Consideration of Discrepancy between Needle-Washout Thyroglobulin and Serum Thyroglobulin of Recurrent Papillary Thyroid Cancer

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1 , December 2014 pissn: I eissn: CASE REPORT Consideration of Discrepancy between Needle-Washout Thyroglobulin and Serum Thyroglobulin of Recurrent Papillary Thyroid Cancer So Ra Kim 1, Mi-Kyung Kwak 1, Hye Ran Kang 1, Seug Yun Yoon 1, Seong Soon Kwon 1, Bo Young Kim 1, Hoo Nam Choi 1, Hye Jeong Kim 1, Jae Wook Kim 2, So-Young Jin 3, Hyeong Kyu Park 1, Dong Won Byun 1, Kyoil Suh 1, Myung-Hi Yoo 1 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Departments of 2 Otorhinolaryngology-Head and Neck Surgery and 3 Pathology, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea Although the prognosis of papillary thyroid cancer (PTC) is extremely good, locoregional recurrences after initial treatment occur. Thyroglobulin (Tg) is a reliable tumor marker to detect recurrence or persistence of PTC. However, occasionally serum Tg may miss the detection of a recurrence. We report a 54-year-old female presented with hoarseness due to cervical recurrence without concomitant elevation of serum Tg and anti-tg antibody, in contrast to extremely increased needle-washout Tg, who had undergone a total thyroidectomy and radioiodine ablation as initial therapies for PTC. Several factors causing such discrepancy between needlewashout Tg and serum Tg can be suggested including site of recurrence, volume of tumor, interference by some kind of plasma antibodies other than anti-tg antibody, and any conformational defect of Tg protein. Among them, the most convincing explanation is that any conformational defect of Tg may lead to impaired secretion of Tg to blood. We suggest that more studies are needed to find the cause for potential mechanisms involved in PTC recurrences without increased serum Tg. Keywords: Papillary thyroid carcinoma; Recurrence; Thyroglobulin INTRODUCTION CASE REPORT Although the vast majority of patients with papillary thyroid cancer (PTC) have an excellent prognosis, disease recurrences do occur. During follow-up after initial surgery and/or radioiodine therapy, serum thyroglobulin (Tg) measurement, neck ultrasound, and/or diagnostic whole-body radioiodine scan are recommended depending on the risk for recurrence in a patient with PTC [1,2]. Particularly, serum Tg is the most sensitive biomarker of recurrence for well-differentiated thyroid cancer. Since Tg is synthesized only by thyroid follicular cells, measurements of serum Tg provide important information about the presence of residual, recurrent, or metastatic disease in patients with differentiated thyroid cancer [3]. However, occasionally serum Tg may miss the detection of a recurrence. Here, we report a case of cervical recurrence without a concomitant increase in serum Tg and anti-tg antibody in a patient with PTC who had undergone a total thyroidectomy and radioiodine ablation as initial therapies. A 54-year-old female with suspicious malignant nodule in thyroid was referred to Soonchunhyang University Hospital. The initial serum thyroid-stimulating hormone (TSH) level was 0.92 mu/ L (reference range, 0.40 to 5.00 mu/l), and the preoperative levels of serum Tg (IRMA kit; Cisbio Bioassay, Codolet, France; functional sensitivity, 0.7 μg/l) and anti-tg antibody (RIA kit; RSR Ltd., Cardiff, UK) were μg/l (reference range, 0 to 35 μg/l) and negative (reference range, 0 to 60 μg/l), respectively. Thyroid ultrasound revealed a calcified nodule in left lobe. An ultrasound-guided fine needle aspiration (FNA) biopsy results showed suspicious for PTC. She underwent a total thyroidectomy and central neck dissection with preserving the recurrent laryngeal nerve for thyroid cancer in September In the thyroidectomy specimen, a 1.6- cm tumor in the left lobe was noted. Microscopic findings showed proliferation of papillary structures or follicles lined by cuboidal tumor cells with enlarged ground glass nuclei, irregular nuclear out- Correspondence to: Myung-Hi Yoo Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul , Korea Tel: , Fax: , mhyoo@schmc.ac.kr Received: Sep. 18, 2014 / Accepted after revision: Oct. 2, Soonchunhyang Medical Research Institute This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (

consistent with typical type of papillary carcinoma. like human anti-mouse antibodies by adding a protection in the It spread to the perithyroidal soft tissue (Fig. 1A).

In December 2009, she received radioiodine ablation with 150 mci of false positive or false negative due to the presence of interferences like heterophile antibodies (HAB) in the patient samples.

2 Kim SR, et al. Recurrent PTC without Increased Serum Tg line, nuclear grooves, and occasional intranuclear inclusion on the the immunoassay used is protected against potential interferences sclerotic stroma, consistent with typical type of papillary carcinoma. like human anti-mouse antibodies by adding a protection in the It spread to the perithyroidal soft tissue (Fig. 1A). Dissected lymph tracer, it cannot be guaranteed that there will never be detection of nodes showed reactive hyperplasia without tumor metastasis. In December 2009, she received radioiodine ablation with 150 mci of false positive or false negative due to the presence of interferences like heterophile antibodies (HAB) in the patient samples. So, to de- 131 I. A post-therapy whole-body scan showed only focal uptake in termine whether HAB to Tg were present in our patient s serum, we the neck (Fig. 2). Stimulated serum Tg level obtained after thyroxine performed test by two methods. First, precipitation method using withdrawal was 9.56 μg/l and serum TSH level was mu/l. serum of the patient and four euthyroid controls was performed. She was followed by clinical examination, assessment of serum Tg The amount of 100 μl of each serum was incubated at 37 C for 1 levels and anti-tg antibody, and ultrasound of the neck every 6 to 12 months without evidence of disease. TSH suppression therapy by levothyroxine was maintained to achieve a serum TSH less than 0.10 mu/l (Table 1). At 3 years after surgery, she complained of hoarseness for the past 6 weeks. Laryngoscopic examination showed left vocal cord palsy. Thyroid ultrasound revealed two small lymph nodes at right level IV and a 1.2-cm sized mass at left level VI suspicious for lymph node metastasis. The ultrasound-guided FNA was performed, and the needle-washout fluid was analyzed both cytological examination and Tg assay. The cytology specimen showed PTC recurrence. The level of needle-washout Tg was 3,825.3 μg/l in right level IV and 3,355.7 μg/l in left level VI. Serum TSH level was 0.02 mu/l, Tg was 0.09 μg/l, and anti-tg antibody was negative at that time. Although A Fig. 2. A post-therapeutic radioactive iodine scan showed focal increased uptake in the neck. B Fig. 1. Microscopic findings of primary tumor and metastatic lesions. It shows follicular to papillary proliferation of tumor cells on the sclerotic background. (A) Their nuclei have enlarged characteristic ground glass nuclei and nuclear grooves (H&E, 100). (B) The recurrent tumor nodules of the neck are lymph nodes involved by metastatic papillary carcinoma of the thyroid (H&E, 40)

Three months later, a dose 3,000 rpm for 30 minutes. Radioactivity of the precipitate were mea- of 150 mci of 131I was administered and post-therapy whole-body sured using gamma counter.

3 Recurrent PTC without Increased Serum Tg Kim SR, et al. hour with 500 μl of the 125I-labelled Tg analog. The 1 ml of 20% immediately recovered from hoarseness and vocal cords are fully polyethylene glycol (PEG) was added. Then, that was centrifuged at adducted on laryngoscopic examination. Three months later, a dose 3,000 rpm for 30 minutes. Radioactivity of the precipitate were mea- of 150 mci of 131I was administered and post-therapy whole-body sured using gamma counter. When the radioactivity of the precipi- scan demonstrated no abnormal increased uptake. Stimulated se- tate was expressed as a percentage of total radioactivity, there were rum Tg level obtained after thyroxine withdrawal was 0.63 μg/l and no significant differences between the patient and controls. Second, serum TSH level was mu/l. She is receiving TSH suppression 50 μl of each serum and 1 ml of I-labelled Tg analog were mixed therapy and followed without evidence of disease until now. 125 in anti-tg antibody coated tube and shaken for 2 hours. The 1 ml of 30% PEG was added, then, centrifuged and measured radioactivity DISCUSSION of each tube. There were no significant differences of radioactivity between the patient and controls. Selective neck dissection was per- According to recent Korean [1] and American [2] management formed for right lateral and left central neck. Pathology specimens guideline for patients with thyroid cancer, measurements of serum were confirmed PTC at right level IV and left level VI, and histolog- Tg, anti-tg antibody and TSH at 6- to 12-month intervals and neck ic features are same as the initial mass (Fig. 1B). After surgery, she ultrasound 6 to 12 months postoperatively and then periodically depending on the patient s risk for recurrent disease are recommended. Tg is a highly sensitive and specific marker for detection Table 1. Serum TSH, Tg, and anti-tg antibody levels during follow-up Date April 2010 December 2010 June 2011 June 2012 September 2012 At recurrence Months TSH (mu/l) Tg (μg/l) since thyroidectomy 7 months 1 year and 3 months 1 year and 9 months 2 years and 9 months 2 years and 11 months 3 years Anti-Tg antibody of recurrent or residual disease after initial therapy [3]. After total expected to be very low (< 1 to 2 μg/l), either on TSH suppression thyroidectomy and radioiodine ablation, serum Tg levels would be therapy or after thyroid hormone withdrawal, if the patient is cured [4]. As a single investigation, serum Tg measurement is more sensitive than radioiodine uptake scanning [5-9]. Previous studies suggested that patients with low levels of serum Tg during suppression therapy may have a high probability of being free of disease [10,11]. TSH, thyroid-stimulating hormone; Tg, thyroglobulin. A B Fig. 3. Immunohistologic findings. (A) The primary and (B) the metastatic tumors are strongly positive for thyroglobulin in the both cytoplasm of tumor cells and colloid (thyroglobulin, 100)

4 Kim SR, et al. Recurrent PTC without Increased Serum Tg The present case represented PTC recurrences despite the absence of detectable serum Tg and the negativity of anti-tg antibody contradictory to high needle-washout Tg level. There are several potential mechanisms that might be involved in PTC recurrence with such discrepancy between needle-washout Tg and serum Tg. First, tumor cells might be poor secretor. It means tumor could have synthesized Tg but had some defects on secretion process. To date, 43 inactivating mutations have been reported in the human TG gene [12]. Some Tg mutants have defective intracellular transport and accumulate within the rough endoplasmic reticulum, so cannot be released into the follicle lumen [12-16]. We performed immunostaining for Tg from primary mass and recurrent lymph nodes specimens. Immunohistochemical stains demonstrated strong positive staining for Tg in the tumor cells and colloid of the both initial mass and metastatic nodule (Fig. 3). So it is less likely that tumor cells had some defect of intracellular transport of Tg to colloid. Instead, Tg protein may had any conformational change leading to failure of secretion from colloid to blood. It also may be the reason of negative serum Tg versus positive needle-washout Tg. Further pathologic examination by electron microscope may be needed. Second, the site of recurrence may influence serum Tg level. Patients with distant metastases to lung or bone have higher Tg levels than those with lymph node metastases [11]. Our patient had metastases only to cervical lymph nodes and no distant metastases. However, this fact may explain the result of negative serum Tg, but not that of high needle-washout Tg level. Third, the volume of metastatic tumor may be too small to increase serum Tg level enough [17,18]. Bachelot et al. [17] measured Tg level after thyroid hormone withdrawal and the tumor mass in thyroid cancer patients who underwent surgery with the use of an intraoperative probe for lymph node metastases with 131 I uptake. Patients were classified into one of three groups according to the Tg level: undetectable (n=18); 1 to 10 ng/ml (n= 21); and greater than 10 ng/ml (n=33). They concluded that total surface or total volume is the characteristic that best summarizes the influence of the disease on the serum Tg level. In undetectable Tg group, median total surface was 9.5 mm 2 and mean total volume was 9.2 mm 3. The estimated total surface and total volume of metastatic tumor in this case were 272 mm 2 and 1,888 mm 3. Therefore, the serum Tg levels of present case were oddly low considering tumor surface and volume. When we assume that there is any conformational defect on Tg leading secretory failure, it can be explained that serum Tg level is low despite of the relative large volume of tumor producing enough Tg. Fourth, interference by HAB may lead to false decreases and increases in Tg concentrations [19]. HAB interference is relatively prevalent (range, 1.5% to 3%) in a commonly used automated Tg assay, so HAB interference should be suspected if Tg results do not fit the clinical picture [19]. HAB did not significantly interfere with Tg measurement in FNA washout fluid, probably because of the very high Tg concentrations in the needle-washout fluids [20]. However, we could not identify HAB interference in patient s serum. The present case has some limitations. Most of all, serum Tg level after thyroid hormone withdrawal were not measured. However, it is usually adopted measuring of serum Tg on thyroxine because of its high sensitivity and the inconvenience of withdrawal of thyroid hormone. Furthermore, patients with a TSH-suppressed serum Tg concentration < 0.1 μg/l were unlikely to have an stimulated Tg above 2.0 μg/l [21]. In summary, we report an unusual case of PTC recurrence without a concomitant increase in serum Tg and anti-tg antibody, in contrast to extremely increased needle-washout Tg, in a patient who had undergone a total thyroidectomy and radioiodine ablation as initial therapies. It is important that PTC patients need to be followed by clinical examination and ultrasound of the neck as well as assessment of serum Tg levels and anti-tg antibodies. We suggest that more studies are needed to find the cause for potential mechanisms involved in PTC recurrences without concomitant elevation of serum Tg levels in the absence anti-tg antibody. REFERENCES 1. Korean Thyroid Association. Revised Korean Thyroid Association management guidelines for patients with thyroid nodules and thyroid cancer [Internet]. Seoul: Korean Thyroid Association; 2010 [cited 2014 Jul 12]. Available from: 2. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19: Kim TY. Postoperative follow-up of differentiated thyroid cancer: use of thyroglobulin assay. J Korean Thyroid Assoc 2012;5: Spencer CA, Wang CC. Thyroglobulin measurement: techniques, clinical benefits, and pitfalls. Endocrinol Metab Clin North Am 1995;24: Van Sorge-van Boxtel RA, van Eck-Smit BL, Goslings BM. Comparison of serum thyroglobulin, 131I and 201Tl scintigraphy in the postoperative follow-up of differentiated thyroid cancer. Nucl Med Commun 1993;14 : Lubin E, Mechlis-Frish S, Zatz S, Shimoni A, Segal K, Avraham A, et al. 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5 Recurrent PTC without Increased Serum Tg Kim SR, et al. Nucl Med 1994;35: Pineda JD, Lee T, Ain K, Reynolds JC, Robbins J. Iodine-131 therapy for thyroid cancer patients with elevated thyroglobulin and negative diagnostic scan. J Clin Endocrinol Metab 1995;80: Sulman C, Gosselin P, Carpentier P, Lemaire B. Value of the estimation of thyroglobulin levels in the surveillance of treated differentiated thyroid carcinoma. J Clin Chem Clin Biochem 1984;22: Ng Tang Fui SC, Hoffenberg R, Maisey MN, Black EG. Serum thyroglobulin concentrations and whole-body radioiodine scan in follow-up of differentiated thyroid cancer after thyroid ablation. Br Med J 1979;2: Black EG, Cassoni A, Gimlette TM, Harmer CL, Maisey MN, Oates GD, et al. Serum thyroglobulin in thyroid cancer. Lancet 1981;2: Girelli ME, Busnardo B, Amerio R, Scotton G, Casara D, Betterle C, et al. Serum thyroglobulin levels in patients with well-differentiated thyroid cancer during suppression therapy: study on 429 patients. Eur J Nucl Med 1985;10: Pardo V, Vono-Toniolo J, Rubio IG, Knobel M, Possato RF, Targovnik HM, et al. The p.a2215d thyroglobulin gene mutation leads to deficient synthesis and secretion of the mutated protein and congenital hypothyroidism with wide phenotype variation. J Clin Endocrinol Metab 2009; 94: Vono-Toniolo J, Rivolta CM, Targovnik HM, Medeiros-Neto G, Kopp P. Naturally occurring mutations in the thyroglobulin gene. Thyroid 2005; 15: Medeiros-Neto G, Kim PS, Yoo SE, Vono J, Targovnik HM, Camargo R, et al. Congenital hypothyroid goiter with deficient thyroglobulin: identification of an endoplasmic reticulum storage disease with induction of molecular chaperones. J Clin Invest 1996;98: Peteiro-Gonzalez D, Lee J, Rodriguez-Fontan J, Castro-Piedras I, Cameselle-Teijeiro J, Beiras A, et al. New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter. J Clin Endocrinol Metab 2010;95: Bachelot A, Leboulleux S, Baudin E, Hartl DM, Caillou B, Travagli JP, et al. Neck recurrence from thyroid carcinoma: serum thyroglobulin and high-dose total body scan are not reliable criteria for cure after radioiodine treatment. Clin Endocrinol (Oxf) 2005;62: Bachelot A, Cailleux AF, Klain M, Baudin E, Ricard M, Bellon N, et al. Relationship between tumor burden and serum thyroglobulin level in patients with papillary and follicular thyroid carcinoma. Thyroid 2002;12: Schlumberger M, Berg G, Cohen O, Duntas L, Jamar F, Jarzab B, et al. Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective. Eur J Endocrinol 2004;150: Preissner CM, O Kane DJ, Singh RJ, Morris JC, Grebe SK. Phantoms in the assay tube: heterophile antibody interferences in serum thyroglobulin assays. J Clin Endocrinol Metab 2003;88: Boi F, Baghino G, Atzeni F, Lai ML, Faa G, Mariotti S. The diagnostic value for differentiated thyroid carcinoma metastases of thyroglobulin (Tg) measurement in washout fluid from fine-needle aspiration biopsy of neck lymph nodes is maintained in the presence of circulating anti-tg antibodies. J Clin Endocrinol Metab 2006;91: Spencer C, Fatemi S, Singer P, Nicoloff J, Lopresti J. Serum Basal thyroglobulin measured by a second-generation assay correlates with the recombinant human thyrotropin-stimulated thyroglobulin response in patients treated for differentiated thyroid cancer. Thyroid 2010;20:

A variation in recurrence patterns of papillary thyroid cancer with disease progression: A long-term follow-up study

ORIGINAL ARTICLE A variation in recurrence patterns of papillary thyroid cancer with disease progression: A long-term follow-up study Joon-Hyop Lee, MD, Yoo Seung Chung, MD, PhD,* Young Don Lee, MD, PhD