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Mar 12, 2009 - Parathyroid Adenoma: Cytologic Findings From 53 Patients. Archana M. Agarwal, M.D.,1* Joel S. Bentz, M.D.,1 Ryan Hungerford, M.D.,2.
Parathyroid Fine-Needle Aspiration Cytology in the Evaluation of Parathyroid Adenoma: Cytologic Findings From 53 Patients Archana M. Agarwal, M.D.,1* Joel S. Bentz, and Dev Abraham, M.D.2

1 M.D.,

Ryan Hungerford,

This study was designed to assess the utility of fine-needle aspiration cytology (FNAC) in the preoperative localization of parathyroid adenoma (PA). Fifty-seven samples from fifty-three cases of PA (four patients had bilateral disease) were obtained by ultrasound (US)-guided fine-needle aspiration. Parathyroid hormone (PTH) estimation was performed on the supernatant of the aspirated fluid on all cases. Subsequently, all of them underwent cytologic evaluation. The cytology slides were evaluated using the following criteria: Cellularity, architectural patterns, bare nuclei in the background, nuclear morphology, and background features (colloid-like material or macrophages). Parathyroid cells were seen in 23 samples (40.4%). The cellularity of the smears was insufficient for interpretation in 16 samples (28.1%); and thyroid follicles and colloid were seen in 18 samples (31.5%). Majority of the samples with parathyroid cells showed moderate cellularity with monomorphous round to slightly oval cells predominantly arranged in loose two-dimensional clusters with occasional papillary fragments. Majority of them exhibited a stippled nuclear chromatin. No significant pleomorphism, mitotic activity, or prominent nucleoli were observed. Most samples showed bare nuclei in the background. In conclusion, US-guided FNAC has its limitations because of low sensitivity in primary localization of the parathyroid adenoma in cases of primary hyperparathyroidism and is not a useful mode of investigation in cases of PA. Diagn. Cytopathol. 2009;37:407– 410. ' 2009 Wiley-Liss, Inc. Key Words: sound

parathyroid adenoma; fine-needle aspiration; ultra-

1

Department of Pathology, University of Utah, Salt Lake City, Utah Department of Internal Medicine, University of Utah, Salt Lake City, Utah *Correspondence to: Archana M. Agarwal, M.D., University of Utah Health Sciences Center, Department of Pathology, 30 North 1900 East, Salt Lake City, Utah 84132. E-mail: [email protected] Received 18 July 2008; Accepted 18 November 2008 DOI 10.1002/dc.21020 Published online 12 March 2009 in Wiley InterScience (www.interscience. wiley.com). 2

'

2009 WILEY-LISS, INC.

2 M.D.,

Primary hyperparathyroidism (PHPT) is the commonest cause of hypercalcemia in the outpatient setting. Single adenomas account for up to 89% of cases of primary hyperparathyroidism. Double adenomas are found in an additional 5%, diffuse glandular hyperplasia account for 6%, and carcinoma in 1 to 2%.1,2 The initial diagnosis is usually made by finding an inappropriately elevated serum parathyroid hormone (PTH) level associated with hypercalcemia. The role of fine-needle aspiration cytology (FNAC) in the preoperative localization and diagnosis of PA is unclear.3,4 In addition, the literature regarding the cytomorphological features of PA is limited and contradictory. In this study, we attempted to determine the role of FNAC in the diagnostic evaluation of PA and discuss its cytomorphological features.

Materials and Methods Subjects We evaluated FNA specimens from 53 patients (43 women and 12 men) of well-documented cases of PA (based on the ultrasound, available histology and PTH levels on the aspirated needle rinsing) at the University of Utah from February 2004 to August 2006. The PTH estimation on the aspirates in these patients was compared with those from 13 proven thyroid nodules. Approval was obtained from the Institutional Review Board of the University of Utah Medical Center. The average age was 50year-old (range 12–88) at the time of FNA. Average serum calcium level of study patients was 10.8 mg/dl (range 8.9–12.6). Nephrolithiasis was the most commonly associated clinical condition seen in the study population (12 of 53 patients, 22%), though the majority of patients (43 of Diagnostic Cytopathology, Vol 37, No 6

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Diagnostic Cytopathology DOI 10.1002/dc

AGARWAL ET AL. Cytologic Features of the Samples with Parathyroid Cells (23)

Table I.

Cytomorphologic features Bare nuclei in the background Loose two dimensional cluster Microfollicels Nucleomegaly Mitosis Stippled chromatin Colloid-like material in the background Macrophages in the background

Number of cases

Percentage

20 17 7 7 0 21 2 2

86 73 30 30 0 91 9 9

53 patients, 81%) were either asymptomatic or had clinical features not clearly related to hyperparathyroidism. All patients underwent minimally invasive parathyroidectomy with intraoperative PTH estimation.

Methods All patients were subjected to high-resolution ultrasonography using 7.5 and 10 MHz frequencies with color flow Doppler capability. Parathyroid adenomas were identified by their extra-thyroidal location, hypodense appearance, and the presence of one or more vascular pedicles. All subjects then underwent US-guided FNA of the suspected adenoma. One to two passes were made using 27 G needles.

Biochemical Testing Serum calcium and intact PTH levels were determined for all subjects. The fresh FNA specimen from the adenoma was smeared onto a glass slide, and the rest of the specimen in the syringe was rinsed in 1.5 ml of saline. The cellular debris was removed by centrifugation, and the supernatant was frozen prior to transportation to the laboratory. PTH estimation was performed on the supernatant using Roche modular E170 analyzer.

Cytological Assessment Smears prepared from the FNA were stained using Diff Quick-Wright modified Giemsa stain. All samples were evaluated using the following criteria: Cellularity, architectural patterns, cell size and shape, nuclear morphology (size, shape, chromatin pattern, nucleoli, mitosis), and background features (colloid-like material or macrophages).

Results The mean PTH in the FNA syringe washings in the 53 subjects who underwent FNA/PTH estimation was 23.0 6 6.9 ng/ml. This result was significantly different (P < 0.001) from the mean PTH level in 13 thyroid nodules (9.0+/ 1.0 pg/ml). All the patients underwent minimally invasive parathyroidectomy with a decline of more than 50% intraoperative PTH levels. Out of a total of 57 sam408

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Fig. 1. Parathyroid cells showing moderate cellularity with monomorphous round to slightly oval cells. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

ples obtained by FNA, parathyroid cells were seen in 23 samples (40.4%). The cellularity of the smear was insufficient for interpretation in 16 samples (28.1%); and thyroid follicles and colloid were seen in 18 samples (31.5%). Three patients had a mixture of parathyroid and thyroid cells. Out of 23 samples in which parathyroid cells were seen, the cellularity was scant in three samples (13%) and moderate to high in 20 samples (87%). The cytomorphologic findings from the smears are summarized in Table I. Majority of the cases with parathyroid cells show moderate cellularity with monomorphous round to slightly oval cells that exhibited a stippled nuclear chromatin (Figs. 1 and 2). No significant pleomorphism, mitotic activity, or prominent nucleoli were observed. The cells were arranged predominantly in loose two-dimensional clusters with occasional papillary fragments (Fig. 3). Most cases showed bare nuclei in the background.

Discussion Minimally invasive surgery (MIS) is an accepted treatment option for primary hyperparathyroidism resulting from parathyroid adenoma. The surgical success of the MIS depends on accurate preoperative localization of parathyroid adenoma.5 Ultrasound is a simple tool that can be used in the office setting to localize parathyroid adenoma. The sensitivity and specificity of high-resolution ultrasound have been reported to be between 51 and 87% and between 90 and 98%, respectively.6–8 It is an operatordependent technique and gives good result when the parathyroid adenoma is located behind the thyroid gland or in the lower pole of the thyroid. Normal parathyroid glands are not visualized by ultrasonography. Parathyroid adenomas

Diagnostic Cytopathology DOI 10.1002/dc

PARATHYROID FNAC IN EVALUATION OF PA

Fig. 2. Parathyroid cells showing stippled nuclear chromatin. [Color figure can be viewed in the online issue, which is available at www. interscience.wiley.com.]

Fig. 3. A sample of PA showing loose two-dimensional clusters with papillary fragments. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

appear as hypervascular, hypoechoic ovoid, or lobulated mass. The characteristic ultrasonographic appearance is an extrathyroidal feeding artery that helps in localization.9 In this study, we assess the role of FNAC in the preoperative localization of parathyroid adenoma in cases of primary hyperparathyroidism. We also performed PTH estimation on the fine-needle aspirate of all the cases for the confirmation of parathyroid origin and only included cases with increased PTH in this study. In previously reported studies, the smear inadequacy ranges from 8.3 to 17%.4,10,11 We had a higher percentage of smear inadequacy in our study (28.1%). This could be related to number of passes made. The sensitivity of identifying parathyroid cells in the FNAC of the parathyroid adenoma was *40.4%. We also observed significant contamination with thyroid epithelial cells (31.5%), which seems to be higher compared to the previous reported literature (8.3– 28%).4,11 This could happen because of the location of the PA. During fine-needle aspiration, the needle traverses the thyroid tissue, leading to incidental contamination. Previous literature has described difficulty in distinguishing thyroid from parathyroid cells histologically.12–14 However, recently Dimashkieh and Krishnamurthy12 have described few criteria favoring parathyroid over thyroid cells. These are as follows: presence of stippled nuclear chromatin, usual presence of vascular network with attached epithelial cells, and the frequent occurrence of single cells. We also found these criteria to be useful in our study. In our study, out of 23 samples with parathyroid cells, 20 (86%) had bare nuclei in the background. Majority of them had stippled chromatin. The cellularity of this range from low (13%) to abundant cellularity (87%). Rare nuclear pleomorphism and nuclear atypia were seen. Occasionally, vascular network with attached

epithelial cells was seen. We also found that the parathyroid cells are smaller in size with abundant pale cytoplasm. Colloid like material and macrophages were seen in *9% of our cases, which is similar to those reported in the past4,15 and are not specific for thyroid lesions. In a recent article, Owens et al.16 advocated the use of parathyroid hormone assay in fine-needle aspirate from the neck/thyroid to distinguish between parathyroid tissue and thyroid neoplasm’s to avoid misdiagnosis. We also feel that because of low sensitivity of detecting parathyroid tissue and some overlapping histological features, ancillary studies might be helpful for a definitive diagnosis. In conclusion, ultrasound-guided FNAC without ancillary studies have low sensitivity in primary localization of the parathyroid adenoma in cases of primary hyperparathyroidism. However, it is an easily performed, outpatient-based technique and as reported recently,5,16 it might prove to be more useful in conjunction with simultaneous determination of PTH level in the aspirate for preoperative localization of parathyroid before surgery.

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AGARWAL ET AL. 6. Ghaheri BA, Koslin DB, Wood AH, Cohen JI. Preoperative ultrasound is worthwhile for reoperative parathyroid surgery. Laryngoscope 2004;114:2168–2171. 7. Hajioff D, Iyngkaran T, Panagamuwa C, Hill D, Sterans MP. Preoperative localization of parathyroid adenomas: Ultrasonography, sestamibi scintigraphy, or both? Clin Otolaryngol Allied Sci 2004; 29:49–52. 8. Purcell GP, Dirbas FM, Jeffrey RB, et al. Parathyroid localization with high-resolution ultrasound and technetium Tc 99m sestamibi. Arch Surg 1999;134:824–828. 9. Lane MJ, Desser TS, Weigel RJ, Jeffrey RB. Use of color and power doppler sonography to identify feeding arteries associated with parathyroid adenomas. AJR Am J Roentgenol 1998;171:819– 823. 10. Abati A, Skarulis MC, Shawker T, Solomon D. Ultrasoundguided fine-needle aspiration of parathyroid lesions: A morphological and immunocytochemical approach. Hum Pathol 1995;26: 338–343.

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11. Halbauer M, Crepinko I, Tomc Brzc H, Simonovic I. Fine needle aspiration cytology in the preoperative diagnosis of ultrasonically enlarged parathyroid glands. Acta Cytol 1991;35:728–735. 12. Dimashkieh H, Krishnamurthy S. Ultrasound guided fine needle aspiration biopsy of parathyroid gland and lesions. Cytojournal 2006;3:6. 13. Glenthoj A, Karstrup S. Parathyroid identification by ultrasonically guided aspiration cytology: Is correct cytological identification possible? Apmis 1989;97:497–502. 14. Tseleni-Balafouta S, Gakiopoulou H, Kavantzas N, Agrogiannis G, Givalos N, Patsouris E. Parathyroid proliferations. Cancer 2007;111: 130–136. 15. Bondeson L, Bondeson AG, Nissborg A, Thompson NW. Cytopathological variables in parathyroid lesions: A study based on 1,600 cases of hyperparathyroidism. Diagn Cytopathol 1997;16:476–482. 16. Owens C, Rekhtman N, Sokill L, Ali S. Parathyroid hormone assay in fine needle aspirate is useful in differentiating inadvertently sampled parathyroid tissue from thyroid lesions. Diagn Cytopathol 2008;36:227–231.