The diagnostic dilemma of follicular variant of papillary thyroid carcinoma

The diagnostic dilemma of follicular variant of papillary thyroid carcinoma Susan B. Kesmodel, MD, Kyla P. Terhune, BA, Robert J. Canter, MD, Susan J. Mandel, MD, MPH, Virginia A. LiVolsi, MD, Zubair W. Baloch, MD, PhD, and Douglas L. Fraker, MD, Philadelphia, Pa

Background. Given the difference in surgical management between follicular neoplasms and papillary thyroid carcinoma (PTC), we sought to determine the sensitivity of fine-needle aspiration (FNA) and intraoperative pathologic study (IP), frozen section and cytologic study, in establishing a diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC) and how these techniques impact operative management. Methods. A retrospective chart review was performed of patients who underwent thyroidectomy for nodular disease between June 1997 and June 2002 identifying patients with a final diagnosis of FVPTC. FNA and IP results were reviewed in this group of patients and correlated with those of final histopathologic study. The sensitivity of FNA and IP was calculated. Results. Eighty-two patients had a final diagnosis of FVPTC. Eighty-six preoperative FNAs were obtained in 80 patients, leading to a diagnosis of PTC in 7 (sensitivity 9%). Intraoperative pathologic study was performed in 31 patients with suspicious FNA results, of which 13 were definitive for PTC (sensitivity 42%). Overall, IP was obtained in 42 patients, of which 15 were positive for PTC (sensitivity 36%). Conclusion. Although the sensitivity of FNA in establishing a diagnosis of FVPTC is low, FNA identifies patients with suspicious lesions in whom IP is important in guiding operative management. (Surgery 2003;134:1005-12.) From the Departments of Surgery, Department of Pathology and Laboratory Medicine, and Medicine, Division of Endocrinology, Hospital of the University of Pennsylvania, Philadelphia, Pa

THE FOLLICULAR VARIANT OF papillary thyroid carcinoma (FVPTC) is the most common subtype of papillary thyroid carcinoma (PTC) after classic PTC, accounting for 10% to 15% of all cases. First defined by Lindsay in 1960 and later redescribed by Chem and Rosai,1 FVPTC is defined by a follicular architecture with nuclear features of classic PTC (Fig 1). Because FVPTC is believed to behave clinically in a manner similar to classic PTC, the management of FVPTC lesions is identical to that of classic PTC. Therefore, if a preoperative or intraoperative diagnosis of FVPTC can be established, definitive surgical treatment may be provided. Fine-needle aspiration (FNA) and frozen section (FS) are techniques that are routinely used in the Presented at the 24th Annual Meeting of the American Association of Endocrine Surgeons, San Diego, California, May 11-14, 2003. Reprint requests: Douglas L. Fraker, MD, Hospital of the University of Pennsylvania, 4th Floor Silverstein Building, 3400 Spruce St, Philadelphia, PA 19104. Ó 2003, Mosby, Inc. All rights reserved. 0039-6060/2003/$30.00 + 0 doi:10.1016/S0039-6060(03)00486-0

evaluation of thyroid nodules. In the case of classic PTC, distinct nuclear features have been described that make definitive diagnosis with FNA possible2 (Fig 2). Accordingly, FNA has been shown to have high sensitivity and specificity for the diagnosis of classic PTC, allowing endocrine surgeons to proceed with total thyroidectomy in patients with this FNA diagnosis.3-7 In the case of follicular neoplasms, FNA is mainly used to select patients for surgery because approximately 20% of these lesions will be malignant.8-10 The utility of FS in the management of follicular neoplasms, however, is controversial, with most endocrine surgeons and endocrine pathologists believing that limited information is obtained for that histologic study.8,9,11,12 Therefore standard treatment for follicular neoplasms consists of unilateral thyroid lobectomy, with completion thyroidectomy performed in those patients found to have a malignancy. The diagnosis of FVPTC by FNA and FS, however, is challenging because the classic nuclear features of PTC in cases of FVPTC may be subtle on FNA or may be obscured by freezing artifact on FS. (Figs 3 and 4, A) As a result, these lesions are often misclassified as follicular neoplasms. In addition, SURGERY 1005

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Fig 1. Histologic section of follicular variant of PTC; variant of papillary carcinoma shows follicle formation with nuclear features of PTC (inset). (Hematoxylin and eosin staining.)

sampling error may occur if PTC nuclear features are focal rather than diffuse, leading to falsenegative results. A more recent technique that may improve the sensitivity of intraoperative evaluation by preserving nuclear features, is intraoperative cytologic study.13,14 (Fig 4, A) This technique is currently recommended for the intraoperative evaluation of suspicious thyroid nodules.15 Given that the surgical management of follicular neoplasms and PTC differs, a preoperative FNA or intraoperative FS or cytologic diagnosis of FVPTC allows for total thyroidectomy at initial operation, which may reduce costs and decrease patient morbidity. Therefore, to define the roles of FNA and intraoperative pathologic study (IP), FS and cytologic study in the management of FVPTC, we sought to determine the sensitivity of these techniques in establishing a diagnosis of FVPTC and their impact on operative management. PATIENTS AND METHODS Patients. A retrospective chart review was performed of patients who underwent thyroid resection by a single surgeon for nodular disease between June 1997 and June 2002 identifying patients with a final histopathologic diagnosis of FVPTC. FNA and IP results were reviewed in this group of patients and correlated with final histopathologic study. Results of additional preoperative imaging studies were reviewed including ultrasonography, radioiodine scanning, and crosssectional imaging of the neck. FNA results were grouped into 5 categories: nondiagnostic, benign/ hyperplastic (B), follicular neoplasm (FN), follicu-

Fig 2. A, Papanicolaou-stained smear shows cytologic features of classic PTC; in that nuclei are enlarged and elongated and show nuclear chromatin clearing, intranuclear grooves (arrow) and inclusions (asterisk). B, Histologic section of classic papillary carcinoma shows papillary formation with nuclear features of PTC. (Hematoxylin and eosin staining.)

lar neoplasm with papillary features (FNPF), or papillary thyroid carcinoma/thyroid carcinoma (PTC). Most FNAs from outside institutions were also reviewed at our institution before surgical intervention. Intraoperative pathologic study was obtained in patients with (1) suspicious FNA results, (2) FNA results that were nondiagnostic, (3) incidental thyroid nodules identified during neck surgery for other indications, or (4) intraoperative findings suggestive but not conclusive for carcinoma. Intraoperative pathologic study results were grouped into 4 categories: benign (B), follicular neoplasm (FN), suspicious for papillary thyroid carcinoma (SPTC), or papillary thyroid carcinoma/thyroid carcinoma (PTC). Operative management was changed from a thyroid lobectomy to a total thyroidectomy when IP results were

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Fig 3. A and B, Papanicolaou-stained smears from case of follicular variant of PTC shows nuclear chromatin clearing (asterisk) and rare intranuclear grooves (arrow). Notice lack of intranuclear inclusions.

definitive for PTC. Final histopathologic study was reviewed for tumor size, invasion, evidence of multifocal disease, and lymph node metastases. The sensitivity of FNA and IP was calculated as true positives/(true positives + false negatives). All patients provided written, informed operative consent, and approval was obtained from the Institutional Review Board to conduct this retrospective study. FNA. FNA procedures at our institution were generally performed with ultrasound guidance. On average, 2 passes were made with a 25-gauge needle connected to a 10-mL syringe, with specimens divided for air-dried and alcohol-fixed smears and Millipore-filter preparations. Air-dried smears were stained with Diff-Quik for immediate cytologic evaluation of cellularity, background colloid, cellular architecture, cell type, and nuclear features of papillary carcinoma. Additional material was obtained if the specimen was deemed inadequate,

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Fig 4. A, Frozen section of follicular variant of papillary carcinoma shows follicular patterned tumor with thick eosinophilic colloid. Notice lack of nuclear features of papillary carcinoma in frozen section. (Hematoxylin and eosin staining.) B, Intraoperative scrape smear stained with Ultrafast-Papanicolaou technique shows nuclear cytologic condition of PTC; intranuclear grooves (arrow) and nuclear chromatin clearing (asterisk).

and a preliminary on-site diagnosis was given. Alcohol-fixed smears were stained by a modified Papanicolaou technique to evaluate nuclear features of papillary carcinoma.15,16 Intraoperative pathologic study (frozen section and cytologic study). Thyroid specimens were obtained from the operating room and measured. The outside surface was inked, and the specimen was divided to identify thyroid nodules. At least one representative section was frozen from each lesion. In addition, beginning in June 1999, in cases that were classified as suspicious for FVPTC, the tumor surface was scraped and smeared on a clean glass slide and stained with Ultrafast-Papanicolaou technique14 (Fig 4).

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Table I. FNA results in patients with a final diagnosis of follicular variant of papillary thyroid carcinoma by histologic study FNA result Nondiagnostic Benign Follicular neoplasm Follicular neoplasm with Papillary features Papillary thyroid carcinoma Total

Outside institutions Our institution 6 6 18 13

(13%) (13%) (39%) (28%)

3 (7%) 46

1 1 6 29

(3%) (3%) (15%) (73%)

3 (8%) 40

Table II. Review of FNA results from outside institutions in patients with a final diagnosis of follicular variant of papillary thyroid carcinoma by histology FNA result Nondiagnostic Benign Follicular neoplasm Follicular neoplasm with papillary features PTC

Outside diagnosis

Our diagnosis (no. of FNAs)

3 3 11 9

ND (3) B (1)*, FN (2) FN (5), FNPF (6) FN (3), FNPF (5), PTC (1)

3

FNPF (1), PTC (2)

*Repeat FNA performed at our institution was suspicious for FVPTC.

RESULTS Patient demographics. Of 523 patients who underwent thyroid resection for nodular disease from June 1997 to June 2002, 82 (16%) had a final histopathologic diagnosis of FVPTC. This group of patients was comprised of 69 women (84%) and 13 men (16%) with a median age of 42 years (range 20 to 79). Preoperative imaging included thyroid ultrasound in 65 patients (79%), radioiodine scans in 21 patients (26%), of which 17 demonstrated cold or hypofunctioning nodules (81%), and crosssectional imaging of the neck in 6 patients (7%). Additional patient characteristics included 2 patients with Grave’s disease, 1 patient with Hashimoto’s thyroiditis, and 3 patients with a history of radiation exposure. FNA. Eighty-six preoperative FNAs were obtained in 80 patients. Forty-six of these were performed at outside institutions, with results as follows: 6 nondiagnostic (13%), 6 B (13%), 18 FN (39%), 13 FNPF (28%), and 3 PTC (7%). The remaining 40 FNAs were performed at our institution with the following results: 1 nondiagnostic (3%), 1 B (3%), 6 FN (15%), 29 FNPF (73%), 3 PTC (8%) (Table I). In addition, 29 of the FNAs obtained at outside institutions were reviewed by pathologists at our institution with discordance in 13 out of 29 cases (45%). Nine FNA results were upgraded, 1 to PTC, 6 to FNPF, and two to FN, and four were downgraded, one to FNPF and three to FN (Table II). Overall, 7 of 80 patients had a definitive diagnosis of thyroid carcinoma by preoperative FNA (sensitivity 9%). FNA results in the remaining patients included 46 patients (58%) with at least 1 FNA result of FNPF, 19 patients (24%) with a result of FN, 4 patients (5%) with benign results, and 4 patients (5%) with ND results. The 4 patients with benign preoperative FNA results underwent surgery for symptoms related to their thyroid lesions. Two patients in this series did

not undergo preoperative FNA but had thyroid nodules identified at the time of neck exploration for primary hyperparathyroidism that were subsequently diagnosed as FVPTC on final histologic study. Intraoperative pathologic study. Of the 46 patients with preoperative FNA results of FNPF, IP was obtained in 31 (67%). Of these, 13 were definitive for PTC (42%), 3 were read as SPTC (10%), 14 were identified as FN (45%), and 1 was classified as benign (3%) (Table III). Total thyroidectomy was performed in all 13 patients with a definitive diagnosis of thyroid carcinoma by IP. In addition, in one patient with an IP result of SPTC, operative management was changed from unilateral thyroid lobectomy to total thyroidectomy. Therefore the combination of a preoperative FNA result of FNPF and IP established a definitive diagnosis of FVPTC in 42% of these patients and resulted in a changed in surgical management in 45%. Intraoperative pathologic study was obtained in an additional 11 patients, with the following results: 2 PTC (18%), 1 SPTC (9%), and 8 FN (73%). Therefore the sensitivity of IP in this group of patients was only 18%. Overall, intraoperative pathologic evaluation of thyroid nodules was obtained in 42 patients (51%), of which 15 were definitive for PTC (sensitivity 36%) (Table III). Operative procedure. Total or near-total thyroidectomy was performed in 35 patients (43%), thyroid lobectomy, and isthmusectomy followed by completion thyroidectomy in 46 patients (56%), and a thyroid lobectomy and isthmusectomy only in 1 patient (1%). In most cases in which a total or near-total thyroidectomy was performed, the procedure was planned before operation on the basis of a definitive diagnosis of PTC by FNA, evidence of bilateral thyroid nodules requiring surgical resection, or a history of radiation expo-

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sure. The 1 patient who underwent thyroid lobectomy and isthmusectomy only had a history of metastatic endometrial cancer. In this patient thyroid resection was performed to exclude malignancies that would prevent the patient from being enrolled in investigational treatment protocols for her metastatic endometrial cancer. The completion thyroidectomy was not performed because of this secondary aggressive malignancy. During surgery, 2 patients had evidence of invasion into the strap muscles, and 1 had invasion into the left internal jugular vein requiring resection of these structures. In addition, 1 patient had evidence of lymph node metastases requiring central neck dissection. Histopathologic study. Final histopathologic study revealed a median tumor size of 2.0 cm (range 0.8 to 8.0 cm). There was evidence of invasion in 25 patients (30%). Seventeen patients (21%) had capsular invasion only, 4 patients (5%) had capsular and vascular invasion, one patient (1%) had capsular invasion and extrathyroidal tumor extension, and 3 patients (4%) had capsular and vascular invasion and extrathyroidal tumor extension. In addition, multifocal disease was present in 43 patients (52%). In 30 patients (37%), this disease was bilobar, whereas in the remaining 13 patients (16%), this was confined to a single thyroid lobe. DISCUSSION FNA and IP are techniques that are routinely used in the diagnosis and management of thyroid nodules. Although the role of these techniques in the evaluation of PTC and follicular neoplasms is well defined, their value for the diagnosis of FVPTC is controversial. A preoperative or intraoperative diagnosis of PTC is important, given that the operative management of PTC and follicular neoplasms differs. For lesions larger than 1 cm that clearly have papillary features on FNA or IP, definitive surgical therapy by total thyroidectomy may be provided with a single procedure, thereby decreasing patient morbidity rates and reducing costs. However, for follicular neoplasms most investigators believe that FS does not allow accurate definitive diagnosis, and a unilateral thyroid lobectomy is the standard initial operation. In this study, we attempted to determine the utility of FNA and IP in the diagnosis and management of FVPTC and whether these techniques may be used to guide operative management. The use of FNA to direct surgical management in patients with PTC is supported by multiple studies.6,7,11,12 In most series, the sensitivity of FNA

Table III. Intraoperative pathology results in patients with a final diagnosis of FVPTC by histologic study

IP Result Benign Follicular neoplasm suspicious for papillary Thyroid Carcinoma PTC Total

Patients with a All patients preoperative FNA in which IP result of FNPF was obtained 1 (3%) 14 (45%)

1 (2%) 22 (52%)

3 (10%) 13 (42%) 31

4 (10%) 15 (36%) 42

for diagnosing PTC has been reported to be greater than 60%, and in several studies the sensitivity was found to be greater than 90%.3-5,17 In addition, specificity as high as 98% has been reported.6,7 Chen et al7 evaluated the role of FNA in the management of PTC and concluded that with a specificity of 98%, an FNA diagnosis of PTC was sufficient to warrant definitive surgical resection. Several small series have evaluated the sensitivity of FNA specifically for the diagnosis of FVPTC. Although most of these studies have found sensitivities ranging from 25% to 37%, sensitivities as high as 75% have been reported.5,15,17-19 For example, Tielens et al5 reported a sensitivity of 75% for FNA for the diagnosis of FVPTC. These results may be misleading, however, because patients with suspicious FNA results were included as truepositive results, leading to an apparent increase in the calculated sensitivity. When these suspicious FNA results were eliminated from the analysis, the sensitivity dropped to 31%, which is comparable to other studies. In this study, only 7 patients of 80 had a definitive preoperative diagnosis of thyroid carcinoma by FNA, yielding a sensitivity of 9%. Although this sensitivity is lower than that reported by other investigators, it clearly demonstrates that FNA is not sufficient in most patients with FVPTC to establish a diagnosis and plan definitive surgical management. To improve the ability to diagnosis FVPTC by FNA, several investigators have attempted to identify nuclear features that may be used to differentiate FVPTC from other thyroid lesions.18,20-22 Most of these studies found nuclear grooves, intranuclear cytoplasmic inclusions, and powdery chromatin to be the most consistent nuclear features characteristic of FVPTC (Fig 3). Nevertheless, in spite of these distinct nuclear features, the diagnosis of FVPTC by FNA remains challenging for several reasons. First, FVPTC shares architectural features with both benign and

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malignant follicular neoplasms and often displays only subtle nuclear features of classic PTC. Consequently, FVPTC lesions may be misclassified as follicular neoplasms by FNA. Second, macrofollicular architectures have been described that may be confused with adenomatous nodules.20,23 Finally, the characteristic nuclear features of FVPTC may be scattered within a lesion rather than diffuse, which may lead to sampling error during FNA and false-negative results.15,19,24,25 The role of IP in the evaluation of thyroid nodules is not as well defined as FNA. Several studies have evaluated the utility of FS in the management of follicular neoplasms and have shown no benefit because of significant false negative rates.8,9,11,12 Possible roles for FS that have been proposed include (1) evaluation of nodules in which the FNA is suspicious for malignancy, (2) evaluation of nodules in which a nondiagnostic FNA is obtained, (3) evaluation of incidental nodules found at the time of surgery for other indications, and (4) identification of lymph node metastases. In cases of FVPTC, intraoperative FS and cytologic study are used to identify the specific nuclear characteristics that define PTC. This feature is in distinction to FS of follicular neoplasms in which the follicular architecture is identical in adenomas and carcinomas. Because nuclear features may be obscured by freezing artifact on FS, intraoperative cytologic study is currently recommended when a diagnosis of FVPTC is in question.13-15 (Fig 4, A) Intraoperative cytologic study preserves nuclear features that are critical in establishing a diagnosis of FVPTC, making it a useful adjunct in the intraoperative evaluation of suspicious thyroid nodules13-15 (Fig 4, B). In this study IP was primarily obtained in patients with preoperative FNA results suspicious for FVPTC. In this group of patients, IP is important given that the likelihood of malignancy approaches 70%.15 Intraoperative pathologic study was obtained in 31 patients in this group, establishing a definitive diagnosis of PTC in 13 (42%) and resulting in a change in surgical management. Because the use of intraoperative cytologic study was not routine at our institution until June 1999 and because the results of FS and cytologic study are reported jointly, it is difficult to determine the relative contributions of these 2 techniques. However, the sensitivity of IP in this group of patients (42%) is higher than the sensitivity of FS reported by other investigators (27% to 29%). This increased diagnostic yield likely reflects the use of in-

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traoperative cytologic study in the evaluation of these patients.5,15,17 Overall, the combination of a suspicious FNA result followed by IP resulted in a change in surgical management in 14 patients (45%), 13 with an IP result definitive for PTC and 1 with an IP result suspicious for PTC. At our institution, the average charges for a thyroid lobectomy and total thyroidectomy are $14,500 and $19,250, respectively, whereas the charge for intraoperative FS and cytologic study is $1350. On the basis of these numbers, the addition of IP in the 31 patients with suspicious FNA results led to savings of $94,650. Therefore the use of intraoperative FS and cytologic study in patients with suspicious FNA results appears to be cost-effective. More importantly, IP clearly decreased patient morbidity by reducing the number of completion thyroidectomies that were required. One of the challenges for pathologists is that no accepted minimal criteria have been established for the diagnosis of FVPTC, and therefore there is controversy with regard to how the cytohistologic condition of these lesions should be reported.24,26 This may lead to significant interobserver variability, which is highlighted in this series by the high discordance rate (45%) between those FNAs read at outside institutions and subsequently reviewed at our institution. For treatment and staging purposes, some pathologists advocate reporting entire lesions as FVPTC if there are any papillary nuclear features within a follicular architecture.25 The rationale for this approach is that whether focal or diffuse papillary features are present, in most cases these lesions are believed to behave like classic PTC and therefore should be managed similarly. A review of several small series has shown that lymph node metastases developed in up to 30% of patients with FVPTC.26 In addition, there have been anecdotal reports of distant metastases developing in patients with encapsulated FVPTC originally diagnosed as follicular adenoma.27 Surgical management in 43% of the patients in this study was by total or near-total thyroidectomy and in 56% was by thyroid lobectomy followed by completion thyroidectomy. On the basis of prognostic factors, one could argue that total thyroidectomy was not necessary in all these patients, thereby decreasing the number of completion thyroidectomies required. However, there are several arguments to support total thyroidectomy in this group of patients. Studies have shown that recurrence rates are lower after total thyroidectomy because PTC may be multinodular and bilobar.28-30 In this study alone, 30 patients (37%) had evidence

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of multinodular, bilobar disease that would not have been adequately managed by thyroid lobectomy alone. In addition, total thyroidectomy facilitates the use of postoperative radioiodine to ablate residual disease and enables endocrinologists to monitor patients for recurrence by use of thyroglobulin levels.28-30 In summary, it is clear that the diagnosis of FVPTC remains a challenge for pathologists. Although a definitive diagnosis of FVPTC by FNA is limited by low sensitivity, FNA is important in identifying patients with suspicious lesions in whom IP may provide valuable information. In this study, the combination of a suspicious FNA followed by IP resulted in a definitive diagnosis of PTC in 42% of these patients and a change in surgical management in 45%. Therefore, for patients with a preoperative FNA result suspicious for FVPTC, intraoperative cytologic and histologic evaluation should be obtained to help guide operative management. REFERENCES 1. Chem KT, Rosai J. Follicular variant of thyroid papillary carcinoma: a clinicopathologic study of six cases. Am J Surg Pathol 1977;1:123-30. 2. Kini SR, Miller JM, Hamburger JI, Smith MJ. Cytopathology of papillary carcinoma of the thyroid by fine needle aspiration. Acta Cytol 1980;24:511-21. 3. Gharib H, Goellner JR, Johnson DA. Fine-needle aspiration cytology of the thyroid. A 12-year experience with 11,000 biopsies. Clin Lab Med 1993;13:699-709. 4. Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: an appraisal. Ann Intern Med 1993;118:282-9. 5. Tielens ET, Sherman SI, Hruban RH, Ladenson PW. Follicular variant of papillary thyroid carcinoma. A clinicopathologic study. Cancer 1994;73:424-31. 6. Akerman M, Tennvall J, Biorklund A, Martensson H, Moller T. Sensitivity and specificity of fine needle aspiration cytology in the diagnosis of tumors of the thyroid gland. Acta Cytol 1985;29:850-5. 7. Chen H, Zeiger MA, Clark DP, Westra WH, Udelsman R. Papillary carcinoma of the thyroid: can operative management be based solely on fine-needle aspiration? J Am Coll Surg 1997;184:605-10. 8. Chen H, Nicol TL, Udelsman R. Follicular lesions of the thyroid. Does frozen section evaluation alter operative management? Ann Surg 1995;222:101-6. 9. Udelsman R, Westra WH, Donovan PI, Sohn TA, Cameron JL. Randomized prospective evaluation of frozen-section analysis for follicular neoplasms of the thyroid. Ann Surg 2001;233:716-22. 10. McHenry CR, Thomas SR, Slusarczyk SJ, Khiyami A. Follicular or Hurthle cell neoplasm of the thyroid: can clinical factors be used to predict carcinoma and determine extent of thyroidectomy? Surgery 1999;126:798-802; discussion 802-4. 11. Davoudi MM, Yeh KA, Wei JP. Utility of fine-needle aspiration cytology and frozen-section examination in the operative management of thyroid nodules. Am Surg 1997;63:1084-9; discussion 1089-90.

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12. Aguilar-Diosdado M, Contreras A, Gavilan I, EscobarJimenez L, Giron JA, Escribano JC, et al. Thyroid nodules. Role of fine needle aspiration and intraoperative frozen section examination. Acta Cytol 1997;41:677-82. 13. Shen PU, Kuhel WI, Yang GC, Hoda SA. Intraoperative touch-imprint cytological diagnosis of follicular variant of papillary thyroid carcinoma. Diagn Cytopathol 1997; 17:80-3. 14. Basolo F, Baloch ZW, Baldanzi A, Miccoli P, LiVolsi VA. Usefulness of Ultrafast Papanicolaou-stained scrape preparations in intraoperative management of thyroid lesions. Mod Pathol 1999;12:653-7. 15. Logani S, Gupta PK, LiVolsi VA, Mandel S, Baloch ZW. Thyroid nodules with FNA cytology suspicious for follicular variant of papillary thyroid carcinoma: follow-up and management. Diagn Cytopathol 2000;23:380-5. 16. Baloch ZW, Tam D, Langer J, Mandel S, LiVolsi VA, Gupta PK. Ultrasound-guided fine-needle aspiration biopsy of the thyroid: role of on-site assessment and multiple cytologic preparations. Diagn Cytopathol 2000;23:425-9. 17. Lin HS, Komisar A, Opher E, Blaugrund SM. Follicular variant of papillary carcinoma: the diagnostic limitations of preoperative fine-needle aspiration and intraoperative frozen section evaluation. Laryngoscope 2000;110: 1431-6. 18. Goodell WM, Saboorian MH, Ashfaq R. Fine-needle aspiration diagnosis of the follicular variant of papillary carcinoma. Cancer 1998;84:349-54. 19. Baloch ZW, Gupta PK, Yu GH, Sack MJ, LiVolsi VA. Follicular variant of papillary carcinoma. Cytologic and histologic correlation. Am J Clin Pathol 1999;111:216-22. 20. Mesonero CE, Jugle JE, Wilbur DC, Nayar R. Fine-needle aspiration of the macrofollicular and microfollicular subtypes of the follicular variant of papillary carcinoma of the thyroid. Cancer 1998;84:235-44. 21. Harach HR, Zusman SB. Cytologic findings in the follicular variant of papillary carcinoma of the thyroid. Acta Cytol 1992;36:142-6. 22. Leung CS, Hartwick RW, Bedard YC. Correlation of cytologic and histologic features in variants of papillary carcinoma of the thyroid. Acta Cytol 1993;37:645-50. 23. Albores-Saavedra J, Gould E, Vardaman C, Vuitch F. The macrofollicular variant of papillary thyroid carcinoma: a study of 17 cases. Hum Pathol 1991;22:1195-205. 24. Renshaw AA, Gould EW. Why there is the tendency to ‘‘overdiagnose’’ the follicular variant of papillary thyroid carcinoma. Am J Clin Pathol 2002;117:19-21. 25. Baloch ZW, Livolsi VA. Follicular-patterned lesions of the thyroid: the bane of the pathologist. Am J Clin Pathol 2002;117:143-50. 26. Chan JK. Strict criteria should be applied in the diagnosis of encapsulated follicular variant of papillary thyroid carcinoma. Am J Clin Pathol 2002;117:16-8. 27. Baloch ZW, LiVolsi VA. Encapsulated follicular variant of papillary thyroid carcinoma with bone metastases. Mod Pathol 2000;13:861-5. 28. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 1990;71:414-24. 29. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418-28. 30. Clark OH. Total thyroidectomy: the treatment of choice for patients with differentiated thyroid cancer. Ann Surg 1982;196:361-70.