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ORIGINAL ARTICLE
Year : 2016  |  Volume : 20  |  Issue : 3  |  Page : 359-363

Estimation of thyroglobulin in lymph node aspirates: Pilot experience from a tertiary referral cancer center


1 Department of Endocrinology, Diabetes and Bariatric Medicine, Narayana Health City, Bangaluru, Karnataka, India
2 Head and Neck Surgical Oncology and Reconstructive Surgery, Narayana Health City, Bangaluru, Karnataka, India
3 Department of Laboratory Medicine, Narayana Health City, Bangaluru, Karnataka, India
4 Department of Pathology, Narayana Health City, Bangaluru, Karnataka, India
5 Department of Radiology, Narayana Health City, Bangaluru, Karnataka, India

Date of Web Publication11-Apr-2016

Correspondence Address:
Subramanian Kannan
Department of Endocrinology, Diabetes and Bariatric Medicine, Narayana Health City, 258/A, Bommasandra Industrial Area, Hosur Road, Bengaluru - 560 099, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2230-8210.179987

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   Abstract 

Background: Assessment of cervical lymph node involvement in patients with thyroid cancer either during preoperative surgical mapping or detection of recurrences during follow-up is a crucial step in the management of differentiated thyroid cancers (DTCs). In most patients, fine needle aspiration cytology (FNAC) confirms the presence of metastasis in lymph node. However, in cases of paucicellular lymph node aspirate or discordant sonogram and cytology results, thyroglobulin (Tg) measurement in the lymph node aspirate (FNA-Tg) is useful and a value >1 ng/ml is considered consistent with metastatic disease. Context: The addition of FNAC to the US improves the specificity, but 5–10% are nondiagnostic and 6–8% rate of false-negative results. Several studies have reported that the detection of Tg in FNA-needle washes improves the evaluation of suspicious lymph nodes in patients with DTC.Data from Indian centers on FNA-Tg are limited. Aims: We piloted the utility of FNA-Tg in patients with sonographically suspicious cervical lymph node enlargement in the setting of suspicious thyroid nodule or in the follow-up of thyroid cancer. Settings and Design: Prospective data collection. Results: We measured Tg in 13 lymph node aspirates (12 patients, 10 females) among whom 4 patients had a total thyroidectomy and 1 had a hemithyroidectomy. Eight of the 13 lymph node aspirates had FNA-Tg values >150 ng/ml, all of them had unequivocal malignant cytology and four among them had proven metastatic DTC on surgical pathology. The median FNA-Tg of the patients with malignant cytology was 7550 ng/ml with a range of 162–30,000 ng/ml. Among the remaining 5 lymph node aspirate, 2 lymph nodes showed cytological features suggestive of reactive lymphadenitis (FNA-Tg <0.2 ng/ml) and were not operated, 1 had a high-grade malignancy consistent with anaplastic thyroid cancer (FNA-Tg <0.2 ng/ml), and 2 had nondiagnostic cytology (one had non-caseating granuloma on surgical pathology [FNA-Tg 1.3 ng/ml] and in the other patient [FNA-Tg <0.2 ng/ml] surgical intervention was deferred). Conclusions: FNA-Tg was concordant with positive cytology in all patients with DTC and may serve as a useful tool in patients with negative and nondiagnostic cytology to guide surgical management.

Keywords: Cytology, differentiated thyroid cancer, lymph node aspirate, thyroglobulin


How to cite this article:
Kannan S, Chauhan S, Naveen, Latha B S, Raju N, Chandrasekhar NH, Kekatpure V, Kuriakose MA, Manjunath P. Estimation of thyroglobulin in lymph node aspirates: Pilot experience from a tertiary referral cancer center. Indian J Endocr Metab 2016;20:359-63

How to cite this URL:
Kannan S, Chauhan S, Naveen, Latha B S, Raju N, Chandrasekhar NH, Kekatpure V, Kuriakose MA, Manjunath P. Estimation of thyroglobulin in lymph node aspirates: Pilot experience from a tertiary referral cancer center. Indian J Endocr Metab [serial online] 2016 [cited 2020 Apr 8];20:359-63. Available from: http://www.ijem.in/text.asp?2016/20/3/359/179987


   Introduction Top


Thyroglobulin (Tg) is a 660,000 molecular weight glycoprotein produced exclusively by the follicular cells of the thyroid. It is secreted into the follicular lumen, where it serves as the precursor of, and storage reservoir for, thyroxine (T4) and triiodothyronine (T3). T4 and T3 are released after Tg is endocytosed and proteolytically degraded in the thyrocyte. Since Tg is produced only by follicular thyrocyte-derived cells, measurement of serum Tg levels in athyreotic patients enables detection of persistence, recurrence, or metastasis of differentiated thyroid carcinoma (DTC).[1] In addition, because of the thyroid specificity of Tg, its measurement in biopsy specimens of nonthyroidal tissues may assist in confirming and localizing metastatic disease. Papillary thyroid cancer (PTC) accounts for more than 80% of all DTC.[2] Most metastatic disease in PTC occurs in locoregional lymph nodes in the neck, which are easily examined by ultrasound. Ultrasonography (US) is highly sensitive in the detection of cervical metastases with sonographic features of abnormal metastatic lymph nodes include enlargement, loss of the fatty hilum, a rounded rather than oval shape, hypoechogenicity, cystic change, calcifications, and peripheral vascularity.[3] However, it has a low specificity (37%) because benign lymphadenopathies are extremely frequent.[4],[5] Occult thyroid cancer is well-described to present as an isolated cystic mass in the lateral neck,[6],[7] where thyroid sonography may be normal. In addition, cystic changes in metastatic lymph nodes can cause diagnostic problems for the cytopathologist. The addition of fine needle aspiration cytology (FNAC) to the US improves the specificity, but 5–10% are nondiagnostic and 6–8% rate of false-negative results.[5],[8] Several studies have reported that the detection of Tg in FNA-needle washes improves the evaluation of suspicious lymph nodes in patients with DTC.[9],[10],[11],[12],[13] Data from Indian centers on FNA-Tg are limited.


   Subjects and Methods Top


Patients

FNA-Tg was performed in 13 cervical nodes of 12 patients (10 females) with mean (+standard deviation) age of 37 + 16 years (range: 26–65 years) from July 2014 to March 2015 at the Mazumdar Shaw Medical Center. All patients were subjected to physical examination, neck US, biochemical estimation of serum thyroid stimulating hormone, and Tg. FNAC of sonographically suspicious cervical lymph nodes were sent for cytology and FNA-Tg. Four patients had previously undergone total thyroidectomy for PTC and one hemithyroidectomy. In the remaining 7 patients, FNA-Tg was performed for preoperative surgical planning. The thyroid nodule FNAC in 6 of 7 patients was highly suspicious for malignancy (Bethesda class V), while one patient had indeterminate cytology (class III). Majority of the lymph nodes (11/13) chosen for FNA were in the lateral cervical compartment while 2 patients had central level VI lymph node aspirated.

Fine needle aspiration-thyroglobulin estimation

The FNAC aspirate was sent for cytology analysis, and a dedicated aspirate was washed in 0.5 ml normal saline and sent for Tg estimation. The specimen was centrifuged and cellular debris removed, and Tg was measured in the supernatant using solid-phase chemiluminescent immunometric assay (Siemens ® Immulite 1000; analytic range 0.1–1000 ng/ml and CV 7.5%). All (except one patient C) specimens were re-tested in dilution to exclude “hook effect.” Cytological smears were evaluated by the pathologist, and final surgical pathology was available in patients underwent surgery.


   Results Top


The patient details are summarized in [Table 1]. Eight of the 13 lymph node aspirates had FNA-Tg values >150 ng/ml, all of them had unequivocal malignant cytology and 4 among them had proven metastatic DTC on surgical pathology. The remaining patients are awaiting surgery. The median FNA-Tg of the patients with malignant cytology was 7550 ng/ml with a range of 162–30,000 ng/ml. The patient (C) with FNA-Tg of 162 ng/ml was not performed in dilution, and it is likely that hook effect might have contributed to the apparently “lower” Tg estimate. In 4 athyreotic patients, the FNA-Tg was concordant with cytology and helped plan surgical neck dissection. In the remaining 4 patients, FNAC was performed as a preoperative procedure. FNA-Tg was concordant with cytology and helped plan appropriate neck dissection along with total thyroidectomy as the initial surgery in these patients. In one of the patients (patient G), the thyroid nodule FNA Bethesda class was atypia of undetermined significance (III) and the concordant cytology, and FNA-Tg results from the lymph node changed the surgical decision from a diagnostic hemithyroidectomy to a total thyroidectomy and neck compartment dissection. Similarly, in patient (TD), preoperative imaging showed an indeterminate level III lymph node. The concordance between the negative cytology and FNA-Tg <0.2 ng/ml results helped restrict the surgery to a total thyroidectomy, and lateral neck dissection was avoided.
Table 1: Details of patients who underwent fine needle aspiration cytology of lymph node and the outcomes

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Among the remaining 5 lymph node aspirate, 2 lymph nodes had cytological evidence of reactive lymphadenitis, and FNA-Tg <0.2 ng/ml and were not operated. One of those patients (patient A), who had a previous total thyroidectomy and presented with iodine (I 131)-scan negative but fluorodeoxyglucose (FDG) avid bilateral neck lymph adenopathy [Figure 1]. FNA-Tg and cytology confirmed reactive lymphadenitis from one side and metastatic lymph node on the opposite side. This converted the surgical plan from a bilateral lateral neck dissection to unilateral one.
Figure 1: Fluorodeoxyglucose uptake seen on the right-sided level IV cervical lymph nodes and left-sided level II lymph nodes

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Patient (ST) presented with a 4 weeks duration of rapidly enlarging thyroid swelling and FNA from thyroid nodule, and lymph node showed high-grade malignancy [Figure 2]a and [Figure 2]b. Since the FNA-Tg < 0.2 ng/ml and the FDG avid thyroid mass with FDG avid scapular metastasis [Figure 3], and rapid clinical progression, a diagnosis of anaplastic thyroid cancer was made.
Figure 2: (a) Low power view (×10 field) - Smear shows markedly increased cellularity and is composed of sheets of moderate to highly pleomorphic cells. (b) Higher power (×20 field) - On higher power, the cells appear discohesive and show occasional large highly pleomorphic bizarre nuclei. The cytoplasm is dense and eosinophilic in appearance. No papillary nor follicular arrangement is seen. No usual nuclear features of papillary thyroid cancer such as neither nuclear grooves nor intranuclear cytoplasm inclusions are noted. No definite background colloid is seen

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Figure 3: Fluorodeoxyglucose-positron emission tomography avid thyroid nodule (arrowhead) with lymph nodes (star) and scapular metastasis (circle)

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Two patient had nondiagnostic lymph node FNAC, one of them had noncaseating granuloma on surgical pathology (FNA-Tg 1.3 ng/ml), and the other patient had right hemithyroidectomy for 2.5 cm classic PTC. On follow-up of the patient with hemithyroidectomy, neck US noted a 1 cm left level VI lymph node which was indeterminate on sonography, but cytology was nondiagnostic and FNA-Tg <0.2 ng/ml and hence surgery was deferred.


   Discussion Top


The diagnosis of lymph node involvement in thyroid carcinoma is important as it changes the surgical management and prognosis of the patient with DTC. FNA-Tg is recommended as an adjunct to cytology in the diagnosis of lymph node metastasis. FNA-Tg is unaffected by the presence of serum Tg antibodies. Snozek et al. and Moon et al. reported that an FNA-Tg cutoff of 1 ng/mL provided excellent sensitivity (100% and 93%, respectively) and specificity (96% in both studies) for the detection of metastatic thyroid carcinoma in lymph nodes, respectively.[10],[11] Moon et al. showed that combining FNA-Tg and FNA cytology showed superior diagnostic power (sensitivity, 98.4%; specificity, 94.4%) when compared with diagnostic strategy using either FNA cytology or FNA-Tg alone.[11] While the FNA-Tg value of 1.0 ng/L is the optimal cutoff for athyreotic patients, the diagnostic performance of FNA-Tg is poorer in patients before thyroidectomy.[14] FNA-Tg levels are expected to be higher in patients with thyroid glands because Tg secreted by normal thyroid can affect the FNA-Tg level due to contamination with blood during the procedure.[8],[15] Studies on the FNA-Tg cutoff value in patients with thyroid glands are limited, and cutoff values have varied from 1 to 50 ng/ml.[11],[12],[15],[16],[17] It is also well-known that Tg synthesis is lost in dedifferentiated thyroid cancer and anaplastic thyroid cancer, and FNA-Tg is likely to be low or undetectable in these cases.[15] This is consistent with one of our patients (ST) whose clinical presentation, cytology, and imaging features was consistent with that of anaplastic carcinoma.

In our pilot study, FNA-Tg had 100% correlation with positive cytology and values are unequivocally high (>150 ng/ml) regardless of the thyroidectomy status. However, the real utility was in patients with negative cytology, where FNA-Tg <0.2 ng/ml was confirmatory of the negative cytology and reassuring in patients with nondiagnostic cytology thus helping guide surgical interventions.


   Conclusions Top


FNA-Tg was concordant with positive cytology in all patients with DTC and may serve as a useful tool in patients with negative and nondiagnostic cytology to guide surgical management.

Acknowledgment

Dr. Sabari Das for Biochemistry support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
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;19:1167-214.  Back to cited text no. 1
    
2.
Davies L, Welch HG. Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg 2014;140:317-22.  Back to cited text no. 2
    
3.
Leenhardt L, Erdogan MF, Hegedus L, Mandel SJ, Paschke R, Rago T, et al. 2013 European thyroid association guidelines for cervical ultrasound scan and ultrasound-guided techniques in the postoperative management of patients with thyroid cancer. Eur Thyroid J 2013;2:147-59.  Back to cited text no. 3
    
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Baskin HJ. Detection of recurrent papillary thyroid carcinoma by thyroglobulin assessment in the needle washout after fine-needle aspiration of suspicious lymph nodes. Thyroid 2004;14:959-63.  Back to cited text no. 4
    
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Frasoldati A, Valcavi R. Challenges in neck ultrasonography: Lymphadenopathy and parathyroid glands. Endocr Pract 2004;10:261-8.  Back to cited text no. 5
    
6.
Monchik JM, De Petris G, De Crea C. Occult papillary carcinoma of the thyroid presenting as a cervical cyst. Surgery 2001;129:429-32.  Back to cited text no. 6
    
7.
Kessler A, Rappaport Y, Blank A, Marmor S, Weiss J, Graif M. Cystic appearance of cervical lymph nodes is characteristic of metastatic papillary thyroid carcinoma. J Clin Ultrasound 2003;31:21-5.  Back to cited text no. 7
    
8.
Frasoldati A, Toschi E, Zini M, Flora M, Caroggio A, Dotti C, et al. Role of thyroglobulin measurement in fine-needle aspiration biopsies of cervical lymph nodes in patients with differentiated thyroid cancer. Thyroid 1999;9:105-11.  Back to cited text no. 8
    
9.
Pacini F, Fugazzola L, Lippi F, Ceccarelli C, Centoni R, Miccoli P, et al. Detection of thyroglobulin in fine needle aspirates of nonthyroidal neck masses: A clue to the diagnosis of metastatic differentiated thyroid cancer. J Clin Endocrinol Metab 1992;74:1401-4.  Back to cited text no. 9
    
10.
Snozek CL, Chambers EP, Reading CC, Sebo TJ, Sistrunk JW, Singh RJ, et al. Serum thyroglobulin, high-resolution ultrasound, and lymph node thyroglobulin in diagnosis of differentiated thyroid carcinoma nodal metastases. J Clin Endocrinol Metab 2007;92:4278-81.  Back to cited text no. 10
    
11.
Moon JH, Kim YI, Lim JA, Choi HS, Cho SW, Kim KW, et al. Thyroglobulin in washout fluid from lymph node fine-needle aspiration biopsy in papillary thyroid cancer: Large-scale validation of the cutoff value to determine malignancy and evaluation of discrepant results. J Clin Endocrinol Metab 2013;98:1061-8.  Back to cited text no. 11
    
12.
Kim DW, Jeon SJ, Kim CG. Usefulness of thyroglobulin measurement in needle washouts of fine-needle aspiration biopsy for the diagnosis of cervical lymph node metastases from papillary thyroid cancer before thyroidectomy. Endocrine 2012;42:399-403.  Back to cited text no. 12
    
13.
Cunha N, Rodrigues F, Curado F, Ilhéu O, Cruz C, Naidenov P, et al. Thyroglobulin detection in fine-needle aspirates of cervical lymph nodes: A technique for the diagnosis of metastatic differentiated thyroid cancer. Eur J Endocrinol 2007;157:101-7.  Back to cited text no. 13
    
14.
Grani G, Fumarola A. Thyroglobulin in lymph node fine-needle aspiration washout: A systematic review and meta-analysis of diagnostic accuracy. J Clin Endocrinol Metab 2014;99:1970-82.  Back to cited text no. 14
    
15.
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;91:1364-9.  Back to cited text no. 15
    
16.
Sigstad E, Heilo A, Paus E, Holgersen K, Grøholt KK, Jørgensen LH, et al. The usefulness of detecting thyroglobulin in fine-needle aspirates from patients with neck lesions using a sensitive thyroglobulin assay. Diagn Cytopathol 2007;35:761-7.  Back to cited text no. 16
    
17.
Sohn YM, Kim MJ, Kim EK, Kwak JY. Diagnostic performance of thyroglobulin value in indeterminate range in fine needle aspiration washout fluid from lymph nodes of thyroid cancer. Yonsei Med J 2012;53:126-31.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]


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