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C Cell and Follicular Epithelial Cell Precursor Lesions of the Thyroid.

Diseases of the thyroid can arise from follicular epithelial cells or from C cells and include hyperplastic and neoplastic processes. The existence of a precursor lesion of follicular cell-derived tumors is still debated. There are data to suggest that some benign nodules may harbor malignant potential, with microscopic foci of malignancy being identified in an otherwise benign background. In addition, follicular tumors with borderline nuclear features of papillary thyroid carcinoma (PTC) or well-differentiated tumors of uncertain malignant potential have been proposed as potential precursor lesions. Preneoplastic changes in follicular epithelial cells have been suggested by the presence of atypical follicular proliferations in a background of severe, chronic lymphocytic thyroiditis (CLT). The role of C-cell hyperplasia (CCH) in the development of familial medullary thyroid carcinoma (MTC) has been studied extensively, and the preneoplastic nature of CCH in this setting is well established. However, the clinical implication of physiologic/reactive CCH is less well understood. In this review, the available clinical, histologic, and molecular evidence for possible precursor lesions of thyroid follicular epithelial cells and C cells is discussed.

C-CELL PRECURSOR LESIONS

C cells are neural crest-derived cells arising from ultimobranchial bodies. The usual distribution of C cells is in the middle to upper lateral lobes of the thyroid gland because the ultimobranchial bodies fuse with that portion of the gland during embryogenesis. (1) C cells are located between the follicular epithelial cells and their basement membranes and, hence, are also referred to as parafollicular cells, a term first coined by Jose Fernandez Nonidez. (2,3) C cells produce calcitonin, which is involved in calcium homeostasis. They stain for cytokeratin, calcitonin, carcinoembryonic antigen, and other markers, including chromogranin and neuron-specific enolase. (4,5) On routine hematoxylin-eosin staining, normal C cells are often difficult to identify and are only highlighted with a calcitonin immunostain. C cells give rise to MTC, which accounts for 5% to 10% of thyroid carcinomas. (1) Medullary thyroid carcinoma occurs in sporadic and familial forms, with sporadic MTC accounting for most cases (75%). Familial cases occur in the setting of multiple endocrine neoplasia 2A/2B and familial MTC. Activating point mutations in the RET proto-oncogene are responsible for familial forms of MTC and also occur in up to 80% of sporadic cases. (1)

In the early 1960s, evidence for the origin of calcitonin from the thyroid was provided by Hirsch and Foster. (6,7) The term C cell originated with Pearse, (8) and later, Bussolati et al (9) localized calcitonin to C cells by immunofluorescence. The first association between C cells and MTC was proposed by Williams et al (10) in 1966 who suggested the origin of MTC from a neuroectodermal cell. The relationship of CCH to MTC was subsequently described by Wolfe et al (11) in 1973, who described CCH in association with familial MTC and recognized it as a precursor.

C-cell hyperplasia is broadly defined as an increase in the number of C cells within the follicles of the thyroid. It can be further categorized histologically into focal, diffuse, and nodular CCH. Focal CCH is defined by partial or segmental involvement of the follicle, diffuse CCH refers to circumferential involvement of the follicle, and nodular CCH is a Ccell proliferation with complete obliteration of the follicle. (4) However, the definition of CCH remains controversial because of a lack of uniform histologic criteria. Multiple definitions have been employed, including requiring at least 50 C cells in at least one low-power field (X100), requiring 50 C cells in 50 low-power fields (X100), and requiring 40 C cells/[cm.sup.2]. (12,13,14) These various explanations are due in part to the fact that the density and distribution of healthy C cells in the thyroid are variable and not well established (15,16) and can vary with age, sex, and other associated thyroid pathologies. (17) The upper and lower reference ranges of CCH are still debatable, and the true prevalence of CCH is, therefore, not known. By current definitions, much of the healthy population would be defined as having CCH. (2)

C-cell hyperplasia is divided into reactive or physiologic CCH and neoplastic CCH. Most studies have examined CCH in the setting of familial MTC syndromes. However, it has subsequently been recognized that CCH can occur in conditions unrelated to MTC. In the 1990s, the term neoplastic CCH was proposed for CCH associated with familial MTC to distinguish it as a precursor lesion distinct from reactive or physiologic CCH seen in a number of thyroid pathologies unrelated to MTC. (4) Neoplastic CCH and reactive or physiologic CCH have been recognized as 2 distinct biologic and histologic entities with different neoplastic potential. (18)

Neoplastic CCH is considered a precursor of MTC and is seen most often in multiple endocrine neoplasia 2A/2B and familial MTC and is described as a proliferation of C cells in an intrafollicular location with associated cytologic atypia that is recognized on hematoxylin-eosin and often shows strong staining for calcitonin (Figure 1, A and B). Perry et al (18) and Krueger et al (19) both stress the irrelevance of the number of C cells and the importance of atypia in defining neoplastic CCH. This morphologic distinction between neoplastic CCH and reactive or physiologic CCH is supported by work from Komminoth and colleagues, (20) who used neural cell adhesion molecules to show staining in neoplastic CCH and associated MTC and the reported lack of staining in reactive or physiologic CCH, supporting a biologic differences between these 2 entities.

Mutational analysis also supports the concept of CCH as a neoplastic lesion in the familial setting. C-cell hyperplasia in multiple endocrine neoplasia 2A has demonstrated monoclonality, down-regulated apoptosis, and tumor-suppressor gene abnormalities consistent with intraepithelial neoplasia. (21) The progressive accumulation of molecular alterations in support of a preinvasive carcinoma has led some authors to prefer the term medullary carcinoma in situ or C-cell dysplasia over neoplastic CCH because it better reflects its true biologic nature. (18,22,23)

The differential diagnosis of neoplastic CCH includes solid cell nests, palpation thyroiditis, intrathyroidal thymic or parathyroid rests, intraglandular spread of MTC, and medullary microcarcinoma. (1) In some cases, distinguishing CCH from medullary microcarcinoma can be difficult. Analysis of defects in the basement membrane by immunohistochemistry for collagen and the presence of fibrosis can be helpful. (1,24)

Whether neoplastic CCH, as currently defined, is found only as a precursor in familial MTC is unknown. Neoplastic CCH has been reported in sporadic MTC and may also be the precursor of sporadic MTC in some cases. (18,25) Controversy also exists as to how reliable the pathologic distinction between reactive or physiologic CCH and neoplastic CCH is and the clinical correlation of these lesions. (23) Although Perry et al (18) stated that neoplastic CCH can be distinguished from reactive/physiologic CCH by cytologic atypia and identification on routine hematoxylin-eosin, other authors have not corroborated that, and they stress the variable morphology and inability in most cases to distinguish one type from the other. (26,27) In a study by Verga et al, (28) the patterns and cytologic features seen in neoplastic CCH with familial MTC were also demonstrated in the CCH identified in benign nodular disease and sporadic MTC with stimulated calcitonin levels greater than 50 pg/ml. The authors concluded that the only reliable way to distinguish reactive or physiologic CCH from neoplastic CCH is by the presence or absence of a RET mutation. However, they also suggest that CCH has a possible preneoplastic potential for sporadic MTC in the absence of RET. Therefore, neoplastic CCH may not always imply a familial syndrome. Genetic testing remains the most accurate method for identifying familial CCH. (4)

Reactive or physiologic CCH is defined as an increase in the number of healthy-appearing C cells (>50 per low-power field) that lack cytologic atypia and are not easily recognized by routine hematoxylin-eosin, often requiring a calcitonin immunostain. The C cells are often difficult to distinguish from adjacent follicular cells and histiocytes (Figure 2, A through D). Classically, reactive or physiologic CCH is predominantly focal and diffuse. (18) Reactive and physiologic CCH has been described in association with non-MTC, thyroiditis, nodular hyperplasia, aging, adenomas, and hyperparathyroidism. (4,13,14,29) Its pathogenesis is less well understood. Overstimulation by thyroid-stimulating hormone and hypercalcemia was implicated in some of those cases. (17)

Although the preneoplastic nature of CCH in familial MTC is well recognized, the preneoplastic nature and malignant potential of reactive or physiologic CCH and its role in the development of sporadic MTC is still being debated. The absence of RET mutations in some studies of sporadic CCH suggests that CCH is not a risk for factor for the development of sporadic MTC. (30) Reports of reactive or physiologic CCH with progression are rare, and its preneoplastic nature is not easy to prove. (29)

FOLLICULAR EPITHELIAL CELL PRECURSOR LESIONS

Thyroid nodules are common in the US population with most nodules being benign. Thyroid nodules can be classified as hyperplastic or neoplastic. The question as to whether hyperplastic or benign nodules can harbor malignant potential is debated. Unlike C cells, the existence of a precursor lesion or dysplastic lesions of follicular cell-derived tumors is less well established and has not been well defined.

Although clonal analysis often shows neoplasia (eg, follicular adenoma) to be monoclonal and hyperplasia to be polyclonal, it also often demonstrates clonality in hyperplastic and adenomatous nodules in multinodular goiters, (31,32,33) suggesting a potential transition from hyperplasia to neoplasia in this background. The potential for neoplastic transformation might also be suggested by flow cytometric analysis in thyroid nodules, where aneuploidy has been identified in follicular adenomas. (34,35) However, multiple studies refute the significance of aneuploidy in determining malignancy. (36,37)

Mutational analysis in benign and malignant thyroid nodules has been studied extensively. RET/PTC gene rearrangements, leading to activation of the RET protooncogene, have been identified in PTC, with a prevalence ranging from 3% to 85%. (38) RET/PTC rearrangements have also been identified in benign thyroid nodules, suggesting that they may be involved in malignant transformation. (39,40,41) The identification of RAS gene mutations in benign tumors by some authors has suggested that RAS may also have a role in early tumorigenesis. (42,43,44) However, the high interobserver variability in the diagnosis between follicular adenoma and follicular variant of papillary thyroid carcinoma (FVPTC) might explain this finding as well as the variable frequency of mutations. (38) PAX8/PPARG gene rearrangements, initially reported in follicular thyroid carcinoma, have been identified in follicular adenoma and FVPTC, suggesting at least some of these tumors have malignant potential. (45,46)

On occasion, malignancy has been shown to arise in preexisting, benign thyroid lesions (Figure 3, A through C). Papillary thyroid carcinoma and FVPTC have been reported in follicular adenoma, hyperplastic nodules, and Hurthle (oncocytic) cell adenomas. (47,48) The presence of malignancies arising in benign nodules has been attributed by some authors to progression of nuclear atypia from low-grade to eventual high-grade intrafollicular neoplasia followed by intrafollicular PTC. These changes may represent dysplastic lesions and potential precursors of PTC. (49)

The possibility of a precursor lesion for follicular epithelial-derived neoplasms of the thyroid has been suggested for follicular lesions with borderline cytologic features of PTC. There has been considerable interobserver variability in the diagnosis of follicular lesions, with borderline tumors presenting the greatest challenge. (50-53) Williams (54) proposed the term well-differentiated tumors of uncertain malignant potential for such lesions when the cytologic features are not developed sufficiently to ensure an unequivocal diagnosis of PTC, and those tumors have been suggested as being possible precursors to invasive PTC. (55-57) Immunohistochemical studies using HBME-1, galectin-3, CITED1, cytokeratin 19 (CK19), and cyclin D1 in these borderline follicular lesions have shown heterogeneous and intermediate staining patterns compared with PTC, suggesting a potential relationship to carcinoma and a role as precursor lesions. (55,58-62)

Molecular studies have been undertaken to further characterize these lesions. Fusco et al (57) studied 46 tumors with incomplete or minimal nuclear features of PTC and found genetic heterogeneity, with RET/PTC rearrangements being identified in areas with PTC-like nuclear features and being absent in areas without PTC-like nuclear features. Those foci may precede the development of invasive cancer. This suggests that RET/PTC rearrangements may be involved in malignant transformation and that encapsulated follicular tumors with nuclear atypia are potential premalignant lesions. In addition, DNA microarray gene profiling and microRNA analyses have discriminated benign from malignant thyroid tumors (63-65) and borderline lesions. In some cases, these borderline tumors have revealed intermediate profiles between benign and malignant tumors, suggesting they may represent early lesions in transformation with a more-complete carcinoma phenotype requiring additional genetic events. (66-69)

It is likely that some of these borderline tumors and well-differentiated tumors of uncertain malignant potential correspond to the described well-circumscribed/encapsulated FVPTC because different diagnostic criteria and thresholds have been employed by different researchers to classify these lesions. (70) Nonetheless, follow-up studies of these borderline lesions as well as the circumscribed or encapsulated FVPTC without invasion demonstrate that they behave in an indolent fashion and have an excellent prognosis. (62,71-74) These tumors likely represent a heterogeneous group of tumors with borderline or low malignant potential. As such, a recent nomenclature revision for these lesions was proposed to reflect more accurately the biological and clinical characteristics of these lesions. The term noninvasive follicular thyroid neoplasm with papillary-like nuclear features was proposed. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features has a high prevalence of RAS mutations that are typically associated with follicular-patterned lesions of the thyroid, including follicular adenoma, follicular thyroid carcinoma, and encapsulated FVPTC. Therefore, it has been suggested that noninvasive follicular thyroid neoplasm with papillary-like nuclear features likely represents a precursor of invasive encapsulated FVPTC. (75) The change in terminology will affect the reported frequencies of molecular alterations in PTC, but, importantly, it may reduce the significant interobserver disagreements in diagnosis and prevent overtreatment.

The concept of dysplasia and precursor lesions has been further explored in the thyroid in the background of CLT. Although many epidemiologic studies have suggested an increased risk of PTC with CLT, others offer contradicting opinions, (76-83) and the association between CLT and PTC is still being debated. Areas of cytologic atypia of the follicular epithelium are frequently seen in CLT and can be prominent, especially in areas of intense inflammation (Figure 4, A and B). These changes can be mistaken for PTC; however, they generally lack invasive growth and other cytologic features of PTC. (84,85) Some authors have suggested that this atypical follicular epithelium may represent a precursor lesion to PTC. (77,86,87) Chui et al (87) proposed the term follicular epithelial dysplasia for these atypical follicular epithelial proliferations that are distinct from reactive atypia. In addition, these proliferations demonstrate an immunohistochemical profile similar to PTC, with strong staining with HBME-1, galectin-3, CK19, and cyclin D1, supporting the concept of a premalignant lesion. Other studies have shown increased expression of PTC-associated markers in atypical areas of CLT with PTC-like nuclear features. Ma et al (88) showed increased expression of PTC-associated markers, such as neutrophil gelatinase-associated lipocalin, CK19, and claudin 1, in foci of atypical follicular epithelium compared with peritumoral benign thyroid tissue, whereas Prasad et al (89) identified the expression of HBME-1, galectin-3, CK19, CITED1, and fibronectin in PTC-like nuclear alterations of CLT. However, the utility of immunohistochemical stains in the assessment of PTC has been questioned by some authors.

Mutational analysis and genetic studies have also been performed in tumors with CLT, although they have not yielded consistent results. Gasbarri et al (85) identified a subset of Hashimoto thyroiditis that expressed galectin-3 and demonstrated a loss of heterozygosity in specific chromo somal regions. Loss of heterozygosity, affecting tumor-suppressor genes in atypical foci of CLT, was also reported by Hunt et al. (90) Some studies have identified RET/PTC rearrangements in Hashimoto thyroiditis, (91,92) supporting the hypothesis of a premalignant lesion, whereas other studies have shown the absence of BRAF mutations in atypical foci of CLT, suggesting evidence against a premalignant lesion. (93,94) The morphologic, immunohistochemical, and molecular alterations reported in these foci of atypical follicular epithelium in CLT provide support for the hypothesis that these foci represent preneoplastic changes in the follicular cells.

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Theresa Scognamiglio, MD

Accepted for publication December 27, 2016.

Published as an Early Online Release June 23, 2017.

From the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York; and New York Presbyterian Hospital, New York.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: Theresa Scognamiglio, MD, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 525 East 68th St, Starr 10th Floor, New York, NY 10021 (email: ths9004@ med.cornell.edu).

Caption: Figure 1. C-cell hyperplasia (CCH) in a patient with multiple endocrine neoplasia 2A. Diffuse (A) and nodular neoplastic (B) CCH. The C cells are easily recognized on hematoxylin-eosin stain and show cytologic atypia (arrows) (original magnification X400 [A and B]).

Caption: Figure 2. Physiologic or reactive C-cell hyperplasia (CCH) adjacent to nodular hyperplasia. A, Focal and diffuse patterns are often seen. The C cells can be difficult to distinguish from adjacent follicular cells. B, C cells are better highlighted by a calcitonin immunostain. C and D, A nodular pattern can also be seen in reactive or physiologic CCH (hematoxylin-eosin, original magnification X200 [A and C]; calcitonin, original magnification X200 [B and D]).

Caption: Figure 3. Papillary thyroid carcinoma arising in a follicular adenoma (hematoxylin-eosin, original Magnifications X40 [A], X200 [B], and X400 [C]).

Caption: Figure 4. Atypical follicular epithelial proliferations in severe chronic lymphocytic thyroiditis. A and B, The follicular cells show atypia but lack sufficient cytologic and architectural criteria for the diagnosis of papillary thyroid carcinoma (hematoxylin-eosin, original magnifications X200 [A] and X400 [B]).

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Author:Scognamiglio, Theresa
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Date:Dec 1, 2017
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