Institutional experience of PTH evaluation on fine-needle washing after aspiration biopsy to locate hyperfunctioning parathyroid tissue^#

Institutional experience of PTH evaluation on fine-needle washing after aspiration biopsy to locate hyperfunctioning parathyroid tissue # # 1 first-author †E-mail:magius@unige.it †E-mail:magius@unige.it magius@unige.it 1 1 2 1 1 1 2 1 Department of Endocrinology, San Martino University Hospital, I-16100 Genoa, Italy Department of Endocrinology, San Martino University Hospital, I-16100 Genoa, Italy Analysis Laboratory, San Martino University Hospital, I-16100 Genoa, Italy Analysis Laboratory, San Martino University Hospital, I-16100 Genoa, Italy Assaying parathyroid hormone (PTH) in the washing liquid after fine-needle aspiration biopsy (FNAB) seems to be a valid approach to locate parathyroid tissue. PTH-FNAB was evaluated in 47 patients with a clinical picture of primary hyperparathyroidism (PHP) and ultrasonography (US) suggestive of parathyroid lesion. The patients were subdivided into two groups on the basis of the absence or presence of US thyroid alterations. The result of PTH-FNAB was compared with those of cytology, scintigraphy and, in 24 patients, surgical outcome. PTH-FNAB samples with a value higher than that recorded in the serum and higher than our institutional cut-off were deemed to be probable samples of parathyroid tissue. Cytology proved diagnostic for benign thyroid lesions, non-diagnostic for thyroid lesions, hyperplastic parathyroid tissue, undetermined or malignant thyroid lesions and other lesions in 45%, 30%, 17%, 4%, and 4% of cases, respectively. In 47% of cases, PTH-FNAB indicated that the sample had been taken in parathyroid tissue. In patients without US alterations, the diagnostic accuracy of PTH-FNAB was greater than that of scintigraphy. After surgery, comparison between the results of PTH-FNAB and scintigraphy, in terms of positive predictive value (PPV), revealed the superiority of PTH-FNAB; PPV was 94% for FNAB and 71% for scintigraphy, while sensitivity was 83% and 69%, respectively. PTH-FNAB evaluation after FNAB appears to be more diagnostic than cytology and scintigraphy. Of all the procedures used, PTH-FNAB appears to be the method of choice when the target is US suggestive and reachable. PTH-FNAB appears to be a useful method of guiding surgical intervention. Primary hyperparathyroidism Nodular goitre Scintigraphy Ultrasonography Fine-needle aspiration biopsy (FNAB) Parathyroid hormone (PTH)-FNAB INTRODUCTION 1 Primary hyperparathyroidism (PHP) is a common cause of hypercalcemia; in the majority of patients, it is due to a parathyroid adenoma. The standard therapeutic approach entails surgical removal of all enlarged parathyroid tissue and bilateral exploration of the neck. Surgery has a high rate of success and a low rate of adverse events when performed by an expert surgeon. More recently, minimally invasive parathyroidectomy (MIP) has been considered the surgical procedure of choice when the location of the hyperfunctioning parathyroid tissue is undoubted and intra-operative parathyroid hormone (PTH) assay is available (Rodgers et al., 2008 2008 ). Ultrasonography (US) and 99m Tc-methoxyisobutylisonitrile (MIBI) scintigraphy are currently the most widely used methods of locating hyperfunctioning parathyroid tissue. US can be considered the first-line technique; if this proves inconclusive, MIBI is required (Bhansali et al., 2006 2006 ; Grosso et al., 2007 2007 ). However, one of the main obstacles to imaging studies is the high incidence of false positive results due to other cervical abnormalities, such as non-nodular or nodular goitre, or false negative results due to the size and location of hyperfunctioning parathyroid tissue (Masatsugu et al., 2005 2005 ). Fine-needle aspiration biopsy (FNAB) of suspected parathyroid tissue and PTH assay on the needle wash-out after preparation of cytological specimens are further methods of localizing parathyroid adenomas. In 1983 this procedure was described by Doppman et al.( 1983 1983 ); since then, several reports on US-guided PTH-FNAB have been published (Abraham et al., 2007 2007 ; Barczynski et al., 2006 2006 ; Erbil et al., 2006 2006 ; 2007 2007 ; Kiblut et al., 2004 2004 ; Marcocci et al., 1998 1998 ; Maser et al., 2006 2006 ). This approach enables sonographic, cytological and biochemical results to be combined in order to localize parathyroid tissue with greater certainty. The contribution of PTH-FNAB to localizing parathyroid adenomas in patients with PHP and concomitant thyroid nodules has not yet been fully evaluated (Marcocci et al., 1998 1998 ; Erbil et al., 2007 2007 ). The aim of the present prospective study was to evaluate the diagnostic role of PTH-FNAB in our series of patients with PHP. In our hands, PTH-FNAB seems more diagnostic than cytology and scintigraphy in patients without echographic thyroid alterations. Of all the procedures used, PTH-FNAB appears to be the method of choice when the target is echographically suggestive and reachable. MATERIALS AND METHODS 1 Patients and protocol 2 We studied 47 consecutive outpatients (38 females, 9 males) aged 38~89 years (mean age (63.6±11.8) years; mean± SD ) undergoing endocrine evaluation for PHP. The biochemical diagnosis of PHP was performed by standard criteria. At the time of FNAB evaluation, PTH, total calcium, free-thyroxine (f-T4), thyroid stimulating hormone (TSH), and thyroglobulin (Tg) were further evaluated in all patients (Table 1 1 ). Patients were divided into two groups on the basis of absence (Group 1) or presence (Group 2) of concomitant thyroid abnormalities on US. Written informed consent was obtained from all patients. FNAB was performed under US guidance on each nodular lesion suspected of being enlarged parathyroid tissue. One pass was generally made. Data from cytology evaluation and from biochemical evaluation of PTH on needle washing (PTH-FNAB) were recorded. As a negative control value for sampling in parathyroid tissue, Tg was also evaluated in needle washing (Tg-FNAB). When necessary, FNAB was also performed on thyroid nodules, and the data were regarded as an internal negative control. Cytological and biochemical results and those of US-guided FNAB were compared with the results yielded by parathyroid MIBI scintigraphy. After diagnostic evaluation, parathyroid surgery was performed in several patients and the histological result was further evaluated. Data are expressed as mean± SEM , except those for age as mean± SD 2 2 Value 2 Significance Group 1 Group 2 Age (year) 69.3±10.7 61.7±11.7 P =0.03 PTH (ng/L) 232.8±56.5 285.6±55.0 ns Calcium (mmol/L) 2.77±0.10 2.75±0.05 ns F-T4 (pmol/L) 13.5±1.7 14.8±0.5 ns TSH (mU/L) 1.5±0.2 1.4±0.3 ns Patient number  Sex, M/F 2/8 7/30 −  US finding −   Normal 10 −   Multi-nodular goitre 2 − 18   Uni-nodular goitre − 12   Thyroid remnant − 3   Goitre − 2   Diffuse hypoechogenic − 2 Instrumental evaluation 2 Neck US examination was carried out by means of an Esaote AU5 Idea equipped with a 7.5 MHz linear transducer of 60 mm length (Esaote, Genoa, Italy). The usual location of parathyroid glands was scanned to detect any lesion suggestive of parathyroid pathology. Any hypoechogenic lesion that was retro-thyroid or polar in relation to the thyroid lobe, which had one or more vascular stalks, was suspected of being parathyroid tissue. In addition, solid hypoechogenic intra-thyroid lesions were also regarded as suspect when no other extra-thyroid lesions were seen in overt clinical PHP. If suspected parathyroid tissue was located, US-guided FNAB was performed by using a 21-gauge needle attached to a 10-ml syringe. The needle was inserted into the suspicious parathyroid tissue and negative pressure was applied. A smear from the needle used for aspiration was collected on a glass slide and the needle was then washed with 1 ml of normal saline solution. Cell debris were removed by centrifugation and the supernatant was collected for biochemical evaluations. 99m Tc-MIBI was administered intravenously and images were acquired 10 min and 2~3 h post-injection. Early and late anterior planar images of the neck and mediastinum were compared for focal abnormalities and for areas of increased retention of MIBI. Parathyroid scintigraphy was interpreted by an experienced nuclear physicist, who was unaware of the results of the PTH-FNAB. Biochemical and cytological analyses 2 PTH was analyzed by chemiluminescence immunoassay (Immulite 2000, Diagnostic Products, San Juan Capistrano, CA, USA). Intra- and inter-assay variations, expressed as coefficients of variation (CVs), were 4% and 6%, and assay sensitivity was 2 ng/L. In our laboratory, the normal PTH range in sera is <65 ng/L. Tg was assayed by chemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany). The functional sensitivity is ≤0.5 μg/L. In our laboratory, the intra- and inter-assay CVs were 5% and 8%, respectively. In patients without goitre, normal Tg values are 1.5~78.0 μg/L. PTH-FNAB and Tg-FNAB levels were also assayed by means of the same methods on needle wash-out (1 ml of saline solution) after preparation of cytological specimens. PTH-FNAB and Tg-FNAB levels are expressed respectively in ng/L and μg/L regardless of dilution. F-T4 and TSH levels were measured by means of chemiluminescence immunoassay (Roche Diagnostics). Normal ranges are 12.0~22.0 pmol/L and 0.3~4.2 mU/L for f-T4 and TSH, respectively. Serum total-calcium was determined by fully automatic equipment (Modular P800, Roche Diagnostics). In our laboratory, normal calcium levels are 2.12~2.70 mmol/L. The sample material obtained from FNAB was smeared between 2 slides, fixed by means of Cytofix, and stained with Papanicolau or dried and stained with May Grunwald-Giemsa. When cellularity was adequate (>50 cells), the parathyroid origin of the specimens was determined according to cell distribution and characteristics and background. FNAB results are frequently classified as Thy 1 to Thy 5 according to the diagnostic categories of the British Thyroid Association (BTA). Statistical analysis 2 In any given patient, we regarded a PTH-FNAB value greater than that found in sera, and in any case greater than 132 ng/L, as indicative of sampling in parathyroid tissue. This value is the mean±2.5 SD of PTH-FNAB performed in thyroid nodules in a group of 24 patients without PHP. The Tg-FNAB value was considered a further parameter of judgment. In 64 evaluations of thyroid nodules, we found a Tg-FNAB value ranging from 2 to over 2500 μg/L (median 804 μg/L; mean± SEM (1354±146) μg/L). The sensitivity and positive predictive value (PPV) of cytology and PTH-FNAB versus MIBI alone were evaluated. Data were analyzed by means of the Prism 4.0 software (GraphPad Software, San Diego, CA, USA). All values quoted are mean± SEM . Significance was taken as P < 0.05. To compare continuous or percentage data, the Mann-Whitney test and Fisher’s exact test were used. RESULTS 1 Only 10 patients showed a normal thyroid pattern on US (Group 1), while thyroid abnormalities were observed in the remaining 37 patients (Group 2). Single or multiple thyroid nodules, a diffuse goitre or hypoechogenic pattern, and a non-nodular thyroid remnant of previous thyroid surgery were found in 30, 4, and 3 patients, respectively (Table 1 1 ). A significant difference in age was noted between Group 1 and Group 2 ( P =0.03). On average, f-T4 and TSH levels were similar in both groups (Table 1 1 ). At the time of FNAB, the average value of serum calcium was (2.75±0.05) mmol/L. No difference in average calcemia was noted between Group 1 and Group 2 (Table 1 1 ). PTH levels varied widely, ranging from 65 to 1674 ng/L, with a mean value of (275.3±45.7) ng/L (median 169 ng/L). No difference was noted in PTH levels between Group 1 (median 250 ng/L; range 69~624 ng/L) and Group 2 (median 160.5 ng/L; range 65~1674 ng/L) (Table 1 1 ). On US, the average size of lesions suspected of being enlarged parathyroid glands was (18.0±1.2) mm, with no significant difference between Group 1 ((15.0±1.5) mm) and Group 2 ((18.7±1.5) mm). Post-FNAB cytology was indicative of sampling in thyroid tissue in the majority of patients (79%, 37/47), but a precise Thy score (from 2 to 5 according to the BTA) was obtained in only 38% cases (14/37). In 2 patients of Group 2 (cases 5 and 18) cytology prompted surgical evaluation. In 8 patients, cytological results were indicative of sampling in hyperplastic parathyroid tissue (Group 1: 30%, 3/10; Group 2: 13.5%, 5/37; ns) (Table 2 2 ). Table 2 2 reports individual PTH-FNAB and Tg-FNAB values. In 47% (22/47) of patients PTH-FNAB values were indicative of sampling in parathyroid tissue, while Tg-FNAB values were elevated in 51% (22/43) of patients, as a result of thyroid contamination (Group 1: 67%, 6/9; Group 2: 47%, 16/34). No correlation was found between PTH-FNAB and Tg-FNAB. Cytological diagnoses are reported according to the BTA when follicular cells were seen; the other cytological diagnoses were: HP: hyperplastic parathyroid cells; FC: fat cells; LN: lymph node cells. Location (R: right side; L: left side; I: inferior; S: superior; C: cystic) of target is reported. FNAB was not repeated owing to a concomitant disease diagnosed (prostatic cancer); hyperparathyroidism was considered to be secondary (creatinine 141.4 μmol/L). FNAB was also performed on isthmic thyroid nodule (size 5 mm): PTH-FNAB 15 ng/L; Tg-FNAB >2500 μg/L; Thy 2. FNAB was also performed on R cystic thyroid nodule (size 12 mm): PTH-FNAB 27 ng/L; Tg-FNAB 1245 μg/L; Thy 1. FNAB was also performed on R cystic thyroid nodule (size 13 mm): PTH-FNAB 2 ng/L; Tg-FNAB >2500 μg/L; Thy 1. FNAB was also performed on isthmic thyroid nodule (size 22 mm): PTH-FNAB 27 ng/L; Tg-FNAB >2500 μg/L; Thy 2. FNAB was also performed on L thyroid nodule (size 22 mm): PTH-FNAB 3 ng/L; Tg-FNAB >2500 μg/L; Thy 2. FNAB was also performed on L thyroid nodule (size 5 mm): PTH-FNAB 2 ng/L; Tg-FNAB >2500 μg/L; Thy 2. FNAB was also performed on L nodule (size 36 mm): PTH-FNAB 2 ng/L; Tg-FNAB 84 μg/L; Thy 2. Patient lost to follow-up. FNAB was also performed on R thyroid nodule (size 23 mm): PTH-FNAB 114 ng/L; Tg-FNAB >2500 μg/L; Thy 2. FNAB was also performed on L thyroid nodule (size 14 mm): PTH-FNAB 2 ng/L; Tg-FNAB 2460 μg/L; Thy 1. FNAB was also performed on L thyroid nodule (size 15 mm): PTH-FNAB 3 ng/L; Tg-FNAB 1475 μg/L; Thy 2 Case Ø target size (mm) FNAB cytology [1] [1] Location [2] [2] PTH-FNAB (ng/L) Tg-FNAB (μg/L) 6 Group 1 1 22 Thy 1 L, I 260 >2500 2 18 Thy 1 L 5 747 3 12 Thy 1 L >2000 >2500 4 8 Thy 1 R, I >2000 >2500 5 19 Thy 1 L >2000 >2500 6 21 HP R, I 1854 7 12 HP L, S >2000 >2500 8 [3] [3] 15 Thy 1 R, S 2 3 9 18 HP R, I >2000 >2500 10 10 Thy 1 L, I 23 36 6 Group 2 1 31 Thy 2 R, I, C >2000 >2500 2 10 Thy 2 R, S <2 3 18 Thy 2 L, I 4 >2500 4 24 HP R >2000 >2500 5 10 Thy 5 R 6 >2500 6 46 FC R, I >2000 >2500 7 [4] [4] 16 HP L, I 820 820 8 [5] [5] 22 Thy 1 R, I, C 156 3 9 17 LN L 2 1097 10 12 Thy 1 L, I >2000 199 11 [6] [6] 15 Thy 2 L, I >2000 274 12 [7] [7] 11 Thy 2 R 20 >2500 13 [8] [8] 9 Thy 2 R 5 >2500 14 24 Thy 2 L, I >2000 466 15 [9] [9] 16 Thy 2 L, I 734 1 16 11 Thy 2 L 12 1000 17 26 Thy 2 L 2 >2500 18 20 Thy 3 R, I 33 274 19 22 HP R, I >2000 54 20 8 Thy 1 R, I 11 4 21 17 HP R, I 1715 674 22 20 Thy 2 L, I 5 23 [10] [10] 10 Thy 2 R, I 2 799 24 11 Thy 2 L, I 3 30 25 11 Thy 2 R, S 14 >2500 26 31 Thy 2 L 7 >2500 27 14 Thy 1 R, I >2000 28 30 Thy 2 R 3 1839 29 [11] [11] 12 Thy 1 L, I 2 >2500 30 [12] [12] 21 Thy 2 L 111 76 31 [13] [13] 9 Thy 2 L 2 >2500 32 45 Thy 2 R 2 370 33 16 Thy 2 R, I 2 771 34 15 Thy 1 R, I 1249 8 35 [14] [14] 13 Thy 2 R 3 431 36 22 Thy 1 R >2000 652 37 28 HP R, C >2000 2 Cytology plus US-guided PTH-FNAB indicated that the sample had been taken in parathyroid tissue in 47% (22/47) of patients, positivity being higher ( P =0.08, ns) in Group 1 (70%, 7/10) than in Group 2 (38%, 14/37) patients. MIBI proved positive for parathyroid localization in 64% (21/33) (Group 1: 57%, 4/7; Group 2: 65%, 17/26) of assessable patients. A concordance between FNAB and MIBI was observed in 66% (22/33) of patients (positive concordance n =12; negative concordance n =10). Surgery was not undertaken on account of mild PHP ( n =9) and/or high surgical risk ( n =7), multiple type-1 endocrine neoplasia diagnosed ( n =1), and death of patient from gastric carcinoma and cardiovascular events ( n =2). Surgery was our choice in 28 cases and was accepted by 86% (24/28) of patients. The surgical outcome is reported in Table 3 3 . A parathyroid adenoma was located and removed in 21 out of 24 patients (87%; Group 1: 100%, 7/7; Group 2: 82%, 14/17; ns) (Table 3 3 ). Table 4 4 reports the sensitivity and PPV of FNAB and MIBI. FNAB evaluation yielded a higher number of true positive cases than MIBI ( P =0.04), while no difference was observed in false positive or false negative cases. PPV was 94% and 71% for FNAB and MIBI, while sensitivity was 83% and 69%, respectively (Table 4 4 ). FNAB and MIBI results: P: positive; N: negative. The location (R: right side; L: left side; I: inferior; S: superior) of PA is reported in brackets. Other diagnosis after histological evaluation or clinical follow-up: DTC (differentiated thyroid carcinoma); Other diagnosis after histological evaluation or clinical follow-up: ATD (autoimmune thyroid disease); A hyperplastic R I parathyroid gland also surgically removed FNAB result MIBI result Surgical outcome 4 Group 1 1 [1] [1] P (L, I) P (R) PA (L, I) 2 [1] [1] N N PA (L) 3 [2] [2] P (L) PA (L) 4 P (R, I) P (R, I) P (L) 5 P (L) N PA (L, I) 7 P (L, S) PA (L, S) 9 P (R, I) PA (R, I) 4 Group 2 1 P (R, I) N PA (R, I) 4 P (R) P (R) PA (R) 5 [1] [1] N PA not located 6 P (R, I) P (R, I) PA (R, S) 7 P (L, I) P (L, I) PA (L, I) 10 P (L, I) P (L, I) PA (L, I) 11 [3] [3] P (L, I) P (L) PA (L, I) 12 N N PA (ectopic) 13 N P (L) PA (R, I) 15 P (L, I) P (L, I) PA (L, I) 19 P (R, I) P (R, I) PA (R, I) 21 P (R, I) P (R) PA (R, I) 23 N P (R, I) PA not located 27 P (R, I) PA (R) 28 N P (R, I) PA not located 34 P (R, I) PA (R, I) 36 P (R) P (R, I) PA (R, I) Sensitivity= TP /( TP + FN ); PPV= n 1 /( n 1 + n 2 ), where n 1 is the number of patients with correspondence between pre-operative result and post-surgical histology in locating parathyroid adenoma (PA); n 2 is the number of patients with positive pre-surgical localization but PA in a different location on surgery. ns: not significantly TP FP FN PPV sensitivity FNAB 20/24 (84%) 1/24 (4%) 3/24 (12%) 94% 83% MIBI 9/18 (50%) 5/18 (28%) 4/18 (22%) 71% 69% 6 Significance P =0.04 ns ns DISCUSSION 1 MIP is now the most attractive surgical choice, as it requires less surgery time, shorter hospitalization, and lower overall costs (Miccoli and Berti, 2001 2001 ). The outcome of MIP is linked to accurate localization of the hyperfunctioning gland. As demonstrated by our study, when PHP is suspected, a US search for parathyroid tissue, together with cytological examination and PTH-FNAB whenever possible, is always justified, irrespective of PTH and calcium levels. MIBI is widely used in the preoperative localization of parathyroid adenoma (Allendorf et al., 2003 2003 ; Bhansali et al., 2006 2006 ; Calva-Cerqueira et al., 2007 2007 ; Grosso et al., 2007 2007 ); its sensitivity is greater in isolated adenomas than in multiple adenomatosis (Allendorf et al., 2003 2003 ). False negative results are unavoidable, owing to the size, site and histological characteristics of such lesions. The most frequent cause of false positive results is the concomitant presence of thyroid nodules (Allendorf et al., 2003 2003 ; Mihai et al., 2006 2006 ). Normal parathyroid glands are not visible on US and false positive results are due to thyroid nodules, blood vessels, oesophagus, long collum muscle, and lateral cervical lymph nodes, while false negative results are due to atypical parathyroid location (Solbiati et al., 2001 2001 ). Thyroid nodules were reported during neck US in 20%~80% of PHP cases (Abraham et al., 2007 2007 ; Erbil et al., 2007 2007 ; Lumachi et al., 2003 2003 ; Marcocci et al., 1998 1998 ; Mihai et al., 2006 2006 ). Moreover, sensitivity and PPV were heavily influenced by concomitant uni- or multi-nodular thyroid goitre (Erbil et al., 2007 2007 ; Mihai et al., 2006 2006 ). However, it is well known that the majority of parathyroid adenomas have an inferior extrathyroid localization (Abraham et al., 2007 2007 ); this finding was confirmed in 58% of our patients who underwent surgery. The use of PTH-FNAB in PHP has recently been reassessed. A value of PTH in the needle-washing fluid, which is even slightly higher than that in blood, should be considered diagnostic for parathyroid localization, on account of the hormone dilution in PTH-FNAB (Marcocci et al., 1998 1998 ). An institutional cut-off is needed. In the present study, a PTH-FNAB value higher than that of the peripheral sample and/or greater than 132 ng/L was considered to indicate that the sample was of parathyroid tissue. Our cut-off is similar to that reported by Kiblut et al.( 2004 2004 ). During intra-operative FNAB before thyroid and/or parathyroid removal, they found a PTH-FNAB value < 100 ng/L in the thyroid; when sampling takes place in normal or adenomatosous parathyroid tissue, this value is widely variable and higher than 100 ng/L. An intra-operative PTH-FNAB value > 1000 ng/L has been reported in 88% of patients with parathyroid adenoma. Maser et al.( 2006 2006 ) reported that a PTH-FNAB value > 1000 ng/L unequivocally indicates sampling in parathyroid tissue. In our series, only 38% of patients showed PTH-FNAB values > 1000 ng/L. However, our data demonstrate that even a PTH-FNAB value above our institutional cut-off is still a valid indication that hyperfunctioning parathyroid tissue has been sampled. Finally, Marcocci et al.( 1998 1998 ) regarded a PTH-FNAB > 50 ng/L as positive for sampling in parathyroid tissue; considering dilution, this value could correspond to a PTH-FNAB value > 1000 ng/L. Moreover, Maser et al.( 2006 2006 ) considered only PTH-FNAB < 45 mg/L to be inadequate in localizing PHP. In addition, our study shows that contamination of the needle with thyroid material is rather frequent when the target of FNAB is within or adjacent to the thyroid or posterior to the thyroid lobe. A high Tg-FNAB value does not exclude a possible parathyroid nature of the lesion sampled, even though a high Tg-FNAB value associated to a low PTH-FNAB value increases the probability that the lesion pertains to the thyroid. In our experience, only in 17% (8/47) of patients was parathyroid tissue suspected on the basis of cytology. However, cytological evaluation is an integral part of localizing techniques in PHP, even though it is less sensitive than PTH-FNAB owing to inadequate (Marcocci et al., 1998 1998 ; Solbiati et al., 1983 1983 ) or insufficient (Bergenfelz et al., 1991 1991 ) smeared material or confusing results when thyroid nodules are concomitant (Marcocci et al., 1998 1998 ; Solbiati et al., 1983 1983 ). In the present study, 79% (37/47) of PHP patients had thyroid alterations, generally nodules, while this finding was reported only in 30%, 45%, and 50% of patients in the studies by Abraham et al.( 2007 2007 ), Marcocci et al.( 1998 1998 ), and Erbil et al.( 2007 2007 ), respectively. In addition, the present study seems to indicate that US, FNAB, and PTH-FNAB together are more diagnostic when a thyroid disease is absent. By contrast, concomitant thyroid pathology raises the age at which diagnostic evaluation is undertaken and consequently delays the diagnosis of PHP. Recently, Erbil et al.( 2007 2007 ) reported that thyroid nodules reduce the diagnostic power of imaging studies by 20%~30% in PHP, but not the sensitivity of PTH-FNAB evaluation, in which thyroid nodules can be used as an internal control for suspected parathyroid lesions. The size of the target can influence FNAB results. In the present experience, the mean diameter of suspected parathyroid lesions was 18 mm. Abraham et al.( 2007 2007 ) reported a positive correlation in parathyroid lesions ( n =34; average size 8 mm) between the patient’s age and the size of the target, and between PTH-FNAB and peripheral PTH values. These authors obtained a direct diagnosis of hyperplastic parathyroid cells in 58% of samples adequate for cytology. The discrepancies between our results and those of Abraham et al.( 2007 2007 ) could be due to the smaller number of patients with thyroid abnormalities and to differences in biopsy needles and the number of passes performed. On the other hand, it has been suggested that performing several passes could cause parathyromatosis, hematomas and adhesions around the gland, thus rendering subsequent surgery more difficult (Kendrick et al., 2001 2001 ). No adverse events were reported in our study or in that of Erbil et al.( 2006 2006 ; 2007 2007 ). Maser et al.( 2006 2006 ), who made 2~9 passes, reported 1 in situ infection, while Abraham et al.( 2007 2007 ) reported 1 syncope and Marcocci et al.( 1998 1998 ) 1 local haemorrhage. So far, more than 12 months after successful surgery, no recurrence of hyperparathyroidism as an expression of FNAB parathyromatosis has been noted in our series of patients; similar results were reported by Marcocci et al.( 1998 1998 ). However, the number of passes should strike a balance between diagnostic power and the risk of parathyromatosis; more than 2 passes are justified only in patients with a clear target and in whom previous surgery has failed. In our hands, MIBI often proved non-diagnostic, except in patients with thyroid abnormalities. In the study by Erbil et al.( 2007 2007 ), the sensitivity of MIBI was 80% in patients with thyroid nodules and 96% in those without, and PPV was 85% and 100%, respectively. By contrast, we recorded a sensitivity of 69% and a PPV of 71% on comparing MIBI results with those of post-surgical histological analyses. Our data show a greater localizing power of PTH-FNAB than that of MIBI; PTH-FNAB and MIBI yielded true positive results in 83% and 50% of cases, respectively, while false positives plus false negatives were 17% and 50%. Several variables (operator and equipment, sample size, percentage of thyroid abnormalities, and percentage of patients with ectopic parathyroid glands) could explain the differences in the data reported. In the study by Abraham et al.( 2007 2007 ), cytological results and PTH-FNAB values were compared with MIBI results in a small number ( n =18) of patients; concordance between evaluations and the results of post-surgical histological analysis was observed in 44% of patients, while MIBI alone yielded incorrect or no localization in 17% and 38% of patients, respectively. It is important to note that, in the study by Abraham et al.( 2007 2007 ), only 2 out of 7 MIBI-negative patients were also PTH-FNAB negative. Therefore, in our opinion, when MIBI is associated to US evaluation, its diagnostic power increases; however, it is strongly operator- and machine-dependent and is further influenced by abnormal thyroid morphology. PTH-FNAB sensitivity (91%) and specificity (100%) are very high (Barczynski et al., 2006 2006 ). Erbil et al. ( 2007 2007 ) reported 100% sensitivity and 100% PPV for PTH-FNAB; these percentages are higher than those reported for US (96% and 91%) and MIBI (92% and 87%) or for both investigations combined (95% and 91%). In conclusion, our study confirms the importance of US-guided PTH-FNAB in locating hyperfunctioning parathyroid tissue. PTH-FNAB data were confirmed by post-surgical histology in 100% of patients without thyroid abnormalities; this success rate fell to 82% when thyroid abnormalities were present. 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