Follicular Carcinoma of the Thyroid

Background

This is the malignant counterpart for follicular adenomas of the thyroid. The tumors most commonly present as a solitary mass. Unlike papillary carcinoma, this tumor shows a propensity to metastasize via vascular and not lymphatic invasion.

EPIDEMIOLOGY CHARACTERIZATION

INCIDENCE 5% of thyroid carcinomas
As much as 25-40% of thyroid carcinomas in iodine deficient areas

EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION

Iodine deficiency

Older age

Female gender

Radiation exposure

LABORATORY/RADIOLOGIC/OTHER TESTS CHARACTERIZATION

Laboratory Markers

Flow cytometry 60% show aneuploid populations

HISTOLOGICAL TYPES CHARACTERIZATION

General
Minimum criteria for diagnosis:

Invasion of the capsule
Invasion through the capsule
Invasion into veins in or beyond the capsule

Some have required invasive tounges of tumor

Currently, there is debate over whether capsular invasion is sufficient for the diagnosis of cancer
Pathol Annu 1983;18 (Pt 1):221-253
In this study, 1/7 (14%) patients with capsular invasion demonstrated metastases
Cancer 1984;54:535-540
In this study, 3/7 (43%) patients had metastases but metastases were already present at time of initial diagnosis

Some feel that vascular invasion is a more reliable marker of metastatic potential

VARIANTS

Metastatic minimally invasive (encapsulated) follicular and Hurthle cell thyroid carcinoma: a study of 34 patients.

oldstein NS, Czako P, Neill JS.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.

Mod Pathol 2000 Feb;13(2):123-30 Abstract quote

Most studies that have examined minimally invasive, encapsulated, follicular carcinoma (FC) or Hurthle cell carcinomas (HCs) have contained only a few metastatic neoplasms.

We studied 34 patients with a single, minimally invasive, metastatic FC or HC and compared them with 38 patients with similar, nonmetastatic FCs or HCs. The numbers of incomplete capsular penetration (neoplasm into but not through the capsule), complete capsular penetration (neoplasm through the capsule), and vascular invasion foci were quantified.

The median number (three), range, and distribution of complete capsular penetration and vascular invasion foci were similar in the nonmetastatic and metastatic carcinomas. All of the metastatic FCs and HCs had at least one vascular invasion or complete capsular penetration focus. Sixty-two percent of the metastatic carcinomas had two to four complete capsular penetration foci, and 60% had two to four vascular invasion foci. Two metastatic neoplasms had incomplete capsular penetration but had one and two vascular invasion foci, respectively. One tumor had no vascular invasion but had four complete capsular penetration foci. No metastatic neoplasms had incomplete capsular penetration only. There were no differences in the number of vascular invasion or complete capsular penetration foci between metastatic and nonmetastatic FCs and HCs and between metastatic FCs and HCs.

Most metastatic neoplasms had vascular space invasion and complete capsular penetration. The number of complete capsular penetration or vascular invasion foci was not associated with the initial site of metastasis or the interval between the surgery and the metastasis.

Poorly Differentiated Follicular Thyroid Carcinoma with Rhabdoid Phenotype: A Clinicopathologic, Immunohistochemical and Electron Microscopic Study of Two Cases
Mod Pathol 2001;14:98-104 (Abstract quote)

We report two unique thyroid neoplasms that we interpreted as poorly differentiated follicular carcinomas.

Results:
Nodular, trabecular, and sheetlike patterns predominated in both tumors. They were composed of cells that were focally immunoreactive for thyroglobulin and had large vesicular nuclei with prominent nucleoli. A variable number of cells showed rhabdoid phenotype. The rhabdoid inclusions did not stain for thyroglobulin but contained whorls of intermediate filaments that were vimentin positive. There were foci of necrosis and numerous mitotic figures. Both patients were adults and died with multiple pulmonary metastases.

Conclusion:
The presence of rhabdoid cells in poorly differentiated follicular carcinomas broadens the spectrum of tumors with rhabdoid phenotype. More cases are needed to determine whether the rhabdoid phenotype is a marker for poorly differentiated follicular carcinoma as well as an independent adverse prognostic factor.

Why Do Frozen Sections Have Limited Value in Encapsulated or Minimally Invasive Follicular Carcinoma of the Thyroid?

Emmanuelle Leteurtre, etal.

Am J Clin Pathol 2001;115:370-374 (Abstract quote)

The diagnosis of encapsulated or minimally invasive follicular carcinoma of the thyroid requires the proof of vascular or capsular invasion. The aim of the present study was to evaluate the relationship between intraoperative diagnosis (benign, suggestive of carcinoma, or malignant) and the final histopathologic criteria for encapsulated or minimally invasive follicular carcinoma (tumor size, capsular invasion, vascular invasion, and differentiation).

This was a retrospective study of 63 cases of encapsulated or minimally invasive carcinomas, with the final histopathologic diagnosis taken as the "gold standard."

The sensitivity of frozen sections for the diagnosis of malignant neoplasm was 17%. The median number of vascular invasions was 1, identified with a mean number of 9 paraffin-blocks of the tumor.

In most cases, intraoperative frozen sections are unable to establish the proof of malignant neoplasm. Intraoperative study of tumor differentiation is useful to select follicular tumors that require a rapid definitive diagnosis and a completion thyroidectomy within 48 to 72 hours (73% of the cases in our study).

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

Prognostic Factors Poor prognosis include:

Widely invasive tumors
Metastases
Multiple sites of metastases
Age >50 years
Large tumor size
Extensive vascular invasion
Extracapsular extension
Poorly differentiated areas of tumor

Survival Encapsulated tumors confined to thyroid have 10 YRS of 80%

Metastasis
Bone, lungs, brain, liver
Lymph nodes usually spared since tumor tends to spread via blood vessels and not lymphatics

Most metastases occur within 5 years after thyroidectomy although long gaps have been noted

Treatment Total thyroidectomy is usually appropriate for encapsulated cancers

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

Commonly Used Terms

Follicular Adenoma

Thyroid

Last Updated 8/5/2002

Send mail to psdermpath@earthlink.net with questions or comments about this web site.
Copyright � 2002 The Doctor's Doctor

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Minimum criteria for diagnosis: Invasion of the capsule Invasion through the capsule Invasion into veins in or beyond the capsule Some have required invasive tounges of tumor Currently, there is debate over whether capsular invasion is sufficient for the diagnosis of cancer Pathol Annu 1983;18 (Pt 1):221-253 In this study, 1/7 (14%) patients with capsular invasion demonstrated metastases Cancer 1984;54:535-540 In this study, 3/7 (43%) patients had metastases but metastases were already present at time of initial diagnosis Some feel that vascular invasion is a more reliable marker of metastatic potential
VARIANTS
Metastatic minimally invasive (encapsulated) follicular and Hurthle cell thyroid carcinoma: a study of 34 patients. oldstein NS, Czako P, Neill JS. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.	Mod Pathol 2000 Feb;13(2):123-30 Abstract quote Most studies that have examined minimally invasive, encapsulated, follicular carcinoma (FC) or Hurthle cell carcinomas (HCs) have contained only a few metastatic neoplasms. We studied 34 patients with a single, minimally invasive, metastatic FC or HC and compared them with 38 patients with similar, nonmetastatic FCs or HCs. The numbers of incomplete capsular penetration (neoplasm into but not through the capsule), complete capsular penetration (neoplasm through the capsule), and vascular invasion foci were quantified. The median number (three), range, and distribution of complete capsular penetration and vascular invasion foci were similar in the nonmetastatic and metastatic carcinomas. All of the metastatic FCs and HCs had at least one vascular invasion or complete capsular penetration focus. Sixty-two percent of the metastatic carcinomas had two to four complete capsular penetration foci, and 60% had two to four vascular invasion foci. Two metastatic neoplasms had incomplete capsular penetration but had one and two vascular invasion foci, respectively. One tumor had no vascular invasion but had four complete capsular penetration foci. No metastatic neoplasms had incomplete capsular penetration only. There were no differences in the number of vascular invasion or complete capsular penetration foci between metastatic and nonmetastatic FCs and HCs and between metastatic FCs and HCs. Most metastatic neoplasms had vascular space invasion and complete capsular penetration. The number of complete capsular penetration or vascular invasion foci was not associated with the initial site of metastasis or the interval between the surgery and the metastasis.
Poorly Differentiated Follicular Thyroid Carcinoma with Rhabdoid Phenotype: A Clinicopathologic, Immunohistochemical and Electron Microscopic Study of Two Cases	Mod Pathol 2001;14:98-104 (Abstract quote) We report two unique thyroid neoplasms that we interpreted as poorly differentiated follicular carcinomas. Results: Nodular, trabecular, and sheetlike patterns predominated in both tumors. They were composed of cells that were focally immunoreactive for thyroglobulin and had large vesicular nuclei with prominent nucleoli. A variable number of cells showed rhabdoid phenotype. The rhabdoid inclusions did not stain for thyroglobulin but contained whorls of intermediate filaments that were vimentin positive. There were foci of necrosis and numerous mitotic figures. Both patients were adults and died with multiple pulmonary metastases. Conclusion: The presence of rhabdoid cells in poorly differentiated follicular carcinomas broadens the spectrum of tumors with rhabdoid phenotype. More cases are needed to determine whether the rhabdoid phenotype is a marker for poorly differentiated follicular carcinoma as well as an independent adverse prognostic factor.
Why Do Frozen Sections Have Limited Value in Encapsulated or Minimally Invasive Follicular Carcinoma of the Thyroid? Emmanuelle Leteurtre, etal.	Am J Clin Pathol 2001;115:370-374 (Abstract quote) The diagnosis of encapsulated or minimally invasive follicular carcinoma of the thyroid requires the proof of vascular or capsular invasion. The aim of the present study was to evaluate the relationship between intraoperative diagnosis (benign, suggestive of carcinoma, or malignant) and the final histopathologic criteria for encapsulated or minimally invasive follicular carcinoma (tumor size, capsular invasion, vascular invasion, and differentiation). This was a retrospective study of 63 cases of encapsulated or minimally invasive carcinomas, with the final histopathologic diagnosis taken as the "gold standard." The sensitivity of frozen sections for the diagnosis of malignant neoplasm was 17%. The median number of vascular invasions was 1, identified with a mean number of 9 paraffin-blocks of the tumor. In most cases, intraoperative frozen sections are unable to establish the proof of malignant neoplasm. Intraoperative study of tumor differentiation is useful to select follicular tumors that require a rapid definitive diagnosis and a completion thyroidectomy within 48 to 72 hours (73% of the cases in our study).

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE	5% of thyroid carcinomas As much as 25-40% of thyroid carcinomas in iodine deficient areas

EPIDEMIOLOGIC ASSOCIATIONS	CHARACTERIZATION
Iodine deficiency
Older age
Female gender
Radiation exposure

LABORATORY/RADIOLOGIC/OTHER TESTS	CHARACTERIZATION
Laboratory Markers
Flow cytometry	60% show aneuploid populations

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
Prognostic Factors	Poor prognosis include: Widely invasive tumors Metastases Multiple sites of metastases Age >50 years Large tumor size Extensive vascular invasion Extracapsular extension Poorly differentiated areas of tumor
Survival	Encapsulated tumors confined to thyroid have 10 YRS of 80%
Metastasis	Bone, lungs, brain, liver Lymph nodes usually spared since tumor tends to spread via blood vessels and not lymphatics Most metastases occur within 5 years after thyroidectomy although long gaps have been noted
Treatment	Total thyroidectomy is usually appropriate for encapsulated cancers