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.

OUTLINE

Epidemiology
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

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

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
Iodine deficiency
Older age
Female gender
Radiation exposure

 

PATHOGENESIS	CHARACTERIZATION
PAX8-PPAR-GAMMA
PAX8-PPAR? Rearrangement in Thyroid Tumors: RT-PCR and Immunohistochemical Analyses Marina N. Nikiforova, M.D.; Paul W. Biddinger, M.D.; Christy M. Caudill, B.S.; Todd G. Kroll, M.D., Ph.D.; Yuri E. Nikiforov, M.D., Ph.D.	Am J Surg Pathol 2002; 26(8):1016-1023 Abstract quote A PAX8-PPAR? rearrangement has been recently identified in follicular thyroid carcinomas, but not in follicular adenomas or other thyroid tumors. We report here the analyses of PAX8-PPAR? in a series of 118 thyroid tumors using a newly developed RT-PCR assay to detect this rearrangement in frozen and paraffin-embedded tissues and using immunostaining with a PPAR? antibody. PAX8-PPAR? was detected by RT-PCR in eight of 15 (53%) follicular carcinomas and two of 25 (8%) follicular adenomas but not in 35 papillary carcinomas (including 12 follicular variants), 12 Hurthle cell carcinomas, 12 Hurthle cell adenomas, two anaplastic carcinomas, one poorly differentiated carcinoma, or 16 hyperplastic nodules. The prevalence was higher in follicular carcinomas from patients with a history of radiation exposure (three of three). Strong, diffuse nuclear immunostaining with the PPAR? antibody correlated with the presence of PAX8-PPAR? detected by RT-PCR. Most sporadic follicular carcinomas positive for PAX8-PPAR? were overtly invasive, whereas tumors lacking the rearrangement were predominantly minimally invasive. The two follicular adenomas positive for PAX8-PPAR? had trabecular growth pattern and thick capsule, but no invasion, and thus may represent "pre-invasive" follicular carcinomas. The absence of PAX8-PPAR? rearrangements in Hurthle cell tumors and papillary thyroid carcinomas highlights the differences in the molecular pathogenesis of these thyroid tumors.

 

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
Interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma. Franc B, de la Salmoniere P, Lange F, Hoang C, Louvel A, de Roquancourt A, Vilde F, Hejblum G, Chevret S, Chastang C. Department of Pathology, Ambroise Pare Hospital, Boulogne, France.	Hum Pathol. 2003 Nov;34(11):1092-100 Abstract quote.   We evaluated the interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma (FTC). Forty-one anonymous FTC pathology slides were independently reviewed by 5 pathologists, and 31 of them were also evaluated twice by the same pathologist. A final consensus diagnosis (FCD) was made at the end of the study. Interobserver and intraobserver agreement was determined as the kappa statistic for qualitative data and intraclass correlation coefficient for quantitative data. The agreement between the 5 observers' initial diagnosis and the FCD was 0.69, 0.41, 0.35, 0.28 and 0.11, respectively, strongly suggesting a leadership phenomenon. The FCD classified 30 cases as malignant, including 24 cases diagnosed as FTC. There was unanimous agreement about 13 of the 24 FTCs. Diagnostic reproducibility was found to be acceptable for the nonminimally invasive FTC. Diagnostic discrepancies occurred in 57% of the seven cases classified as minimally invasive FTC by the FCD. FCD excluded malignancy in 11 cases including 6 atypical adenomas. Interobserver and intraobserver agreement for FTC diagnosis was 0.23 (standard error [SE], 0.04) and 0.68, respectively. Interobserver and intraobserver agreement for the presence of vascular invasion was 0.20 (SE, 0.04) and 0.51, respectively, contrasting with a moderate to substantial level of agreement when considering the number of vascular invasion. Interobserver and intraobserver agreement for nucleus optical clearing were slight and moderate, respectively. The importance of the study is the confirmation that diagnostic reproducibility of minimally invasive FTC is low and that this has clinical implications, and also implications for the design of studies into the treatment and outcome of FTC.
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
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/ IMMUNO-HISTOCHEMISTRY	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
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.
CYCLOOXYGENASE
Immunohistochemical expression of cyclooxygenase 2 in follicular carcinomas of the thyroid. Haynik DM, Prayson RA. Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.	Arch Pathol Lab Med. 2005 Jun;129(6):736-41. Abstract quote   CONTEXT: Cyclooxygenase 2 (COX-2) has been shown to be up-regulated and/or overexpressed in a variety of human neoplasms. However, limited data exist on the role of COX-2 in follicular carcinomas of the thyroid. Studies in this area are potentially significant, since therapeutic agents that inhibit COX-2 are currently available and could play a role in treatment. DESIGN: A retrospective clinicopathologic review with COX-2 immunohistochemical staining of 34 follicular carcinomas and 7 follicular adenomas with incomplete capsular penetration was performed. RESULTS: The study included 41 patients (25 women; mean age, 50.9 years). All patients underwent gross total resection of the neoplasm. Fifteen carcinoma patients received adjuvant radiotherapy. Seven patients with follicular carcinomas developed recurrent disease: 3 patients were alive (mean follow-up, 10.1 years) and 4 patients died of metastatic disease (mean follow-up, 3.5 years). All remaining patients were disease free (mean follow-up, 5.9 years). Only 1 follicular adenoma with incomplete capsular penetration recurred (patient alive at 9 years). The remaining patients were disease free (mean follow-up, 4.9 years). The COX-2 staining was positive in 11 tumors (9 of 34 follicular carcinomas, 2 of 7 follicular adenomas with incomplete capsular penetration). A greater percentage of recurrences (36% COX-2 positive vs 13% COX-2 negative) and fatal tumors (18% COX-2 positive vs 7% COX-2 negative) occurred in patients who had COX-2-positive staining neoplasms. CONCLUSION: Only a few follicular carcinomas (26%) and follicular adenomas with incomplete capsular penetration (29%) express COX-2 by immunohistochemical analysis. The data suggest that such expression of COX-2 may correlate with increased tumor recurrence and death; however, studies with larger numbers of patients will be needed to establish this.
METASTASES	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
Thyroid Carcinomas With Distant Metastases: A Review of 111 Cases With Emphasis on the Prognostic Significance of an Insular Component Myriam Decaussin, M.D.; Marie Hélène Bernard, M.D.; Patrice Adeleine, Ph.D.; Isabelle Treilleux, M.D., Ph.D.; Jean Louis Peix, M.D., F.R.C.S.; Michel Pugeat, M.D.; Jacques Tourniaire, M.D.; Nicole Berger, M.D.	Am J Surg Pathol 2002; 26(8):1007-1015 Abstract quote Distant metastases (DM) are rare in well-differentiated thyroid carcinomas and correlate with a poor survival. Among the histologic subtypes, insular carcinoma has an intermediate prognosis that lies between well and undifferentiated carcinomas. To assess the characteristics that could predict a worse prognosis, we reviewed the initial thyroid cancer slides from patients with DM. We achieved a comparative statistical analysis with a control group without DM. Among 1230 differentiated carcinomas treated from 1960 to 1999, 9% developed DM. In this group the mean age was 53 years, with a 73% rate of death. The histologic slides were available in 80 cases. The primary thyroid tumors were classified as papillary (51 cases), follicular (25), and pure insular carcinomas (4). Extrathyroidal extension was present in 47% of papillary carcinomas. The mean tumor size was above 5 cm for all the histologic subtypes, and at least a vascular invasion was found in 69%. Fifty-four percent of these tumors had an insular component compared with only 6.5% in the control group. The statistical analysis confirmed by univariate and multivariate logistic regression that the risk of DM was highly elevated in the presence of insular carcinoma. Our study indicates that elevated age, large tumor size, vascular invasion, and extrathyroidal extension are important prognostic factors in well-differentiated carcinomas. We also demonstrate that the presence of an insular component in an otherwise differentiated carcinoma is a strong independent poor prognostic factor.
SURVIVAL	Encapsulated tumors confined to thyroid have 10 YRS of 80%
TREATMENT	Total thyroidectomy is usually appropriate for encapsulated cancers

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Last Updated June 7, 2005

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