A 54-Year-Old Woman with Papillary Thyroid Carcinoma Associated with Secondary Amyloid Goiter and Thyroid Lipomatosis

Background

Amyloid goiter, a rare entity first recognized by Beckmann in 1858, is defined as a clinically detectable enlarged thyroid gland due to the extracellular deposition of insoluble protein fibrils accompanied by varying degrees of fat deposition [1]. It may be caused by primary amyloidosis, associated with plasma cell dyscrasias, or, more frequently, by secondary amyloidosis, usually triggered by an inflammatory disease such as tuberculosis, bronchiectasis, familial Mediterranean fever, cystic fibrosis, ulcerative colitis, Crohn’s disease, or rheumatoid arthritis, among others [2]. Amyloid goiter has been reported to be associated with diffuse thyroid lipomatosis [3,4], a rare condition characterized by infiltration of mature adipose tissue in the thyroid stroma without evidence of encapsulation [5]. Papillary thyroid carcinoma is the most common thyroid malignancy [6] and rare case reports have mentioned its occurrence associated with amyloid goiter [7–10]. Even more unusual is the synchronous occurrence of papillary thyroid carcinoma, amyloid goiter, and diffuse thyroid lipomatosis [7]. We report a rare case of a 54-year-old woman with papillary thyroid carcinoma associated with secondary amyloid goiter and diffuse thyroid lipomatosis.

Case Report

A 54-year-old female patient with a history of neurogenic bladder, chronic renal failure due to chronic pyelonephritis, and bronchiectasis associated with multiple respiratory infections presented at our Department of Endocrinology with thyroid gland enlargement, hoarseness, and dysphagia, with nearly 4 months of evolution. Physical examination revealed a large bilateral goiter mainly affecting the right side of the neck, where a mass of approximately 3 cm was palpable. Thyroid function test results were in the normal range, with free T4 14.1 pmol/L (reference range, 12–24), free T3 3.9 pmol/L (reference range, 3.1–6.8), and thyroid-stimulating hormone (TSH) 0.8 µUI/mL (reference range, 0.27–4.20). Serum anti-thyroperoxidase and anti-thyroglobulin antibodies, as well as calcitonin levels, were undetectable. Cervical ultrasound (US) showed a diffusely swollen thyroid and a well-defined nodule in the right lobe, which was solid, isoechoic, taller than wide, with no calcifications, measuring 28×19×29 mm (anteroposterior×width×length); without laterocervical adenopathies. Fine-needle aspiration cytology of the nodule was suspicious for follicular neoplasm (Bethesda IV category). In addition to what was previously described in the US, computed tomography (CT) showed an enlarged thyroid, leading to a slight reduction of tracheal sagittal diameter and areas of low attenuation suggestive of diffuse lipomatosis of the gland (Figure 1). The total thyroidectomy specimen weighed 81 grams, the left lobe measured 32×67×28 mm, isthmus 26×45×20 mm, and the right lobe 45×75×34 mm. Histological study revealed the presence of papillary carcinoma of follicular variant, measuring 34×32×25 mm, without lymphovascular invasion or microscopic extrathyroidal extension (pT2, according to AJCC/ TNM 8th edition) [11] (Figure 2). Thyroid follicles were admixed with mature adipose tissue, and the stroma was replaced mainly by amorphous eosinophilic material (Figure 3), which was confirmed to be amyloid deposition by orangeophilic staining with Congo red and positive apple-green birefringence under polarized light (Figure 4). A final diagnosis of papillary carcinoma and diffuse lipomatosis of the thyroid gland with amyloid deposition was established. TSH suppression therapy was provided, aiming for a TSH level of 0.5–2.0 µUI/mL. The patient was referred to an Internal Medicine appointment to proceed with the investigation of amyloidosis, and an abdominal fat aspirate showed amyloid deposits typed as serum amyloid A protein by immunohistochemical staining, confirming the diagnosis of secondary amyloidosis. Unfortunately, the patient died 5 months after the amyloid goiter diagnosis due to a urinary tract infection that developed into sepsis.

Discussion

This case represents an unusual occurrence of papillary thyroid carcinoma in an amyloid goiter subsequently found to be a manifestation of secondary amyloidosis in a patient with chronic pyelonephritis and bronchiectasis. We highlight the need for inclusion of amyloid goiter and diffuse lipomatosis in the differential diagnosis of thyroid enlargement, and the need for exclusion of a differentiated thyroid carcinoma within an amyloid goiter. As shown in this report, amyloid goiter can be associated with diffuse fatty proliferation, probably due to tissue hypoxia secondary to progressive capillary and thyroid follicle destruction leading to metaplasia of stromal fibroblasts [12]. The amyloid deposition has also been reported in association with thyroid malignancies. Medullary thyroid carcinoma often has a amyloid stromal deposition, and it has been suggested that it can be synthesized locally by tumor cells as excess calcitonin aggregates into insoluble fibrils [13]. Papillary thyroid carcinoma has rarely been associated with amyloid goiter, with just a few cases reported, and the mechanism remains unknown [7–10]. Liftin [8] reported a case of mixed papillary and follicular thyroid carcinoma associated with amyloid goiter in a patient with rheumatoid arthritis. Coli et al [7] reported an amyloid goiter with diffuse lipomatosis and papillary thyroid carcinoma in a patient with probable secondary amyloidosis. Coca-Pelaz et al [9] and Nessim et al [10] reported a papillary thyroid carcinoma within an amyloid goiter due to primary amyloidosis. As in our case, most patients with amyloid goiter present with an enlarged thyroid gland, usually bilateral and diffuse, which can rapidly progress over weeks to months [3,4,9] and it can be associated with compressive symptoms such as dysphagia, dysphonia, and dyspnea [4,9,10]. Thyroid function is usually normal [3,4,7,9,10], but a minority of patients have hyper- or hypo-thyroidism [14]. As previously stated, our patient had normal levels of T4, T3, and TSH. Imaging findings can vary according to the amount of amyloid. Hyperechogenicity in the US and low density on CT, as in our case, may be found in the presence of infiltration of fat tissue [3,4]. Diagnosis of amyloid goiter requires histologic analysis of the excised gland. At histological observation, amyloid deposition appears as an amorphous, extracellular, proteinaceous substance. It shows positivity to Congo red staining, imparting an apple-green birefringence when viewed under polarized light, which is considered a pathognomonic feature [15]. Immunohistochemical studies can help to define the origin of the amyloid protein deposits, with the presence of light chains in primary amyloidosis and serum amyloid A protein in secondary amyloidosis [16].

Conclusions

The presentation of secondary amyloidosis as a diffuse goiter with extensive fatty infiltration must be considered in the differential diagnosis of thyroid enlargement, especially in cases with rapid onset, particularly in patients with a history of chronic inflammatory disorders or chronic infections predisposing to amyloid deposition. Rarely, differentiated thyroid carcinoma is found within an amyloid goiter and it must be excluded.