Unstimulated Serum Thyroglobulin Levels after Thyroidectomy and Radioiodine Therapy for Intermediate-Risk Thyroid Cancer Are Not Always a Reliable Marker of Lymph Node Recurrence: Case Report and a Lesson for Clinicians

Abstract

Over 50% of patients with papillary thyroid carcinoma (PTC) have cervical lymph-node metastasis on diagnosis, and up to 30% show nodal recurrence after surgery plus radioactive iodine (131I) (RAI) therapy. The combination of ultrasonography (US) and fine-needle aspiration cytology (FNAC) and the measurement of thyroglobulin (Tg) in washout fluid are cornerstones in the diagnosis of nodal metastasis. In the absence of anti-Tg antibodies, unstimulated serum thyroglobulin (Tg) levels are generally a reliable marker of recurrent disease, and 18F-FDG positron emission tomography (PET)/computed tomography (CT) plays an important role in the imaging work-up. We report the case of a 65-year-old man evaluated for a large multinodular goitre which caused compressive symptoms; the dominant nodule in the left lobe presented suspicious features on US. Thyroid function showed subclinical hypothyroidism, calcitonin was normal, serum thyroglobulin levels were low, and anti-thyroid antibodies were absent. The prevalent left nodule showed an intense uptake on 18F-FDG PET/CT but proved benign at FNAC. On the basis of the suspicious clinical and imaging features, total thyroidectomy was performed. Histology revealed a tall-cell variant of PTC with scattered expression of Tg and diffuse high expression of cytokeratin (CK) 19; RAI therapy was performed. Within 6 years of surgery, left laterocervical lymph-node recurrence was twice detected (first at levels II and III, then at levels IV and VI) by US and 18F-FDG-PET/CT and was confirmed by FNAC. Tg levels in the washout fluid proved clearly diagnostic of metastasis only in the second, larger, recurrence, whereas serum Tg levels (in the absence of anti-Tg antibodies) always remained undetectable on L-thyroxine therapy. Surgery was performed on both recurrences, and histology confirmed lymph-node metastasis of PTC. Immunohistochemical expression of Tg and CK 19 was similar to that of the primary tumour. No further relapses have occurred to date. Posttherapy (surgery and RAI) unstimulated serum Tg levels may not be a reliable marker of nodal recurrence in patients with differentiated thyroid cancer (DTC) that produces low amounts of Tg.

Figure 1

Ultrasonographic suspicious features of the large solid hypoechoic and taller-than-wide shape thyroid nodule located in the mid-inferior part of the left lobe (a), which showed significant tracer uptake at 18F-FDG PET/CT (arrow, (b)).

Figure 2

Histology after thyroidectomy showing a tall-cell variant of papillary thyroid carcinoma: papillary architecture neoplasm consisting of proliferation of elongated cells with a large eosinophilic cytoplasm, “ground glass” nuclei, and evident nuclear grooves and pseudoinclusions (haematoxylin-eosin stain, 40X, (a)). The tumour showed scattered thyroglobulin cytoplasmatic staining of different intensity (20X, (b)) and strong and diffuse CK19 cytoplasmatic staining (40X, (c)). Immunohistochemical staining was performed using specific antibodies by indirect biotin streptavidin 3, 3′-diaminobenzidine (DAB) system.

Figure 3

During the fourth year of follow-up after surgery and radioactive 131I therapy, ultrasonography showed small (maximum 1.5 cm) suspicious laterocervical lymph nodes with oval shape and no visible hilum (a, b, arrows).

Figure 4

Fine needle aspiration cytology of the left laterocervical lymph-node recurrence detected during the fourth year of follow-up after surgery and radioactive 131I therapy, which showed three-dimensional papillary flaps of medium size cells with pseudoinclusions and grooves which proved compatible with metastasis of papillary thyroid carcinoma (ThinPrep method, Papanicolaou stain, 40X).

Figure 5

Histology of lymph node metastasis (first recurrence detected during the fourth year of follow-up after surgery and radioactive 131I therapy) of tall-cell variant of papillary thyroid carcinoma: proliferation of cells with a large eosinophilic cytoplasm, “ground glass” nuclei, and evident nuclear grooves and pseudoinclusions (left side) and residual patrimonial lymphoid tissue (right side) (haematoxylin-eosin stain, 40X, (a)). The neoplastic thyroid cells showed scattered thyroglobulin cytoplasmatic staining of different intensity (40X, (b)) and diffuse strong cytoplasmatic CK19 staining (40X, (c)). Immunohistochemical staining was performed using specific antibodies by indirect biotin streptavidin 3, 3′-diaminobenzidine (DAB) system.

Figure 6

Ultrasonographic features of second nodal recurrences (6 years after surgery and radioactive iodine 131I therapy) of papillary thyroid carcinoma (two laterocervical metastatic hypoechoic lymph nodes, 2.2 cm and 1 cm, respectively) with irregular shape, no visible hilum and focal hyperechogenicity ((a), arrows). At 18F-FDG PET/CT, both lymph nodes showed significant tracer uptake (arrows) (the larger one: SUV max: 20.7; the smaller one: SUV max: 11) (b).