Background

We have all seen pictures of people with goiters, with enlargement of the neck.  Fortunately, iodized salt has eliminated most cases of nutritional goiter, though goiter still exists but for other reasons.  A pathologist often performs a fine needle aspiration when a mass can be felt.  Examination of the cytology smear can often produce a definitive diagnosis, obviating the need for a surgical biopsy. Intraoperative consultations usually require a frozen section to assess the margins of the tumor or to make a definitive diagnosis.

General Reference

• American Thyroid Association
• Normal Thyroid-Gross Photo
• Normal Thyroid-Microscopic Photo
• Normal Thyroid C Cells-Microscopic Photo

Anaplastic Carcinoma of the Thyroid
Follicular Adenoma
Follicular Carcinoma
Hashimoto's Thyroiditis
Hyalinizing Trabecular Tumors of the Thyroid
Hurthle Cell Tumors
Lymphoma of the Thyroid
Medullary Carcinoma of the Thyroid
Mucoepidermoid Carcinoma of the Thyroid
Papillary Carcinoma of the Thyroid

OUTLINE

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

DISEASE ASSOCIATIONS	CHARACTERIZATION
OVARIAN ADENOFIBROMAS
The association of benign and malignant ovarian adenofibromas with breast cancer and thyroid disorders. Silva EG, Tornos C, Malpica A, Deavers MT, Tortolero-Luna G, Gershenson DM. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.	Int J Surg Pathol 2002 Jan;10(1):33-9 Abstract quote An unexpected association with breast cancer and thyroid disorders was found during a review of 91 cases of benign and malignant ovarian adenofibromas. Sixty-three tumors were benign, 11 had areas of borderline neoplasms, and 17 had a component of carcinoma. Such tumors were divided into glandular/cystic (61 cases) and papillary (30 cases) according to their gross and microscopic appearance. Among the 61 patients with glandular/cystic adenofibromas, 13 (21%) had breast cancer and 19 (31%) also had thyroid disorders. Among the 30 patients with papillary adenofibromas there were no cases of breast cancer and only 2 patients had thyroid disorders. The average age of the patients with ovarian adenofibroma and breast cancer or thyroid disorders was higher (66 years) than that of patients without breast cancer or thyroid disorders (55 years). More patients with breast cancer and thyroid disorders had bilateral adenofibromas than patients without breast cancer or thyroid disorders. We also reviewed the medical records of 100 patients with ovarian cancer without adenofibroma component, 100 patients with breast cancer, and 100 patients with ovarian and breast cancer. Six percent of patients with ovarian cancer had breast cancer and 16% of each one of these groups had thyroid disorders. This unexpected association found between glandular/cystic adenofibromas, breast cancer, and thyroid disorders might be explained by defects common to these organs. Disorders of some of these organs have been linked by common genetic changes and it is known that these organs are under the influence of similar hormones. Mutations of PTEN have been found in breast and thyroid cancer. The thyroid and ovaries are controlled by glycoprotein hormones of the pituitary gland, which have common alpha subunits.

 

PATHOGENESIS	CHARACTERIZATION
ESTROGEN RECEPTORS
Estrogen Receptors (alpha and beta) and 17beta-Hydroxysteroid Dehydrogenase Type 1 and 2 in Thyroid Disorders: Possible In Situ Estrogen Synthesis and Actions. Kawabata W, Suzuki T, Moriya T, Fujimori K, Naganuma H, Inoue S, Kinouchi Y, Kameyama K, Takami H, Shimosegawa T, Sasano H. Department of Pathology, Tohoku University School of Medicine (WK, TS, TM, HS), Sendai, Japan.	Mod Pathol 2003 May;16(5):437-44 Abstract quote Both epidemiological and experimental findings suggest the possible roles of sex steroids in the pathogenesis and/or development of various human thyroid disorders. In this study, we evaluated the expression of estrogen receptors (ER) alpha and beta in normal thyroid glands (N = 25; female: n = 13, male: n = 10, unknown: n = 2) ranging in age from fetus to adult. Furthermore, using immunohistochemistry, we investigated the expression of ERalpha and beta in 206 cases of thyroid disorders, including 24 adenomatous goiters, 23 follicular adenomas, and 159 thyroid carcinomas. In addition, we also studied the mRNA expression of ERalpha and beta and 17beta-hydroxysteroid dehydrogenase Type 1 and 2, enzymes involved in the interconversion between estrone and estradiol, using reverse transcription polymerase chain reaction (RT-PCR), in 48 of these 206 cases (10 adenomatous goiters, 10 follicular adenomas, and 28 papillary thyroid carcinomas) in which fresh frozen tissues were available for examination to further elucidate the possible involvement of intracrine estrogen metabolism and/or actions in thyroid disorders. ERalpha labeling index, or percentage of cells immunopositive for ERalpha, was significantly higher in adenomatous goiter (14.2 +/- 6.4), follicular adenoma (13.4 +/- 5.1), and thyroid carcinoma (16.4 +/- 2.1) than in normal thyroid gland (0; P <.05). Few follicular cells were positive for ERalpha in normal thyroid glands. In papillary carcinoma, ERalpha labeling index was significantly higher in premenopausal women (28.1 +/- 4.5) than in postmenopausal women (14.2 +/- 2.9) and in men of various ages (7.6 +/- 2.7; P <.05). In other histological types of thyroid carcinoma, no significant correlations were detected. ERbeta immunoreactivity was detected in both follicular and C-cells of normal thyroid glands, including those in developing fetal thyroid glands. In addition, ERbeta immunoreactivity was detected in the nuclei of various thyroid lesions. But no significant correlations were detected between ERbeta labeling index and clinicopathological findings including age, menopausal status, gender, and/or histological type of thyroid lesions. 17beta-hydroxysteroid dehydrogenase Type 1 expression was detected in 31/48 (64.0%) of the cases examined, whereas Type 2 was detected only in 3/46 (6.3%) of all the cases examined. These results demonstrated that estrogens may influence the development, physiology, and pathology of human thyroid glands, and these effects, especially through ERalpha, may become more pronounced in neoplasms, particularly in papillary carcinoma arising in premenopausal women.

 

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
FINE NEEDLE ASPIRATION
Interobserver variability in thyroid fine-needle aspiration interpretation of lesions showing predominantly colloid and follicular groups. Stelow EB, Bardales RH, Crary GS, Gulbahce HE, W Stanley M, Savik K, E Pambuccian S. Department of Pathology and Laboratory Medicine, University of Virginia, Charlottesville.	Am J Clin Pathol. 2005 Aug;124(2):239-44. Abstract quote   We studied interobserver variability (IV) in the assessment of thyroid fine-needle aspiration (FNA). We limited our cases to those showing predominantly colloid and follicular cell groups. Twenty cases of thyroid FNA diagnosed by 1 experienced cytopathologist were reviewed by 4 other cytopathologists who made their own diagnoses while unaware of the original diagnoses. Two cytopathologists then assessed the cytologic features of the 20 cases. IV was calculated for noncollapsed and collapsed diagnoses. Diagnoses and observer agreement were compared with cytologic features. There was little correlation among observers regarding the diagnosis of follicular "lesion" vs "neoplasm." IV was somewhat poor before data were collapsed to treatment recommendations (k = 0.35) but was relatively good when data were collapsed (k = 0.65). Cellularity, cyst change, and amount of colloid correlated with treatment recommendations; no specific features correlated with poor performance. Thyroid FNA shows good interobserver agreement in the diagnoses of lesions showing predominantly colloid or follicular cells (when collapsed). We speculate that IV is poor in some cases owing to difficulty assessing thin colloid, some lack of agreement regarding criteria for adequacy, and a possible "gray zone" that might exist with lesions showing colloid and abundant follicular cells.
Accuracy of Thyroid Fine-Needle Aspiration Using Receiver Operator Characteristic Curves Andrew A. Renshaw, MD	Am J Clin Pathol 2001;116:477-482 Abstract quote Although many large series demonstrate the effectiveness of thyroid fine-needle aspiration (FNA), measuring its accuracy has been suboptimal owing to inappropriate statistical methods. All thyroid fine-needle aspirates were correlated with corresponding histologic and cytologic follow-up for a 4-year period, and the accuracy was determined using receiver operator characteristic curves, which allow inclusion of nondiagnostic and indeterminate cases. There were 1,085 cases, 291 with follow-up. The overall accuracy was 0.90 ± 0.02 for a single aspiration session. A nondiagnostic aspirate was associated with a significant risk of malignancy (16%). However, 70% of patients who underwent reaspiration had adequate and negative results, and reaspiration significantly increased overall accuracy. Subcategorizing the nondiagnostic category did not affect accuracy, but did define categories with a significantly different chance of a negative diagnosis on repeated aspiration. Although subcategories of papillary carcinoma were associated with significantly different risks of carcinoma (40% vs 81%), they did not significantly improve overall accuracy. Receiver operator characteristic curves can be used to define the accuracy of thyroid FNA. This method demonstrates significantly increased accuracy with repeated aspiration of nondiagnostic cases and demonstrates that subcategorization does not improve the overall accuracy of the test.
Evidence-based criteria for adequacy in thyroid fine-needle aspiration. Renshaw AA. Department of Pathology, Baptist Hospital of Miami, FL 33176, USA.	Am J Clin Pathol 2002 Oct;118(4):518-21 Abstract quote To determine whether some thyroid fine-needle aspirates classified as nondiagnostic correlate with benign thyroid nodules and can be distinguished from other nondiagnostic aspirates, I reviewed (from a total of 1,581) 80 nondiagnostic cases, all of which were hypocellular and lacked colloid, and correlated the cytologic findings with the results of pathologic follow-up. Of the 80, 16 had carcinoma at follow-up and 64 were benign. The cellularity of the carcinoma cases ranged from 0 to 100 cells (mean, 20 cells), but every case with epithelial cells had Hurthle cell change or atypia suggestive of papillary carcinoma. The cellularity of the 64 benign cases ranged from 0 to 120 cells (mean, 40 cells), 17 of which had Hurthle cell change. There were 25 cases with at least 10 benign-appearing follicular cells without atypia or Hurthle cell change; all 25 cases were associated with benign follow-up. While these results need to be confirmed by others, the evidence suggests that a proportion of thyroid aspirates that do not meet traditional criteria for adequacy still may be associated strongly with a benign thyroid nodule and can be distinguished from other nondiagnostic aspirates.
HOT NODULES
Pathology of the autonomously functioning (hot) thyroid nodule H. Rubén Harach, MD Soledad Solis Sánchez, MD E. Dillwyn Williams, MD	Ann Diagn Pathol 6: 10-19, 2002 Abstract quote We describe the pathologic findings of 73 clinically and scintigraphically confirmed hot nodules. In general, hot nodules from an unselected group primarily treated by surgery were smaller and the sex ratio was closer to equality compared with the ample female predominance in the referral, pre-, and post-prophylaxis groups. Malignancy was observed in six cases (8.2%) (5 follicular, 1 papillary). Of the 67 benign tumors, 48 (71.6%) were adenomas which showed the cytoarchitectural features of hot nodules described previously, and 19 (28.3%) were less well-differentiated adenomas that included a few oxyphil tumors. Intracolloid oxalate crystals from background thyroid tissue were present in 59 assessable cases (83%) overall, the majority showed more than occasional crystals that had a tendency to increase in number with decreasing morphologic activity of the thyroid epithelium. Thyroglobulin protein and mRNA stainings tended to be more pronounced in cell cytoplasm of the tumors than in background thyroid. This study shows that hot nodules may show a wide morphologic spectrum of follicular neoplasms and can be occasionally malignant. It is inferred from the morphologic and other findings that it is likely that some, if not all, of the primary follicular cancers associated with hyperfunction arise by clonal progression from benign hot nodules. This progression is rare, probably because most hot nodules present with the symptoms of hyperfunction and receive early treatment.

 

HISTOPATHOLOGY	CHARACTERIZATION
ECTOPIC THYROID
Benign ectopic thyroid tissue in a cutaneous location: a case report and review. Maino K, Skelton H, Yeager J, Smith KJ. Department of Dermatology, National Naval Medical Center, Bethesda, MD, and Departments of Dermatology and Pathology, University of Alabama, Birmingham, AL, USA.	J Cutan Pathol. 2004 Feb;31(2):195-8. Abstract quote   BACKGROUND: For many years, lateral, aberrant thyroid tissue in adults was a term used almost exclusively for metastatic thyroid carcinoma. However, aberrant, benign ectopic thyroid tissue does occur, and it is most commonly found as a part of the evaluation of endocrine dysfunction. Rarely, aberrant, benign ectopic thyroid presents as a primary mass. CASE REPORT: We present a 35-year-old female who presented for removal of a lifelong posterior lateral neck nodule. RESULTS: Histologic examination and immunohistochemical studies confirmed the presence of aberrant, benign ectopic thyroid tissue. The patient had no endocrine problems, and she had a normally located and functioning thyroid gland. CONCLUSIONS: This case illustrates that not all aberrant thyroid tissues in adults are malignant or associated with endocrine disorders. This case also illustrates the rare association of ectopic thyroid and a normally located and functioning thyroid gland. In this patient, a somatic mutation in a transcription factor important in thyroid migration could explain these findings.
SOLID CELL NESTS
p63 Expression in Solid Cell Nests of the Thyroid: Further Evidence for a Stem Cell Origin. Reis-Filho JS, Preto A, Soares P, Ricardo S, Cameselle-Teijeiro J, Sobrinho-Simoes M. Institute of Molecular Pathology and Immunology (J.S.R.-F.A.P., P.S., S.R., M.S.-S.) and Medical Faculty (P.S., M.S.-S.), University of Porto, Porto, Portugal.	Mod Pathol 2003 Jan;16(1):43-8 Abstract quote Solid cell nests of the thyroid are embryonic remnants of endodermal origin that may be difficult to distinguish from squamous metaplasia, metastatic squamous carcinoma, papillary microcarcinoma, medullary carcinoma, and C-cell hyperplasia. These embryonic structures are composed of main cells and C-cells; cystic structures and mixed follicles are sometimes observed intermingled with solid cell nests. Recently, p63, a p53 homologue that is consistently expressed in basal/stem cells of stratified epithelia and plays a major role in triggering the differentiation of some specific cell lineages, has been characterized. We evaluated the immunohistochemical expression of p63, cytokeratins (CAM 5.2, AE1/AE3, 34betaE12, 7, and 20), carcinoembryonic antigen, thyroid transcription factor 1 (TTF-1), thyroglobulin, and calcitonin using the streptavidin-biotin-peroxidase complex technique in 6 bona fide solid cell nests. We observed that main cells of solid cell nests are strongly decorated by p63, while C-cells and all other thyroid structures were consistently negative. Moreover, main cells expressed carcinoembryonic antigen and all cytokeratins but cytokeratin 20 and lacked TTF-1, thyroglobulin and calcitonin. In contrast to this, C-cells of solid cell nests were immunoreactive for calcitonin, CAM 5.2, AE1/AE3, and cytokeratin 7; focal immunoreactivity for TTF-1 was also observed in some C-cells. We conclude that main cells of the solid cell nests display a basal/stem cell phenotype (p63 and basal cytokeratin positivity), whereas C-cells show features of parafollicular differentiation. We conclude, furthermore, that p63 antibodies may help in distinguishing solid cell nests from their mimics.
THYROID IMPLANTS
Thyroid implants after surgery and blunt trauma. Harach HR, Cabrera JA, Williams ED.	Ann Diagn Pathol. 2004 Apr;8(2):61-8. Abstract quote The differential diagnosis of thyroid tissue found laterally in the neck includes several conditions: lymph node deposits of thyroid carcinoma, "benign metastatic thyroidosis," detached thyroid nodules, and true ectopic thyroid tissue. We have studied nine cases with thyroid deposits in the soft tissues of the neck that do not conform to these diagnoses. We present evidence that they represent surgical or traumatic implantation of thyroid neoplasms. Eight of the nine cases presented one to 26 years after initial surgery. Adequate information of the operative procedure was available in seven cases, one patient underwent subtotal lobectomy and six subtotal thyroidectomy for a nodular gland. The nodules occurred within the operation field with no evidence that they were within lymph nodes. In six cases, birefringent particles consistent with talc from the earlier operation were found adjacent to the nodules. Three cases showed implants of colloid nodules, three of follicular adenoma, one of oncocytic (Hurthle) cell adenoma and one of follicular carcinoma. In the ninth case, infiltrating thyroid tissue in muscle and fibrous tissue presented 3 years after major blunt trauma to the neck. The tissue resembled that in a disrupted thyroid nodule present in the gland itself and was regarded as traumatically implanted. The observation that surgery or trauma to a nodular thyroid can occasionally lead to multiple subcutaneous thyroid implants has implication for management of thyroid disease. Therapy may be difficult; recurrence followed surgical removal of the nodules in three cases, and radioiodine may be a more effective therapy. Recognition of this entity is important for accurate pathologic diagnosis. It is apparently limited to implantation of tumor. The absence of implantation of normal or hyperplastic thyroid, despite the high frequency of partial thyroidectomy in Graves' disease, has pathobiological implications. These findings also support the generally held view that lobectomy rather than nodulectomy is the operation of choice for a solitary nodule.

 

SPECIAL STAINS/ IMMUNO-HISTOCHEMISTRY	CHARACTERIZATION
GENERAL
Immunohistochemical Expression of Galectin-3 in Benign and Malignant Thyroid Lesions. Herrmann ME, LiVolsi VA, Pasha TL, Roberts SA, Wojcik EM, Baloch ZW. Department of Pathology, University of Pennsylvania, Philadelphia (Drs Herrmann, LiVolsi, and Baloch; Ms Pasha; and Ms Roberts); and the Department of Pathology, Loyola University Chicago, Maywood, Ill (Dr Wojcik). Dr Herrmann is now with the Armed Forces Institute of Pathology, Washington, DC.	Arch Pathol Lab Med 2002 Jun;126(6):710-713 Abstract quote Context.-The expression of galectin-3, a human lectin, has been shown to be highly associated with malignant behavior of thyroid lesions. Design.-We studied the immunohistochemical expression pattern of galectin-3 in a variety of follicular-derived thyroid lesions (13 benign and 62 malignant), including Hurthle cell and follicular carcinoma, papillary carcinomas and variants, and anaplastic and poorly differentiated carcinomas. Results.-Immunoreactivity was strongest in papillary thyroid carcinomas, whereas staining was less intense in Hurthle cell and anaplastic carcinomas, and even weaker in the follicular variant of papillary thyroid carcinoma. Staining was absent or weak in the 3 follicular thyroid carcinomas and was negative in both insular carcinomas. In several tumors, staining was stronger at the advancing invasive edge of the lesion than in the central portion of the tumor. Galectin-3 was also expressed focally and weakly in reactive follicular epithelium and entrapped follicles in chronic lymphocytic thyroiditis. A variety of thyroid lesions showed prominent endogenous, biotin-like activity, which could cause flaws in interpretation if a biotin-detection system were used. Conclusion.-We conclude that galectin-3 immunostaining, when used in biotin-free detection systems, may be useful as an adjunct to distinguish benign from malignant thyroid lesions.
Changes in Galectin-7 and Cytokeratin-19 Expression during the Progression of Malignancy in Thyroid Tumors: Diagnostic and Biological Implications Sandrine Rorive, M.D., Brahim Eddafali, M.D., Sergio Fernandez, M.D., Christine Decaestecker, Ph.D., Sabine André, Ph.D., Herbert Kaltner, Vet.M.D, Ichiro Kuwabara, Ph.D., Fu-Tong Liu, Ph.D., Hans-Joachim Gabius, Ph.D., Robert Kiss, Ph.D. and Isabelle Salmon, M.D., Ph.D. Laboratory of Pathology, Cliniques Universitaires de Bruxelles, Hôpital Erasme (SR, BE, SF, IS), and Laboratory of Histopathology, Faculty of Medicine, Université Libre de Bruxelles (CD, RK), Brussels, Belgium; Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University (SA, HK, H-JG), Munich, Germany; and Department of Dermatology, School of Medicine, University of California, Davis (IK, F-TL), Sacramento, California	Modern Pathology 2002;15:1294-1301 Abstract quote Galectin-7 is associated with p53-dependent onset of apoptosis and proliferation control/differentiation in keratinocyte development. It is also up-regulated in chemically induced rat mammary carcinogenesis. Because the levels of expression of galectin-7 have never been investigated in thyroid tumors (in contrast to those of galectin-1 and -3 associated with malignancy), we initiated analysis of the expression of galectin-7 in benign and malignant thyroid lesions together with that of cytokeratin-19 (CK19), a marker already demonstrated to be useful in diagnosing this kind of lesion. The immunohistochemical expression levels were quantitatively determined by means of computer-assisted microscopy on a series of 84 thyroid lesions including 10 multinodular goiters, 32 adenomas, and 42 carcinomas. Our data clearly indicate a marked down-regulation of galectin-7 expression in a large proportion of adenomas (including the normomacrofollicular, microfollicular, and trabecular variants) if compared with carcinomas. In accordance with results of previous studies, a marked up-regulation of CK19 expression was observed in the thyroid carcinomas, and this contrasted in particular with the low CK19 expression observed in the microfollicular adenomas. Of importance for diagnostic implications, the combination of these two markers enabled our series of microfollicular adenomas (characterized by low galectin-7 and CK19 expression) to be efficiently distinguished from the encapsulated follicular variant of papillary thyroid carcinomas (high galectin-7 and CK19 expression).

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
PSAMMOMA BODIES
Non-tumor-associated psammoma bodies in the thyroid. Hunt JL, Barnes EL. Department of Pathology, University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213, USA.	Am J Clin Pathol 2003 Jan;119(1):90-4 Abstract quote Psammoma bodies in the thyroid are common in glands with papillary thyroid carcinoma. Psammoma bodies that are not associated with tumor cells, however, represent a diagnostic problem for pathologists. Should we treat isolated psammoma bodies as representing metastatic disease? This study included patients who had non-tumor-associated psammoma bodies in their thyroids or in the perithyroidal lymph nodes. Clinical, pathologic, and follow-up information was obtained for the patients. Our results indicate that 27 of 29 patients had a contralateral or an ipsilateral tumor, the majority of which were papillary. We noted a high frequency of microscopic carcinomas (12/27) and of tall cell variants of papillary thyroid carcinoma (8/27 cases). Based on these findings, we recommend that thyroid glands with non-tumor-associated psammoma bodies and no histologically identified carcinoma be entirely submitted to identify any microscopic carcinoma. If no carcinoma is identified in a lobectomy, discussion with the surgeon should indicate the need for close clinical follow-up.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

C-cells-These cells are found along the lateral border of the thyroid and produce the hormone calcitonin. These cells also give rise to medullary carcinomas. In children, groups of up to 6 cells may be normal with up to 100 cells present in a low power field. In the adult, no more than 10 cells per low power field should be found.

Hurthle Cell-Also known as oncocyte.   These cells are derived from the follicular cells and have abundant eosinophilic staining cytoplasm.  They are present in benign and malignant states.

Orphan Annie Nuclei-Also known as optically clear nuclei.  A clearing change of thyroid epithelial cell nuclei, often associated with papillary carcinoma of the thyroid.

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Last Updated August 5, 2005

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