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Follicular Adenoma

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Definition

Benign encapsulated thyroid tumor that shows evidence of follicular cell differentiation.

Clinical Features

Most common thyroid neoplasm
Usually occurs in euthyroid adult
Thyroid lump
Scan of lump:
- usually ‘cold’
- sometimes ‘cool’ or ‘warm’
- rarely ‘hot’
Elevated thyroglobulin levels common1 but clinical hyperthyroidism (toxic adenomas) uncommon2,3
Autonomously functioning tumors may be more common in regions with iodine deficiency 4

Gross Pathology

Characteristically:
- solitary (except when part of a genetically determined syndrome)
- secondary degenerative changes, especially for larger tumors such as
  - hemorrhage (Figs 1 and 2
    Fig. 1: Gross appearance of follicular adenoma showing focal hemorrhagic areas.
    Fig. 2: Gross appearance of follicular adenoma showing focal hemorrhagic areas.
    )
  - edema
  - fibrosis
  - calcification
  - bone formation
  - cystic degeneration
- surrounded by a generally thin capsule that is grossly and microscopically complete (Fig. 3
  Fig. 3: Intact fibrous capsule around a follicular adenoma.
  )
Architectural and cytologic features differ from those of surrounding gland, which usually shows signs of compression

Histopathology

A variety of patterns, singly or in combination:
- normofollicular (simple)
- macrofollicular (colloid)
- microfollicular (fetal; Fig. 4
  Fig. 4: Microfollicular pattern of growth in a follicular adenoma.
  )
- trabecular/solid (embryonal)
Morphologic differences between patterns may be striking, but no apparent clinical significance
Mitoses:
- rare or absent
- not necessarily indicators of malignancy
- when present in appreciable numbers, sample and examine the specimen with care
Sometimes:
- vessels in the capsule and at the periphery of hyperplastic nodules show prominent focal thickenings of their wall (muscular cushions)5
- papillary or pseudopapillary structures (may prompt confusion with papillary carcinoma) - follicular adenoma with papillary architecture6
The microscopic appearance has some correlation with activity as judged by the scan appearance:7,8
- in general, hyperfunctioning (hot) adenomas are more cellular and the cells have more abundant cytoplasm (and a lower nucleocytoplasmic ratio) than nonfunctioning (cold) tumors
Hot thyroid nodules exhibit a wide range of morphologic appearances, including less well differentiated and oncocytic patterns.

Special Stains and Immunohistochemistry

Name	+/-	% positive	References
Thyroglobulin	+	100	2 references
TTF	+	100	1 reference
AE1 AE3	+	100	1 reference

Thyroglobulin: Limited value
TTF: Limited value
AE1 AE3: Limited value

Enzyme histochemical and immunohistochemical profile mirrors that of the normal follicle 9
Reactivity for:
- low-molecular-weight keratin and thyroglobulin in the cytoplasm
- laminin and other basement membrane components around the follicles10
DNA ploidy analysis does not add to the prognostic prediction after a properly performed microscopic examination11–14
DNA aneuploidy:
- found in about one-quarter of follicular adenomas
- slightly more common in cellular types
- not an indicator of clinical malignancy or increased risk of tumor recurrence

Diagnosis

Several variants have been described, including:
- Hürthle cell adenoma
- hyalinizing trabecular adenoma
Atypical adenoma:
- no capsular or blood vessel invasion 15–17
Adenoma with bizarre nuclei:
- no features of malignancy (Figs 5 and 6
  Fig. 5: Low-power view of follicular adenoma with bizarre nuclei. This feature is not a sign of malignancy and is analogous to that seen in many other endocrine tumors.
  Fig. 6: High-power view of follicular adenoma with bizarre nuclei. This feature is not a sign of malignancy and is analogous to that seen in many other endocrine tumors.
  )
- analogous to that seen in parathyroid adenomas and other endocrine neoplasms
Rare types of follicular adenoma:
- clear cell changes (including signet ring, mucin-producing, and lipid-rich types)
- adipose metaplasia of the stroma (adenolipoma)18
- cartilaginous metaplasia (adenochondroma)19
- massive deposition of cytoplasmic black pigment following minocycline therapy (black adenoma)20

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Follicular Adenoma

Dominant nodule of nodular hyperplasia
Minimally invasive follicular carcinoma
Follicular variant of papillary carcinoma
Vascular tumors:
- some follicular adenomas are highly vascularized

Genetics

Analysis of X chromosomes in mice21 and humans.22,23 support a clonal origin
No consistent abnormalities in oncogenes 24
Abnormalities in the terminal region of the long arm of chromosome 1925
Cowden's disease:
- genetically determined
- variety of thyroid abnormalities - multiple follicular adenomas are the most common, often associated with hyperplastic nodules26

Management

Standard therapy is lobectomy
Enucleation should not be attempted
Results of suppression with levothyroxine and treatment of toxic adenoma with 131I less than satisfactory27,28

Prognosis

Hot thyroid nodules are usually benign 29

References

1 Shlossberg AH, Jacobson JC, Ibbertson HK. Serum thyroglobulin in the diagnosis and management of thyroid carcinoma. Clin Endocrinol. 1979;10:17–27.

2 Mizukami Y, Michigishi T, Nonomura A, Yokoyama K, Noguchi M, Hashimoto T, et al. Autonomously functioning (hot) nodule of the thyroid gland. A clinical and histopathologic study of 17 cases. Am J Clin Pathol. 1994;101:29–35.

3 Panke TW, Croxson MS, Parker JW, Carriere DP, Rosoff L, Warner NE. Triiodothyronine-secreting (toxic) adenoma of the thyroid gland. Light and electron microscopic characteristics. Cancer. 1978;41:528–537.

4 Belfiore A, Sava L, Runello F, Tomaselli L, Vigneri R. Solitary autonomously functioning thyroid nodules and iodine deficiency. J Clin Endocrinol Metab. 1983;56:283–287.

5 Sapino A, Cassoni P, Papotti M, Bussolati G. Muscular cushions of the vessel wall at the periphery of thyroid nodules. Mod Pathol. 1999;12:879–884.

6 Mai KT, Landry DC, Thomas J, Burns BF, Commons AS, Yazdi HM, et al. Follicular adenoma with papillary architecture: a lesion mimicking papillary thyroid carcinoma. Histopathology. 2001;39:25–32.

7 Campbell WL, Santiago HE, Perzin KH, Johnson PM. The autonomous thyroid nodule. Correlation of scan appearance and histopathology. Radiology. 1973;107:133–138.

8 Hamburger JI. Solitary autonomously functioning thyroid lesions. Diagnosis, clinical features and pathogenetic considerations. Am J Med. 1975;58:740–748.

9 Cohen MB, Miller TR, Beckstead JH. Enzyme histochemistry and thyroid neoplasia. Am J Clin Pathol. 1986;85:668–673.

10 Miettinen M, Virtanen I. Expression of laminin in thyroid gland and thyroid tumors. An immunohistologic study. Int J Cancer. 1984;34:27–30.

11 Hostetter AL, Hrafnkelsson J, Wingren SO, Enestrom S, Nordenskjöld B. A comparative study of DNA cytometry methods for benign and malignant thyroid tissue. Am J Clin Pathol. 1988;89:760–763.

12 Hruban RH, Huvos AG, Traganos F, Reuter V, Lieberman PH, Melamed MR. Follicular neoplasms of the thyroid in men older than 50 years of age. A DNA flow cytometric study. Am J Clin Pathol. 1990;94:527–532.

13 Oyama T, Vickery AL, Preffer FI, Colvin RB. A comparative study of flow cytometry and histopathological findings in thyroid follicular carcinomas and adenomas. Hum Pathol. 1994;25:271–275.

14 Zedenius J, Auer G, Backdahl M, Falkmer U, Grimelius L, Lundell G, et al. Follicular tumors of the thyroid gland. Diagnosis, clinical aspects and nuclear DNA analysis. World J Surg. 1992;16:589–594.

15 Fukunaga M, Shinozaki N, Endo Y, Ushigome S. Atypical adenoma of the thyroid. A clinico-pathologic and flow cytometric DNA study in comparison with other follicular neoplasms. Acta Pathol Jpn. 1992;42:632–638.

16 Hazard JB, Kenyon R. Atypical adenoma of the thyroid. Arch Pathol. 1954;58:554–563.

17 Lang W, Georgii A, Stauch G, Kienzle E. The differentiation of atypical adenomas and encapsulated follicular carcinomas in the thyroid gland. Virchows Arch [A]. 1980;385:125–141.

18 Gnepp DR, Ogorzalek JM, Heffess CS. Fat-containing lesions of the thyroid gland. Am J Surg Pathol. 1989;13:605–612.

19 Visoná A, Pea M, Bozzola L, Stracca-Pansa V, Meli S. Follicular adenoma of the thyroid gland with extensive chondroid metaplasia. Histopathology. 1991;18:278–279.

20 Koren R, Bernheim J, Schachter P, Schwartz A, Siegel A, Gal R. Black thyroid adenoma: Clinical, histochemical, and ultrastructural features. AIMM. 2000;8:80–84.

21 Thomas GA, Williams D, Williams ED. The clonal origin of thyroid nodules and adenomas. Am J Pathol. 1989;134:141–147.

22 Hicks DG, LiVolsi VA, Neidich JA, Puck JM, Kant JA. Clonal analysis of solitary follicular nodules in the thyroid. Am J Pathol. 1990;137:553–562.

23 Namba H, Matsuo K, Fagin JA. Clonal composition of benign and malignant human thyroid tumors. J Clin Invest. 1990;86:120–125.

24 Karga H, Lee JK, Vickery AL, Thor A, Gaz RD, Jameson JL. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab. 1991;73:832–836.

25 Dal Cin P, Sneyers W, Aly MS, Segers A, Ostijn F, Van Damme B, et al. Involvement of 19q13 in follicular thyroid adenoma. Cancer Genet Cytogenet. 1992;60:99–101.

26 Harach HR, Soubeyran I, Brown A, Bonneau D, Longy M. Thyroid pathologic findings in patients with Cowden disease. Ann Diagn Pathol. 1999;3:331–340.

27 Gharib H, James EM, Charboneau JW, Naessens JM, Offord KP, Gorman CA. Suppressive therapy with levothyroxine for solitary thyroid nodules. A double-blind controlled clinical study. N Engl J Med. 1987;317:70–75.

28 Goldstein R, Hart IR. Follow-up of solitary autonomous thyroid nodules treated with 131I. N Engl J Med. 1983;309:1473–1476.

29 Harach HR, Sanchez SS, Williams ED. Pathology of the autonomously functioning (hot) thyroid nodule. Ann Diagn Pathol. 2002;6:10–19.

Last updated: 27 Nov 2005