Case 3 -

Amyloid Goiter Edmund S. Cibas Brigham & Women's Hospital Boston, MA

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Clinical History: 31 year old man with longstanding juvenile rheumatoid arthritis and chronic renal failure. Now with diffuse enlargement of the thyroid. Thyroid FNA (all images: Papanicolaou-stained smear). Case 3 - Figure 1 The smears contained several chunks of dense orange-red material with irregular edges. Case 3 - Figure 2 Another field shows two additional chunks of dense orange-red material with irregular edges. Case 3 - Figure 3 High magnification reveals dense, hyaline material with embedded elongated nuclei. Case 3 - Figure 4 Some fragments appear acellular. Case 3 - Figure 5 Other fragments contain occasional stretched and distorted nuclei. Case 3 - Figure 6 Some fragments contain more numerous nuclei. Aside from their occasionally distorted appearance, the nuclei lack atypia. Case 3 - Figure 7 A Congo red stain on the smear shows apple- green birefringence under polarized light. Case 3 - Figure 8 An autopsy 3 years later revealed an enlarged thyroid gland with extensive interfollicualr and parafollicular amyloid deposition. Case 3 - Figure 9 The elongated nuclei seen on FNA correspond to the nuclei of fibroblasts and endothelial cells entrapped in amyloid deposits. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The alcohol-fixed, Papanicolaou-stained smears from this 1990 case were sparsely cellular. There were only rare sheets of benign follicular cells and scant colloid. The diagnostic findings, easy to overlook, consisted of chunks of orange-red, hyaline-like material with embedded elongated nuclei. Differential Diagnoses: The differential diagnosis includes: Riedel's thyroiditis schwannoma medullary carcinoma plamacytoma amyloid goiter Examined out of context, the smears can be misinterpreted as a spindle-cell proliferation like Riedel's thyroiditis or a schwannoma. The distorted, spindle-shaped nuclei are, in fact, merely normal thyroid fibroblasts and endothelial cells embedded in dense amyloid deposits. The embedded elongated nuclei are in fact a characteristic feature of amyloid goiter on FNA, highlighted by Gharib and Goellner in a letter to the New England Journal of Medicine in 1981 (see references). Although amyloid goiter can be nodular, it is more often a diffuse enlargement, as in this case, making Riedel's thyroiditis and a neoplasm unlikely. Other amyloid- containing neoplasms like medullary carcinoma and the rare plasmacytoma of the thyroid are similarly unlikely causes of a diffuse thyroid enlargement. Final Diagnosis: Amyloid goiter Case Discussion: This case of amyloid goiter was unforgettable because: 1. it illustrates a very rare entity, but one that can be diagnosed by FNA; 2. it is easily misdiagnosed as a spindle-cell lesion because the elongated nuclei are "red herrings;" 3. it is an elegant example of a difficult case made easy by the integration of clinical and other diagnostic data. The key to the diagnosis in this case lay in the integration of the clinical history of a chronic illness (juvenile rheumatoid arthritis) and the clinical signs (a diffuse rather than nodular thyroid enlargement) with the curious but distinctive cytologic findings. Follow-up: This patient developed systemic amyloidosis and lived for 3 years after this FNA. He eventually succumbed to sepsis. The thyroid at autopsy weighed 370 grams (normal, 25 grams) and showed marked amyloid deposition. Review of the Literature/Treatment Options: Amyloid goiter (AG) was first described in the 1850s. It is a diffuse or nodular enlargement of the thyroid gland, sometimes with alarming clinical symptoms such as rapid growth (over several months), dyspnea, dysphagia, or hoarseness. Patients are usually euthryoid. AG occurs in association with both primary and secondary amyloidosis, more commonly in the latter. Patients with AG associated with secondary amyloidosis have a chronic illness; common examples include rheumatoid arthritis (as in this case), inflammatory bowel disease, and tuberculosis. Amyloid deposits in the thyroid in patients with secondary amyloidosis consist of AA proteins. The AA protein fibrils are derived by proteolysis from a larger serum protein called serum amyloid-associated protein that is synthesized in the liver. Production of SAA is increased in inflammatory states as part of the "acute phase response." AG related to secondary amyloidosis also occurs with hereditary diseases like familial Mediterranean fever (FMF). In FMF, the deposits consist also of AA proteins, suggesting that this form of amyloidosis is also related to recurring bouts of inflammation. Pathologically, the thyroid interstitium is infiltrated by dense amyloid deposits. Infiltration/replacement of the thyroid by adipose tissue is a common finding, and adipocytes can be seen on FNA. There may be a lymphocytic infiltrate, and some cases have by multinucleated giant cells. The diagnosis can be established by FNA. Follicular cells are typically scant. The diagnosis rests on recognizing amyloid, which is similar to but more dense than colloid. Amyloid is described as sinilar to but more dense than colloid. It stains green or orange-red with alcohol-fixed Papanicolaou-stained preparations. The amyloid in amyloid goiter contains stretched and distorted fibroblast nuclei. These embedded elongated nuclei are a characteristic feature of amyloid goiter on FNA, a fact that was highlighted by Gharib and Goellner in a letter to the New England Journal of Medicine in 1981. These authors championed FNA as a cost-effective, low-morbidity method for the diagnosis of AG. A conclusive diagnosis rests on identifying the characteristic apple-green birefringence with the Congo red stain. There is no effective medical treatment of AG. Patients with dyspnea or dysphagia may be treated by partial or total thyroidectomy for symptomatic relief. Conclusion(s): Fine needle aspiration is an effective method for the diagnosis of amyloid goiter. References: Gharib H, Goellner JR. Diagnosis of amyloidosis by fine- needle aspiration biopsy of the thyroid [Letter]. N Engl J Med 1981;305:586. Hamed G, Heffess CS, Shmookler BM, Wenig BM. Amyloid goiter: a clinicopathologic study of 14 cases and review of the literature. Am J Clin Pathol 1995;306-312. Ozdemir BH, Uyar P, Ozdemir FN. Diagnosing amyloid goiter with thyroid aspiration biopsy. Cytopathol 2006; 17: 262-66. Villa F, Dionigi G, Tanda ML, Rovera F, Boni L. Amyloid goiter. Int J Surg 2008; 6 (Suppl 1: 16-8). Yaeger KA, Hysell C, Pitman MB. Diagn Cytopathol 2009. Yidiz L, Kefeli M, Kose B, Baris S. Amyloid goiter: two cases and a review of the literature. Ann Saudi Med 2009; 29: 138-41.