C Cell and Follicular Epithelial Cell Precursor Lesions of the Thyroid.
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.
(1.) Rosai J, DeLellis RA, Carcangiu ML, Frable WJ, Tallini G, eds. Tumors of the Thyroid and Parathyroid Glands. Silver Spring, MD: American Registry of Pathology Press;2014. Silverberg SG, ed. AFIP Atlas of Tumor Pathology; 4th series, fascicle 21.
(2.) Matias-Guiu X, De Lellis R. Medullary thyroid carcinoma: a 25-year perspective. Endocr Pathol. 2014;25(1):21-29.
(3.) de Lellis RA, Wolfe HJ. The pathobiology of the human calcitonin (C)-cell: a review. Pathol Annu. 1981;16(pt 2):25-52.
(4.) Matias-Guiu X, Moley JF, Gagel RF, et al. Medullary thyroid tumors. In DeLellis RA, Lloyd RV, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press;2004:86-91. World Health Organization Classification of Tumours; vol 8.
(5.) Mete O, Asa SL. Precursor lesions of endocrine system neoplasms. Pathology. 2013;45(3):316-330.
(6.) Hirsch PF, Gauthier GF, Munson PL. Thyroid hypocalcemic principle and recurrent laryngeal nerve injury as factors affecting the response to parathyroidectomy in rats. Endocrinology. 1963;73:244-252.
(7.) Foster GV, Baghdiantz A, Kumar MA, Slack E, Soliman HA, Macintyre I. Thyroid origin of calcitonin. Nature. 1964;202:1303-1305.
(8.) Pearse AG. Common cytochemical properties of cells producing polypeptide hormones, with particular reference to calcitonin and the thyroid C cells. Vet Rec. 1966;79(21):587-590.
(9.) Bussolati G, Foster GV, Clark MB, Pearse AG. Immunofluorescent localisation of calcitonin in medullary C-cell thyroid carcinoma, using antibody to the pure porcine hormone. Virchows Arch B Cell Pathol. 1969;2(3):234-238.
(10.) Williams ED. Histogenesis of medullary carcinoma of the thyroid. J Clin Pathol. 1966;19(2):114-118.
(11.) Wolfe HJ, Melvin KE, Cervi-Skinner SJ, et al. C-cell hyperplasia preceding medullary thyroid carcinoma. N Engl J Med. 1973;289(9):437-441.
(12.) LiVolsi VA, Feind CR, LoGerfo P, Tashjian AH Jr. Demonstration by immunoperoxidase staining of hyperplasia of parafollicular cells in the thyroid gland in hyperparathyroidism. J Clin Endocrinol Metab. 1973;37(4):550-559.
(13.) Albores-Saavedra J, Monforte H, Nadji M, Morales AR. C-cell hyperplasia in thyroid tissue adjacent to follicular cell tumors. Hum Pathol. 1988;19(7):795-799.
(14.) Guyetant S, Wion-Barbot N, Rousselet MC, Franc B, Bigorgne JC, Saint-Andre JP. C-cell hyperplasia associated with chronic lymphocytic thyroiditis: a retrospective quantitative study of 112 cases. Hum Pathol. 1994;25(5):514-521.
(15.) Gibson WC, Peng TC, Croker BP. C-cell nodules in adult human thyroid: a common autopsy finding. Am J Clin Pathol. 1981;75(3):347-350.
(16.) Wolfe HJ, DeLellis RA, Voelkel EF, Tashjian AH Jr. Distribution of calcitonin-containing cells in the normal neonatal human thyroid gland: a correlation of morphology with peptide content. J Clin Endocrinol Metab. 1975; 41(06):1076-1081.
(17.) Albores-Saavedra JA, KruegerJE. C-cell hyperplasia and medullary thyroid microcarcinoma. Endocr Pathol. 2001;12(4):365-377.
(18.) Perry A, Molberg K, Albores-Saavedra J. Physiologic versus neoplastic Ccell hyperplasia of the thyroid: separation of distinct histologic and biologic entities. Cancer. 1996;77(4):750-756.
(19.) Krueger JE, Maitra A, Albores-Saavedra J. Inherited medullary microcarcinoma of the thyroid: a study of 11 cases. Am J Surg Pathol. 2000;24(6):853858.
(20.) Komminoth P, Roth J, Saremaslani P, Matias-Guiu X, Wolfe HJ, Heitz PU. Polysialic acid of the neural cell adhesion molecule in the human thyroid: a marker for medullary thyroid carcinoma and primary C-cell hyperplasia: an immunohistochemical study on 79 thyroid lesions. Am J Surg Pathol. 1994;18(4): 399-411.
(21.) Diaz-Cano SJ, de Miguel M, Blanes A, Tashjian R, Wolfe HJ. Germline RET 634 mutation positive MEN 2A-related C-cell hyperplasias have genetic features consistent with intraepithelial neoplasia. J Clin Endocrinol Metab. 2001;86(8): 3948-3957.
(22.) Carney JA, Sizemore GW, Hayles AB. Multiple endocrine neoplasia, type 2b. Pathobiol Annu. 1978;8:105-153.
(23.) LiVolsi VA. C cell hyperplasia/neoplasia [comment]. J Clin Endocrinol Metab. 1997;82(1):39-41.
(24.) McDermott MB, Swanson PE, Wick MR. Immunostains for collagen type IV discriminate between C-cell hyperplasia and microscopic medullary carcinoma in multiple endocrine neoplasia, type 2a. Hum Pathol. 1995;26(12):1308-1312.
(25.) Kaserer K, Scheuba C, Neuhold N, et al. C-cell hyperplasia and medullary thyroid carcinoma in patients routinely screened for serum calcitonin. Am J Surg Pathol. 1998;22(6):722-728.
(26.) Hinze R, Gimm O, Brauckhoff M, Schneyer U, Dralle H, Holzhausen HJ. "Physiological" and "neoplastic" C-cell hyperplasia of the thyroid: morphologically and biologically distinct entities [in German]? Pathologe. 2001;22(4):259-265.
(27.) Kaserer K, Scheuba C, Neuhold N, et al. Sporadic versus familial medullary thyroid microcarcinoma: a histopathologic study of 50 consecutive patients. Am J Surg Pathol. 2001;25(10):1245-1251.
(28.) Verga U, Ferrero S, Vicentini L, et al. Histopathological and molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic Ccell hyperplasia? Endocr Relat Cancer. 2007;14(2):393-403.
(29.) Livolsi VA, Feind CR. Incidental medullary thyroid carcinoma in sporadic hyperparathyroidism: an expansion of the concept of C-cell hyperplasia. Am J Clin Pathol. 1979;71(5):595-599.
(30.) Saggiorato E, Rapa I, Garino F, et al. Absence of RET gene point mutations in sporadic thyroid C-cell hyperplasia. J Mol Diagn. 2007;9(2):214-219.
(31.) Namba H, Matsuo K, Fagin JA. Clonal composition of benign and malignant human thyroid tumors. J Clin Invest. 1990;86(1):120-125.
(32.) Hicks DG, LiVolsi VA, Neidich JA, Puck JM, Kant JA. Clonal analysis of solitary follicular nodules in the thyroid. Am J Pathol. 1990;137(3):553-562.
(33.) Apel RL, Ezzat S, Bapat BV, Pan N, LiVolsi VA, Asa SL. Clonality of thyroid nodules in sporadic goiter. Diagn Mol Pathol. 1995;4(2):113-121.
(34.) Joensuu H, Klemi P, Eerola E. DNA aneuploidy in follicular adenomas of the thyroid gland. Am J Pathol. 1986;124(3):373-376.
(35.) Schelfhout LJ, Cornelisse CJ, Goslings BM, et al. Frequency and degree of aneuploidy in benign and malignant thyroid neoplasms. Int J Cancer. 1990;45(1): 16-20.
(36.) Lukacs GL, Balazs G, Zs-Nagy I, Miko T. Clinical meaning of DNA content in the long term behaviour of follicular thyroid tumours: a 12-year follow up. Eur J Surg. 1994;160(8):417-423.
(37.) Backdahl M, Wallin G, Askensten U, Auer G, Grimelius L, Lowhagen T. Nuclear DNA measurements in follicular thyroid adenomas. Eur J Surg Oncol. 1989;15(2):125-129.
(38.) Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6(4):292-306.
(39.) 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(2):186-193.
(40.) Elisei R, Romei C, Vorontsova T, et al. RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metab. 2001;86(7):3211-3216.
(41.) Ishizaka Y, Kobayashi S, Ushijima T, Hirohashi S, Sugimura T, Nagao M. Detection of retTPC/PTC transcripts in thyroid adenomas and adenomatous goiter by an RT-PCR method. Oncogene. 1991;6(9):1667-1672.
(42.) Lemoine NR, Mayall ES, Wyllie FS, et al. High frequency of RAS oncogene activation in all stages of human thyroid tumorigenesis. Oncogene. 1989;4(2): 159-164.
(43.) Liu RT, Hou CY, You HL, et al. Selective occurrence of ras mutations in benign and malignant thyroid follicular neoplasms in Taiwan. Thyroid. 2004; 14(8):616-621.
(44.) Namba H, Rubin SA, Fagin JA. Point mutations of RAS oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol. 1990;4(10):1474-1479.
(45.) Dwight T, Thoppe SR, Foukakis T, et al. Involvement of the PAX8/ peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88(9):4440-4445.
(46.) 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(5):2318-2326.
(47.) Evans HL, Vassilopoulou-Sellin R. Follicular and Hurthle cell carcinomas of the thyroid: a comparative study. Am J Surg Pathol. 1998;22(12):1512-1520.
(48.) Park SH, Suh EH, Chi JG. A histopathologic study on 1,095 surgically resected thyroid specimens. Jpn J Clin Oncol. 1988;18(4):297-302.
(49.) Pennelli N, Pennelli G, Merante Boschin I, Pelizzo MR. Thyroid intrafollicular neoplasia (TIN) as a precursor of papillary microcarcinoma. Ann Ital Chir. 2005;76(3):219-224.
(50.) Elsheikh TM, Asa SL, Chan JK, et al. Interobserver and intraobserver variation among experts in the diagnosis of thyroid follicular lesions with borderline nuclear features of papillary carcinoma. Am J Clin Pathol. 2008; 130(5):736-744.
(51.) 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(10):1336-1340.
(52.) Franc B. Observer variation of lesions of the thyroid [comment]. Am J Surg Pathol. 2003;27(8):1177-1179.
(53.) Hirokawa M, Carney JA, Goellner JR, et al. Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol. 2002; 26(11):1508-1514.
(54.) Williams ED. Two proposals regarding the terminology of thyroid tumors [editorial]. Int J Surg Pathol. 2000;8(3):181-183.
(55.) Papotti M, Rodriguez J, De Pompa R, 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(4):541-546.
(56.) Vasko VV, Gaudart J, Allasia C, et al. Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma. Eur J Endocrinol. 2004;151(6):779-786.
(57.) 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(6):2157-2167.
(58.) Yassin FEL-Z. Diagnostic criteria of well differentiated thyroid tumor of uncertain malignant potential; a histomorphological and immunohistochemical appraisal. J Egypt Natl Canc Inst. 2015;27(2):59-67.
(59.) Scognamiglio T, Hyjek E, KaoJ, Chen YT. Diagnostic usefulness of HBME1, galectin-3, CK19, and CITED1 and evaluation of their expression in encapsulated lesions with questionable features of papillary thyroid carcinoma. Am J Clin Pathol. 2006;126(5):700-708.
(60.) Prasad ML, Pellegata NS, Huang Y, Nagaraja HN, de la Chapelle A, Kloos RT. Galectin-3, fibronectin-1, CITED-1, HBME1 and cytokeratin-19 immunohistochemistry is useful for the differential diagnosis of thyroid tumors. Mod Pathol. 2005;18(1):48-57.
(61.) Nechifor-Boila A, Borda A, Sassolas G, et al. Thyroid tumors of uncertain malignant potential: morphologic and imunohistochemical analysis of 29 cases. Pathol Res Pract. 2015;211(4):320-325.
(62.) Liu Z, Zhou G, Nakamura M, et al. Encapsulated follicular thyroid tumor with equivocal nuclear changes, so-called well-differentiated tumor of uncertain malignant potential: a morphological, immunohistochemical, and molecular appraisal. Cancer Sci. 2011;102(1):288-294.
(63.) Huang Y, Prasad M, Lemon WJ, et al. Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. Proc Natl Acad Sci USA. 2001; 98(26):15044-15049.
(64.) Finley DJ, Zhu B, Barden CB, Fahey TJ III. Discrimination of benign and malignant thyroid nodules by molecular profiling. Ann Surg. 2004;240(3):425-436; discussion 436-437.
(65.) Chevillard S, Ugolin N, Vielh P, et al. Gene expression profiling of differentiated thyroid neoplasms: diagnostic and clinical implications. Clin Cancer Res. 2004;10(19):6586-6597.
(66.) Jacques C, Guillotin D, Fontaine JF, et al. DNA microarray and miRNA analyses reinforce the classification of follicular thyroid tumors. J Clin Endocrinol Metab. 2013;98(5):e981-e989.
(67.) Arora N, Scognamiglio T, Lubitz CC, et al. Identification of borderline thyroid tumors by gene expression array analysis. Cancer. 2009;115(23):5421-5431.
(68.) Chen YT, Kitabayashi N, Zhou XK, Fahey TJ III, Scognamiglio T. MicroRNA analysis as a potential diagnostic tool for papillary thyroid carcinoma. Mod Pathol. 2008;21(9):1139-1146.
(69.) Lubitz CC, Ugras SK, Kazam JJ, et al. Microarray analysis of thyroid nodule fine-needle aspirates accurately classifies benign and malignant lesions. J Mol Diagn. 2006;8(4):490-498; quiz 528.
(70.) Kakudo K, Bai Y, Liu Z, Ozaki T. Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer. Pathol Int. 2012;62(3):155-160.
(71.) Piana S, Frasoldati A, Di Felice E, Gardini G, Tallini G, Rosai J. Encapsulated well-differentiated follicular-patterned thyroid carcinomas do not play a significant role in the fatality rates from thyroid carcinoma. Am J Surg Pathol. 2010;34(6):868-872.
(72.) Ganly I, Wang L, Tuttle RM, et al. Invasion rather than nuclear features correlates with outcome in encapsulated follicular tumors: further evidence for the reclassification of the encapsulated papillary thyroid carcinoma follicular variant. Hum Pathol. 2015;46(5):657-664.
(73.) Rivera M, Tuttle RM, Patel S, Shaha A, Shah JP, Ghossein RA. Encapsulated papillary thyroid carcinoma: a clinico-pathologic study of 106 cases with emphasis on its morphologic subtypes (histologic growth pattern). Thyroid. 2009; 19(2):119-127.
(74.) Liu J, Singh B, Tallini G, et al. Follicular variant of papillary thyroid carcinoma: a clinicopathologic study of a problematic entity. Cancer. 2006; 107(6):1255-1264.
(75.) Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016.
(76.) Noureldine SI, Tufano RP. Association of Hashimoto's thyroiditis and thyroid cancer. Curr Opin Oncol. 2015;27(1):21-25.
(77.) ArifS, Blanes A, Diaz-Cano SJ. Hashimoto's thyroiditis shares features with early papillary thyroid carcinoma. Histopathology. 2002;41(4):357-362.
(78.) Singh B, Shaha AR, Trivedi H, Carew JF, Poluri A, Shah JP. Coexistent Hashimoto's thyroiditis with papillary thyroid carcinoma: impact on presentation, management, and outcome. Surgery. 1999;126(6):1070-1076; discussion 1076-1077.
(79.) Ott RA, McCall AR, McHenry C, et al. The incidence of thyroid carcinoma in Hashimoto's thyroiditis. Am Surg. 1987;53(8):442-445.
(80.) Strauss M, Laurian N, Antebi E. Coexistent carcinoma of the thyroid gland and Hashimoto's thyroiditis. Surg Gynecol Obstet. 1983;157(3):228-232.
(81.) Tamimi DM. The association between chronic lymphocytic thyroiditis and thyroid tumors. Int J Surg Pathol. 2002;10(2):141-146.
(82.) Holm LE, Blomgren H, Lowhagen T. Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl J Med. 1985;312(10):601-604.
(83.) Okayasu I, FujiwaraM, Hara Y, Tanaka Y, Rose NR. Association of chronic lymphocytic thyroiditis and thyroid papillary carcinoma: A study of surgical cases among Japanese, and white and African Americans. Cancer. 1995;76(11):2312-2318.
(84.) Berho M, Suster S. Clear nuclear changes in Hashimoto's thyroiditis: a clinicopathologic study of 12 cases. Ann Clin Lab Sci. 1995;25(6):513-521.
(85.) Gasbarri A, Sciacchitano S, Marasco A, et al. Detection and molecular characterisation of thyroid cancer precursor lesions in a specific subset of Hashimoto's thyroiditis. Br J Cancer. 2004;91(6):1096-1104.
(86.) Di Pasquale M, Rothstein JL, Palazzo JP. Pathologic features of Hashimoto's-associated papillary thyroid carcinomas. Hum Pathol. 2001;32(1):24-30.
(87.) Chui MH, Cassol CA, Asa SL, Mete O. Follicular epithelial dysplasia of the thyroid: morphological and immunohistochemical characterization of a putative preneoplastic lesion to papillary thyroid carcinoma in chronic lymphocytic thyroiditis. Virchows Arch. 2013;462(5):557-563.
(88.) Ma H, Yan J, Zhang C, et al. Expression of papillary thyroid carcinoma-associated molecular markers and their significance in follicular epithelial dysplasia with papillary thyroid carcinoma-like nuclear alterations in Hashimoto's thyroiditis. Int J Clin Exp Pathol. 2014;7(11):7999-8007.
(89.) Prasad ML, Huang Y, Pellegata NS, de la Chapelle A, Kloos RT. Hashimoto's thyroiditis with papillary thyroid carcinoma (PTC)-like nuclear alterations express molecular markers of PTC. Histopathology. 2004;45(1):39-46.
(90.) Hunt JL, Baloch ZW, Barnes L, et al. Loss of heterozygosity mutations of tumor suppressor genes in cytologically atypical areas in chronic lymphocytic thyroiditis. Endocr Pathol. 2002;13(4):321-330.
(91.) Rhoden KJ, Unger K, Salvatore G, et al. RET/papillary thyroid cancer rearrangement in nonneoplastic thyrocytes: follicular cells of Hashimoto's thyroiditis share low-level recombination events with a subset of papillary carcinoma. J Clin Endocrinol Metab. 2006;91(6):2414-2423.
(92.) Sheils OM, O'Eary JJ, Uhlmann V, Lattich K, Sweeney EC. ret/PTC-1 activation in Hashimoto thyroiditis. Int J Surg Pathol. 2000;8(3):185-189.
(93.) Sargent R, LiVolsi V, Murphy J, Mantha G, Hunt JL. BRAF mutation is unusual in chronic lymphocytic thyroiditis-associated papillary thyroid carcinomas and absent in non-neoplastic nuclear atypia of thyroiditis. Endocr Pathol. 2006;17(3):235-241.
(94.) Nasr MR, Mukhopadhyay S, Zhang S, Katzenstein AL. Absence of the BRAF mutation in HBME1+ and CK19+ atypical cell clusters in Hashimoto thyroiditis: supportive evidence against preneoplastic change. Am J Clin Pathol. 2009;132(6): 906-912.
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]).
[Please Note: Illustration(s) are not available due to copyright restrictions.]
|Printer friendly Cite/link Email Feedback|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Dec 1, 2017|
|Previous Article:||Cervical Adenocarcinoma: Diagnosis of Human Papillomavirus--Positive and Human Papillomavirus--Negative Tumors.|
|Next Article:||Current Concepts in Diagnosis, Molecular Features, and Management of Lobular Carcinoma In Situ of the Breast With a Discussion of Morphologic...|