Hurthle Cell Carcinoma

Back

Background

Hürthle cell carcinoma of the thyroid gland is an unusual and relatively rare type of differentiated thyroid cancer. Hürthle cell cancer accounts for only about 3-10% of all differentiated thyroid cancers; therefore, few institutions have extensive experience with Hürthle cell neoplasms. According to the World Health Organization (WHO), these neoplasms are considered a variant of follicular carcinoma of the thyroid and are referred to as follicular carcinoma, oxyphilic type. See the image below.


View Image

A monomorphous cell population of Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant gra....

Some investigators believe that this condition is distinct from other follicular cell neoplasms. Hürthle cells are observed in both neoplastic and nonneoplastic conditions of the thyroid gland (eg, Hashimoto thyroiditis, nodular and toxic goiter).

Oncocytic cells in the thyroid are often called Hürthle cells, and oncocytic change is defined as cellular enlargement characterized by an abundant eosinophilic granular cytoplasm as a result of accumulation of altered mitochondria. This is a phenomenon of metaplasia that occurs in inflammatory disorders, such as thyroiditis, or other situations that result in cellular stress. The proliferation of oncocytes gives rise to hyperplastic and neoplastic nodules.[1]

The cytological features for Hürthle cell neoplasms are hypercellularity with a predominance of Hürthle cells (usually >75%), few or no lymphocytes, and scanty or absent colloid. In 1898, Askanasy described Hürthle cells; however, they are mistakenly named for the German physiologist who actually described the interfollicular C-cell.[2] Hürthle cells are large and polygonal in shape, with indistinct cell borders. They have a large pleomorphic hyperchromatic nucleus, a prominent nucleolus, and intensely pink, fine, granular cytoplasm with hematoxylin-eosin staining. Hürthle cells are also found in other tissues, such as the salivary gland, parathyroid gland, esophagus, pharynx, larynx, trachea, kidney, pituitary, and liver. Controversy exists about the origin of Hürthle cells, which generally are thought to derive from the follicular epithelium.

A Hürthle cell neoplasm is defined generally as an encapsulated thyroid lesion consisting of at least 75% of Hürthle cells. Distinguishing a benign neoplasm from a malignant neoplasm based on cytologic analysis of fine-needle aspiration (FNA) biopsy is not possible. Features such as pleomorphism, anaplasia, hyperchromatism, and atypia are also observed in benign follicular adenomas; therefore, definitive differentiation of Hürthle cell carcinoma from Hürthle-cell adenoma is based on vascular invasion and/or capsular invasion, as well as on permanent histologic sections or extrathyroidal tumor spread and lymph node and systemic metastases.

In the literature, the incidence of malignancy in Hürthle-cell neoplasms is variable, ranging from 13-67%. Overall, only about 33% of Hürthle cell tumors demonstrate signs of that invasive growth that indicates malignancy and the possibility of metastasizing. On balance, Hürthle cell tumors may be considered to be more likely to metastasize than follicular tumors. The likelihood of nodal metastases is greater in Hürthle cell tumors than in follicular tumors; it is, however, not as great as with papillary tumors.

Permissive histologic interpretation may result in the designation of some non-neoplastic Hürthle cell lesions as malignant tumors. Obviously, this factor has a major impact in interpreting the natural history of this disease and adds to the controversy about the aggressiveness of Hürthle cell carcinoma. This leads to reported overall mortality rates ranging from 9-28%.

Tumor size is an important feature for biological behavior. A 1988 study found that a Hürthle tumor that is 4 cm or larger has an 80% chance of histologic evidence of malignancy.[3] In another study by Pisanu et al,[4] in a series of 23 patients, the mean tumor size was significantly greater for carcinomas than adenomas (3.1 cm vs 1.9 cm).

In another study done at Memorial Sloan-Kettering Cancer center,[5] outcomes of 56 patients with Hürthle cell cancer were analyzed. In this study, recurrence was a significant predictor of tumor-related mortality, and the most significant predictor of outcome was extent of invasion. In addition, tumor size, extrathyroidal disease extension, and initial nodal or distant metastasis were found to be associated with an adverse outcome.[6]

Hürthle cell cancer has the highest incidence of metastasis among the differentiated thyroid cancers. Metastatic disease is reported at the time of initial diagnosis in 10-20% of patients and in 34% of the patients overall. Metastasis usually occurs hematogenously, but lymph node metastasis is also not uncommon and more frequently involves the regional lymph nodes. Some studies suggest that lymph node metastases at initial diagnosis may not be an unfavorable prognostic factor.[7] The lungs, bones, and central nervous system are the most prevalent sites of metastases.

Pathophysiology

No widely accepted paradigm exists for the pathogenesis of follicular and Hürthle cell cancer of the thyroid. Some evidence suggests that a multistep adenoma-to-carcinoma pathway may be involved; however, this concept is not universally accepted. Many of the cells probably develop from preexisting adenomas, but a follicular carcinoma in situ is not recognized pathologically.

Progressive transformation through somatic mutations of genes that are important in growth control are involved in follicular thyroid cancer formation. Low iodide intake is a key environmental factor determining the relative incidence of follicular and papillary cancers. Most follicular adenomas and all follicular carcinomas are thought to have monoclonal origin.

Oncogene activation, particularly by mutation or translocation of the ras oncogene, is common in both follicular adenomas and follicular thyroid carcinomas (around 40%), supporting a role in early tumorigenesis. Such ras oncogene mutations are not specific for follicular tumors and also occur in papillary thyroid cancer (PTC). The ras oncogene is frequently involved in the pathogenesis of Hürthle cell tumors. In papillary thyroid cancers and in many Hürthle cell tumors, RET rearrangements are found; these are not found in follicular tumors. Local spread may be found in RET- positive cases; RET- negative cases, as in follicular cancer cases, are more likely to spread through the bloodstream to distant metastatic sites.

An association also was found between overexpression of the p53 gene product and a subset of Hürthle cell carcinomas. Reduced immunoexpression of E-cadherin exists, with a trend to a diffuse cytoplasmic pattern, both in benign and malignant Hürthle cell tumors and in papillary, poorly differentiated, and undifferentiated thyroid carcinomas. Isolated studies indicate overexpression of the N-myc oncogene, tumor growth factor (TGF)-alpha, TGF-beta, insulinlike growth factor (IGF)-1, and somatostatin receptor in Hürthle cell carcinomas.

Cytogenetic abnormalities and evidence of genetic loss are more common in follicular thyroid cancer than in papillary thyroid cancer. These abnormalities occur in follicular adenomas, suggesting that cell cycle control, mitotic spindle formation, DNA repair, or more than one of these mechanisms may be impaired in these neoplasms, possibly at an earlier stage.

Activating mutations of genes encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein are also reported in some follicular carcinomas. These losses are associated particularly with chromosomes 3, 10, 11, and 17. The deletions and/or rearrangements involving the p (short) arm of chromosome 3 are the most common. Loss of a tumor suppressor on chromosome arm 3p has been postulated to be specific for follicular thyroid cancer and may be involved in adenoma-to-carcinoma progression.

Restriction fragment length polymorphism (RFLP) analysis demonstrates that unbalanced losses of genetic material are relatively common in Hürthle cell neoplasms. Loss of heterozygosity from the q (long) arm of chromosome 10 is also detected in oncocytic tumors. Evidence suggests that some Hürthle cell adenomas and carcinomas can express an RET/PTC gene arrangement, which is more unique to papillary thyroid carcinoma.

Because of this gene arrangement, another subclassification of Hürthle cell neoplasms has been proposed, namely the papillary variant of Hürthle cell cancer (ie, Hürthle cell papillary thyroid carcinoma), in addition to Hürthle cell cancer and adenoma. Clinically, tumors in this group tend to behave like papillary thyroid carcinoma; however, they are more indolent, with a propensity for lymph node metastasis rather than hematogenous spread. In 2006, Maxwell et al reported that the Hürthle cell tumors with RET/PTC - positive gene arrangement have higher incidence of regional metastatic disease and more aggressive treatment has been recommended.[8]

As reported by Asa, many Hürthle cell tumors, whether benign or malignant, show papillary change. This is a pseudopapillary phenomenon because Hürthle cell tumors have only scant stroma and may fall apart during manipulation, fixation, and processing. True oxyphilic, or Hürthle cell, papillary carcinoma has been reported to comprise 1-11% of all papillary carcinomas. These tumors have a papillary architecture but are composed predominantly, or entirely, of Hürthle cells.[1]

Mitochondrion-related alterations, such as mutations in mitochondrial DNA, are also described in Hürthle cell tumors. Defects of cytochrome c oxidase and the deletion of mitochondrial DNA occur frequently in Hürthle cell tumors and in Hürthle cells of Hashimoto thyroiditis. In one study, almost all Hürthle cells displayed a common deletion, somatic mitochondrial point mutations, or both.[9] Activating gene mutations encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein are also reported in some follicular carcinomas.

DNA content profiles after flow cytometry are commonly abnormal. Hürthle cell neoplasms, including histologically benign tumors, are often aneuploid. This finding parallels with nuclear atypia and anisocytosis. The demonstration of aneuploidy may be a marker for a particularly aggressive clinical behavior compared with euploid tumors. In a recent Italian study, p27 and cyclin D3 proteins were found to be overexpressed in Hürthle cell carcinoma cell lines and clinical samples of thyroid cancer.[10, 11] The accumulation of p27 was found to be associated to the overexpression of cyclin D3 in Hürthle cell carcinoma of the thyroid.

A study analyzing genomic dissection of Hurthle cell carcinoma has indicated that Hurthle cell carcinoma could be a unique type of malignancy. In this study, unsupervised hierarchical clustering of gene expression showed 3 groups of Hurthle cell tumors; Hurthle cell adenomas, minimally invasive Hurthle cell carcinoma, and widely invasive Hurthle cell carcinoma. These are clustered separately, with a marked difference between widely invasive Hurthle cell carcinoma and Hurthle cell adenoma. Molecular pathways that differentiate Hurthle cell adenomas from widely invasive Hurthle cell carcinomas included the PIK3CA-Akt-mTOR and Wnt/β -catenin pathways, potentially providing a rationale for new targets for the treatment of this type of thyroid carcinoma.[12]

Epidemiology

Frequency

United States

Thyroid cancer is uncommon, and among all cancers, it accounts for 0.74% in men and 2.3% in women. The average age-adjusted annual incidence for thyroid cancer is less than 40 cases per 1 million people. Among thyroid neoplasms, Hürthle cell carcinomas account for about 3-10% of these cancers.

For thyroid cancers as a whole, in the US for 2009, the projected new thyroid cancer cases are 37,200 : 27,200 in females and 10,000 in males. The estimated deaths are 1,630: 940 in females and 690 in males. It is reasonable to estimate that Hürthle cell cancer cases will be about 3-10% of these.[13]

International

Worldwide frequency likely approximates that of the United States. In general, the annual incidence of thyroid cancer in various parts of the world is 0.5-10 cases per 100,000 population. Approximately 3-10% of these cases are Hürthle cell carcinomas.

Mortality/Morbidity

Hürthle cell cancer reportedly behaves in a more aggressive fashion than other well-differentiated thyroid cancers, with a tendency to higher frequency of metastasis and a lower survival rate. This is truer for the lesions that are clearly demonstrated to be malignant and in patients who are considered to be at high risk based on such factors as age, tumor size, invasiveness, and the presence of metastasis. Widely invasive tumors behave more aggressively. Recurrent Hürthle cell carcinomas are considered to be incurable.

Ghossein et al at Memorial Sloan Kettering Cancer center reported that in encapsulated ("minimally invasive") Hürthle cell carcinomas, the extent vascular invasion strongly correlated with recurrence. Presence of mitosis and a solid/trabecular tumor growth pattern also correlated with higher risk of recurrence.[14]

Race

All races appear to be affected equally.

Sex

See Frequency.

Age

The age range of patients presenting with this condition is 20-85 years. The mean age is usually 50-60 years, approximately 10 years older than the age associated with other types of differentiated thyroid cancers.

History

Physical

The most common physical examination finding is a palpable single neck mass. Less often, patients may have multiple palpable masses.

Causes

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Common histological malignancy criteria, such as architectural distortion, cellular atypia, or pleomorphism, are encountered in both benign and malignant follicular adenomas; these histological criteria are not helpful while evaluating a thyroid mass.

The cytologic features for Hürthle cell neoplasms are hypercellularity, with a predominance of Hürthle cells usually above 75%, few or no lymphocytes, and scanty or absent colloid. Hürthle cells are large and polygonal in shape, with indistinct cell borders. They have a large pleomorphic hyperchromatic nucleus, a prominent nucleolus, and intensely pink fine granular cytoplasm with hematoxylin-eosin staining. See the image below.


View Image

A monomorphous cell population of Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant gra....

Papillary structures and intranuclear inclusions, features that are not ordinarily associated with Hürthle cell lesions, are occasionally noted. The electron microscopic examination of Hürthle cells in tumor formation is unique, revealing a large cytoplasm that is almost completely filled with mitochondria. This examination also reveals large lysosomelike dense bodies and dilated Golgi zones confined to the apical portion of the cytoplasm. Unusual richness of chromatin is clumped against the inner nuclear membrane and nuclei that are observed as round and dense, with separation of fibrillar and granular substances.

Histopathologic differentiation of Hürthle cell carcinoma from Hürthle cell adenoma is based on vascular and capsular invasion. Capsular invasion refers to tumor cell penetration of the capsule of the neoplasm. Vascular invasion is defined by the presence of tumor penetration of blood vessels within or outside of the capsule of the Hürthle cell lesion. Capsular invasion, vascular invasion, or both diagnose Hürthle cell carcinoma.

Benign diseases (eg, Hashimoto disease, nodular goiter, toxic goiter) usually have no encapsulation. Hürthle cell changes are part of an inflammatory process.

In a study by Volante et al, the role of galectin-3 and HBME-1 (an antimesothelial monoclonal antibody that recognizes an unknown antigen on microvilli of mesothelial cells) tumor markers, as well as the peroxisome proliferator-activated receptor (PPAR) gamma protein expression, were assessed in oncocytic Hürthle cell tumors, including Hürthle cell adenomas, Hürthle cell carcinomas, and an oncocytic variant of papillary carcinoma. In these 152 Hürthle cell tumors (50 Hürthle cell adenomas, 70 Hürthle cell carcinomas, and 32 oncocytic variant of papillary carcinoma), the sensitivity of galectin-3 was 95.1%, the sensitivity of HBME-1 was 53%, and a combination of galectin-3 and HBME-1 was high at 99%. However, the specificity for both markers was 88%, lower than for nononcocytic follicular tumors.[23]

Interestingly, PPAR gamma protein overexpression was absent in all Hürthle cell adenomas tested and present in only 10% of Hürthle cell carcinomas, similar to other reports that confirm the low prevalence of PAX8-PPAR gamma translocations in Hürthle cell carcinomas.

Staging

Different prognostic criteria and staging systems are used in differentiating thyroid cancer and Hürthle cell cancer. No uniformly accepted staging system and prognostic classification exists for Hürthle cell carcinoma.

The tumor, node, metastases (TNM) system is the most widely used staging system, as depicted in the image below. Most classification systems used in the evaluation of patients with Hürthle cell carcinoma consider such factors as tumor size, patient age, presence of metastases, and major capsular invasion (extensive capsular invasion in multiple sites). The other classification systems used for assessing Hürthle cell carcinoma are conducted with scoring systems, using the generally accepted prognostic factors, such as age, metastasis, extent of disease at operation, and size (AMES) and age, grade, extent, and size (AGES). See the image below.


View Image

Tumor, lymph node, metastases (TNM) staging system for papillary and follicular thyroid carcinoma.

Medical Care

Surgical Care

Consultations

Management of thyroid cancer is a team effort, and the following consultations should be obtained:

Diet

No particular diet is recommended, but an iodide-free diet is recommended at least 1 week prior to scanning to minimize the interference.

Activity

Activity may be performed as tolerated.

Medication Summary

The goals or pharmacotherapy are to reduce morbidity, induce remission, and prevent complications.

Levothyroxine (Synthroid, Levoxyl)

Clinical Context:  In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development. Children require treatment with higher doses than adults.

Class Summary

Levothyroxine treatment is started after the treatment dose of131 I is administered.

Further Inpatient Care

Further Outpatient Care

Inpatient & Outpatient Medications

Levothyroxine: The dose should be titrated to a subnormal TSH concentration.

Deterrence/Prevention

No specific prevention is available, although avoidance of radioactive exposure and adequate iodide intake can be considered preventive measures.

Complications

Surgical complications include laryngeal nerve injury and transient or permanent hypoparathyroidism manifested as hypocalcemia. Hypothyroidism can occur if replacement therapy is inadequate. Hyperthyroidism can occur if the patient is overtreated with levothyroxine. Surgical scars in the neck also can be cosmetically disturbing in certain individuals.

Prognosis

Author

Serhat Aytug, MD, Endocrinologist, Division of Endocrinology, Diabetes and Metabolism, St Jude Heritage Medical Group

Disclosure: Nothing to disclose.

Coauthor(s)

Lawrence E Shapiro, MD, Chief, Division of Endocrinology and Metabolism, Professor of Medicine, Department of Medicine, Winthrop University Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Antoni Ribas, MD, Assistant Professor of Medicine, Division of Hematology-Oncology, University of California at Los Angeles Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Disclosure: Nothing to disclose.

References

  1. Asa SL. My approach to oncocytic tumours of the thyroid. J Clin Pathol. Mar 2004;57(3):225-32. [View Abstract]
  2. Lyos AT. Hürthle Cell Neoplasms of the Thyroid. Baylor College of Medicine. Available at http://www.bcm.edu/oto/grand/21392.html. Accessed October 15, 2009.
  3. Bronner MP, Clevenger CV, Edmonds PR, Lowell DM, McFarland MM, LiVolsi VA. Flow cytometric analysis of DNA content in Hürthle cell adenomas and carcinomas of the thyroid. Am J Clin Pathol. Jun 1988;89(6):764-9. [View Abstract]
  4. Pisanu A, Sias L, Uccheddu A. Factors predicting malignancy of Hürthle cell tumors of the thyroid: influence on surgical treatment. World J Surg. Aug 2004;28(8):761-5. [View Abstract]
  5. Stojadinovic A, Ghossein RA, Hoos A, Urist MJ, Spiro RH, Shah JP. Hürthle cell carcinoma: a critical histopathologic appraisal. J Clin Oncol. May 15 2001;19(10):2616-25. [View Abstract]
  6. Strazisar B, Petric R, Sesek M, Zgajnar J, Hocevar M, Besic N. Predictive factors of carcinoma in 279 patients with Hürthle cell neoplasm of the thyroid gland. J Surg Oncol. Jun 1 2010;101(7):582-6. [View Abstract]
  7. Guerrero MA, Suh I, Vriens MR, Shen WT, Gosnell J, Kebebew E, et al. Age and tumor size predicts lymph node involvement in Hürthle Cell Carcinoma. J Cancer. Jun 2 2010;1:23-6. [View Abstract]
  8. Maxwell EL, Palme CE, Freeman J. Hürthle cell tumors: applying molecular markers to define a new management algorithm. Arch Otolaryngol Head Neck Surg. Jan 2006;132(1):54-8. [View Abstract]
  9. Máximo V, Sobrinho-Simões M. Hürthle cell tumours of the thyroid. A review with emphasis on mitochondrial abnormalities with clinical relevance. Virchows Arch. Aug 2000;437(2):107-15. [View Abstract]
  10. Troncone G, Iaccarino A, Russo M, Palmieri EA, Volante M, Papotti M, et al. Accumulation of p27(kip1) is associated with cyclin D3 overexpression in the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma. J Clin Pathol. Apr 2007;60(4):377-81. [View Abstract]
  11. Troncone G, Iaccarino A, Russo M, Palmieri EA, Volante M, Papotti M, et al. Accumulation of p27(kip1) is associated with cyclin D3 overexpression in the oxyphilic (Hurthle cell) variant of follicular thyroid carcinoma. J Clin Pathol. Apr 2007;60(4):377-81. [View Abstract]
  12. Ganly I, Ricarte Filho J, Eng S, et al. Genomic dissection of Hurthle cell carcinoma reveals a unique class of thyroid malignancy. J Clin Endocrinol Metab. May 2013;98(5):E962-72. [View Abstract]
  13. American Cancer Society. Cancer Facts & Figures 2009. American Cancer Society. Available at http://www.cancer.org/downloads/STT/500809web.pdf. Accessed October 2009.
  14. Ghossein RA, Hiltzik DH, Carlson DL, Patel S, Shaha A, Shah JP, et al. Prognostic factors of recurrence in encapsulated Hurthle cell carcinoma of the thyroid gland: a clinicopathologic study of 50 cases. Cancer. Apr 15 2006;106(8):1669-76. [View Abstract]
  15. Cooper DS, Schneyer CR. Follicular and Hürthle cell carcinoma of the thyroid. Endocrinol Metab Clin North Am. Sep 1990;19(3):577-91. [View Abstract]
  16. Kushchayeva Y, Duh QY, Kebebew E, Clark OH. Prognostic indications for Hürthle cell cancer. World J Surg. Dec 2004;28(12):1266-70. [View Abstract]
  17. Máximo V, Botelho T, Capela J, Soares P, Lima J, Taveira A, et al. Somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid. Br J Cancer. May 23 2005;92(10):1892-8. [View Abstract]
  18. Pryma DA, Schoder H, Gonen M, Robbins RJ, Larson SM, Yeung HW, et al. Diagnostic accuracy and prognostic value of 18F-FDG PET in Hurthle cell thyroid cancer patients. J Nucl Med. Aug 2006;47(8):1260-6. [View Abstract]
  19. Elliott DD, Pitman MB, Bloom L, Faquin WC. Fine-needle aspiration biopsy of Hurthle cell lesions of the thyroid gland: A cytomorphologic study of 139 cases with statistical analysis. Cancer. Apr 25 2006;108(2):102-9. [View Abstract]
  20. Jacques C, Guillotin D, Fontaine JF, et al. DNA microarray and miRNA analyses reinforce the classification of follicular thyroid tumors. J Clin Endocrinol Metab. May 2013;98(5):E981-9. [View Abstract]
  21. Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. Aug 23 2012;367(8):705-15. [View Abstract]
  22. Paphavasit A, Thompson GB, Hay ID, Grant CS, van Heerden JA, Ilstrup DM, et al. Follicular and Hürthle cell thyroid neoplasms. Is frozen-section evaluation worthwhile?. Arch Surg. Jun 1997;132(6):674-8; discussion 678-80. [View Abstract]
  23. Volante M, Bozzalla-Cassione F, DePompa R, Saggiorato E, Bartolazzi A, Orlandi F, et al. Galectin-3 and HBME-1 expression in oncocytic cell tumors of the thyroid. Virchows Arch. Aug 2004;445(2):183-8. [View Abstract]
  24. Fernández CA, Puig-Domingo M, Lomeña F, Estorch M, Camacho Martí V, Bittini AL, et al. Effectiveness of retinoic acid treatment for redifferentiation of thyroid cancer in relation to recovery of radioiodine uptake. J Endocrinol Invest. Mar 2009;32(3):228-33. [View Abstract]
  25. Kim WG, Kim EY, Kim TY, Ryu JS, Hong SJ, Kim WB, et al. Redifferentiation therapy with 13-cis retinoic acids in radioiodine-resistant thyroid cancer. Endocr J. Mar 2009;56(1):105-12. [View Abstract]
  26. Foote RL, Brown PD, Garces YI, McIver B, Kasperbauer JL. Is there a role for radiation therapy in the management of Hürthle cell carcinoma?. Int J Radiat Oncol Biol Phys. Jul 15 2003;56(4):1067-72. [View Abstract]
  27. Haugen BR, Sherman SI. Evolving approaches to patients with advanced differentiated thyroid cancer. Endocr Rev. Jun 2013;34(3):439-55. [View Abstract]
  28. Younes MN, Yigitbasi OG, Park YW, Kim SJ, Jasser SA, Hawthorne VS, et al. Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation. Cancer Res. Jun 1 2005;65(11):4716-27. [View Abstract]
  29. Younes MN, Yazici YD, Kim S, Jasser SA, El-Naggar AK, Myers JN. Dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition with NVP-AEE788 for the treatment of aggressive follicular thyroid cancer. Clin Cancer Res. Jun 1 2006;12(11 Pt 1):3425-34. [View Abstract]
  30. Mills SC, Haq M, Smellie WJ, Harmer C. Hürthle cell carcinoma of the thyroid: Retrospective review of 62 patients treated at the Royal Marsden Hospital between 1946 and 2003. Eur J Surg Oncol. Mar 2009;35(3):230-4. [View Abstract]
  31. Goffredo P, Roman SA, Sosa JA. Hurthle cell carcinoma: a population-level analysis of 3311 patients. Cancer. Feb 1 2013;119(3):504-11. [View Abstract]
  32. Arganini M, Behar R, Wu TC, Straus F 2nd, McCormick M, DeGroot LJ, et al. Hürthle cell tumors: a twenty-five-year experience. Surgery. Dec 1986;100(6):1108-15. [View Abstract]
  33. Azadian A, Rosen IB, Walfish PG, Asa SL. Management considerations in Hürthle cell carcinoma. Surgery. Oct 1995;118(4):711-4; discussion 714-5. [View Abstract]
  34. Chen H, Nicol TL, Zeiger MA, Dooley WC, Ladenson PW, Cooper DS, et al. Hürthle cell neoplasms of the thyroid: are there factors predictive of malignancy?. Ann Surg. Apr 1998;227(4):542-6. [View Abstract]
  35. Cheung CC, Ezzat S, Ramyar L, Freeman JL, Asa SL. Molecular basis off hurthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab. Feb 2000;85(2):878-82. [View Abstract]
  36. Devita VT, Hellman S, Rosenberg SA. Cancer of the Endocrine System. In: Cancer: Principles and Practice of Oncology. 7th Ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2004.
  37. Fagin JA. Molecular genetics of tumors of thyroid follicular cells. In: Werner & Ingbar's The Thyroid. Philadelphia, Pa: Lippincott, Williams, & Wilkins; 2000:886-94.
  38. Gosain AK, Clark OH. Hürthle cell neoplasms. Malignant potential. Arch Surg. May 1984;119(5):515-9. [View Abstract]
  39. Grant CS. Operative and postoperative management of the patient with follicular and Hürthle cell carcinoma. Do they differ?. Surg Clin North Am. Jun 1995;75(3):395-403. [View Abstract]
  40. Grünwald F, Menzel C, Bender H, Palmedo H, Otte R, Fimmers R, et al. Redifferentiation therapy-induced radioiodine uptake in thyroid cancer. J Nucl Med. Nov 1998;39(11):1903-6. [View Abstract]
  41. Larsen PR, Davies TF, Hay IA. Molecular Pathogenesis (Follicular carcinoma). In: Williams Textbook of Endocrinology. Philadelphia, Pa: WB Saunders, Co; 1998:490-3.
  42. Luna-Ortiz K, Hurtado-Lopez LM, Valderrama-Landaeta JL, Ruiz-Vega A. Thyroglossal duct cyst with papillary carcinoma: what must be done?. Thyroid. May 2004;14(5):363-6. [View Abstract]
  43. Mazzaferri EL. Thyroid cancer in thyroglossal duct remnants: a diagnostic and therapeutic dilemma. Thyroid. May 2004;14(5):335-6. [View Abstract]
  44. McDonald MP, Sanders LE, Silverman ML, Chan HS, Buyske J. Hürthle cell carcinoma of the thyroid gland: prognostic factors and results of surgical treatment. Surgery. Dec 1996;120(6):1000-4; discussion 1004-5. [View Abstract]
  45. McHenry CR, Sandoval BA. Management of follicular and Hurthle cell neoplasms of the thyroid gland. Surg Oncol Clin N Am. Oct 1998;7(4):893-910. [View Abstract]
  46. Papotti M, Torchio B, Grassi L, Favero A, Bussolati G. Poorly differentiated oxyphilic (Hurthle cell) carcinomas of the thyroid. Am J Surg Pathol. Jun 1996;20(6):686-94. [View Abstract]
  47. Ron E, Schneider AB. Thyroid Cancer. In: Schottenfeld, D Fraumeni J eds. Cancer. Epidemiology and Prevention. 3rd ed. Oxford University Press: 2006.
  48. Rosen IB, Luk S, Katz I. Hürthle cell tumor behavior: dilemma and resolution. Surgery. Oct 1985;98(4):777-83. [View Abstract]
  49. Sanders LE, Silverman M. Follicular and Hurthle cell carcinoma: predicting outcome and directing therapy. Surgery. Dec 1998;124(6):967-74. [View Abstract]
  50. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med. Jan 29 1998;338(5):297-306. [View Abstract]
  51. Tallini G. Oncocytic tumours. Virchows Arch. Jul 1998;433(1):5-12. [View Abstract]
  52. Watson RG, Brennan MD, Goellner JR, van Heerden JA, McConahey WM, Taylor WF. Invasive Hürthle cell carcinoma of the thyroid: natural history and management. Mayo Clin Proc. Dec 1984;59(12):851-5. [View Abstract]

A monomorphous cell population of Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant granular cytoplasm with well-defined cell borders. The nuclei are enlarged and have a central prominent macronucleolus.

A monomorphous cell population of Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant granular cytoplasm with well-defined cell borders. The nuclei are enlarged and have a central prominent macronucleolus.

Tumor, lymph node, metastases (TNM) staging system for papillary and follicular thyroid carcinoma.

Tumor, lymph node, metastases (TNM) staging system for papillary and follicular thyroid carcinoma.

A monomorphous cell population of Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant granular cytoplasm with well-defined cell borders. The nuclei are enlarged and have a central prominent macronucleolus.