size and shape; powdery or dusty chromatin pattern (the nuclear clearing "orphan Annie" seen in histologic preparations are not found in cytologic preparations); ntranuclear (pseudo)inclusions (cytoplasmic invaginations); nuclear grooves; nuclear crowding or overlapping. The cytoplasm is usually abundant and include a pale, vacuolated or foamy appearance; the cytoplasmic features are not of much assistance in the diagnosis. Psammoma bodies can be seen and are very helpful in the diagnosis of papillary carcinoma. Multinucleated cells can be seen and sometimes are abundant. Gross The majority of TPC are solid with poor circumscription and/or apparent infiltration into adjacent thyroid parenchyma with or without grossly identifiable extrathyroidal extension into perithyroidal soft tissues. TPC may vary from tan-white, solid tumors with a rubbery to firm consistency to partly cystic or wholly cystic tumors; cystic TPCs are usually encapsulated, filled with clear to yellow/brown fluid. A papillary appearance may be apparent by macroscopic examination. Multifocal disease is common. Fibrosis is a common finding in and around TPC. TPC may have a gritty consistency due to the presence of psammoma bodies; extensive foci of calcification or ossification may be present. TPC can be divided by size and extent of invasion into: Microcarcinoma (occult, minute, or microscopic) = < 1.0 cm; Intrathyroidal – encapsulated, invasive, diffuse and/or cystic; and extrathyroidal (massive). Histology The histologic diagnosis of TPC is based on both the architectural and cytomorphologic features (Table 2). Table 2. Histomorphologic Features of Papillary Carcinoma Architectural Features Cytomorphologic Features 1. Growth patterns: - papillary, follicular, solid, trabecular, organoid; multiple growth patterns can occur; 2. Elongated or twisted follicles with little colloid; 3. Psammoma bodies; 4. Intratumoral irregular fibrosis; 5. Inspissated colloid (darker appearing colloid as compared to the surrounding thyroid). 6. Papillary protrusions into follicles; 7. Squamous metaplasia 1. Nuclear enlargement; 2. Nuclear irregularities in size and shape; 3. Dispersed to optically clear appearing ("Orphan Annie") nuclear chromatin; 4. Margination of the chromatin along the nuclear membrane; 5. Loss of nuclear basal polarity with haphazardly arrayed nuclei within the cell; 6. Crowding and overlapping nuclei; 7. Eosinophilic nuclear (pseudo)inclusions; 8. Nuclear grooves; 9. When present, nucleoli tend to localize along the nuclear membrane; 10. Nondescript cytoplasmic changes. Architecture Growth Patterns The classic example of TPC includes the presence of papillary growth. The papillae are narrow with thin fibrovascular cores and show complexity in growth with arborization. TPC may lack papillary growth and be entirely composed of a tumor with a follicular growth (See follicular variant of TPC later in this handout). Other growth patterns in TPC include solid, trabecular, microfollicular, macrofollicular, insular and cystic; these patterns may be the only one seen in any given tumor or multiple patterns can be seen in any one tumor. A diagnosis of TPC should be highly suspected in a single tumor that demonstrates multiple growth patterns. Predominantly solid tumors are those in which solid elements make up nearly all of the neoplasm. The follicles in TPC often are elongated or twisted in appearance: this is an extremely valuable (but not pathognomonic) feature in those papillary cancers without a papillary architecture; not a feature usually seen in follicular adenomas or carcinomas. Psammoma Bodies These are round, calcified concretions with concentric lamination; psammoma bodies are felt to represent necrotic tumor cell(s) that form the nidus for deposition of calcium salts. The name derived from Greek and means "salt-like. Psammoma bodies are identified in up to 50% of TPC. Located in the tip of papillary stalk but can be found in solid neoplastic component or in the stroma between neoplastic follicles. Microcalcifications with an appearance similar to psammoma bodies may be found within follicle lumens but are not diagnostic and should be disregarded; these microcalcifications represent inspissated colloid and usually lack the concentric laminations seen in psammoma bodies. "Naked" psammoma bodies represent the presence of TPC; this is true whether found in normal thyroid or in cervical lymph nodes. Psammoma bodies are not specific for TPC but considered rare in benign thyroid diseases. Intratumoral Fibrosis The dense fibrosis is arranged in an irregular pattern and is a common feature of TPC. Inspissated Appearing Colloid The colloid seen in TPC is thicker (more intensely eosinophilic on H&E) than the colloid of adjacent non-neoplastic thyroid follicles; This is a weak criteria but it may be helpful in the overall histologic picture in the diagnosis of TPC. Cytomorphology = Nuclear Features Note: In order to properly evaluate the nuclear features in thyroid lesions well-fixed and thin sections (4 microns) are recommended. The nuclear features are paramount in the diagnosis of TPC and generally remain constant irrespective of the type of TPC under consideration. In the presence of nuclear changes that are diagnostic for TPC, the diagnosis of TPC can be rendered in the absence of invasion (i.e., invasion is not a requisite finding for the diagnosis of TPC). The diagnosis of TPC is predicated on the constellation of nuclear alterations and should not be decided on a single alteration. The changes in the nuclei seen in TPC include: 1) Nuclear Enlargement As a general rule, the nuclei in papillary carcinoma are always larger than those of adenomatoid nodules and follicular tumors (adenomas, carcinomas). Irregularities in size and shape of the nuclei; the nuclei may take on many appearances including semi-lunar, crenated or convoluted. Note: the presence of cytoplasmic oxyphilia seen in numerous thyroid lesions may induce nuclear enlargement suggesting a diagnosis of TPC. Other cytomorphologic features are required for the diagnosis of TPC. 2) Nuclear Chromatin Varies from very fine and evenly dispersed to ground glass in appearance; the optically clear (so-called "Orphan Annie eyes") nuclei represent an artifact of fixation (a feature not identified in frozen sections). The nuclear chromatin typically marginates along the nuclear membrane creating a fine but distinct appearing nuclear membrane. 3) Nuclear Orientation Crowding or overlapping; loss of basal polarity of the nuclei, which appear randomly dispersed in all portions of the cell. 3) Nuclear Grooving This is often utilized as an essential and diagnostic feature of TPC; while helpful in the diagnosis of TPC, nuclear grooves are not specific for, nor diagnostic of TPC but can be seen in non-neoplastic and other thyroid neoplasms (benign and malignant). 4) Intranuclear Inclusions If identified, intranuclear inclusions represent a reliable feature in the diagnosis of TPC but are only identified in a minority of cases. These appear as large, round eosinophilic inclusions with sharp borders and represent cytoplasmic invaginations into the nucleus. Distortional changes in processing may result in intranuclear "bubbles" that simulate the appearance of the true intranuclear inclusions of TPC; in order to prevent this artifact, proper fixation and thin sections are recommended. 5) Nucleoli When present, nucleoli are located along the nuclear membrane; this is a soft criteria and does not always hold true. In comparison, the nucleoli (when present) in follicular adenomas/carcinomas tend to be centrally situated within the nucleus. 6) Cytoplasmic Appearance There are no specific cytoplasmic changes that assist in diagnosing a papillary carcinoma. There are certain variants of papillary carcinoma that are named according to their cytoplasmic appearance (oxyphilic cell TPC, clear cell TPC). Table 3 lists of the diagnostic criteria for TPC. Table 3. Thyroid Papillary Carcinoma: Diagnostic Major and Minor Criteria* Most Important Criteria (in order of importance) [brackets contain percentage of cases showing these features] 1. Cytoplasmic invaginations (pseudoinclusions) into nucleus [25%] 2. Abundant nuclear grooves [100%] 3. Ground glass nuclei [98%] 4. Psammoma bodies [16%] 5. Enlarged overlapping nuclei [99%] 6. Irregularly shaped nuclei [100%] Less Important Criteria Dark staining colloid [86%] Irregular contours of follicles [64%] Scalloping of colloid [59%] Elongated follicles [80%] Multinucleated macrophages in lumen of follicles [14%] (*From Lloyd et al) Numbers in brackets include percentage of cases reported with these findings Additional features that can be seen in association with TPC include: associated lymphocytic infiltration; associated squamous metaplasia; lymph-vascular space invasion; multifocality or multicentricity which may represent intraglandular metastasis; based on ancillary testing these foci have been shown to demonstrate monoclonality and different RET/PTC profiles supporting the concept that these are independent primary tumors. Pleomorphism, mitotic activity and necrosis are generally not seen in the majority of TPCs. Special Studies Immunohistochemistry: - Thyroglobulin, TTF-1 and cytokeratin positive; thyroglobulin staining is diminished to absent in foci of squamous metaplasia; - cytokeratin 19 has been suggested as a differentiating stain between TPC (CK19+) versus papillary hyperplasia, follicular adenoma and follicular carcinoma (CK19-); this is not definitive; further, CK19 positivity can be seen in foci of squamous metaplasia and in nodular follicular epithelial cell foci in lymphocytic thyroiditis; - HBME has also been suggested as being a differentiating stain between TPC (HBME+) versus non-papillary lesions/neoplasms; this is not definitive. - calcitonin, chromogranin and synaptophysin negative; Note: To date, there is no single immunohistochemical marker or panel of immunohistochemical markers that are specific (or diagnostic) for TPC. Cytogenetics and Molecular Genetics Thyroid papillary carcinoma have activating mutations of genes coding for proteins which signal along the mitogen-activated protein kinase pathway (MAPK); thyroid papillary carcinomas commonly have three genetic alterations including RET/PTC rearrangements, RAS point mutations or BRAF point mutations; mutations in RET, BRAF and RAS genes found in approximately 70% of all thyroid papillary carcinomas but rarely overlap in the same tumor. RET Protooncogene: A specific molecular event in TPC is the activation of the RET protooncogene; RET protooncogene encodes two isoforms of a transmembrane tyrosine kinase receptor (which is involved in the development of the neural crest and the kidney); somatic rearrangements of RET have been identified in TPC and are referred to as RET/PTC. In TPC there is fusion of the tyrosin kinase region of the RET protooncogene with different activating sequences expressed in thyroid epithelial cells; to date, five fusion proteins have been identified (RET/PTC1-5). RET/PTC translocation is reported in up to 60% of TPC. RET/PTC1 is the most common in sporadic TPC. RET/PTC3 is more common than the other fusion proteins in solid tumors and in radiation induced TPC especially in children exposed to the radiation fallout from the Chernobyl accident. RET/PTC rearrangement is implicated in the early stages of TPC and represents an early event in the development of TPC. Familial adenomatous polyposis (FAP)- associated TPC also show RET/PTC rearrangement. RET/PTC also found in multiple endocrine neoplasia MEN2a and MEN2b, and in thyroid medullary carcinoma. RAS: point mutations involve several specific sites (codons 12, 13, 61) of N-RAS, H-RAS or K-RAS; found in 10-15% of tumors; BRAF:belongs to the RAF family of protein kinases important components of the mitogen-activated protein kinase (MAPK) signaling pathway mediating cell growth, differentiation and survival; activating point mutations of the BRAF serine/threonine kinase reported as the most common genetic event in sporadic thyroid papillary carcinoma found in approximately 40% of these tumors; virtually all mutations involve nucleotide 1799 resulting in valine-to-glutamate substitution at residue 600 (V600E) previously referred to as V599E; among thyroid tumors; BRAF mutations are restricted to thyroid papillary carcinoma, poorly-differentiated thyroid carcinomas and anaplastic carcinomas arising from thyroid papillary carcinoma. Recent evidence has documented the following findings relative to RET, BRAF and RAS genetic alterations in thyroid papillary carcinomas: RET/PTC rearrangements found in younger aged patients, predominantly in cases of histologically typical thyroid papillary carcinomas, frequent psammoma bodies and high rate of lymph node metastases; RAS mutations found exclusively in the follicular variant of thyroid papillary carcinoma correlating with significantly less prominent nuclear features and low rate of lymph node metastases; BRAF mutations associated with older aged patients, cases of histologically typical thyroid papillary carcinoma or the tall cell variant, higher rate of extrathyroidal extension and more advanced tumor stage at presentation; The above findings suggest that RET/PTC, RAS and BRAF mutations are associated with distinct microscopic, clinical and biologic features of thyroid papillary carcinomas. Treatment and Prognosis The standard treatment for TPC is surgery. The extent of surgery remains a controversial area varying from lobectomy to subtotal thyroidectomy to total thyroidectomy. The standard approach for tumors measuring ≥ 1.5 cm is total thyroidectomy, nodal sampling of palpable lymph nodes and subsequent radioactive iodine ablation (iodine-131). Total thyroidectomy is traditionally been advocated due to the high frequency of tumor multifocality; For tumors measuring < 1.5 cm a more conservative approach can be taken to include lobectomy and subtotal thyroidectomy; however, recommendations for a more aggressive surgical approach have been advocated in the presence of smaller foci of TPC (i.e., micropapillary carcinomas), including total thyroidectomy and radioiodine ablation. Presently, there is still no standard method in the surgical treatment of thyroid papillary carcinoma. Some surgeons advocate total thyroidectomy with postoperative radioactive iodine therapy, and other surgical groups take a less radical approach by performing lobectomy with or isthmusectomy or subtotal thyroidectomy followed by suppression of thyroid-stimulating hormone secretion. This approach would seem the most reasonable given the circumstances in which the tumor occurs in a low-risk patient population, is localized to a single lobe, and does not belong to a histologic unfavorable category. In patients falling into this low-risk group, the conservative approach to therapy has been shown to be as effective with similar outcomes as the more aggressive approaches to management. The more aggressive intervention (i.e., total thyroidectomy, radioactive iodine, nodal dissection) is justified in higher risk groups. In the absence of cervical lymph node enlargement, a (modified) neck dissection need not be performed. However, in the face of apparent nodal involvement by tumor, a modified lymph node dissection with preservation of the sternocleidomastoid muscle is performed. Complications of total thyroidectomy may include hypoparathyroidism and vocal cord paralysis. The rationale for radioactive iodine (iodine-131) ablation includes: destruction of all thyroid tissue to include occult foci of carcinoma; facilitation of postablative thyroid scanning in order to exclude persistent disease; the administration of iodine-131 cannot be performed in the presence of residual normal thyroid gland, hence the desire to perform total thyroidectomy; since the normal thyroid would concentrate the majority of the radioactive iodine, the goal of destroying occult foci of carcinoma may not be achieved; radioactive iodine ablation is generally not administered in low-risk groups (see below) since surgery is considered sufficient. TPC tends to be biologically indolent with an excellent prognosis (> 90% at 20 years). Relapse after initial therapy is highest in the 1st decade and may be associated with increased mortality; relapses may be delayed for decades (20-30 years) after the initial diagnosis. Incomplete surgical resection is associated with increase risk of recurrence. Local recurrence in any residual thyroid tissue and/or in soft tissues of the neck can occur. Metastatic spread is preferentially via lymphatic drainage manifesting as intrathyroidal and/or regional lymph node metastasis. Distant (visceral) metastatic disease is unusual occurring in from 5-7% of cases; the lung is the most common visceral metastatic site (bone, liver and brain metastasis may also occur). The overall mortality rates for thyroid carcinoma is 0.2%; survival rates measured over 20 years vary per risk group: low-risk: 99% 20 year survival; intermediate risk: 88% 20-year survival; high-risk: 43% 20-year survival. There are a variety of prognostic factors associated with TPC; among the most important prognostic factors are age, tumor size and staging. Factors associated with an adverse prognosis include: 1) Age and Gender: mortality increase with age ( patients < 40 years generally not associated with death from TPC as compared to patients > 40 years); women fare better than men. Low-Risk group: men ≤ 40 years of age women ≤ 50 years of age High-Risk group: men > 40 years of age women > 50 years of age. 2) Tumor Size: risk of death increases with increasing tumor size: tumor recurrence and spread increases when the tumors are large (measuring > 4 - 5 cm); best prognosis is seen with tumors ≤ 1.5 cm in diameter). 3) Staging: - Extrathyroidal Extension (See later in handout): The presence of extrathyroidal extension of tumor (i.e., extension beyond the confines of the thyroid gland into adjacent soft tissues) represents one of the worst prognostic indicators in TPC. Microscopic foci of extrathyroidal extension have outcomes that are better than those TPCs with extensive invasion outside the gland. Invasion into adjacent anatomic structures (e.g., trachea, esophagus, other) is an unfavorable prognostic finding associated with decreased survival. Encapsulated tumors and/or tumors showing limited invasion are associated with a favorable prognosis. - Distant Metastasis: the presence of distant metastasis is associated with a worse prognosis. The site of the distant metastasis impacts on prognosis: osseous and visceral (other than pulmonary) metastasis represents an ominous prognostic finding; pulmonary metastasis is not associated with as dire a prognosis as with osseous (or other distant) metastatic disease, but is associated with a moderate adverse outcome. Histologically proven angioinvasion may be considered as a sign of an increased tendency toward hematogenous spread and consequent increase in the relative percentage of metastases impacting negatively on prognosis. - Nodal Metastasis: in general the presence of nodal metastasis has limited impact on survival; however, the presence of extranodal extension of tumor into soft tissues adversely impacts on survival with increased risk of distant metastasis and worse prognosis. 4) Histology (type & differentiation): adverse prognosis has been related to the cell type and/or growth pattern (e.g. columnar cell, tall cell, insular and diffuse sclerosing variants) with some variants of TPC associated with more aggressive clinical course and higher mortality rates. However, this has not been definitively proven but these histologic types of TPC may have an associated adverse prognostic feature (e.g. older age, male predilection, extrathyroidal extension) that better correlates with a more aggressive behavior. The same cannot be said of undifferentiated or anaplastic carcinoma that by virtue of their histology are associated with a poor prognosis. 5) Factors associated with adverse prognosis but still of questionable prognostic significance include: - Angioinvasion, especially into large caliber sized vascular spaces; - Tumor ploidy: aneuploid tumors particular occurring in older aged patients (greater than 60 years) are associated with a worse prognosis; - Histologic growth patterns: solid or trabecular areas; - Immunoreactivity for LeuM1, epithelial membrane antigen, and p53, and absence-to-diminished reactivity for E-cadherin and retinoblastoma protein; - Oncogene abnormalities: the presence of point mutations such as in N-ras gene may be associated with a more aggressive behaving TPCs; 6) Factors associated with better prognosis but still of questionable prognostic significance include: - encapsulated tumors; - prominent papillary architecture and presence of psammoma bodies; - presence of lymphocytic thyroiditis in the adjacent thyroid parenchyma; - diploid tumors. The effect of treatment (surgery, external radiation, radioactive iodine or chemotherapy) does not appear to be a significant predictor of survival in thyroid papillary carcinoma. Variants of "Conventional" Thyroid Papillary Carcinoma (Table 4) Note: The demographics including gender predilection, age range, the clinical presentation (except for occult TPC), risk factors, treatment, prognosis, and prognostic factors are the same as conventional TPC. Table 4. Histologic Types of TPC I. Variants of the "Conventional" Thyroid Papillary Carcinoma Microcarcinoma (Occult, small or microscopic) Encapsulated variant Follicular variant Macrofollicular variant Oncocytic or oxyphilic variant Clear cell variant Solid variant or radiation-induced pediatric variant Cribriform-morular variant Warthin-like variant Diffuse follicular variant II. Biologically Aggressive Variants of TPC Diffuse sclerosing variant Tall cell variant Columnar cell variant Poorly-differentiated Anaplastic carcinoma Thyroid Papillary Microcarcinoma Synonyms: Occult thyroid papillary carcinoma; occult sclerosing thyroid papillary carcinoma; microscopic thyroid papillary carcinoma; latent thyroid papillary carcinoma. A recent proposal suggests alternative designation of papillary microtumor for this tumor type. Defined as a papillary carcinoma measuring < 1.0 cm in size. Usually an incidental finding in a thyroid removed for other reasons or at autopsy; may present as an occult primary tumor with cervical lymph node metastasis. Occult or latent papillary carcinomas may be microcarcinomas (measuring < 1.0 cm) but these are not exclusively microcarcinomas and may be larger tumors not representing microcarcinomas. Histology includes nonencapsulated or encapsulated. Nonencapsulated microcarcinomas are often sclerotic and focally invasive; in the presence of prominent sclerosis a stellate appearance may be identified. Most show a predominant follicular growth pattern although papillary architecture may be present. Typical nuclear features of TPC are present. May be multifocal in the same lobe or in the opposite lobe. Loss of heterozygosity mutational profiles not different from larger thyroid papillary carcinomas. May metastasize to regional lymph nodes in approximately 16% of cases; these metastatic foci are often microscopic. Distant metastasis may occur but are a rare occurrence. Excellent prognosis; finding a microscopic focus of TPC is generally of limited to no biologic import. The diagnosis of papillary microcarcinoma is not, in and of itself, an indication for additional surgical intervention. Experience with Chernobyl-related cases has shown that clinical insignificance of tumors less than 1 cm cannot be assumed in children (19 years of age or less); therefore, the suggestion has been made that the term papillary microcarcinoma be reserved for use only in adults. The approach to the therapeutic management of papillary microcarcinomas appears to be changing based on more recent findings reported in the literature: - patients with primary tumors measuring equal to or greater than 5mm treated by partial thyroidectomy alone were reported to have a prevalence of recurrent disease higher than in patients treated by total thyroidectomy and radioiodine ablation; - some groups have reported a high incidence (16%) of metastases from papillary microcarcinomas; - based on the above findings, some authorities believe it is reasonable to perform total thyroidectomy (possibly associated with central compartment node dissection), radioiodine ablation thetrapy and TSH-suppressive hormonal therapy in patients with papillary microcarcinomas; - despite reported recurrences and/or metastases, the prognosis for patients with papillary microcarcinomas is excellent with 100% survival and no deaths due to the papillary microcarcinomas; - papillary microcarcinomas appear to have a similar biology to other low risk papillary thyroid cancers and, according to some authorities, may warrant similar treatment. Encapsulated Variant Comprises approximately 10% of all TPC. Well-defined capsule separating the neoplastic follicles from the adjacent thyroid parenchyma. Capsular invasion can be seen; despite the capsular invasion, these are still considered encapsulated tumors and invasive growth does not alter the prognosis. Architecturally, this variant may be papillary or follicular; these tumors may also be partly or completely cystic. Cytomorphologic features are the typical ones of TPC. Examples of encapsulated (noninvasive) follicular tumors with limited foci (small percentage) showing diagnostic nuclear features for thyroid papillary carcinoma or equivocal diagnostic findings for thyroid papillary carcinoma have been termed well-differentiated (follicular) tumor of uncertain malignant potential: recent immunohistochemical findings have shown that: HBME-1 and Galectin-3 are heterogeneously distributed in equivocal (borderline) tumors; strong and diffuse expression of HBME-1 and (to a lesser extent) Galectin-3 preferentially seen in examples where the nuclear morphology were similar but less developed as compared to conventional thyroid papillary carcinoma; these findings suggest that the tumors with equivocal (borderline) nuclear changes are pathogenetically linked to thyroid papillary carcinoma.. Treatment and prognosis is the same as that of conventional TPC. Cervical lymph node metastases may occur but the frequency of nodal metastasis is lower (<40%) in comparison to conventional TPC. Excellent overall prognosis. Follicular Variant Architectural features exclusively composed of a follicular pattern of growth. Despite absence of papillary growth, other architectural features of TPC can be seen including elongated and/or twisted follicles; internal irregular fibrosis; presence of psammoma bodies in interfollicular stroma. If enough sections are taken, foci of papillary growth may be found. Most are encapsulated but areas of capsular invasion may be seen (which does not alter the prognosis). The diagnosis is primarily based on the cytomorphologic (nuclear) features which are those of conventional TPC. A high frequency of RAS point mutations have been identified in the follicular variant of TPC and as previously noted RAS mutations found exclusively in the follicular variant of thyroid papillary carcinoma correlating with significantly less prominent nuclear features and low rate of lymph node metastases. Recent studies have shown overlapping molecular features between follicular variant of thyroid papillary carcinoma with follicular adenomas and follicular carcinomas: frequency of PAX8-PPAR gamma rearrangement similar in follicular variant of thyroid papillary carcinoma (38%), follicular carcinomas (46%) and follicular adenomas (33%); frequency and type of RAS mutations similar in follicular variant of thyroid papillary carcinoma (25%), follicular carcinomas (22%) and follicular adenomas (33%); the significance of these findings remains uncertain but does raise possible clinical significance relative to possibility of blood-born metastases of PAX8-PPARgamma rearrangement, RAS mutations, and BRAF(K601E) in follicular variants of thyroid papillary carcinomas. Immunohistochemical tissue microarray analysis has shown diagnostic value in the expression of HBME-1, anti-MAP kinase (ERK) and p16 in potentially differentiating benign (i.e., nodules, lymphocytic thyroiditis, adenomas) from malignant (i.e., follicular carcinoma and variants, papillary carcinoma and variants, anaplastic carcinoma, poorly-differentiated carcinoma) follicular-derived lesions of the thyroid: HBME-1, ERK and p16 were found to be more specific for malignancy; CK19 and galectin 3 (GAL-3) stained with a higher frequency and were not specific for malignant follicular-derived lesions of the thyroid; RET-oncoprotein showed poor sensitivity and specificity Using tissue microarray analysis and immunohistochemical staining, separation of follicular adenoma from follicular variant of thyroid papillary carcinoma in conjunction with light microscopic analysis has been reported: - combination of markers including HBME-1, galectin-3 and CK19 or HBME-1, CITED1 and galectin-3 reported to be effective in distinguishing follicular adenoma from follicular variant of thyroid papillary carcinoma; - panel of HBME-1 plus galectin-3 plus CK19 showed 87% sensitivity and 89% specificity for follicular variant of thyroid papillary carcinoma while only positive in 11% of follicular adenomas; - panel of HBME-1 plus galectin-3 plus CITED-1 showed 76% sensitivity and 96% specificity for follicular variant of thyroid papillary carcinoma while only positive in 1% of follicular adenomas. Treatment and prognosis is that of conventional TPC. Share biologic behavior of conventional TPC. The classification of an encapsulated follicular tumor showing equivocal cytomorphologic features for thyroid papillary carcinoma or isolated limited foci diagnostic for thyroid papillary carcinoma remains controversial: - if the extent of change is significant/widespread (to date there is no clear definition of what constitutes "significant" or "widespread") then the diagnosis of encapsulated thyroid papillary carcinoma, follicular variant can be made; - if the features are equivocal and there is no invasion then this tumor can be termed as an atypical adenoma; - if the features are equivocal but there is definitive evidence of invasion then the tumor can be diagnosed as carcinoma; in such circumstances the specific designation of the type of carcinoma (i.e., papillary versus follicular) is academic since treatment should be the same; so, depending on one's level of confidence the following designations can be utilized: carcinoma, favor thyroid papillary carcinoma, follicular variant; carcinoma, favor follicular carcinoma, minimally invasive; well-differentiated carcinoma, not otherwise specified or well-differentiated (follicular) tumor of uncertain malignant potential: recent immunohistochemical findings have shown that: HBME-1 and Galectin-3 are heterogeneously distributed in equivocal (borderline) tumors; strong and diffuse expression of HBME-1 and (to a lesser extent) Galectin-3 preferentially seen in examples where the nuclear morphology were similar but less developed as compared to conventional thyroid papillary carcinoma; these findings suggest that the tumors with equivocal (borderline) nuclear changes are pathogenetically linked to thyroid papillary carcinoma.. - Irrespective of the specific designation, it should be noted that in such examples the prognosis is excellent. Macrofollicular Variant In all regards, this variant of TPC is essentially the same as the follicular variant except that the neoplastic follicles are large (macrofollicles) and > 50% are comprised of these macrofollicles. This variant of papillary carcinoma bears the most resemblance to adenomatoid or hyperplastic nodules, and without evaluating the cellular content may be misdiagnosed as such. The majority of these tumors are encapsulated. A potential hint suggesting the diagnosis is the presence of cellular foci seen throughout the neoplasm both in central and peripheral locations. The cellular foci show characteristic nuclear features of TPC; however, cells with less clear nuclei and coarse chromatin as well as low cuboidal cells with hyperchromatic nuclei may be identified. The presence of papillae are not required for a diagnosis but abortive papillary structures can usually be found. May metastasize to regional lymph nodes. The histology in metastasis often is similar to primary tumor with a macrofollicular architecture. Rare example reported of anaplastic transformation. Treatment and prognosis is the same as that of conventional TPC. Other less common variants include Diffuse (Multinodular) Follicular Variant Solid Variant and Radiation-Induced Pediatric Thyroid Cancers Oxyphilic or Oncocytic Variant Warthin Tumor-like Variant TPC with Nodular Fasciitis-like Stroma Clear Cell Variant Cribriform-Morular Variant Biologically Aggressive Variants of TPC (Table 4) These variants of thyroid papillary carcinoma have a tendency to occur in older aged patients (except for the diffuse sclerosing variant); generally are large measuring more than 5 cm; often present with extrathyroidal extension; tend to disseminate early in the disease course with regional lymph node metastasis as well as distant metastasis particularly to the lung; are treated more aggressively than the conventional type of TPC or the less aggressive variants of TPC. Some of the tumors included within the aggressive variants of TPC have been designated according to a particular cell type (e.g. tall, columnar) while others have been designated according to a growth pattern (e.g. insular); the fact that these tumors are included within the spectrum of the aggressive variants, and treated accordingly, should not be predicated solely on the basis of a particular cell type or growth pattern; rather, each tumor should be evaluated as any other papillary carcinoma, in particular, patient age, tumor size and extent of invasion (i.e., the presence or absence of extrathyroidal extension); given the tendency for these tumors as a group to be large, they may also have a tendency to have extrathyroidal extension; this finding, perhaps with some additional features associated with these tumors (e.g. older age at presentation), probably play a much more significant factor than the individual cell type or growth pattern in predicting the aggressiveness of the tumor; the exception to this would be the anaplastic thyroid carcinoma, which by definition is a high-grade, aggressive tumor. Extrathyroidal Extension Definition: Involvement of the perithyroidal soft tissues by a primary thyroid cancer. The presence of extrathyroidal extension of tumor represents one of the worst prognostic indicators in TPC. Extrathyroidal extension includes invasion beyond the thyroid capsule and/or invasion into perithyroidal soft tissues. The presence of extrathyroidal invasion should be documented in the surgical pathology report. Gross and Microscopic Findings On gross examination, the capsule appears complete but evidence has shown that microscopically the capsule is focally incomplete in a majority of autopsy thyroid glands evaluated. A thin fibrous capsule completely envelops the thyroid gland with septa that divide the thyroid gland incompletely into lobules. The capsule includes sizable vascular spaces as well as small peripheral nerves and is continuous with the pretracheal fascia.In practice, a fibrous capsule of the thyroid gland is often not identifiable by microscopic examination; therefore, criteria for defining (minimal) extrathyroidal extension may be problematic and subjective. Criteria Extracapular extension includes minimal extension and extensive extension. Diagnostic findings for minimal extrathyroid extension includes the presence of cancer extending into perithyroidal soft tissues, including infiltration of adipose tissue and skeletal muscle, as well as around (and into) sizable vascular structures and nerves. Diagnostic findings for extensive extrathyroid extension would include the presence of carcinoma well beyond the thyroid gland proper with direct invasion (i.e., not metastasis) into one or more of the following structures: subcutaneous soft tissues; adjacent viscera, including the larynx, trachea and/or esophagus; the recurrent laryngeal nerve, carotid artery or mediastinal blood vessels. Pitfalls Normal (nonneoplastic) thyroid follicles may be identified in the pericapsular thyroid capsule or as nodular aggregates in pericapsular connective tissue. Such foci should not be mistaken for extrathyroidal extension by carcinoma. Features assisting in not misinterpreting nonneoplastic capsular foci of thyroid follicles as cancer would include isolated nests of histologically unremarkable thyroid follicular epithelial cells with absence of continuity from a histologically identifiable carcinoma , absence of cytomorphologic features diagnostic for thyroid papillary carcinoma, thyroid medullary carcinoma, poorly-differentiated carcinoma or anaplastic carcinoma; absence of a desmoplastic response. Mature adipose tissue may rarely be found be within the thyroid gland under normal conditions and also may be a component of a variety of thyroid lesions including carcinomas; the presence of adipose tissue in association with a thyroid carcinoma should not mistaken for extrathyroidal extension. Diagnostic findings that assist in preventing misinterpretation include: the adipose tissue is intimately admixed with the thyroid lesion within the gland proper; the adipose tissue is clearly not outside the gland proper nor invaded by cancer that is directly extending from a thyroid based carcinoma; absence of a desmoplastic response. Similar to adipose tissue in the thyroid, the presence of skeletal muscle in the thyroid is an incidental finding and may be seen in the thyroid gland under normal conditions as well as in a variety of pathologic conditions. skeletal muscle is typically found in association with the isthmic portion of the thyroid. Diagnostic findings that assist in preventing misdiagnosis include: the skeletal muscle is intimately admixed with the thyroid tissue; absence of a desmoplastic response. Clinical Significance of Extrathyroidal Extension Associated with a worse prognosis. The American Joint Committee on Cancer (AJCC) Staging for Thyroid Cancers includes thyroid papillary carcinomas, thyroid follicular carcinomas, and thyroid medullary carcinomas. All anaplastic carcinomas are considered T4 tumors: T4a intrathyroidal anaplastic carcinoma – surgically resectable; T4b intrathyroidal anaplastic carcinoma – surgically unresectable; The presence of extrathyroid extension "upstages" the thyroid cancer in patients 45 years and older: TX - T2 carcinomas all confined to the thyroid gland; T3 carcinomas includes those tumors with minimal extrathyroidal extension; T4 carcinomas are any cancers extending beyond the thyroid capsule: T4a invades subcutaneous soft tissues or adjacent structures (e.g., larynx, trachea, esophagis or recurrent laryngeal nerve); T4b invades prevertebral fascia or encases carotid artery or mediastinal vessels. Stage III includes any T3 cancer; Stage IV includes any T4a (Stage IVA) or T4b (Stage T4B) cancer. Higher clinical stage cancers are associated with a worse prognosis. Minimal (microscopic) extrathyroidal extension does not confer as worse a prognosis as compared to cancers with extensive extrathyroidal extension. Relative to differentiated thyroid carcinomas, therapy remains the same irrespective of the extent of invasion and usually includes total thyroidectomy and postoperative radioactive iodine therapy. FINAL Diagnosis: Thyroid papillary carcinoma, follicular (and encapsulated) variant. Take Home Messages The differential diagnosis for any "cold" nodule includes a thyroid follicular epithelial neoplasm, including follicular adenoma, follicular carcinoma and thyroid papillary carcinoma. The presence or absence of invasive growth (i.e., capsular invasion and lymph-vascular space invasion) represents the key feature in differentiating a benign follicular epithelial neoplasm (thyroid follicular adenoma) from a malignant follicular epithelial cell neoplasm (thyroid follicular carcinoma, thyroid papillary carcinoma). Diagnostic criteria for thyroid papillary carcinoma are predicated on architectural features but most importantly cytomorphologic (i.e., nuclear) features such that a diagnosis of thyroid papillary carcinoma can be rendered in the absence of a papillary architecture and in the absence of invasive growth. At present, the "gold standard" in the diagnosis of thyroid papillary carcinoma is primarily the light microscopic features; adjunct studies, including immunohistochemistry (e.g., CK19, galectin 3, HBME) are of limited diagnostic utility in the diagnosis and differential diagnosis of thyroid papillary carcinoma. For all thyroid malignant neoplasms, the presence of extrathyroidal extension represents an adverse prognostic finding; the presence or absence of extrathyroidal extension should be included in all surgical pathology reports of thyroid malignant neoplasms. References Follicular Adenoma Akslen LA, Myking AO. Differentiated thyroid carcinomas: the relevance of various pathological features for tumour classification and prediction of tumour progress. Virch Arc A Pathol Anat Histopathol 1992;421:17-23. Barroeta JE, Baloch ZW, Lal P, et al. Diagnostic value of differential expression of CK19, galectin-3, HBME-1, ERK, RET, and p16 in benign and malignant follicular-derived lesions of the thyroid: an immunohistochemical tissue microarray analysis. Endocr Pathol 2006;3:225-234. Belge G, Roque L, Soares J, et al. Cytogenetic investigations of 340 thyroid hyperplasias and adenomas revealing correlations between cytogenetic findings and histology. Cancer Genet Cytogenet 1998;101:42-8. Böcker W, Raille H, Koch G, et al. Immunohistochemical and electron microscope analysis of adenomas of the thyroid gland. II. Adenomas with specific cytologic differentiation. Virch Arch [A] Pathol Anat 1978;380:205-20. Bol S, Belge G, Rippe V, Bullerdiek J. Molecular cytogenetic investigations define a subgroup of thyroid adenomas with 2p21 breakpoints clustered to a region of less than 450 kb. Cytogenet Cell Genet 2001;95:189-91. Castro P, Soares P, Gusmao L, Seruca R, Sobrinho-Simoes M. H-RAS 81 polymorphism is significantly associated with aneuploidy in follicular tumors of the thyroid. Oncogene 2006 Chung DH, Kang GH, Kim WH, Ro JY. Clonal analysis of a solitary follicular nodule of the thyroid with the polymerase chain reaction method. Mod Patho 1999;12:265-71. Evans HL. Follicular neoplasms of the thyroid: A study of 44 cases followed for a minimum of 10 years, with emphasis on differential diagnosis. Cancer 1984;54:535-40. Harrer P, Broecker M, Zint A, Schatz H, Zumtobel V, Derwahl M. Thyroid nodules in recurrent multinodular goiters are predominantly polyclonal. J Endocrinol Invest 1998;21:380-5. Hicks DG, LiVolsi VA, Neidich JA, et al. Clonal analysis of solitary follicular nodules in the thyroid. Am J Pathol 1990;137;553-62. Kim H, Piao Z, Park C, Chung WY, Park CS. Clinical significance of clonality in thyroid nodules. Br J Surg 1998;85:1125-8. Kini SR. Guides to clinical aspiration biopsy: Thyroid. New York. Igaku-Shoin; 1987. Mai KT, Landry DC, Thomas J, et al. Follicular adenoma with papillary architecture: a lesions mimicking papillary thyroid carcinoma. Histopathology 2001;39:25-32. Meiboom M, Murua Escobar H, Pentimalli F, Fusco A, Belge G, Bullerdiek J. A 3.4-kbp transcript of ZNF331 is solely expressed in follicular thyroid adenomas. Cytogenet Genome Res 2003;101:113-7. Nakamura N, Erickson LA, Jin L, et al. Immunohistochemical separation of follicular variant of papillary thyroid carcinoma from follicular adenoma. Endocr Pathol 2006;3:213-224. Raphael SJ, McKeown-Eyssen G, Asa SL. High-molecular-weight cytokeratin and cytokeratin-19 in the diagnosis of thyroid tumors. Mod Pathol 1994;7:295-300. Rippe V, Drieschner N, Meiboom M, et al. Identification of a gene rearranged by 2p21 aberrations in thyroid adenomas. Oncogene 2003;22:6111-4. Roque L, Serpa A, Clode A, Castedo S, Soares J. Significance of trisomy 7 and 12 in thyroid lesions with follicular differentiation: a cytogenetic and in situ hybridization study. Lab Invest 1999 ;79:369-78. Roque L, Rodrigues R, Pinto A, Moura-Nunes V, Soares J. Chromosome imbalances in thyroid follicular neoplasms: a comparison between follicular adenomas and carcinomas. Genes Chromosomes Cancer 2003;36:292-302. Thomas GA, Williams D, Williams ED. The clonal origin of thyroid nodules and adenomas. Am J Pathol 1989;134:141-7. Yamashina M. Follicular neoplasms of the thyroid: total circumferential evaluation of the fibrous capsule. Am J Surg Pathol 1990;16:392-400. Follicular Carcinoma Akslen LA, Myking AO. Differentiated thyroid carcinomas: the relevance of various pathological features for tumour classification and predictiion of tumour progress. Virch Arc A Pathol Anat Histopathol 1992;421:17-23. Barden CB, Shister KW, Zhu B, et al. Classification of follicular thyroid tumors by molecular signature: results of gene profiling. Clin Cancer Res 2003;9:1792-800. Barroeta JE, Baloch ZW, Lal P, et al. Diagnostic value of differential expression of CK19, galectin-3, HBME-1, ERK, RET, and p16 in benign and malignant follicular-derived lesions of the thyroid: an immunohistochemical tissue microarray analysis. Endocr Pathol 2006;3:225-234. Brennan MD, Bregstralh EJ, van Heerden JA, McConahey WM. Follicular thyroid cancer treated at the mayo clinic, 1946 through 1970: initial manifestations, pathologic features, therapy, and outcome. Mayo Clin Proc 1991;66:11-22. Clark OH. Total thyroidectomy: The treatment of choice for patients with differentiated thyroid cancer. Ann Surg 1982;196:361-70. Carcangiu ML. Minomally invasive follicular carcinoma. Endocr Pathol 1997;8:231-4. Chow SM, Law SC, Mendenhall WM, et al. Follicular thyroid carcinoma: prognostic factors and the role of radioiodine. Cancer 2002;95:488-98. Collini P, Sampietro G, Rosai J, Pilotti S. Minimally invasive (encapsulated) follicular carcinoma of the thyroid gland is the low-risk counterpart of widely invasive follicular carcinoma but not of insular carcinoma. Virchows Arch 2003;442:71-6. D'Avanzo A, Treseler P, Ituarte PH, et al. Follicular thyroid carcinoma: histology and prognosis. Cancer 2004;100:1123-9. Delbridge L, Parkyn R, Philips J, Barraclough B, Robinson B. Minimally invasive follicular thyroid carcinoma: completion thyroidectomy or not? ANZ J Surg 2002;72:844-5. Emerick GT, Duh QY, Siperstein AE, et al. Diagnosis, treatment, and outcome of follicular thyroid carcinoma. Cancer 1993;72:3287-95. Evans HL. Follicular neoplasms of the thyroid: A study of 44 cases followed for a minimum of 10 years, with emphasis on differential diagnosis. Cancer 1984;54:535-540. Franc B, de la Salmoniere P, Lange F, et al. Interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma. Hum Pathol 2003;34:1092-100. Fransilla KO, Ackerman LV, Brown CL, Hedinger CE. Follicular carcinoma. Semin Diagn Pathol 1985;2:101-22. French CA, Alexander EK, Cibas ES, et al. Genetic and biological subgroups of low-stage follicular thyroid cancer. Am J Pathol 2003;162:1053-60. Goldstein NS, Czako P, Neill JS. Metastatic minimally invasive (encapsulated) follicular and Hurthle cell thyroid carcinoma: a study of 34 patients. Mod Pathol 2000 Feb13:123-30. Harness JK, Thompson NW, McLeod MK, et al. Follicular carcinoma of the thyroid gland: trends and treatment. Surgery 1984;96:972-80. Hazard JB, Kenyon R. Atypical adenoma of the thyroid. Arch Pathol Lab Med 1954;58:554-63. Hazard JB, Kenyon R. Encapsulated angioinvasive carcinoma (angioinvasive adenoma) of the thyroid gland. Am J Clin Pathol 1954;24:755-66. Hemmer S, Wasenius VM, Knuutila S, Joensuu H, Franssila K. Comparison of benign and malignant follicular thyroid tumours by comparative genomic hybridization. Br J Cancer 1998;78:1012-7. Heffess CS, Thompson LD. Minimally invasive follicular thyroid carcinoma. Endocr Pathol 2001;12:417-22. Hirokawa M, Carney JA, Goellner JR, et al. Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol 2002;16:1508-14. Hruban RH, Huvos AG, Traganos F, et al. Follicular neoplasms of the thyroid in men older than 50 years of age: a DNA flow cytometric study. Am J Clin Pathol 1990;94:527-32. Kahn NF, Perzin KH. Follicular carcinoma of the thyroid: an evaluation of the histologic criteria used for diagnosis. Pathol Annu 1983;18:221-53. Kini SR. Guides to clinical aspiration biopsy: Thyroid. New York. Igaku-Shoin; 1987. Lang W, Georgi A, Stauch G, Kienzle E. The differentiation of atypical adenomas and encapsulated follicular carcinomas in the thyroid gland. Virch Arch [A] Pathol Anat 1980;385:125-41. Lang W, Georgi A. Minimally invasive cancer in the thyroid. Clin Oncol 1982;1;527-37. Lang W, Choritz H, Hundeshagen H. Risk factors in follicular thyroid carcinomas: a retrospective follow-up study covering a 14 year period with emphasis on morphological findings. Am J Surg Pathol 1986;10:246-55. Lui WO, Kytola S, Anfalk L, Larsson C, Farnebo LO. Balanced translocation (3;7)(p25;q34): another mechanism of tumorigenesis in follicular thyroid carcinoma? Cancer Genet Cytogenet 2000;119:109-12. McHenry CR, Sandoval BA. Management of follicular and Hurthle cell neoplasms of the thyroid gland. Surg Oncol Clin N Am. 1998 Oct;7(4):893-910. Nakamura N, Erickson LA, Jin L, et al. Immunohistochemical separation of follicular variant of papillary thyroid carcinoma from follicular adenoma. Endocr Pathol 2006;3:213-224. Nikiforova MN, Lynch RA, Biddinger PW, et al. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab 2003;88:2318-26. Nikiforov YE. Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroida carcinoma. Endocr Pathol 2004;15:319-27. Oyama T, Suzuki T, Hara F, et al. N-ras mutation of thyroid tumor with special reference to the follicular type. Pathol Int 1995;45:45-50. Paul SJ, Sisson JC. Thyrotoxicosis caused by thyroid cancer. Endocrinol Metab Clin North Am 1990;19:593-612. Perrier ND, Ituarte PH, Treseler P, et al. Classification and treatment of follicular thyroid neoplasms are discordant between and within medical specialties. Surgery 1999;126:1063-8; discussion 1069. Roque L, Clode A, Belge G, et al . Follicular thyroid carcinoma: chromosome analysis of 19 cases. Genes Chromosomes Cancer 1998;21:250-5. Rosai J. Follicular carcinoma. In: Rosai J, ed. Ackerman's Surgical Pathology. London; Elsevier; 2004:542-4. Rosai J. Handling of thyroid follicular patterned lesions. 2005 Endocrine Pathology Society Handout. USCAP; Augusta; 2005. Rosai J. Handling of Thyroid Follicular Patterned Lesions. Endocr Pathol 2005;16:279-284. Segal K, Arad A, Lubin E, et al. Follicular carcinoma of the thyroid. Head Neck 1994;16:533-8. Schroder DM, Chambors A, Frances CJ. Operative strategy for thyroid cancer. Is total thyroidectomy worth the price? Cancer 1986;58:2320-8. Schlumberger M, Tubiana M, De Vathaire F, et al. Long-term results of treatment in 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 1986;63:960-7. Sobrinho Simões M, Asa S, Kroll TG, et al. Follicular carcinoma. In: In: DeLellis RA, Lloyd RV, Heitz RU, Eng C, eds. World Health Organization Classification of tumours. Pathology & Genetics Tumours of endocrine organs. Lyon; IARC Press; 2004:67-72. Takano T, Miyauchi A, Yoshida H, Kuma K, Amino N. High-throughput differential screening of mRNAs by serial analysis of gene expression: decreased expression of trefoil factor 3 mRNA in thyroid follicular carcinomas. Br J Cancer 2004;90:1600-5 Thompson LD, Wieneke JA, Paal E, Frommelt RA, Adair CF, Heffess CS. A clinicopathologic study of minimally invasive follicular carcinoma of the thyroid gland with a review of the English literature. Cancer 2001;91:505-24. van Heerden JA, Hay ID, Goellner JR, et al. Follicular thyroid carcinoma with capsular invasion alone: a nonthreatening malignancy. Surgery 1992;112:1130-6; discussion 1136-8. Warren S. Significance of invasion of blood vessels of the thyroid gland. Arch Pathol 1931;11;255-7. Warren S. Invasion of blood vessels in thyroid cancer. Am J Clin Pathol 1956;26:64-5. Williams ED (on behalf of the Chernobyl Pathologists Group). Guest editorial: Two proposals regarding terminology of thyroid tumors. Int J Surg Pathol 2000;8:181-4. Wyllie FS, Lemoine NR, Williams ED, Wynford-Thomas D. Structure and expression of nuclear oncogenes in multi-stage thyroid tumorigenesis. Br J Cancer. 1989;60:561-5. Starnes HF, Brooks DC, Pinkus GS, Brooks JR. Surgery for thyroid cancer. Cancer 1985;55:1376-81. Yamashina M. Follicular neoplasms of the thyroid: total circumferential evaluation of the fibrous capsule. Am J Surg Pathol 1990;16:392-400. Follicular Carcinoma with Oncocytic (Oxyphilic) Cells Abu-Alfa, AK, Straus FH, Montag AG. An immunohistochemical study of thyroid Hürthle cells and their neoplasms. The roles of S100 and HMB-45 proteins. Mod Pathol 1994;7:529-32 Asa SL. My approach to oncocytic tumours of the thyroid. J Clin Pathol 2004;57:225-32. Bejarano PA, Nikiforov YE, Swenson ES, Biddinger PW. Thyroid transcription factor-1, thyroglobulin, cytokeratin 7, and cytokeratin 20 in thyroid neoplasms. Appl Immunohistochem Mol Morphol 2000;8:189-94. Bondeson L, Bondeson A-G, Ljunberg O, Tibblin S. Oxyphil tumors of the thyroid: follow-up of 42 surgical cases. Ann Surg 1981;194:677-80. Bononi M, De Cesare A, Cangemi V, et al. Hurthle cell tumors of the thyroid gland. Personal experience and review of literature. Anticancer Res 200222:3579-82. Bronner MP, LiVolsi VA. Oxyphilic (Askanazy/Hürthle cell) tumors of the thyroid: Microscopic features predict biologic behavior. Surg Pathol 1988;1:137-50. Caplan RH, Abellera Rm, Kisken WA. Hürthle cell tumors of the thyroid gland. A clinicopathologic review and long- term follow-up. JAMA 1984;251:3114-7. Carcangiu ML, Bianchi S, Savino D, et al. Follicular Hürthle cell neoplasms of the thyroid gland. A study of 153 cases. Cancer 1991;68:1944-53. Chiappetta G, Toti P, Cetta F, et al. The RET/PTC oncogene is frequently activated in oncocytic thyroid tumors (Hurthle cell adenomas and carcinomas), but not in oncocytic hyperplastic lesions.J Clin Endocrinol Metab 2002;87:364-9. Dettori T, Frau DV, Lai ML, et al. Aneuploidy in oncocytic lesions of the thyroid gland: diffuse accumulation of mitochondria within the cell is associated with trisomy 7 and progressive numerical chromosomal alterations. Genes Chromosomes Cancer 2003;38:22-31. Evans HL, Vassilopoulou-Sellin R. Follicular and Hürthle cell carcinomas of the thyroid: a comparative study. Am J Surg Pathol 1998;22:1512-20. Finley DJ, Zhu B, Fahey TJ 3rd. Molecular analysis of Hurthle cell neoplasms by gene profiling. Surgery 2004;136:1160-8. Flint A, Lloyd RV. Hürthle-cell neoplasms of the thyroid gland. Pathol Annu 1990;25(Part 1):37-52. Ghossein RA, Hiltzik DH, Carlson DL, et al. Prognostic factors of recurrence in encapsulated Hurthle cell carcinoma of the thyroid gland: A clinicopathologic study of 50 cases. Cancer 2006;106:1669-76. Gosain AK, Clark OH. Hürthle-cell neoplasms. Malignant potential. Arch Surg 1984;119:515-9. Grant CS. Operative and postoperative management of the patient with follicular and Hürthle cell carcinoma. Do they differ? Surg Clin North Am 1995;75:395-403. Gundry SR, Burney RE, Thompson NW, Lloyd R. Total thyroidectomy for Hürthle cell neoplasm of the thyroid. Arch Surg 1983;118:529-32. Johnson TL, Lloyd RV, Burney RE, Thompson NW. Hürthle cell thyroid tumors: An immunohistochemical study. Cancer 1987;59:107-12. Kendall CH, McCluskey E, Naylor J. Oxyphil cells in thyroid disease: a uniform change? J Clin Pathol 1986;39:908-12. Kini SR, Miller JM, Hamburger JI. Cytopathology of Hürthle cell lesions of the thyroid gland by fine needle aspiration. Acta Cytol 1981;25:647-52. Lazzi S, Spina D, Als C, et al. Oncocytic (Hurthle cell) tumors of the thyroid: distinct growth patterns compared with clinicopathological features. Thyroid 1999;9:97-103. Lloyd RV. Oncocytic tumors of the thyroid gland. Adv Anat Pathol 1997;4:306-10. McLeod MK, Thompson NW. Hürthle-cell neoplasms of the thyroid. Otolaryngol Clin North Am 1990;23:441-52. Maximo V, Botelho T, Capela J, et al. Somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid. Br J Cancer 2005 (Epub ahead of publication). Muller-Hocker J, Schafer A, Strowitzki T. Glucose transporter 4 (GLUT 4) is highly expressed in mitochondrial-rich oxyphil cells. Appl Immunohistochem 1998;6:224-7. Muller-Hocker J. Immunoreactivity of p53, Ki-67, and Bcl-2 in oncocytic adenomas and carcinomas of the thyroid gland. Hum Pathol 1999;30:926-33. Nesland JM, Sobrinho-Simões MA, Holm R, Sambade MC, Johannessen JV. Hürthle cell lesions of the thyroid: a combined study using transmission electron microscopy, scanning electron microscopy, and immunocytochemistry. Ultrastruct Pathol 1985;8:269-90. Santeusanio G, D'Alfonso V, Iafrate E, et al. Antibodies to cytokeratin 14 specifically identify oncocytes (Hürthle cells) in thyroid lesions and tumors. Appl Immunohistochem 1997;5:223-8. Sobrinho Simões M, Asa S, Kroll TG, et al. Follicular carcinoma. In: In: DeLellis RA, Lloyd RV, Heitz RU, Eng C, eds. World Health Organization Classification of tumours. Pathology & Genetics Tumours of endocrine organs. Lyon; IARC Press; 2004:67-72. Sobrinho-Simoes M, Preto A, Rocha AS, et al. Molecular pathology of well-differentiated thyroid carcinomas. Virchows Arch 2005;447:787-93. Volante M, Croce S, Pecchioni C, Papotti M. E2F-1 transcription factor is overexpressed in oxyphilic thyroid tumors. Mod Pathol 2002;15:1038-43. Watson RG, Brennan MD, Goellner JR, et al. Invasive Hürthle cell carcinoma of the thyroid: natural history and management. Mayo Clin Proc 1984;59:851-5. Thyroid Papillary Carcinoma Adeniran AJ, Zhu Z, Gandhi M, et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol 2006;30:216-22. Akslen LA, Myking AO. Differentiated thyroid carcinomas: the relevance of various pathological features for tumour classification and prediction of tumour progress. Virch Arc A Pathol Anat Histopathol 1992;421:17-23. Akslen LA, Livolsi VA. Prognostic significanceof histologic grading compared with subclassification of papillary thyroid carcinoma. Cancer 2000;88:1902-8. Baloch ZW, Abraham S, Roberts S, LiVolsi VA. Differential expression of cytokeratins in follicular variant of papillary carcinoma: an immunohistochemical study and its diagnostic utility. Hum Pathol 1999;30:1166-71. Baloch ZW, LiVolsi VA. Etiology and significance of the "optically clear nucleus". Endor Pathol 2003;13:289-99. Bouchard C. Fllow-up of patients with thyroid carcinoma. N Engl J Med 1997;337:928-30. Cameron BR, Berean KW. Cytokeratin subtypes in thyroid tumours: immunohistochemical study with emphasis on the follicular variant of papillary carcinoma. J Otolaryngol 2003;32:319-22. Carcangiu ML, Zampi G, Pupi A, et al. Papillary carcinoma of the thyroid: a clinicopathologic study of 241 cases treated at the University of Florence, Italy. Cancer 1985;55:805-28. Carcangiu ML, Zampi G, Rosai J. Papillary thyroid carcinoma: A study of its many morphologic expressions and clinical correltates. Pathol Annu 1985;20:1-44. Casey MB, Lohse CM, Lloyd RV. Distinction between papillary thyroid hyperplasia and papillary thyroid carcinoma by immunohistochemical staining for cytokeratin 19, galectin-3, and HBME-1. Endocr Pathol 2003;4:55-60. Cerilli LA, Mills SE, Rumpel CA, Dudley TH, Moskaluk CA. Interpretation of RET immunostaining in follicular lesions of the thyroid. Am J Clin Pathol 2002;118:186-93. Chan JKC, Saw D. The grooved nucleus. A useful diagnostic criterion of papillary carcinoma of the thyroid. Am J Surg Pathol 1986;10:672-9. Cheung CC, Ezzat S, Freeman JL, Rones IB, ASa SL. Immunohistochemical diagnosis of papillary thyroid carcinoma. Mod Pathol 2001;14:338-42. Ciampi R, Nikiforov YE. Alterations of the BRAF gene in thyroid tumors. Endocr Pathol 2005;16:163-72. Clark JR, Lai P, Hall F, Borglund A, Eski S, Freeman JL. Variables predicting distant metastases in thyroid cancer. Laryngoscope 2005;115:661-7. Cushing SL, Palme CE, Audet N, Eski S, Walfish PG, Freeman JL. Prognostic factors in well-differentiated thyroid carcinoma. Laryngoscope 2004;114:2110-5. Dinneen SF, Valimaki MJ, Bergstralh EJ, et al. Distant metastases in papillary thyroid cancer: 100 cases observed at one institution during 5 decades. J Clin Endocrinol Metab 1995;80:2041-5. Falvo L, Catania A, D'Andrea V, et al. Prognostic importance of histologic vascular invasion in papillary thyroid carcinoma. Ann Surg 2005;241:640-6. Fernandes JK, Day TA, Richardson MS, Sharma AK. Overview of the management of differentiated thyroid cancer. Curr Treat Options Oncol 2005;6:47-57. Fischer AH, Bond JA, Taysavang P, Battles OE, Wynford-Thomas D. Papillary thyroid carcinoma oncogene (RET/PTC) alters the nuclear envelope and chromatin structure. Am J Pathol 1998;153:1443-50. Francis IM, Das DK, Sheikh ZA, et al. Role of nuclear grooves in the diagnosis of papillary thyroid carcinoma. A quantitative assessment of fine needle aspiration smears. Acta Cytol 1995;39:409-15. Furlan JC, Bedard YC, Rosen IB. Role of fine-needle aspiration biopsy and frozen section in the management of papillary thyroid carcinoma subtypes. World J Surg 2004;28:880-5. Fusco A, Chiappetta G, Hui P, et al. Assessment of RET/PTC oncogene activation and clonality in thyroid nodules with incomplete morphological evidence of papillary carcinoma: a search for the early precursors of papillary cancer. Am J Pathol 2002;160:2157-67. Giordano TJ, Kuick R, Thomas DG, et al. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene 2005;24:6646-56. Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases rom surveillance, epidemiology and end results (SEER) program, 1973-1991. Cancer 1997;79:564-73. Grebe SK, Hay ID. Thyroid cancer nodal metastases: biological significance and therapeutic considerations. Surg Oncol Clin North Am 1996;5:43-63. Guiter GE, DeLellis RA. Multinucleate giant cells in papillary thyroid carcinoma. A morphologic and immunohistochemical study. Am J Clin Pathol 1996;106:765-8. Grossman RF, Tu SH, Siperstein AE, Novosolov F, Clark OH. Familial nonmedullary thyroid cancer. An emerging entity that warrants aggressive management. Arch Surg 1995;130:892-7. Hancock SL, McDougall IR, Constine LS. Thyroid abnormalities after therapeutic external radiation. Int J Radiat Oncol Biol Phys 1995;31:1165-70. Hara H, Fulton N, Yashiro T, et al. N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma. Surgery 1994;116:1010-6. Harach HR, Escalante DA, O_ativia A, et al. Thyroid carcinoma and thyroiditis in an endemic goitre region before and after iodine prophylaxis. Acta Endocrinol 1985;108:55-60. Harach HR, Williams ED. Childhood thyroid cancer in England and Wales. Br J Cancer 1995;72:777-83. Hay ID, Grant CS, Taylor WF, McConahey WM: Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 1987;102:1088-95. Hedman I, Tisell L-E. Associated hyperparathyroidism and nonmedullary thyroid carcinoma. The etiologic role of radiation. Surgery 1984;95:392-7. Hofstädter F. Frequency and morphology of malignant tumours of the thyroid before and after introduction of iodine-prophylaxis. Virchows Arch [A] Pathol Anat 1980;385:263-70. Hunt JL, Barnes EL. Non-tumor-associated psammoma bodies in the thyroid. Am J Clin Pathol 2003;119:90-4. Johannessen JV, Sobrinho-Simões M: The origin and significance of thyroid psammoma bodies. Lab Invest 1980;43:287-96. Jukkola A, Bloigu R, Ebeling T, Salmela P, Blanco G. Prognostic factors in differentiated thyroid carcinomas and their implications for current staging classifications. Endocr Relat Cancer 2004;11:571-9. Kini SR. Thyroid. In: Guides to clinical aspiration biopsy. Vol. 3. New York. Igaku-Shoin; 1987. LiVolsi VA: Papillary neoplasms of the thyroid: pathologic and prognostic features. Am J Clin Pathol 1992;97:426-34. LiVolsi VA, Albores-Saavedra J, ASa SL, et al. Papillary carcinoma. In: In: DeLellis RA, Lloyd RV, Heitz RU, Eng C, eds. World Health Organization Classification of tumours. Pathology & Genetics Tumours of endocrine organs. Lyon; IARC Press; 2004:57-66. Lloyd RV, Erickson LA, Casey MB, et al. Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. Am J Surg Pathol 2004;28:1336-40. Lote K, Andersen K, Nordal E, Brennhovd IO. Familial occurrence of papillary thyroid carcinoma. Cancer 1980;46:1291-7. Kodama Y, Asai N, Kawai K, et al. The RET proto-oncogene: A molecular therapeutic target in thyroid cancer. Cancer Sci 2005;96:143-8. Mazzaferri EL, Young RL, Oertel JE, et al. Papillary thyroid carcinoma: the impact of therapy in 576 patients. Medicine 1977;56:171-96. Mazzaferri EL. Papillary thyroid carcinoma: factors influencing prognosis and current therapy. Sem Oncol 1987;14:315-32. McConahey WM, Hay ID, et al. Papillary thyroid cancer treated at the mayo clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc 1986;61:978-96. Moir CR, Telander RL. Papillary carcinoma of the thyroid in children. Semin Pediatr Surg 1994;3:182-7. Moreno-Egea A, Rodriguez-Gonzalez JM, Sola-Perz J, et al. Mutlivariate analysis of histopathological features as prognostic factors in patients with papillary thyroid carcinoma. Br J Surg 1995;82:1092-4. Nikiforov YE, Heffess CS, Korzenko AV, Fagin JA, Gnepp DR. Characteristics of follicular tumors and nonneoplastic thyroid lesions in children and adolescents exposed to radiation as a result of the Chernobyl disaster. Cancer 1995;76:900-9. Nikiforov YE. Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroid carcinoma. Endocr Pathol 2004;15:319-27. Nikiforova MN, Kumura ET, Gandhi M, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic and poorly-differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 2003;88:5399-404. Patwardhan N, Cataldo T, Braverman LE. Surgical management of the patient with papillary cancer. Surg Clin North Am 1995;75:449-64. Plail RO, Bussey HJ, Glazer G, Thompson JP. Adenomatous polyposis: an association with carcinoma of the thyroid. Br J Surg 1987;74:377-80. Punthakee X, Palme CE, Franklin JH, Zhang I, Freeman JL, Bedard YC. Fine-needle aspiration biopsy findings suspicious for papillary thyroid carcinoma: a review of cytopathological criteria. Laryngoscope 2005;115:433-6. Rosai J. Immunohistochemical markers of thyroid tumors: significance and diagnostic applications. Tumori 2003;89:517-9. Sahoo S, Hoda SA, Rosai J, DeLellis RA. Cytokeratin 19 immunoreactivity in the diagnosis of papillary thyroid carcinoma: a note of caution. Am J Clin Pathol 2001;116:696-702. Sanotoro M, Carlomagno F, Hay ID, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest 1992;89:1517-22. Scopa CD, Melachrinou M, Saradopoulou C, Merino MJ. The significance of the grooved nucleus in thyroid lesions. Mod Pathol 1993;6:691-4. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med 1998;338:297-306. Sobrinho-Simoes M, Preto A, Rocha AS, et al. Molecular pathology of well-differentiated thyroid carcinomas. Virchows Arch 2005;447:787-93. Sridama V, Hara Y, Fauchet R, DeGroot LJ. Association of differentiated thyroid carcinoma and HLA-DR7. Cancer 1985;56:1086-8. Sugg SL, Ezzat S, Rosen IB, Freeman J, Asa SL. Distinct multiple ret/PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab 1998;83:4116-22. Tallini G, Asa SL. RET oncogene activation in papillary thyroid carcinoma. Adv Anat Pathol 2001;8:345-54. Vickery AL, Wang C-A, Walker AM: Treatment of intrathyroidal papillary carcinoma of the thyroid. Cancer 1987;60:2587-95. Vickery AL Jr: Thyroid papillary carcinoma: pathological and philosophical controversies. Am J Surg Pathol 1983;7:797-807. Vini L, Hyer SL, Marshall J, A'Hern R, Harmer C. Long-term results in elderly patients with differentiated thyroid carcinoma. Cancer 2003;97:2736-42. Yamashita H, Noguchi S, Murakami N, et al. Extracapsular invasion of lymph node metastasis is an indicator of distant metastasis and poor prognosis in patients with thyroid papillary carcinoma. Cancer 1997;80:2268-72. Yamashita H, Noguchi S, Murakami N, et al. Extracapsular invasion of lymph node metastases: a goodindicator of disease recurrence and poor prognosis in patients with thyroid papillary carcinoma. Cancer 1999;86:842-9. Thyroid Micropapillary Carcinoma Bondeson L, Ljungberg O. Occult papillary thyroid carcinoma in the young and the aged. Cancer 1984;53:1790-2. Cheema Y, Olson S, Elson D, Chen H. What is the biology and optimal treatment for papillary microcarcinoma of the thyroid? J Surg Res 2006;134:160-162. Franssila KO, Harach HR. Occult papillary carcinoma of the thyroid in children and young adults: a systemic autopsy study in Finland. Cancer 1986;58:715-9. Gikas PW, Labow SS, DiGiulio W, Finger JE. Occult metastasis from occult papillary carcinoma of the thyroid. Cancer 1967;20:2100-4. Ha ID, Grant CS, van Heerden JA, Goellner JR, Ebersold JR, Bergstralh EJ. Papillary thyroid microcarcinoma. A study of 535 cases observed in a 50-year period. Surgery 1992;112:1139-46. Harach HR, Franssila KO, Wasenius VM. Occult papillary carcinoma of the thyroid: a "normal" finding in Finland. A systematic autopsy study. Cancer 1985;56:531-58. Hazard JB. Small papillary carcinoma of the thyroid: a study with special reference to so-called nonencapsulated sclerosing tumor. Lab Invest 1960;9:86-97. Hubert JP Jr, Keirnan PD, Beahrs OH, et al. Occult papillary carcinoma of the thyroid. Arch Surg 1980;115:394-8. Hunt JL, LiVolsi VA, Baloch ZW, et al. Microscopic papillary thyroid carcinoma compared with clinical carcinomas by loss of heterozygosity mutational profile. Am J Surg Pathol 2003;27:159-66. Ito Y, Tomoda C, Uruno T, et al. Papillary microcarcinoma of the thyroid: how should it be treated? World J Surg 2004;28:1115-21. Jarzab B, Wiench M, Fujarewicz K, et al. Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications. Cancer Res 2005;65:1587-97. Kasai N, Sakamoto A. New subgrouping of small thyroid carcinoma. Cancer 1987;60:1767-70. Klinck GH, Winship T. Occult sclerosing carcinoma of the thyroid. Cancer 1955;8:701-6. Lang W, Borrusch H, Bauer L. Occult carcinomas of the thyroid: evaluation of 1020 sequential autopsies. Am J Clin Pathol 1988;90:72-6. Orsenigo E, Beretta E, Fiacco E, et al. Management of papillary microcarcinoma of the thyroid gland. Eur J Surg Oncol 2004;30:1104-6. Pelizzo MR, Boschin IM, toniato A, et al. Papillary thyroid microcarcinoma (PTMC): prognostic factors, management and outcome in 403 patients. Eur J Surg Oncol 2006;32:1144-1148. Rosai J, LiVolsi VA, Sobrinho-Simoes M, Williams ED. Renaming papillary microcarcinoma of the thyroid gland: the Porto proposal. Int J Surg Pathol2003;11:249-51. Solares CA, Penalonzo MA, Xu M, Orellana E. Occult papillary thyroid carcinoma in postmortem species: prevalence at autopsy. Am J Otolaryngol 2005;26:87-90. Strate SM, Lee EL, Childers JH. Occult papillary carcinoma of the thyroid with distant metastases. Cancer 1984;54:1093-1100. Williams ED (on behalf of the Chernobyl Pathologists Group). Guest editorial: Two proposals regarding terminology of thyroid tumors. Int J Surg Pathol 2000;8:181-4. Yamamoto Y, Maeda T, Izumi K, Otsuku H. Occult papillary carcinoma of the thyroid: a study of 408 autopsy cases. Cancer 1990;65:1173-9. Encapsulated Variant Evans HL. Encapsulated papillary neoplasms of the thyroid: a study of 14 cases followed for a minimum of 10 years. Am J Surg Pathol 1987;11:592-7. Papotti M, Rodriguez J, Pompa RD, Bartolazzi A, Rosai J. Galectin-3 and HBME-1 expression in well-differentiated thyroid tumors with follicular architecture of uncertain malignant potential. Mod Pathol 2005;18:541-6. Schröder S, Böcker W, Dralle H, et al. The encapsulated papillary carcinoma of the thyroid: a morphologic subtype of the papillary thyroid carcinoma. Cancer 1984;54:90-3. Follicular Variant Barroeta JE, Baloch ZW, Lal P, et al. Diagnostic value of differential expression of CK19, galectin-3, HBME-1, ERK, RET, and p16 in benign and malignant follicular-derived lesions of the thyroid: an immunohistochemical tissue microarray analysis. Endocr Pathol 2006;3:225-234. Castro P, Rebocho AP, Soares RJ, et al. PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma. J Clin Endocrinol Metab 2006 ;91:213-20. Chen KT, Rosai J. Follicular variant of thyroid papillary carcinoma: a clinicopathologic study of six cases. Am J Surg Pathol 1986;85:77-80. Lloyd RV, Erickson LA, Casey MB, et al. Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. Am J Surg Pathol 2004;28:1336-40. Nakamura N, Erickson LA, Jin L, et al. Immunohistochemical separation of follicular variant of papillary thyroid carcinoma from follicular adenoma. Endocr Pathol 2006;3:213-224. Papotti M, Rodriguez J, Pompa RD, Bartolazzi A, Rosai J. Galectin-3 and HBME-1 expression in well-differentiated thyroid tumors with follicular architecture of uncertain malignant potential. Mod Pathol 2005;18:541-6. Rosai J, Zampi G, Carcangiu ML. Papillary carcinoma of the thyroid: a discussion of its several morphologic expressions, with particular emphasis on the follicular variant. Am J Surg Pathol 1983;7:809-17. Sobrinho-Simoes M, Preto A, Rocha AS, et al. Molecular pathology of well-differentiated thyroid carcinomas. Virchows Arch 2005;447:787-93. Tielens ET, Sherman SI, Hruban RH, Ladenson PW. Follicular variant of papillary thyroid carcinoma. A clinicopathologic study. Cancer 1994;73:424-31. Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol 2003;120:71-7. Extrathyroidal Extension American Joint Committee on Cancer Cancer Staging Manual, Sixth edition. Springer-Verlag, New York, 2002: 69-74. Bellantone R, Lombardi CP, Boscherini M, et al. Prognostic factors in differentiated thyroid carcinoma: a multivariate analysis of 234 consecutive patients. J Surg Oncol 1998;68:237-281. Cady B. Staging in thyroid carcinoma. Cancer 1998;83:844-847. Carcangui ML, Zampi G, Pupi A, Castagnoli A, Rosai J. Papillary carcinoma of the thyroid. A clinicopathologic study of 241 cases treated at the University of Florence, Italy. Cancer 1985;55:805-828. Gardiner WR. Unusual relationships between thyroid gland and skeletal muscle in infants; a review of the literature and four case reports. Cancer 1956;9:681-91. Gnepp DR, Ogorzalek JM, Heffess CS. Fat-containing lesions of the thyroid gland. Am J Surg Pathol 1989;13;605-612. Lerch H, Schober O, Kuwert T, Saur HB. Survival of differentiated thyroid carcinoma studied in 500 patients. J Clin Oncol 1997;15:2067-2075. Komorowski RA, Hanson GA. Occult thyroid pathology in the young adult: an autopsy study of 138 patients without clinical thyroid disease. Hum Pathol 1988;19:689-696. McCaffrey TV, Bergstralh EJ, Hay ID. Locally invasive papillary thyroid carcinoma: 1940-1990. Head Neck 1994;16:165-172. Rosai J, Carcangiu ML, DeLellis RA. The normal thyroid gland. In: Rosai J, ed. Tumors of the thyroid. Atlas of tumor pathology. Facicle 5. Third series. Armed Forces Institute of Pathology. Washington, D.C. 1992; 1-17. Shaha AR, Shah JP, Loree TR. Risk group stratification and prognostic factors in papillary carcinoma of the thyroid. Ann Surg Oncol 1996;3:534-538. Shaha A. Treatment of thyroid cancer based on risk groups. J Surg Oncol 2006;94:683-691. Siironen P, Louhimo J, Nordling S, et al. Prognostic factors in papillary thyroid cancer: an evaluation of 601 consecutive patients. Tumour Biol 2005;26:57-64. Standring S. Thyroid gland. In: Standring S, ed. Gray's anatomy. The anatomical basis of clinical practice. 39th edition. Edinburgh: Elsevier Churchill Livingstone; 2005:560-564.