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Hürthle Cell Carcinoma

Richard F. Grossman, MD, and Orlo H. Clark, MD

Total thyroidectomy with central neck lymph node dissection is the therapy of choice for patients with Hürthle cell carcinoma.

Introduction

Hürthle cell carcinoma of the thyroid is a rare neoplasm comprising about 3% of all differentiated thyroid cancer. Discrimination of Hürthle cell carcinoma from benign Hürthle cell tumors, the natural history of Hürthle cell carcinoma and the optimal treatment of patients who have them, are unsettled issues in thyroid surgery. The terminology itself arose in confusion when Ewing in 1919 mistook the histologic appearance of these oxyphilic tumors and applied to them the name of the man who earlier had described the canine C cell.[1] Hürthle cell tumors appear to be of follicular rather than C cell origin and are also referred to as oxyphil tumors, oncocytomas, mitochondriomas or Askanazy cell tumors. The latter designation honors the description of the oxyphil cell by Askanazy in 1898.[2]

Evidence suggesting that Hürthle cells tumors arise from follicular cells includes histologic features, the frequent production by Hürthle cell carcinomas of thyroglobulin (Tg), and the presence in benign Hürthle cell tumors of an intact thyrotropin receptor adenylate cyclase signal transduction pathway.[3] Hürthle cell carcinomas do not appear to be variants of follicular cell carcinoma, however, as they express different oncogenes.[4]

Presentation and Diagnosis

The predominant presentation of Hürthle or oxyphilic cells in the thyroid is as a nonencapsulated hyperplastic island, termed Hürthle cell change or Hürthle cell hyperplasia, often noted incidentally in the setting of goiter or thyroiditis (Fig 1). Hürthle cell change is generally regarded to be a form of benign metaplasia rather than frank neoplasia. Solitary encapsulated tumors composed of Hürthle cells are neoplastic. Most are benign adenomas.

Absence in the past of uniform pathologic criteria for distinguishing adenoma from malignancy contributed to widely disparate reports of the prevalence of Hürthle cell carcinoma, ranging from 5%[5] to 56% of all Hürthle cell tumors.[6] In our experience, the breakdown of Hürthle cell tumors is approximately 80% benign Hürthle cell adenomas and 20% Hürthle cell carcinomas. Misclassification in older studies of some Hürthle cell carcinomas as benign Hürthle cell tumors, and vice versa, led to the perception that some histologically benign appearing Hürthle cell tumors are malignant.[7] In the past, some authors advocated the use of an "intermediate" category of malignancy based on "partial" angio or capsular invasion.[8] These reports ignited a lively debate over how much thyroid to remove in the surgical treatment of patients with Hürthle cell tumors.

Criteria applied previously that led to the misclassification of some tumors — nuclear atypia, pattern of growth, presence of necrosis, for example — have been abandoned, as has any notion of the existence of an "intermediate" category of malignancy, so that today diagnosis based on permanent sections (Figs 2 and 3) and accurate preoperative staging are reliable and rest on the presence of angioinvasion, capsular invasion, local tissue invasion, lymph node metastasis or distant metastasis. The subtle histologic nature of angio or capsular invasion means that it is often not possible to diagnose Hürthle cell carcinoma until some days after surgery when the permanent sections are completed. In one recent review, only one frozen section in 29 correctly provided a diagnosis of Hürthle cell carcinoma in tumors that all met the permanent section criteria for malignancy.[9] Permanent section results using the criteria set out above are reliable, with benign-appearing tumors, probably representing misdiagnoses based on sampling errors, ultimately displaying malignant behavior in 0% to 1% of cases.[5,10,11]

Cytologic criteria cannot distinguish Hürthle cell adenoma from Hürthle cell carcinoma.[11-13] Aspiration biopsy cytology (ABC) may show only "Hürthle cell neoplasm," which will be Hürthle cell carcinoma in 15% to 20% of cases. Thyroid scanning will show a "cold" nodule except in the rare Hürthle cell carcinoma that takes up iodine.[14] Neither radionuclide scanning nor ultrasound can distinguish Hürthle cell adenomas from Hürthle cell carcinomas.

Fewer than 400 cases of Hürthle cell carcinoma have been reported in the literature over the past 75 years. From the more recent series employing reliable criteria for malignancy, a clinical picture of Hürthle cell carcinoma is beginning to emerge.[8,9,15-20] Hürthle cell carcinoma is a disease with peak incidence in the fifth to seventh decade. Women are predominantly affected by a ratio of 3:1, similar to the other thyroid tumors of follicular origin. Our recent series is unusual in its nearly 2:1 predominance of men.[20] The tumors present as a solitary or dominant mass within the thyroid gland and measure 4.0 to 5.0 cm on average by the time they are resected. Lymphadenopathy, vocal cord paralysis or distant metastases are unusual at presentation but may complicate recurrent disease. Hürthle cell tumors are almost always endocrinologically silent (though they may produce as yet unidentified humoral factors) and patients are euthyroid unless thyroid hormone homeostasis is perturbed for another reason. Hürthle cell carcinomas usually produce Tg but rarely trap radioactive iodine.

Treatment Approach

While numerous studies have questioned which Hürthle cell neoplasms are malignant, few have addressed the treatment of patients with Hürthle cell carcinoma. The debate over how much thyroid to remove follows the controversy over differentiated thyroid carcinoma in general, with some authorities claiming that thyroid lobectomy is adequate in that papillary cancer, in particular, is a well-behaved lesion with little tendency to recur. Our position has been that total thyroidectomy is indicated for well-differentiated thyroid cancer over 1 cm in diameter, because even though the risk of recurrence may be low, the outcome of as many as one third of recurrences is fatal. As long as the operation is performed safely by an experienced endocrine surgeon, total thyroidectomy offers the advantages of removing all diseased gland (up to 85% of papillary thyroid cancers are multifocal or bilateral within the gland), facilitating thyroid scanning with lower doses of radioactive iodine (absence of thyroid gland concentrates uptake into residual or recurrent disease), improving radioablative uptake by metastases, and allowing postoperative surveillance with the measurement of serum Tg levels (in the absence of a thyroid gland, a high postoperative baseline Tg, or a rising Tg later on, is a sensitive marker for residual tumor or tumor recurrence, respectively).

The picture emerging of Hürthle cell carcinoma is that of an aggressive lesion, with a prognosis worse than papillary carcinoma of the thyroid.[20-22] In our series of 14 patients with Hürthle cell carcinoma, four patients have died.[20] Of five patients followed longer than 18 months, four (80%) had recurrence and three (60%) died of Hürthle cell carcinoma. Four of five recurrences were located in the neck, and two of the four deaths were due to locally recurrent disease. The other two deaths were the result of metastatic disease. In the literature, the overall cause-specific mortality rate is 111 patient deaths out of 364 cumulative cases of Hürthle cell carcinoma reported (30% death rate).

A number of factors argue for total thyroidectomy as the initial treatment of patients with Hürthle cell carcinoma, although the incidence of the disease is so low that a prospective, randomized study of treatment options probably will never be conducted. Several studies have confirmed that Hürthle cell carcinoma is multifocal in approximately 30% to 35% of cases[9,20,23]; fewer studies have examined resected glands for the presence of bilateral disease, but we found an incidence of almost 15%.[20] Any operation less than total thyroidectomy might leave behind foci of cancer. Hürthle cell carcinomas generally produce Tg, so removal of the entire gland increases the utility of this marker of recurrence. While the failure of most Hürthle cell carcinomas to take up radioactive iodine means that total thyroidectomy does not offer any advantage in increasing tumoral uptake of the isotope, it does portend that thyroidectomy is the only treatment available, and that because radioactive iodine in ablative doses is usually ineffective for salvage, surgical treatment should be most aggressive at the outset.

We treat patients with Hürthle cell neoplasms in the same manner as patients with follicular neoplasms of the thyroid. We generally obtain an ABC as part of the preoperative workup. We generally do not obtain a preoperative thyroid scan in the evaluation of a patient with a Hürthle cell tumor as so few take up iodine. If indicators during surgery are strong that the Hürthle cell lesion is malignant (eg, gross appearance or frozen section demonstrating local invasion), we perform a total thyroidectomy with ipsilateral central neck lymphadenectomy. Malignancy can be diagnosed in the operating room by frozen section or gross criteria about half the time. If the frozen section appears benign and there are no other indicators of malignancy, we perform thyroid lobectomy and isthmusectomy. No further treatment is necessary if the permanent section confirms a benign histology. If the permanent section shows Hürthle cell carcinoma, we return the patient to the operating room for completion total thyroidectomy. While this algorithm results in two trips to the operating room for about 10% of all patients with Hürthle cell tumor (or 50% of patients with Hürthle cell carcinoma), it succeeds in bringing to the operating room only once that 10% of patients who have carcinoma treated by total thyroidectomy at the outset and that 80% of patients whose final diagnosis is Hürthle cell adenoma who are adequately treated with lobectomy.

The completeness of the total thyroidectomy should be assessed by radioiodine scan three to four months after surgery. We ablate any thyroid remnant with I¹³¹ to eliminate all tissue at risk and to facilitate the use of Tg in surveillance for tumor recurrence. If the serum Tg does not fall to 3 ng/mL or lower after total thyroidectomy or rises during follow-up, residual or recurrent disease, respectively, should be suspected. Thyroid-stimulating hormone elevation occurring when the patient is hypothyroid during preparation for thyroid scanning may elicit rises in Tg that are not otherwise detectable, and this, therefore, is the optimal time to assay Tg in search of early recurrences. Tg elevations noted while the patient is euthyroid, on thyroid hormone replacement, are especially concerning for a larger burden of recurrent disease. Radioiodine scanning should be performed in the workup of possible recurrence to detect the small number of Hürthle cell carcinomas that take up the isotope and may be susceptible to ablation.[14] Recently, abnormal 99mTc-sestamibi accumulation by Hürthle cell carcinoma has been reported to be a sensitive marker of recurrence.[24] Unfortunately, sestamibi cannot be used for ablation.

Follow-up

Most recurrences of Hürthle cell carcinoma are found in the neck, while the lung is the most common site of distant metastasis. Palpation of the neck may reveal recurrent disease, while chest x-ray may suggest metastasis. A computed tomography scan or magnetic resonance imaging of the neck, mediastinum, and chest are valuable adjuncts in diagnosis of recurrent disease.

Recurrent disease is treated surgically with good palliation and appreciable prolongation of life often resulting from local excision and neck dissection for recurrent neck disease or pulmonary wedge resection for lung metastasis.[20,25,26] External beam radiation may be considered for patients with unresectable disease but is not curative. Octreotide has also been employed without success in the treatment of recurrent carcinoma.[27] In our series, patients died of Hürthle cell carcinoma an average of 34 months after recurrence.[20]

References

1. Ewing J. Neoplastic Disease. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1928.
2. Askanazy M. Pathologisch-anatomische Beitrage zur Kenntniss des morbus basedowii, insbesondere uber die dabei auftretende. Muskelerkrankkunz Dtsch Arch Klin Med. 1898;61:118-186.
3. Clark OH, Gerend PL. Thyrotropin receptor-adenylate cyclase system in Hürthle cell neoplasms. J Clin Endocrinol Metab. 1985; 61(4):773-778.
4. Masood S, Auguste LJ, Westerbank A, et al. Differential oncogenic expression in thyroid follicular and Hürthle cell carcinomas. Am J Surg. 1993(166):366-368.
5. Gosain AK, Clark OH. Hürthle cell neoplasms: malignant potential. Arch Surg. 1984;119(5):515-519.
6. Gundry SR, Burney RE, Thompson NW, et al. Total thyroidectomy for Hürthle cell neoplasm of the thyroid. Arch Surg. 1983;118(5):529-532.
7. Thompson NW, Dunn EL, Batsakis JG, et al. Hürthle cell lesions of the thyroid gland. Surg Gynecol Obstet. 1974;139(4):555-560.
8. Arganini M, Behar R, Wu TC, et al. Hürthle cell tumors: a twenty-five-year experience. Surgery. 1986;100(6):1108-1115.
9. Ditkoff BA, Chabot J, Jin S, et al. Hürthle cell cancer of the thyroid: the incidence of multifocal and bilateral disease. Thyroidol Clin Exp. 1995;7:49-53.
10. Massidda B, Nicolosi A, Mura E, et al. Hürthle-cell tumors of the thyroid. Minerva Chir. 1992;47(10):913-917.
11. Grant CS, Barr D, Goellner JR, et al. Benign Hürthle cell tumors of the thyroid: a diagnosis to be trusted? World J Surg. 1988;12(4):488-495.
12. Tyler DS, Winchester DJ, Caraway NP, et al. Indeterminate fine-needle aspiration biopsy of the thyroid: identification of subgroups at high risk for invasive carcinoma. Surgery. 1994;116(6):1054-1060.
13. Caraway NP, Sneige N, Samaan NA. Diagnostic pitfalls in thyroid fine-needle aspiration: a review of 394 cases. Diagn Cytopathol. 1993;9(3):345-350.
14. Caplan RH, Abellera RM, Kisken WA. Hürthle cell neoplasms of the thyroid gland: reassessment of functional capacity. Thyroid. 1994;4(3):243-248.
15. Tollefsen HR, Shah JP, Huvos AG. Hürthle cell carcinoma of the thyroid. Am J Surg. 1975;130(4):390-394.
16. Bondeson L, Bondeson AG, Ljungberg O, et al. Oxyphil tumors of the thyroid: follow up of 42 surgical cases. Ann Surg. 1981;194:677-680.
17. Watson RG, Brennan MD, Goellner JR, et al. Invasive Hürthle cell carcinoma of the thyroid: natural history and management. Mayo Clin Proc. 1984;59(12):851-855.
18. Wallin G, Backdahl M, Lundell G, et al. Nuclear DNA content and prognosis in Hürthle cell tumours of the thyroid gland. Acta Chir Scand. 1988;154(9):501-504.
19. Carcangiu ML, Bianchi S, Savino D, et al. Follicular Hürthle cell tumors of the thyroid gland. Cancer. 1991;68(9):1944-1953.
20. Grossman RF, Tezelman S, Epstein HD, et al. Total Thyroidectomy and Central Neck Lymph Node Dissection: Treatment of Choice for Hürthle Cell Carcinoma. In: International Congress of Endocrinology. 1996. San Francisco, Calif.
21. Herrera MF, Hay ID, Wu PS, et al. Hürthle cell (oxyphilic) papillary thyroid carcinoma: a variant with more aggressive biologic behavior. World J Surg. 1992;16(4):669-675.
22. DeGroot LJ, Kaplan EL, Shukla MS, et al. Morbidity and mortality in follicular thyroid cancer. J Clin Endocrinol Metab. 1995;80(10):2946-2953.
23. Rosen IB, Luk S, Katz I. Hürthle cell tumor behavior: dilemma and resolution. Surgery. 1985;98:777-783.
24. Yen TC, Lin HD, Lee CH, et al. The role of technetium-99m sestamibi whole-body scans in diagnosing metastatic Hürthle cell carcinoma of the thyroid gland after total thyroidectomy: a comparison with iodine-131 and thallium-201 whole-body scans. Eur J Nucl Med. 1994;21(9):980-983.
25. Sloan DA, Vasconez HC, Weeks JA. Mediastinal dissection and reconstruction for recurrent Hürthle cell carcinoma of the thyroid. Head Neck. 1994;16(1):64-71.
26. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery. 1992;111(6):604-609.
27. Zlock DW, Greenspan FS, Clark OH, et al. Octreotide therapy in advanced thyroid cancer. Thyroid. 1994;4(4):427-431.

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