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10.1245/s10434-006-9180-z
Annals of Surgical Oncology 13:1690-1695 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Sonographically Guided Fine Needle Aspiration with Rapid Parathyroid Hormone Assay

Christina Maser, MD1, Patricia Donovan, RN BSN1, Florie Santos, CASCP2, Richard Donabedian, MD2, Christine Rinder, MD3, Leslie Scoutt, MD4 and Robert Udelsman, MD, MBA1

1 Department of Surgery, Yale New Haven Hospital, Yale University School of Medicine, 330 Cedar Street, FMB 102, P.O. Box 208062, New Haven, CT 06520-8062, USA
2 Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA
3 Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA
4 Department of Diagnostic Imaging, Yale University School of Medicine, New Haven, CT, USA

Correspondence: Address correspondence and reprint requests to: Robert Udelsman, MD, MBA, FACE; E-mail: robert.udelsman{at}yale.edu


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Persistent or recurrent primary hyperparathyroidism (1° HPTH) is ideally treated with limited dissection, based on accurate localization, to minimize operative risks. To accurately localize parathyroid tissue, we employed ultrasound-guided fine needle aspiration (US FNA) with an on-site rapid parathyroid hormone (PTH) assay to confirm localization.

Methods: Of the 272 patients evaluated for 1° HPTH, 34 had persistent or recurrent disease. Standard localization was equivocal in 12, who were referred for US FNA. Suspicious tissue was identified on US and FNA was performed. Analysis with a rapid PTH assay provided on-site result within 12 min. Patients were monitored clinically, and then discharged after observation.

Results: Twelve patients were referred for US FNA; eight were female. Ten patients had persistent disease, one had recurrent, and one had 1° HPTH following thyroidectomy. Two of the 12 were excluded due to negative ultrasound examination. Of the remaining ten, positive aspirates were found in nine, and seven proceeded to surgery. In six patients there was 100% correlation between sonographic and operative findings. The remaining patient had no identifiable adenoma, but PTH normalized after arterial ligation. All patients received a limited directed surgical approach, employing cervical block anesthesia in three. Four were discharged on the day of surgery and all were cured. There was one infectious complication of US FNA.

Conclusions: The use of rapid PTH assay can be effectively utilized for localization of parathyroid tissue in remedial parathyroid surgery. Confirmation of localization markedly improves subsequent surgery and allows selective use of minimally invasive techniques.

Key Words: Hyperparathyroidism • Parathyroidectomy • Localization • Remedial surgery • Parathyroid hormone assay


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Primary hyperparathyroidism (1° HPTH) is successfully treated by surgery in 95–98% of cases.14 The small subset of patients that present with either persistent or recurrent 1° HPTH represent a difficult clinical scenario. Re-exploration in these patients is associated with an increased risk of peri-operative morbidity.5 Accordingly, these patients require accurate pre-operative localization to allow for a focused surgical approach to minimize the risks associated with remedial surgery.

Localization tests, including sestamibi scanning and ultrasound (US), can be equivocal in the remedial setting, and further imaging is frequently required. Computed tomography (CT) and magnetic resonance imaging (MRI) can provide adjunctive information, but are often non-informative, misleading, or discordant. It is often necessary to proceed to venous localization which appears to be the most sensitive localization technique in the remedial setting.6,7 While helpful, it is also invasive and costly.

In an effort to provide accurate and less invasive localization, the use of US combined with fine needle aspiration (FNA) has been investigated.810 Measurement of parathyroid hormone (PTH) levels in suspicious tissue, and also performing cytological analysis have been reported; however, there is a significant delay between testing and result. This can limit the usefulness of testing as thyroid nodules and lymph nodes are frequently encountered and can lead to negative FNA results several days after testing was performed. We have previously employed the rapid PTH assay during venous localization testing to provide rapid results in an effort to improve the accuracy of testing.6 Providing real-time feedback employing an assay with a 12 min turnaround time allows the angiographer to adjust their testing. This reliable information can confirm a subtle gradient or terminate a positive study. Accordingly, to improve the accuracy of US in the re-operative neck, we investigated the use of a rapid PTH assay to immediately analyze results obtained from US guided FNA.


    METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Between May 2003 and May 2005, 272 patients were evaluated for 1° HPTH. Of these, 238 had not been explored and underwent de novo exploration. Of the remaining patients, 33 had persistent or recurrent 1° HPTH, and one developed 1° HPTH in the setting of previous thyroidectomy. Localization testing with sestamibi, ultrasound, CT, and venous localization was positive in 22, and these patients went directly for operative intervention. The remaining 12 had equivocal localization; however, they all had suspicious findings on US. These patients were referred for US FNA employing rapid PTH assay.

A dedicated sonographer performed a diagnostic study, and after identification of tissue suspicious for an abnormal parathyroid gland, consent was obtained for FNA. The FNA was performed using a 25 gauge needle under sterile technique and direct US guidance to aspirate the suspicious tissue into a 3 cc syringe containing 1 cc of saline. With the saline present in the syringe, appropriate negative pressure was applied in the standard fashion. The saline was then flushed through the needle containing the specimen into a specimen tube and the resultant solution was analyzed for PTH on site using the portable Nichols intact parathyroid hormone assay (Nichols diagnostics, San Juan Capistrano, CA, USA) in the ultrasound suite. This assay provides a result within 12 min, and depending on the findings, further passes through abnormal tissue were made. Patients were monitored for complications and discharged after 1 h of uneventful observation. Surgical intervention followed on an elective basis.

Data were collected prospectively and included patient demographics, diagnostic work-up, decision making, ultrasound results, operative findings, length of stay, and long-term follow up.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Twelve patients were referred for US FNA; eight female, four male. The mean age was 58.3 years (range = 38–74 years). Ten patients had persistent disease, one had recurrent 1° HPTH, and 1 developed 1° HPTH after previous thyroid surgery. Symptoms consisted of fatigue in six, mental status or mood changes in three, constipation in one patient, and nine patients had signs of the disease including seven with osteopenia/osteoporosis, and two with nephrolithiasis.

Pre-operative imaging was carried out with a combination of modalities. Sestamibi scanning was performed in 11 of these patients and was positive but discordant with the operative history in 8, and negative in the remaining 3. However, all 12 patients underwent an initial diagnostic ultrasound study demonstrating an abnormality suspicious for parathyroid tissue. In two of these patients, the abnormality could not be reproduced at the time of proposed aspiration; these patients underwent venous localization and were excluded from this analysis. Additionally, some patients had adjunctive imaging with CT, MRI, and PET; however these studies were inconsistently obtained and thus not considered in the final analysis.

Of the ten patients with sonographic abnormalities amenable to aspiration, positive results were obtained in nine. In these nine patients with positive aspiration results, two are pending operative intervention, and seven have proceeded to operation. In six of these patients there was 100% correlation between sonographic and operative findings; see Fig. 1Go. Details of the aspiration procedures and operative findings are depicted in Table 1Go. On average, four passes (range 2–9) were made in each patient. Each suspicious lesion was interrogated and the PTH result was deemed positive if the result was higher than normal range (6–40 pg/ml) on our assay; the result was considered negative if less than 40 pg/ml. Most cases revealed an ‘off scale’result meaning that the result was greater than 1,000 pg/ml; these were unequivocally positive. Two patients had results in the 49–65 pg/ml range which represented questionably positive results. One of these patients was found to have a large retroesophaeal adenoma correlating to the ultrasound abnormality, and the other has not yet undergone operative intervention. One patient had no identifiable adenoma at operation despite an ‘off scale’result during aspiration. This patient underwent an extensive exploration, including a formal central neck dissection in the setting of a previous subtotal thyroidectomy. Five specimens were removed; three lymph nodes, and two fragments of soft tissue. Biochemical cure with normalization of the intra-operative PTH was reached after ligation of the inferior thyroid artery; the patient remained normocalcemic at long-term follow-up.


Figure 1
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FIG. 1. Ultrasonographic and operative findings. In six patients there was 100% correlation between ultrasonographic and operatve findings. The remaining patient had an abnormality predicted in the right inferior position; however, no adenoma was identified at operation. This patient was cured after ligation of the inferior thyroid artery.

 

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TABLE 1. Results of aspiration
 
All patients were treated with a focused surgical intervention, either through the previous midline approach or via a lateral approach. Operative details are listed in Table 2Go. This lateral approach was accomplished by utilizing the previous skin incision, but dissecting the plane between the ipsilateral sternocleidomastoid muscle and carotid sheath, and the strap muscles in order to achieve dissection through less scarred tissue to reach the tracheoesophageal groove. One patient had an abnormality in the submandibular position which tested positive for PTH on US FNA. This non-descended parathyroid adenoma was approached through a submandibular incision directly overlying the abnormality.


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TABLE 2. Operative detail and localization studies in patients with persistent or recurrent primary hyperparathyroidism
 
Three patients were explored employing cervical block anesthesia and four required general anesthesia. Four were discharged within 3 h of surgery, and three had a 23 h hospitalization. All seven surgical patients were cured of their disease as evidenced by mean calcium values of 9.8 mg/dL at 6 months follow-up. Intact PTH at 6 months follow-up was not available in four patients, but the remaining three demonstrated a mean level of 26.5 pg/ml (see Fig. 2Go).


Figure 2
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FIG. 2. Biochemical analysis of individual patients: the laboratory values at 3 days after parathyroidectomy for each patient. a Serum intact PTH (normal range = 6–40 pg/ml) b Serum Calcium (normal range = 8.8–10.2 mg/dL). The shaded areas of all graphs re-flect the normal parameters for the values obtained.

 
One patient had a negative FNA result, and subsequently developed an infection at the needle insertion site that responded to superficial incision and drainage performed in the clinic and oral antibiotic therapy. The patient recovered uneventfully from this superficial infection, which was treated on an out-patient basis. This represents the only complication in this series.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The majority of patients with 1° HPTH are cured during their initial exploration. The small group of patients who experience persistent or recurrent disease are faced with a significant surgical risk during subsequent exploration. Although these patients require remedial operative treatment, it can come with significant morbidity as risks of recurrent laryngeal nerve injury and permanent hypoparathyroidism can approach 10 and 35%, respectively.5 These high-risk patients must be handled with care. Integral to their cure are sound data regarding the diagnosis, previous exploration, pathology findings and, most importantly, clear localization in an effort to proceed with a focused re-exploration.

Localization of parathyroid tissue in this population can be difficult. In an effort to prove that an imaged abnormality is a parathyroid tissue, PTH analysis and cytology have been used. Analysis of tissue for routine intact PTH can prove useful; however, the result is not immediately available. The abnormality may eventually prove to be negative for PTH, thus leaving the patient in need of further testing.810 Cytologic analysis is also useful, but results can be misleading as thyroid tissue is often misinterpreted as a parathyroid tissue, leading to a false positive result.11 This method also involves a delay between testing and result, and thus can necessitate further localization procedures.

The use of intra-operative measurement of PTH (IOPTH) has proven valuable in the surgical treatment of 1° HPTH. However, the role of IOPTH in pre-operative localization is now becoming evident. Its usefulness lies not only in its sensitivity and accuracy, but more importantly, also in the prompt result. The use of the quick assay was previously proven useful in improving the accuracy of venous localization of parathyroid tissue.6 The rapid result allows for on-site decisions regarding the indications for additional sampling and has improved the accuracy of this invasive and costly test. Furthermore, the accuracy of the biochemical analysis has led to use of the assay to prove a tissue diagnosis. Several authors have reported that the use of IOPTH can supplant that of frozen section analysis during parathyroidectomy; use of IOPTH is more efficient with regard to both time and cost compared to frozen section.11,12 With this evidence, the accuracy of the use of IOPTH in conjunction with US FNA to localize parathyroid tissue is sound, reliable, and has proven beneficial.

This testing provided helpful information in localization by allowing the ultrasonographer to redirect testing when a negative result was obtained. Due to the reoperative nature of these patients, many demonstrated multiple small nodules in the site of interest. In four cases the most suspicious abnormality was investigated first. If this proved positive with an off scale result, testing was terminated. However, if the first result was negative, immediate attention was directed to other abnormalities in the neck until a positive result was obtained. The most poignant example of this testing is a 48-year-old man with persistent 1° HPTH. He had undergone a previous exploration during which three normal glands were found and biopsy proven. A right thyroid lobectomy was performed to remove suspected intrathyroidal parathyroid tissue, however this was not proven on final pathologic analysis therefore leaving one gland unaccounted. His disease persisted, and subsequent imaging studies, including sestamibi and CT were negative. He underwent a neck ultrasound, where a sub-mandibular abnormality was noted. This was evaluated with US FNA and rapid PTH assay. The assay was positive, confirming parathyroid tissue. The patient was taken to the operating room where, with the aid of intraoperative ultrasound, a localized excision of a non-descended parathyroid adenoma was performed under local anesthesia. The patient was discharged within hours of the surgery and cured, as evidenced by normal serum calcium on long-term follow-up (see Fig. 3a, bGo).


Figure 3
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FIG. 3. A 48-year-old male with persistent primary hyperpara-thyroidism. a Ultrasonographic findings demonstrating a hypoechoic mass in the submandibular space (white arrows). b Operative findings demonstrating a non-descended parathyroid adenoma in the right submandibular space.

 
With the exception of one minor infectious complication, we have found US FNA to be effective and well tolerated. There may be a theoretic concern regarding seeding of the needle track with parathyroid tissue resulting in a parathyromatosis. This theoretical risk may exist; however, the closed neck is likely to be protective against spilling and implantation of cells.

While the concept of testing aspirated tissue for parathyroid is not new, the use of a rapid hormone assay is novel. This method provides accurate, reliable, and immediate results. This adjunctive testing allows for a minimally invasive surgical approach to these otherwise difficult patients, and greatly reduces the risk of surgical intervention.

Received for publication May 23, 2006. Accepted for publication May 23, 2006.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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