Skip Navigation LinksHome > January 2013 - Volume 20 - Issue 1 > Localized Amyloid in Thyroid: Are We Missing It?
Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e31827b6519
Review Articles

Localized Amyloid in Thyroid: Are We Missing It?

Pinto, André MD; Nosé, Vânia MD, PhD

Free Access
Article Outline
Collapse Box

Author Information

Department of Pathology, University of Miami Hospital, University of Miami Miller School of Medicine, Miami, FL

Our work on localized amyloid deposition in thyroid was preliminarily presented at the 101st Annual Meeting of the United States Canadian Academy of Pathology, 2012.

All figures can be viewed online in color at http://www.anatomicpathology.com.

The authors have no funding or conflicts of interest to disclose.

Reprints: Vania Nosé, MD, PhD, Department of Pathology, University of Miami Hospital, University of Miami Miller School of Medicine, 1400 NW 12 Ave., Room 4061, Miami, FL 33136 (e-mail: vnose@med.miami.edu).

Collapse Box

Abstract

When present in thyroid, amyloid is an attribute almost always restricted to medullary thyroid carcinoma. Scant studies in the literature have demonstrated this finding in other thyroid pathologies as papillary thyroid carcinoma, amyloid goiter, and other benign entities. From our experience in thyroid pathology, we analyzed cases on which the stroma contained deposits of amorphous, acellular, and eosinophilic material characteristic of amyloid. Congo red stain on suspicious cases was performed; clinicopathologic investigation was done when results were positive. Seven patients with amyloid infiltration in the thyroid, in association with papillary thyroid carcinoma, and in 4 cases of benign pathologies were found in our own review. The association of amyloid and thyroid is discussed herein, including cases of systemic amyloidosis, malignancies, benign diseases, and thyroid goiter, from our practice and from the available literature.

Amyloidosis is a term used for diseases that have as main feature the extracellular deposition of pathologic insoluble fibrillar proteins in organs and tissues.1 This condition can be seen in a diverse and broad group of diseases and is most commonly associated with multiple myeloma, familial disorders, and chronic inflammatory diseases. Although they all share the same histopathologic attribute of amyloid deposition in tissues, the nature of this protein varies (and consequently, their clinical features) and is disease dependent (Table 1). To date, about 30 different proteins have been identified as causative agents of amyloidosis.2

Table 1
Table 1
Image Tools

The first report of amyloid deposition in thyroid dates from the mid-1800s on a patient with systemic amyloidosis, in studies done by Rokytanksy and Virchow.3–5 Clinically detectable thyroid enlargement due to amyloid was then described less than a decade later, and finally Eiselberg coined the term “amyloid goiter” in 1904.6,7

When present in thyroid tissue, amyloid is a feature almost always restricted to medullary thyroid carcinoma (MTC). The deposition of this protein accompanying MTC is a well-known fact, and the production of calcitonin by neoplastic cells has been demonstrated to be the culprit.8 Some novel studies have recently shown that amyloid aggregation leads to hyperactivation of cyclin-dependent kinase 5 (Cdk5) that would ultimately promote tumor cell proliferation.9,10

Amyloid goiter (AG) is another very uncommon pathology on which the presence of amyloid in the thyroid gland is exuberant. To be classified as AG, clinically and/or radiologically noticeable enlargement of the thyroid has to be seen. This condition is usually diagnosed when one of the above-mentioned diseases are present. Affected patients may have symptoms of compression such as dysphagia, hoarseness, or dyspnea, and this scenario must be distinguished from the more common types of goiter.11 When present, AG is usually composed of serum amyloid A type due to a systemic inflammatory condition,12 but it can also be of different subtypes depending on the main disease. For example, transthyretin has been demonstrated to affect renal allograft recipients13 and immunoglobulin light chain AL disease in multiple myeloma patients.14 A brief review of reported cases with different subtypes of amyloid is summarized on Table 2.

Table 2
Table 2
Image Tools

However, the amyloid in thyroid is not a histologic finding exclusive of medullary cancer or AG. Extremely infrequent publications of papillary thyroid carcinoma (PTC) with amyloid-rich stroma are described in the literature (Table 3). There are only 6 cases of PTC associated with amyloid deposition previously reported; and some of them were either illustrating carcinoma arising on patients with preexisting AG or were found to be 2 distinct and coincidental events.34–36

Table 3
Table 3
Image Tools

In this review, Pubmed-based literature search was performed using the following keywords, with a spectrum of different combinations: “amyloid,” “amyloidosis,” “amyloid goiter,” “amyloid-rich” “papillary thyroid carcinoma,” and “thyroid cancer.”

We also studied a series of cases of PTC in parallel with benign thyroid pathologies, in a referral pathology consultation service, for better understanding this event and to add our own experience to the study. Paraffin-embedded, hematoxylin and eosin–stained slides of a series of cases of PTC and benign thyroid entities were reviewed. Cases on which the stroma contained deposits of amorphous, acellular, and eosinophilic material suspicious for amyloid, congo red stain was performed and slides were analyzed under polarized light. The clinical histories of the positive cases were extensively reviewed to exclude patients with primary or secondary systemic amyloidosis.

Back to Top | Article Outline

AMYLOID IN PAPILLARY THYROID CARCINOMA

In our series, there were 20 cases of PTC on which the stroma had extracellular deposition of material suggestive of amyloid. Congo red stain was performed on these cases, and the slides were then reviewed under polarized light microscopy. Among the neoplastic cases, 7 demonstrated unquestionable apple-green birefringence, with moderate to strong congophilia (Figs. 1A–D).

Figure 1
Figure 1
Image Tools

After identifying the positive cases, we proceeded with extensive evaluation of the electronic records of these individuals and concluded that none of the patients had the diagnosis of systemic amyloidosis. A significant amount of the subjects, however, had some type of chronic pathology (like diabetes, hypertension, or respiratory conditions), but none of them would fit in the group of diseases with known amyloidogenic proprieties. It is important to mention that no clinical and/or radiologic diagnosis of AG was present in any of the cases, and the enlargement seen in some specimens was initially attributed to the main pathology (ie, multinodular goiter or carcinoma).

In the subgroup of PTC cases, most subjects were male (4/7 or 57%), and almost all neoplastic cases had morphologic features of aggressive behavior—either in the form of lymphovascular invasion (71%) or in the form of their histologic subtypes (diffuse sclerosing variant, tall cell variant, columnar cell variant, and oncocytic follicular variant). The findings are described on Table 4.

Table 4
Table 4
Image Tools

Histologically, dense deposition of amyloid was seen in the perifollicullar and interfollicullar areas. Foreign-body–type giant cells and lipomatous metaplasia, relatively common features of AG (Figs. 2A, B), were not seen. The typical histopathologic features of PTC did not differ from a regular (non–amyloid-rich stroma) case.

Figure 2
Figure 2
Image Tools
Back to Top | Article Outline

AMYLOID IN BENIGN THYROID DISEASES

Among the benign cases from our series, we found 4 cases that also demonstrated the presence of amyloid in the stroma confirmed by congo red staining (Figs. 3A–D). They were composed of 2 cases of atrophic end-stage thyroid (in the setting of posttreatment effect), 1 hyperplastic nodule and 1 follicular adenoma. Although no systemic amyloidosis was diagnosed on these patients either, 2 of them also had chronic conditions such as diabetes and recurrent infections, as summarized on Table 5.

Figure 3
Figure 3
Image Tools
Table 5
Table 5
Image Tools

The deposits of this protein seen in these subgroups was also perifollicullar and interfollicular, with different degrees of lymphocytic infiltrate. Atrophy of the follicles present on the cases of end-stage disease made the presence of amyloid more noticeable on light microscopy, but stronger congophilia was not necessarily obtained.

Back to Top | Article Outline

DISCUSSION

The presence of amorphous, acellular deposits on hematoxylin and eosin sections is not difficult to overlook in thyroid, especially on the majority of cases on which the organ has not yet progressed to a prominent enlargement. The abundance of eosinophilic material in the stroma due to collagen (eg, PTC diffuse sclerosing variant) might lead to the false interpretation that the some of the cases may represent elements other than amyloid.

Are we underdiagnosing this finding in non-MTCs? The pathologist should be aware that if a nonconventional thyroid tumor presents with amyloidotic stroma, and morphologic and immunohistochemical studies fail to support the diagnosis of MTC, one should not classify this neoplasm only by the presence of the amyloid-rich stroma.

As any other organ, although, the thyroid gland can also be affected by conditions that lead to increase systemic levels of amyloid proteins—either of primary or secondary origin—but its real incidence is still controversial. Cases are limited to rare single reports; however, a few autopsy studies revealed the presence of some degree of amyloid in the thyroid parenchyma with discrepant variability.6,12,33 Nevertheless, they seem to agree that this event is more frequently seen in secondary rather than primary amyloidosis, despite the fact that primary—AL protein—is more prevalent than secondary disease.6,22,23,40 Previously reported systemic amyloidogenic conditions with thyroid involvement include multiple myeloma/plasma cell dyscrasias (primary amyloidosis), chronic infections, autoimmune/inflammatory conditions, transplant recipients, and familial Mediterranean fever (secondary amyloidosis).13,22,30,40

Fine-needle aspiration can be used to show the amorphous material that can also be analyzed on congo red staining. It is important to keep in mind that this finding can be easily misinterpreted unless amyloid is actively considered in the differential diagnosis when evaluating the slides.

Scattered reviews for AG are in the literature32,33,40 and the histopathologic findings seen in all cases are similar to the ones we found. Lymphocytic infiltrate and foreign-body giant cells can be seen and may be common features. The degree of congophilia varied from mild to strong. In regard to thyroid function, in our experience, all patients except the one, who had a previous thyroidectomy, had normal thyroid function tests.

Interestingly, our own series showed that most of the neoplastic cases of PTC with amyloid-rich stoma had histopathologic indicators of a more aggressive nature. It is hard to explain this association, given the presence of benign cases found.

In opposition to the regular PTC of the general population (with nonamyloidotic stroma), we noticed that the incidence of the events in this study was in an older subgroup of patients (median 68; average 64.2) of a male sex. Both statements go against the natural history of PTC on which the average age of diagnosis is on the 30 to 50 decade of life, and the fact that the disease is more prevalent in women than in men (female to male ratio ranges from 2:1 to 4:1).41

As no underlying chronic inflammatory condition was found on our patients, and amyloid deposition was clinically limited to the thyroid, they would be better classified as localized amyloidosis.

One could argue that the presence of amyloid could represent an effect of therapy-associated changes or even a previous chronic condition of the pretreated thyroid (eg, Graves disease), but until more studies become available those statements would be merely speculations. There are no data demonstrating the relationship between Graves as a cause for amyloid deposition on the literature; however, some patients presenting with nonlocalized amyloidosis due to systemic disease can have hypo or hyperfunctional thyroid.42 The former could be explained by mechanical damage and by the replacement of functional glandular tissue by amyloid; however, this concept is not yet fully understood. What is evident in most of the reports in the literature, is that the vast majority of patients with amyloid in the thyroid have normal hormone levels, regardless of the etiology, even after considerably involvement of the gland.40

We are aware that some tissues and extracellular proteins can represent a pitfall in the sense that could be slightly green refringent and interpreted by one as a being amyloid. Many proteins have been described to display congophilic properties and the characteristic β-pleated sheet configuration, therefore is important for the pathologist to be familiar with other available ancillary tests (ie, immunohistochemistry) for definitive histopathologic classification, if needed.13 However, on the day-to-day practice, the pathologist in the vast majority of cases will diagnose this finding as being true amyloid, and no further studies are usually performed.

We propose a diagnostic algorithm to the practicing pathologist when facing with amyloid deposition in the thyroid, applying on their routine (Fig. 4). Therefore, not only we intend to inform that one should be cautious with the presence of amyloid in thyroid, but also alert that not all the cases of “apple-green refringence” mean amyloid.

Figure 4
Figure 4
Image Tools

In regard to therapy options, surgery should be the treatment of choice on malignant cases not because of the amyloid itself, but because of the underlying neoplasm. There is no evidence in the literature that patients would benefit from excision of the gland in benign cases, unless in cases of compressive symptoms that are common presentation in AG, but by definition should never be present in localized amyloidosis. We recommend clinical investigation on positive cases to rule out cases of systemic amyloidosis, and when confirmed, to treat patients as such.

If more studies succeed in reproducing that cases of PTC with amyloid-rich stroma have indeed features of an increased aggressive behavior, a closer follow-up on these patients will be appropriate.

Back to Top | Article Outline

CONCLUSIONS

We discuss the herein the findings of thyroid localized amyloid deposition in both PTC and in benign thyroid disorders with amyloid-rich stroma. This finding is not exclusive of medullary cancer or of AG, as described in this review. We also propose a diagnostic algorithm to the pathologist when facing presence of amyloid deposition in the thyroid.

The relationship between this finding and its real incidence, and if this represents an evidence of a more aggressive behavior when associated with PTC, are still unclear statements.43

The pathophysiological mechanism of amyloid deposition in benign disease probably differs from when in PTC. Better characterization of the amyloid in further studies will help understand the nature of this phenomenon.

Back to Top | Article Outline

REFERENCES

1. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997;337:898–909

2. Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol. 2010;29:1924–1933

3. Virchow R. Ueber den Gang der amyloiden degeneration. Virchows Arch Pathol Anat. 1855;8:364–368

4. Sipe JD Amyloid Proteins. The Beta Sheet Conformation and Disease. 2005 Weinheim WILEY-VCH Verlag GmbH & Co., KGaA

5. Marrink JavRM Amyloidosis. 1986 Dordrecht Martinus Nijhoff

6. Arean VM, Klein RE. Amyloid goiter. Review of the literature and report of a case. Am J Clin Pathol. 1961;36:341–355

7. Sethi Y, Gulati A, Singh I, et al. Amyloid goiter: a case of primary thyroid amyloid disease. Laryngoscope. 2011;121:961–964

8. Khurana R, Agarwal A, Bajpai VK, et al. Unraveling the amyloid associated with human medullary thyroid carcinoma. Endocrinology. 2004;145:5465–5470

9. Cakir M, Grossman AB. Medullary thyroid cancer: molecular biology and novel molecular therapies. Neuroendocrinology. 2009;90:323–348

10. Lin H, Chen MC, Chiu CY, et al. Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells. J Biol Chem. 2007;282:2776–2784

11. Villa F, Dionigi G, Tanda ML, et al. Amyloid goiter. Int J Surg. 2008;6(suppl 1):S16–S18

12. Siddiqui MA, Gertz M, Dean D. Amyloid goiter as a manifestation of primary systemic amyloidosis. Thyroid. 2007;17:77–80

13. Vanguri VK, Nosé V. Transthyretin amyloid goiter in a renal allograft recipient. Endocr Pathol. 2008;19:66–73

14. Hirota S, Miyamoto M, Kasugai T, et al. Crystalline light-chain deposition and amyloidosis in the thyroid gland and kidneys of a patient with myeloma. Arch Pathol Lab Med. 1990;114:429–431

15. Levesque H, Gancel A, Ducastelle T, et al. Thyroid plasmacytoma with amyloid deposits. Report of a case and review of the literature. Rev Med Interne. 1989;10:553–556

16. Martinez Vea A, Carrera M, Ribalta T, et al. Tuberculous granuloma in an amyloid goiter secondary to multiple myeloma. Rev Clin Esp. 1981;162:283–285

17. Juvara I, Simionescu N, Redulescu D. Amyloid goiter with increased thyroid function in a patient with pulmonary tuberculosis. Khirurgiia (Mosk). 1962;38:133–135

18. Kostina ZI. Amyloid goiter in amyloidosis secondary to pulmonary tuberculosis. Probl Tuberk. 1970;48:40–44

19. Gallardo GL, Moya MP, Rey MD, et al. Amyloid goiter secondary to Crohn’s disease. Endocrinol Nutr. 2009;56:384–386

20. Habu S, Watanobe H, Kimura K, et al. A case of amyloid goiter secondary to Crohn’s disease. Endocr J. 1999;46:179–182

21. Kazdaghli Lagha E, M'Sakni I, Bougrine F, et al. Amyloid goiter: first manifestation of systemic amyloidosis. Eur Ann Otorhinolaryngol Head Neck Dis. 2009;127:108–110

22. Altiparmak MR, Pamuk ON, Pamuk GE, et al. Amyloid goitre in familial Mediterranean fever: report on three patients and review of the literature. Clin Rheumatol. 2002;21:497–500

23. Danovitch GM, Le Roith D, Sikuler SE, et al. Amyloid goitre in familial Mediterranean fever. Clin Endocrinol (Oxf). 1979;11:595–601

24. Ozdemir BH, Akman B, Ozdemir FN. Amyloid goiter in familial Mediterranean fever (FMF): a clinicopathologic study of 10 cases. Ren Fail. 2001;23:659–667

25. Sbai A, Wechsler B, Leenhardt L, et al. Amyloid goiter as the initial manifestation of systemic amyloidosis due to familial Mediterranean fever with homozygous MEFV mutation. Thyroid. 2001;11:397–400

26. Turhan Iyidir O, Altay M, Konca Degertekin C, et al. Diffuse amyloid deposition in thyroid gland: a cause for concern in familial Mediterranean fever. Amyloid. 2012;19:161–162

27. Cohan P, Hirschowitz S, Rao JY, et al. Amyloid goiter in a case of systemic amyloidosis secondary to ankylosing spondylitis. J Endocrinol Invest. 2000;23:762–764

28. Duzgun N, Morris Y, Yildiz HI, et al. Amyloid goiter in juvenile onset rheumatoid arthritis. Scand J Rheumatol. 2003;32:253–254

29. Habbick BF, McDicken IW. Amyloid goitre in a patient with rheumatoid arthritis. Scott Med J. 1967;12:405–407

30. Srivastava A, Baxi M, Yadav S, et al. Juvenile rheumatoid arthritis with amyloid goiter: report of a case with review of the literature. Endocr Pathol. 2001;12:437–441 Winter

31. Pinto Valdivia M, Ortiz Torres M, Villena Chavez J. Amyloid goiter secondary to rheumatoid arthritis: a case report. Endocrinol Nutr. 2011;59:76–78

32. D'Antonio A, Franco R, Sparano L, et al. Amyloid goiter: the first evidence in secondary amyloidosis. Report of five cases and review of literature. Adv Clin Path. 2000;4:99–106

33. Goldsmith JD, Lai ML, Daniele GM, et al. Amyloid goiter: report of two cases and review of the literature. Endocr Pract. 2000;6:318–323

34. Coca-Pelaz A, Vivanco-Allende B, Alvarez-Marcos C, et al. Multifocal papillary thyroid carcinoma associated with primary amyloid goiter. Auris Nasus Larynx. 2012;39:549–551

35. Nessim S, Tamilia M. Papillary thyroid carcinoma associated with amyloid goiter. Thyroid. 2005;15:382–385

36. Weng MT, Wong JM, Shin SR, et al. Papillary thyroid cancer associated with light-chain amyloidosis initially presenting with small-bowel bleeding and protein-losing enteropathy. J Clin Oncol. 2010;28:e557–e559

37. Liftin AJ. Non medullary carcinoma of the thyroid gland in association with amyloid goiter: case report. Mt Sinai J Med. 1985;52:225–227

38. Coli A, Bigotti G, Zucchetti F, et al. Papillary carcinoma in amyloid goitre. J Exp Clin Cancer Res. 2000;19:391–394

39. Polliack A, Freund U. Mixed papillary and follicular carcinoma of the thyroid gland with stromal amyloid. Am J Clin Pathol. 1970;53:592–595

40. Hamed G, Heffess CS, Shmookler BM, et al. Amyloid goiter. A clinicopathologic study of 14 cases and review of the literature. Am J Clin Pathol. 1995;104:306–312

41. LiVolsi VA. Papillary thyroid carcinoma: an update. Mod Pathol. 2011;24(suppl 2):S1–S9

42. Kimura H, Yamashita S, Ashizawa K, et al. Thyroid dysfunction in patients with amyloid goitre. Clin Endocrinol (Oxf). 1997;46:769–774

43. Pinto A, Nosé V. Amyloid deposition in papillary thyroid carcinoma: an overlooked event? Mod Pathol. 2012;25(S2):149

Keywords:

amyloid; amyloid goiter; localized amyloid; congo red; papillary thyroid carcinoma; medullary carcinoma

© 2013 Lippincott Williams & Wilkins, Inc.

Login

Article Tools

Images

Share

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.