Discussion Conclusion Introduction Methods Results

Preoperative Identification of Parathyroid Tissue by an mRNA Classifier on Prospectively Collected Thyroid Nodule Fine-Needle Aspiration Biopsies Kloos R,1 Harrell RM,2 Kennedy GC,1 Monroe RJ,1 Traweek ST,3 Lanman RB1 1 Veracyte, Inc., South San Francisco, CA, USA 2 The Memorial Center for Integrative Endocrine Surgery, Hollywood, FL, USA 3 Thyroid Cytopathology Partners, Austin, TX, USA Introduction Table 1. Clinical Summary of Cases with Positive Parathyroid Classifier Results Discussion The parathyroid glands are located adjacent to the thyroid and occasionally within it. Parathyroid disease was present or suspected in all fifteen cases identified by the Enlarged parathyroid glands can be mistaken as thyroid nodules.1-2 On fine needle aspiration parathyroid classifier while cytology from academic and centralized cytopathology Case Age Gender Cytopathology Surgery Local surgical Hyperpara- Notes biopsy (FNAB) of such lesions, cytology is most often indeterminate and fails to identify its diagnosis pathology diagnosis thyroidism identified the parathyroid origin in only two of fifteen cases (13%). Surgery was avoided in Malignant 1 1 74 Female Yes Parathyroid hyperplasia Primary Discordance between cytology and histology noted parathyroid origin, typically resulting in an unnecessary surgery. The Afirma Gene (parathyroid carcinoma) at least 5 patients, potentially as a result of the parathyroid classifier signature information, Expression Classifier (GEC) identifies genomically benign thyroid nodules amongst those along with other factors. 2 35 Female Follicular Neoplasm Deferred N/A No Parathyroid scan colocalized to biopsied nodule with indeterminate FNAB to prevent unnecessary diagnostic surgery using the mRNA Patient has known chronic kidney disease and Histology identified parathyroid adenoma or hyperplasia in all seven patients (100%) expression profile of 142 genes.3-4 Twenty-five additional genes are used to detect gene 3 74 Female AUS/FLUS Deferred N/A Unknown non-thyroid malignancy undergoing surgery on the index lesion. While sample numbers are limited, this study expression signatures of specific neoplasms difficult to diagnose by cytology, including Malignant Brain metastasis Poorly differentiated Neck mass never resected. Brain surgery with undifferenti- 4 55 Female Primary suggests a high positive predictive value of the parathyroid classifier for parathyroid parathyroid tissue, to provide additional pre-operative clinical information to the physician in (poorly differentiated) resection malignant neoplasm ated neuroendocrine tumor (metastatic brain lesion) Cellular parathyroid tissue. A positive parathyroid classifier result should prompt an evaluation of the patient’s a single test. Here we report the clinical performance of the parathyroid mRNA classifier used 5 26 Female Yes Parathyroid adenoma Unknown tissue parathyroid status and review of the neck ultrasound to evaluate if the diagnosis of with the GEC. 6 61 Female AUS/FLUS Yes Parathyroid adenoma No parathyroid tissue is likely. The avoidance of unnecessary thyroid surgery reduces costs Methods 7 62 Male AUS/FLUS Deferred N/A Secondary Secondary hyperparathyroidism believed to be due to ESRD and patient morbidity. Of note, some patients with confirmed parathyroid tissue in this study did not have biochemical evidence of HPT. The parathyroid classifier was performed by Veracyte, along with the Afirma GEC, on 8 58 Male AUS/FLUS Deferred N/A Secondary Surgery deferred due to class IV CHF and high PTH prospectively collected and submitted FNAB samples with indeterminate cytopathology or The patient case with a concurrent brain lesion and primary HPT is interesting but upon physician request as part of clinical care. From October 15, 2010 through December 16, 9 74 Female AUS/FLUS Yes Parathyroid adenoma Primary challenging to assess. It is unclear whether there is correlation between the positive 2013, the parathyroid classifier resulted in a “suspicious for parathyroid tissue” result in 55 10 71 Female AUS/FLUS Yes Parathyroid hyperplasia Primary parathyroid classifier result and the resected metastatic neuroendocrine carcinoma. cases. Request for clinical information was made from the physicians of all cases. Clinical 11 45 Female AUS/FLUS Yes Parathyroid adenoma No details were obtained in 15 cases, see Table 1. Conclusion 12 60 Female AUS/FLUS Yes Intrathyroidal parathyroid gland No The preoperative genomic identification of parathyroid tissue may allow for more Results 13 72 Female AUS/FLUS Planned N/A Primary appropriate management of parathyroid disorders to replace unnecessary thyroid The cytopathology diagnosis of the fifteen FNAB samples were as follows: eleven AUS/FLUS surgery. As a result, complications such as hypoparathyroidism and those associated with 5 5 14 35 Female AUS/FLUS Unknown N/A Primary (Bethesda Classification III ), one Follicular Neoplasm (Bethesda Classification IV ), one thyroid surgery such as vocal cord paralysis and the requirement for lifelong thyroid 5 Parathyroid Carcinoma (Bethesda Classification VI ) and one Poorly Differentiated Carcinoma 15 65 Female AUS/FLUS Deferred N/A No Physician plans sonographic follow-up hormone replacement therapy may be reduced. (Bethesda Classification VI5), see Figure 1. Seven patients with FNAB samples identified by the parathyroid classifier as suspicious for References parathyroid tissue underwent surgery on the biopsied lesion. No false positive parathyroid 1. Tseleni-Balafouta S, Gakiopoulou H, Kaantzas N, et al. Parathyroid Proliferations, Cancer Cytopathology, 2007, 111:2, Figure 1. Cytology Diagnosis of FNAB Samples with Positive Parathyroid Figure 2: Histology on Parathyroid Classifier Positive Cases that Underwent 130-136. calls were made. Parathyroid adenoma or hyperplasia were identified in all seven cases (one Classifier Results Thyroid Surgery 2. Abdelghani R, Noureldine S, Abbas A, et al, The Diagnostic Value of Parathyroid Hormone Washout After Fine-Needle intrathyroidal), see Figure 2. Three had concomitant primary hyperparathyroidism (HPT), Aspiration of Suspicious Cervical Lesions in Patients with Hyperparathyroidism, Laryngoscope. 123: May 2013. 1310-13. three did not, and the HPT status in one was unknown. 3. Alexander EK, Kennedy GC, Baloch ZW, et al. 2012 Preoperative Diagnosis of Benign Thyroid Nodules with Indeterminate Cytology. New Engl J Med 367:705-715. An additional patient, who had primary HPT and poorly differentiated malignant 100% 4. Chudova D, Wilde JI, Wang ET, et al. 2010 Molecular classification of thyroid nodules using high-dimensionality cytopathology (Bethesda VI) from a mass posterior to the thyroid that was not resected, genomic data. J. Clin. Endocrinol. Metab. 95:5296–5304. underwent brain surgery. The resected brain lesion was compatible with metastatic 80% 5. Cibas ES, Ali SZ 2009 The Bethesda System For Reporting Thyroid Cytopathology. Am. J. Clin. Pathol. 132:658–665. neuroendocrine carcinoma, although a primary parathyroid origin was not entirely excluded. AUS / FLUS The brain lesion had negative PTH (parathyroid hormone) immunostaining, although it is Glossary SFN possible that this expression was lost in the metastasis. 60% PTH: Parathyroid hormone Seven patients with FNAB samples identified by the parathyroid classifier as suspicious for Poorly dierentiated cancer ESRD: End-stage renal disease parathyroid tissue did not undergo surgery. Four of them have primary or secondary HPT. Of CHF: Chronic heart failure 40% these four, surgery was deferred in two with secondary HPT. Of the remaining two patients, Parathyroid carcinoma both had primary HPT. One patient was planned for surgery but the final surgery status was Parathyroid not available at the time of data collection. One patient’s surgery status was unknown. 20% Surgery was deferred for three patients without documented HPT. One had an unrelated cancer and unknown parathyroid status, but known chronic kidney disease, raising the 0% possibility of secondary HPT. The other two had normal serum calcium, and the physicians Parathyroid adenoma or hyperplasia (n=15) elected to follow them with ultrasound. One of them had a positive parathyroid scan (n=7) © 2014 Veracyte, Inc. All rights reserved. co-localized to the biopsied lesion. 7000 Shoreline Court, Suite 250 South San Francisco, CA 94080 The Veracyte and Afirma names and the Veracyte logo are marks of Veracyte. .

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