Follicular Adenoma of the Thyroid

Background

The follicular adenoma of the thyroid is a common benign tumor of the thyroid gland. They present as a solitary nodule, usually as a painless mass. It may be found during a routine physical examination. A physician may order a nuclear medicine thyroid scan which measures uptake of radionucleotide labelled iodine. Adenomas are usually cold nodules since they usually take up less radioactive iodine than normal surrounding gland. On the other hand, about 10% of cold nodules are malignant. Conversely, hot nodules are only rarely malignant.

Once the nodule is identified, additional diagnostic techniques including an ultrasound examination which may identify a cystic component may be helpful. A pathologist may perform a fine needle aspiration biopsy to obtain diagnostic cytology. In the case of a follicular adenoma, a diagnosis of follicular neoplasm-adenoma versus carcinoma, may be rendered. On cytologic examination, a pathologist cannot make the distinction between an adenoma versus a carcinoma. An excisional biopsy must be obtained. The pathologist must carefully embed the entire capsule in order to exclude capsular invasion, the hallmark of malignancy.

OUTLINE

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/Immunohistochemistry/Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

DISEASE ASSOCIATIONS CHARACTERIZATION

EXTERNAL RADIATION Variable delay after exposure
May show aggressive features

Risk of thyroid carcinoma in a female population after radiotherapy for breast carcinoma.

Huang J, Walker R, Groome PG, Shelley W, Mackillop WJ.

The Radiation Oncology Research Unit, Department of Oncology, Queen's University, Kingston Regional Cancer Center, Kingston, Ontario, Canada.

Cancer 2001 Sep 15;92(6):1411-1418 Abstract quote

BACKGROUND: There is increasing concern regarding the risk of developing a second primary tumor in adjacent organs as a result of scattered radiation among patients who have undergone radiotherapy (RT) for breast carcinoma. Previous studies have focused mainly on the possible increase in the incidence of contralateral breast carcinoma. To the authors' knowledge, the risk of thyroid carcinoma among these women has not been explored to date.

METHODS: In this population-based, retrospective cohort study, the authors identified 194,798 women who were diagnosed with invasive breast carcinoma (exclusive of those with distant metastasis) between 1973 and 1993, and ascertained subsequent cases of thyroid carcinoma utilizing data from the Surveillance, Epidemiology, and End Results (SEER) program of the U.S. National Cancer Institute. Poisson regression was used to calculate the age-standardized incidence ratio (SIR) of thyroid carcinoma and to model the influence of RT on the relative risk (RR) between the RT cohort (48,495 women) and the non-RT cohort (146,303 women).

RESULTS: A total of 28 women in the RT cohort and 112 women in the non-RT cohort subsequently developed thyroid carcinoma. The distribution of thyroid carcinoma histologies in both the RT cohort and the non-RT cohort was similar to that in the female general population. Overall, there was no significant increase in the risk of thyroid carcinoma in either the RT cohort or the non-RT cohort compared with the general population; the SIR was 1.1 (95% confidence interval [95% CI], 0.8-1.6) for the RT cohort and 1.2 (95% CI, 1.0-1.4) for the non-RT cohort. When the RT cohort was compared with the non-RT cohort, the RR of thyroid carcinoma was 1.0 (95%CI, 0.7-1.5).

CONCLUSIONS: The risk of radiation-associated thyroid carcinoma after initial RT for breast carcinoma was so low as to be undetectable in the current large population-based study. Continued monitoring of these women will be required to document that these findings are maintained with even longer follow-up periods. However, with 10,895 women having been followed for > 10 years at the time of last follow-up in the current study, these findings should be reassuring to women considering RT for their breast carcinoma. Therefore, women who have received RT for breast carcinoma require no special surveillance for their thyroid gland. Furthermore, previous breast radiation need not be a factor in determining the optimal management of thyroid nodules arising in women who received RT for breast carcinoma.

PATHOGENESIS CHARACTERIZATION

TSH receptor
Couples the alpha subunit of the stimulating guanine nucleotide binding protein Gs

This activates adenylate cyclase leading to intracellular increases of cAMP

This activates genes that control the production of thyroid hormone and proliferation of thyroid epithelial cells

Somatic mutations
Mutations occurring in the components of the signalling system may cause chronic stimulation of the cAMP pathway

Somatic mutations found in Gsalpha in 12-38% of adenomas

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION

General
Solitary, spherical and encapsulated tumor demarcated from the surrounding thyroid gland

Average 3 cm in diameter

May range up to 10 cm

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL Uniform appearing follicles containing colloid

Colloid Large colloid filled follicles

Fetal Numerous small well developed follicles lined by flattened epithelial cells

Trabecular Closely packed cells forming cords or trabeculae

Hurthle Large eosinophilic granular cells

Atypical adenomas Pleomorphism and variability in cell and nuclear size

Is atypical follicular adenoma of the thyroid a preinvasive malignancy?

Tzen CY, Huang YW, Fu YS.

Hum Pathol. 2003 Jul;34(7):666-9. Abstract quote
Among the follicular neoplasms of the thyroid, the definition and nature of atypical adenoma have been confusing. Despite the original speculation about the biologic behavior of preinvasive malignancies, this term is currently used as an expression of uncertainty.

To examine the molecular features of a typical adenoma, we analyzed the p53 genes in 2 atypical adenomas and 12 control lesions (6 typical follicular adenomas and 6 follicular carcinomas). Mutations of p53 were detected in the bizarre cells of the atypical adenomas, but not in the bland-looking follicular cells or in the control specimens. Both atypical adenomas showed an identical point mutation in codon 273 (CGT-->CAT), a common mutation in various human cancers, including anaplastic carcinoma of the thyroid.

This finding supports the view that atypical follicular adenoma is a precursor of thyroid anaplastic carcinoma and suggests that "atypical adenoma" should not be used to express diagnostic uncertainty about the nature of a lesion.

Papillary adenomas
Papillary excrescences within large follicular or cystic spaces

Observer Variation of Encapsulated Follicular Lesions of the Thyroid Gland

Mitsuyoshi Hirokawa, M.D.; J. Aidan Carney, M.D.; John R. Goellner, M.D.; Ronald A. DeLellis, M.D.; Clara S. Heffess, M.D.; Ryohei Katoh, M.D.; Masahiko Tsujimoto, M.D.; Kennichi Kakudo, M.D.

Am J Surg Pathol 2002; 26(11):1508-1514 Abstract quote

Although histologic definition of follicular thyroid lesions is readily available, application of the diagnostic criteria and personal experience may lead to disagreement among pathologists.

To investigate interobserver variation in assessment of encapsulated follicular lesions, eight pathologists (four American and four Japanese) reviewed the same hematoxylin and eosin-stained slide of each of 21 cases of thyroid lesions showing encapsulation and follicular growth pattern. In 10% of the cases, there was complete agreement. At least seven pathologists agreed on the diagnosis in 29% of the cases, and at least six in 76% of the cases. American and Japanese pathologists agreed among themselves in 33% and 52% of cases, respectively.

The frequency of diagnosis of adenomatous goiter among Japanese pathologists (31%) was considerably higher than that among American pathologists (6%). In contrast, the frequency of diagnosis (25%) of papillary carcinoma among American pathologists was considerably higher than that (4%) among Japanese pathologists.

Our analysis revealed three main factors affecting observer variation: 1) interpretation of the significance of microfollicles intimately related to capillaries within the tumor capsule, 2) evaluation of what constituted the type of nuclear clearing indicative of papillary carcinoma, and 3) absence of clear morphologic criteria for separation of adenomatous goiter and follicular adenoma.

To reduce observer variation of encapsulated follicular lesions, it will be necessary to provide more explicit criteria for diagnosis.

VARIANTS

SPINDLE CELL METAPLASIA

Spindle Cell Metaplasia of the Thyroid Arising in Association With Papillary Carcinoma and Follicular Adenoma

JoAnne Vergilio, MD, Zubair W. Baloch, MD, PhD, and Virginia A. LiVolsi, MD

Am J Clin Pathol 2002;117:199-204 Abstract quote

Spindle cell proliferations of the thyroid have been described in association with reactive processes and aggressive malignant neoplasms.

We describe spindle cell proliferations in 10 patients arising in association with papillary carcinoma and follicular adenoma. The spindle proliferations were 0.3 to 3.0 cm in size, constituted from 1% to 95% of the primary neoplasm, and were either admixed with the neoplastic elements or peripherally located within the primary tumor.

Cytologically, these proliferations showed bland-appearing spindle cells with fine chromatin and subtle nucleoli. Mitoses were rare, and inflammation was minimal. Immunostains showed reactivity with thyroglobulin, indicating their follicular origin. We believe it is important to recognize these metaplastic proliferations and distinguish them from aggressive malignant neoplasms.

SPECIAL STAINS/IMMUNOHISTOCHEMISTRY CHARACTERIZATION

RET

Interpretation of RET Immunostaining in Follicular Lesions of the Thyroid

Lisa A. Cerilli, MD, Stacey E. Mills, MD, Craig A. Rumpel, MS, Thomas H. Dudley, MD, and Christopher A. Moskaluk, MD, PhD
Am J Clin Pathol 2002;118:186-193 Abstract quote

We applied monoclonal antibodies against RET and cytokeratin 19 (CK19) to the following tumor sections: classic papillary carcinoma (PC), 16; Hürthle-type PC (HPC), 1; sclerosing PC with nodular fasciitis–like stroma (SPC), 1; PC, follicular variant (FVPC), 12; follicular adenoma (FA), 9; Hürthle cell adenoma (HA), 4; Hürthle cell carcinoma (HC), 3; and follicular carcinoma (FC), 7.

CK19+ tumors included 16 PCs, 1 HPC, 1 SPC, 11 FVPCs, 7 FAs, 4 FCs, and 1 HC. RET+ tumors included 4 HAs, 3 HCs, 1 HPC, 12 PCs, 7 FVPCs, and 2 FAs. Reverse transcriptase–polymerase chain reaction (RT-PCR) revealed a RET transcript in 6 Hürthle cell lesions.

RET immunoreactivity is less sensitive and specific for PC than CK19. CK19 is useful for identifying PC, although only lesions with diffuse, intense staining should be considered positive. The detection of RET protein by immunohistochemical analysis was corroborated by the presence of the RET transcript by RT-PCR. Further study is warranted to determine whether this represents activation by gene fusion or some other mechanism in this subset of thyroid neoplasms.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSIS

CHROMOSOMAL ALTERATIONS

A novel microdissection and genotyping of follicular-derived thyroid tumors to predict aggressiveness.

Hunt JL, Livolsi VA, Baloch ZW, Swalsky PA, Bakker A, Sasatomi E, Finkelstein S, Barnes EL.

University of Pittsburgh Medical Center, Pittsburgh, PA and University of Pennsylvania Medical Center, Philadelphia, PA.

Hum Pathol 2003 Apr;34(4):375-80 Abstract quote
Distinguishing thyroid follicular adenoma from minimally invasive or encapsulated angioinvasive carcinoma can be diagnostically challenging. In some cases, tumors are distorted, fragmented, or stripped of their capsule, and a definitive diagnosis becomes nearly impossible. In other cases, the foci of capsular and/or vascular invasion are subtle, thus making the diagnosis of carcinoma difficult.

We developed a microdissection genotyping assay for assessing a panel of tumor-suppressor genes for loss of heterozygosity mutations. The frequency of allelic loss (FAL) in follicular-derived neoplasms correlates with the histologic aggressiveness of the tumor. Furthermore, we calculated the amount of genetic heterogeneity within each tumor, as a second important measure of a tumor's ability for clonal expansion and a surrogate marker for its malignant potential. The follicular adenomas had a low FAL (average 9%) and low intratumoral heterogeneity (5% variability). The minimally invasive and encapsulated angioinvasive carcinomas had an intermediate FAL (average 30%) and intermediate intratumoral heterogeneity (10% variability). The widely invasive carcinomas had a high FAL (average 53%) and high intratumoral heterogeneity (24% variability).

Although a larger retrospective study is needed to correlate genotyping studies with patient outcome and prognosis, our results indicate that performing a mutational genotyping assay can stratify tumors into the histologically well-defined categories of adenomas, minimally invasive/angioinvasive carcinomas, and widely invasive follicular carcinomas.

Treatment Simple excision

Diagnostic Surgical Pathology Third Edition. Sternberg S. Editor. Lippincott Williams Wilkins 1999.

Commonly Used Terms

Follicular Carcinoma of the Thyroid

Thyroid

Basic Principles of Disease
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Commonly Used Terms
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Diagnostic Process
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Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
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Internet Links

Last Updated 8/1/2003

Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL	Uniform appearing follicles containing colloid
Colloid	Large colloid filled follicles
Fetal	Numerous small well developed follicles lined by flattened epithelial cells
Trabecular	Closely packed cells forming cords or trabeculae
Hurthle	Large eosinophilic granular cells
Atypical adenomas	Pleomorphism and variability in cell and nuclear size
Is atypical follicular adenoma of the thyroid a preinvasive malignancy? Tzen CY, Huang YW, Fu YS.	Hum Pathol. 2003 Jul;34(7):666-9. Abstract quote Among the follicular neoplasms of the thyroid, the definition and nature of atypical adenoma have been confusing. Despite the original speculation about the biologic behavior of preinvasive malignancies, this term is currently used as an expression of uncertainty. To examine the molecular features of a typical adenoma, we analyzed the p53 genes in 2 atypical adenomas and 12 control lesions (6 typical follicular adenomas and 6 follicular carcinomas). Mutations of p53 were detected in the bizarre cells of the atypical adenomas, but not in the bland-looking follicular cells or in the control specimens. Both atypical adenomas showed an identical point mutation in codon 273 (CGT-->CAT), a common mutation in various human cancers, including anaplastic carcinoma of the thyroid. This finding supports the view that atypical follicular adenoma is a precursor of thyroid anaplastic carcinoma and suggests that "atypical adenoma" should not be used to express diagnostic uncertainty about the nature of a lesion.
Papillary adenomas	Papillary excrescences within large follicular or cystic spaces
Observer Variation of Encapsulated Follicular Lesions of the Thyroid Gland Mitsuyoshi Hirokawa, M.D.; J. Aidan Carney, M.D.; John R. Goellner, M.D.; Ronald A. DeLellis, M.D.; Clara S. Heffess, M.D.; Ryohei Katoh, M.D.; Masahiko Tsujimoto, M.D.; Kennichi Kakudo, M.D.	Am J Surg Pathol 2002; 26(11):1508-1514 Abstract quote Although histologic definition of follicular thyroid lesions is readily available, application of the diagnostic criteria and personal experience may lead to disagreement among pathologists. To investigate interobserver variation in assessment of encapsulated follicular lesions, eight pathologists (four American and four Japanese) reviewed the same hematoxylin and eosin-stained slide of each of 21 cases of thyroid lesions showing encapsulation and follicular growth pattern. In 10% of the cases, there was complete agreement. At least seven pathologists agreed on the diagnosis in 29% of the cases, and at least six in 76% of the cases. American and Japanese pathologists agreed among themselves in 33% and 52% of cases, respectively. The frequency of diagnosis of adenomatous goiter among Japanese pathologists (31%) was considerably higher than that among American pathologists (6%). In contrast, the frequency of diagnosis (25%) of papillary carcinoma among American pathologists was considerably higher than that (4%) among Japanese pathologists. Our analysis revealed three main factors affecting observer variation: 1) interpretation of the significance of microfollicles intimately related to capillaries within the tumor capsule, 2) evaluation of what constituted the type of nuclear clearing indicative of papillary carcinoma, and 3) absence of clear morphologic criteria for separation of adenomatous goiter and follicular adenoma. To reduce observer variation of encapsulated follicular lesions, it will be necessary to provide more explicit criteria for diagnosis.
VARIANTS
SPINDLE CELL METAPLASIA
Spindle Cell Metaplasia of the Thyroid Arising in Association With Papillary Carcinoma and Follicular Adenoma JoAnne Vergilio, MD, Zubair W. Baloch, MD, PhD, and Virginia A. LiVolsi, MD	Am J Clin Pathol 2002;117:199-204 Abstract quote Spindle cell proliferations of the thyroid have been described in association with reactive processes and aggressive malignant neoplasms. We describe spindle cell proliferations in 10 patients arising in association with papillary carcinoma and follicular adenoma. The spindle proliferations were 0.3 to 3.0 cm in size, constituted from 1% to 95% of the primary neoplasm, and were either admixed with the neoplastic elements or peripherally located within the primary tumor. Cytologically, these proliferations showed bland-appearing spindle cells with fine chromatin and subtle nucleoli. Mitoses were rare, and inflammation was minimal. Immunostains showed reactivity with thyroglobulin, indicating their follicular origin. We believe it is important to recognize these metaplastic proliferations and distinguish them from aggressive malignant neoplasms.

SPECIAL STAINS/IMMUNOHISTOCHEMISTRY	CHARACTERIZATION
RET
Interpretation of RET Immunostaining in Follicular Lesions of the Thyroid Lisa A. Cerilli, MD, Stacey E. Mills, MD, Craig A. Rumpel, MS, Thomas H. Dudley, MD, and Christopher A. Moskaluk, MD, PhD	Am J Clin Pathol 2002;118:186-193 Abstract quote We applied monoclonal antibodies against RET and cytokeratin 19 (CK19) to the following tumor sections: classic papillary carcinoma (PC), 16; Hürthle-type PC (HPC), 1; sclerosing PC with nodular fasciitis–like stroma (SPC), 1; PC, follicular variant (FVPC), 12; follicular adenoma (FA), 9; Hürthle cell adenoma (HA), 4; Hürthle cell carcinoma (HC), 3; and follicular carcinoma (FC), 7. CK19+ tumors included 16 PCs, 1 HPC, 1 SPC, 11 FVPCs, 7 FAs, 4 FCs, and 1 HC. RET+ tumors included 4 HAs, 3 HCs, 1 HPC, 12 PCs, 7 FVPCs, and 2 FAs. Reverse transcriptase–polymerase chain reaction (RT-PCR) revealed a RET transcript in 6 Hürthle cell lesions. RET immunoreactivity is less sensitive and specific for PC than CK19. CK19 is useful for identifying PC, although only lesions with diffuse, intense staining should be considered positive. The detection of RET protein by immunohistochemical analysis was corroborated by the presence of the RET transcript by RT-PCR. Further study is warranted to determine whether this represents activation by gene fusion or some other mechanism in this subset of thyroid neoplasms.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
CHROMOSOMAL ALTERATIONS
A novel microdissection and genotyping of follicular-derived thyroid tumors to predict aggressiveness. Hunt JL, Livolsi VA, Baloch ZW, Swalsky PA, Bakker A, Sasatomi E, Finkelstein S, Barnes EL. University of Pittsburgh Medical Center, Pittsburgh, PA and University of Pennsylvania Medical Center, Philadelphia, PA.	Hum Pathol 2003 Apr;34(4):375-80 Abstract quote Distinguishing thyroid follicular adenoma from minimally invasive or encapsulated angioinvasive carcinoma can be diagnostically challenging. In some cases, tumors are distorted, fragmented, or stripped of their capsule, and a definitive diagnosis becomes nearly impossible. In other cases, the foci of capsular and/or vascular invasion are subtle, thus making the diagnosis of carcinoma difficult. We developed a microdissection genotyping assay for assessing a panel of tumor-suppressor genes for loss of heterozygosity mutations. The frequency of allelic loss (FAL) in follicular-derived neoplasms correlates with the histologic aggressiveness of the tumor. Furthermore, we calculated the amount of genetic heterogeneity within each tumor, as a second important measure of a tumor's ability for clonal expansion and a surrogate marker for its malignant potential. The follicular adenomas had a low FAL (average 9%) and low intratumoral heterogeneity (5% variability). The minimally invasive and encapsulated angioinvasive carcinomas had an intermediate FAL (average 30%) and intermediate intratumoral heterogeneity (10% variability). The widely invasive carcinomas had a high FAL (average 53%) and high intratumoral heterogeneity (24% variability). Although a larger retrospective study is needed to correlate genotyping studies with patient outcome and prognosis, our results indicate that performing a mutational genotyping assay can stratify tumors into the histologically well-defined categories of adenomas, minimally invasive/angioinvasive carcinomas, and widely invasive follicular carcinomas.
Treatment	Simple excision