
==== Front
World J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central London 1477-7819-2-271530603210.1186/1477-7819-2-27ReviewHürthle cell carcinoma: diagnostic and therapeutic implications Hanief Mohamed R 1hanief@doctors.org.ukIgali Laszlo 2ligali@doctors.org.ukGrama Dimitrie 3digr@sbs.sja.dk1 Imperial College London, Hammersmith Hospital, DuCane Road, London, W12 OHS, UK2 Department of Histopathology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR7 4UY, UK3 Department of Surgery, Sonderborg Central Hospital, 6400 Sonderborg, Denmark2004 11 8 2004 2 27 27 2 5 2004 11 8 2004 Copyright © 2004 Hanief et al; licensee BioMed Central Ltd.2004Hanief et al; licensee BioMed Central Ltd.This is an open-access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background
Hürthle cell carcinoma is a variant of follicular cell carcinoma of thyroid. It may present as a low-grade tumour or as a more aggressive type. Prognosis depends upon the age of the patient, tumour size, extent of invasion and initial nodal or distant metastasis.

Patient and methods
The case of Hürthle cell carcinoma is reported in a 79-year-old man who presented with a rapidly increasing lump on the left side of his neck, having had a right hemithyroidectomy for colloid goitre 24-years-ago. Fine needle aspiration cytology confirmed the presence of Hürthle cells, raising the possibility of a Hürthle cell neoplasm. The patient underwent staging and surgery. Histology showed Hürthle cell carcinoma and the patient underwent adjuvant therapy. The literature on Hürthle cell neoplasms is reviewed.

Conclusions
Fine needle aspiration cytology may recognise Hürthle cell lesion but final diagnosis of carcinoma depends upon histological confirmation of vascular or capsular invasion. Staging and surgery in Hürthle cell carcinoma are similar to follicular carcinoma of thyroid with favourable outcome despite the controversy regarding the histological classification and adjuvant therapy. Elderly patients with Hürthle cell carcinoma need to be made aware of their poorer prognosis and should be offered more radical treatment.
==== Body
Background
The natural history of Hürthle cell carcinoma (HCC) is not well understood. It accounts for <5% of all differentiated thyroid malignancies. Hürthle cells are characterised by eosinophilic cytoplasm with trabecular/follicular growth pattern. [1]. Oncocytes are seen in follicular cell carcinoma but in HCC oncocytes represent more than 75% of cells, which exhibit a rather more trabecular growth pattern [2]. There is much debate regarding its clinical behaviour and little is known about the long-term survival of patients with HCC. Some studies have reported a relatively benign course while others have found the tumour to behave aggressively [3-6]. Most studies show that advanced age (>45), male sex, size of primary tumour (>4 cm), degree of invasion and recurrence are poor prognostic indicators [6-8]. Fine needle aspiration cytology is a good predictor of Hürthle cell neoplasm but is of little diagnostic value in evaluating HCC, since for a tumour to be deemed malignant one has to show vascular or capsular invasion [9]. Intraoperative frozen sections have a low predictive value. Udelsman et al found that in 96.4% cases with follicular neoplasm of thyroid, frozen section was neither informative nor cost-effective [10]. Well-encapsulated HCC run a favourable course while locally advanced HCC are associated with higher mortality and should be treated aggressively [4,11]. In a well-differentiated thyroid carcinoma death resulting from local disease is unusual and most die of distant metastases [12].

We report a case of a Hürthle cell carcinoma presenting in the left lobe of thyroid following a right hemithyroidectomy for a colloid goitre 24 years ago.

Case presentation
A 79-year-old male was referred in March 2003 with a lump on the left side of his neck. The patient had noted a sudden increase in the size of the lump over the preceding two months. He did not report any neck pressure symptoms, weight loss or anorexia. His past history included right partial thyroidectomy for a solitary nodule (colloid goitre) in 1978 and repair of abdominal aortic aneurysm in 1994. He had suffered myocardial infarction in 1995 and had an episode of acute coronary insufficiency in January 2003. His recent coronary angiograms showed an occluded left anterior descending artery and echocardiogram revealed good left ventricular function. He was a non-smoker and consumed alcohol in moderation. He had been taking warfarin, diltiazem MR, lisinopril, uniphyllin, glyceryl trinitrate tablets and buccal suscard.

On examination he had left sided goitre extending superiorly into the posterior triangle and inferiorly into the retrosternal space, with variable consistency. The trachea was deviated to the right and there was cervical lymphadenopathy on the left side. Systemic examination was unremarkable and fine needle aspiration of thyroid gland showed presence of Hürthle cells. Computerised tomographic (CT) scan with contrast enhancement (figure 1 &2) of the neck and thorax revealed large left sided thyroid goitre with significant mediastinal extension. It showed mixed attenuation with foci of calcification peripherally. There was a 3 cm complex mass on the left side of the neck, posterior to the carotid sheath structures and deep to the sternomastoid, indicative of lymph node metastases. Thyroid profile and routine blood investigations were unremarkable.

Figure 1 Superior extension of left goitre with 3 cm diameter complex mass deep to sternomastoid, posterior to carotid sheath. Note the displacement of larynx to the right.

Figure 2 Mediastinal extension of left goitre.

Based on the above findings radical surgery was planned. On exploration of the neck we confirmed left goitre with intrathoracic extension and enlarged lymph nodes under the sternocleidomastoid close to the jugulodigastric muscle and surrounding the carotid sheath. There was no remnant thyroid tissue seen on the right side following the previous thyroid surgery. Left hemithyroidectomy with modified neck dissection (lymphadenectomy, preserving all vessels and nerves) was performed. Macroscopic examination of the thyroid lobe showed a well defined solid pale brown mass approximately 8 cm in maximum dimension, surrounded by a narrow rim of preserved thyroid tissue. The lymph node specimen comprised of several nodules of partly necrotic tissue. Microscopic examination showed the thyroid lobe containing a Hürthle cell neoplasm, which was mostly encapsulated, with foci of capsular and vascular invasion. The two lymph nodes revealed metastatic Hürthle cell carcinoma. [pT3, N1a, Mx], (Figure 3 &4).

Figure 3 Photomicrograph showing capsular invasion (Haematoxylin and Eosin ×200)

Figure 4 photomicrograph showing Hürthle cell note the eosinophilic cytoplasm and prominent nucleoli (Haematoxylin and Eosin ×500).

The patient had adjuvant therapy with oral radioiodine 131 (3060 MBq Sodium Iodine). He was put on a daily dose of 100 mcg of thyroxine. This was to be followed by a second dose of 5911 MBq of radioactive iodine six months from the time of the first dose.

Discussion
Hürthle cell carcinomas are heterogeneous neoplasms that display a wide range of biological behaviour and accounts for less than 5% of all differentiated thyroid malignancies. The term HCC should be restricted to tumours with more than 75% of oncocytic cells [2]. Oncocytes are seen in follicular thyroid cell carcinoma and in papillary thyroid cell carcinoma [13,14]. On one hand patients with HCC live for years with slow growing tumour and lymphatic metastases and on the other hand, patients die of highly aggressive tumour with haematogenous spread.

Our patient had several indicators for poor prognosis such as his advanced age, male gender, large tumour size (8 cm), extra thyroid extension and nodal metastasis. Interestingly enough the patient had no pressure symptoms despite marked deviation of larynx, trachea and oesophagus, which may be due to previous right hemithyroidectomy. In elderly patients with sudden enlargement of neck mass and pre-existing thyroid conditions such as benign thyroid nodule, goitre (as in our case), Grave's disease or differentiated thyroid carcinoma, one has to bear in mind anaplastic thyroid carcinoma (ATC). In ATC local compression symptoms such as hoarseness, strider, dyspnoea and dysphagia occur as a rule [15-17]. In aggressive type of HCC haematogenous spread has been noted, but in ATC, at presentation patients are quite likely to have distant metastases involving lung, bone, brain and soft tissues [15,16].

Our patient had undergone fine needle aspiration cytology, which revealed Hürthle cells. Since the lesion was rapidly growing with mediastinal extension and nodal involvement, the patient underwent staging and left hemithyroidectomy with modified neck dissection. Histology confirmed HCC based on vascular and capsular invasion. Intraoperative frozen sections have low predictive value and are particularly not a sensitive test for diagnosing HCC therefore this was not carried out [10]. McIvor et al have clearly shown that FNAC can easily recognise the tumour as Hürthle cell lesion [9]. Cases with suspicious histology and over 50 years of age carry a high risk of cancer [18].

In the management of HCC the primary mode of treatment is surgical, ranging from hemithyroidectomy to total thyroidectomy. Larger tumours (>T2) require total thyroidectomy and lymphadenectomy if lymph nodes are involved [8]. Adjuvant radioiodine treatment or external beam radiotherapy is used for widely invasive carcinoma or locally advanced disease [8].

Several reports in literature have identified contra lateral foci of carcinoma in 40–70% of cases of HCC [11,19]. HCC is less responsive to radioactive iodine therapy [20] and taking into account the aggressive behaviour, it has been suggested that every Hürthle cell tumour greater than 2 cm should be treated by total thyroidectomy [21]. In 1990 they showed that recurrent disease was noted in 17% of patients treated with total thyroidectomy compared to 59% in cases where a more limited procedure was carried out [21,22]. Other authors support the role of total thyroidectomy as there is 15 to 35% incidence of multiple foci in HCC [23].

There are several reasons favouring the use of 131I remnant ablation after near-total thyroidectomy [24]. First, presence of thyroid remnant can obscure 131I uptake in cervical or lung metastases [25,26]. Second, distant (lung) metastases may be seen only on the post treatment whole body scan after remnant ablation [27]. Finally, remnant ablation may destroy residual normal follicular cells, which may become malignant [28] and any occult cancer that may recur years later.

Radioiodine therapy has no overall effect on mortality but subgroup analysis has shown that those patients who receive radioactive iodine for adjuvant ablation of remnant thyroid tissue have lower mortality rate compared with patients who either did not receive treatment or in whom the indication was the presence of residual disease [29]. Radioiodine uptake in the elderly is much lower. Schlumberger and colleagues noted 131I uptake at metastatic sites in only 53% of patients over 40 years of age, compared to 90% in patients below the age of 40 [30]. Univariate analysis indicated that older age and large tumour size predicted worse survival rates due to aggressive nature of the tumour (extra glandular invasion and multifocal disease). One recent series reviewed medical records of patients between the years 1944 and 1995. Of the 89 HCC cases studied, 29% had only undergone lobectomy as initial treatment and 50% had undergone partial resection. Of the three quarters of the patients in this series who received radioactive iodine, only 38% of patients with known metastases showed positive uptake [29]. Another study clearly suggested that treatment with 131I to ablate the thyroid remnant and to treat residual disease were independent prognostic variables that favourably influenced recurrence, distant recurrence, and cancer death rates [24]. Our patient received radioactive iodine treatment in the postoperative period. He has been followed up with whole body scans (Fig 5 and 6), which indicate his response to adjuvant radioactive iodine therapy. He is on 125 mcg thyroxine in order to maintain a TSH level of less than 0.01 mIU/L and FT4 at the upper limit of normal (8–28 pmol/L).

Figure 5 Whole body scan on November 3, 2003 following 131I ablation therapy on 28th October 2003, with 3060 MBq Sodium Iodine (131I). Increased uptake is seen in the region of the thyroid bed. No abnormal accumulation was noted elsewhere.

Figure 6 Whole body scan on 19th April 2004 following 131I ablation therapy on 13th April 2004 with 5911 MBq Sodium Iodine (131I). Two small focal area of uptake are seen in the thyroid bed. Low uptake focal area in the left lateral aspect of the neck, could possibly represent activity in a cervical node.

Stojdinovic et al have treated 56 patients with HCC between the years 1940 and 2000 [8]. Of these patients 23(41%) had minimally invasive disease with no evidence of extra thyroid invasion (T2 N0 M0) and 33(56%) had widely invasive HCC. Primary mode of treatment was surgery ranging from lobectomy and isthumusectomy to total thyroidectomy with cervical lymphadenectomy in presence of lymph node involvement. Some patients received adjuvant radioiodine or external beam radiotherapy for widely invasive carcinoma. Study end points were relapse free survival and disease specific survival. They reported 8 years survival rate of 100% and 58% for low and high-risk cancers respectively. In their entire study cohort age was not found to predict the outcome but the most significant factor was widely invasive carcinoma.

Khafif et al in their series (42 patients with HCC between 1957–1997) used radioiodine in patients with distant metastases; none had thyroid remnant ablation with radioactive iodine [4]. They reported an overall survival rate of 90.5% and noted that age, size of tumour and extent of resection adversely affected the prognosis.

Hürthle cell lesion can be easily picked up on FNAC but to make a diagnosis of HCC one has to demonstrate vascular or capsular invasion. Intraoperative frozen sections have low predictive value and cases with advanced age (over 50), rapid enlargement of lump and palpable nodes should be regarded with high index of suspicion for presence of HCC. HCC or other differentiated carcinomas of thyroid in the elderly patients are generally more aggressive with less favourable prognosis compared to younger patients. They should be offered total thyroidectomy and selective lymph node dissection (when lymph nodes are involved) followed by ablative radioiodine therapy, provided they can withstand the above treatment. Coexisting medical disorders should be recognized and managed effectively prior to surgery [31]. Further research is needed to clarify the role of adjuvant radioiodine therapy in the management of HCC.

Competing interests
None declared.

Authors' contribution
MRH managed the patient, searched the literature and drafted the manuscript

LI: did the histological study, and contributed to pathological aspects in the present study

DG: Managed the patient, conceptualise the present report, edited the manuscript and coordinated after reviewing the manuscript

Acknowledgement
Patients consent was obtained for publication of his case records.
==== Refs
Baloch ZW Mandel S LiVolsi VA  Combined tall cell carcinoma and Hürthle cell carcinoma (collision tumour) of the thyroid. Arch Pathol Lab Med 2001 125 541 543 11260633 
Rosai J Carcangui ML DeLellis RA  Tumours of thyroid gland. Atlas of tumour pathology Series 3, Fasicle 5 Washington, DC: Armed Forces Institute of Pathology 1992 
Stojadinovic A Ghossein RA Hoos A Urist MJ Spiro RH Shah JP Brennan MF Shaha AR Singh B  Hürthle cell carcinoma: a critical histopathologic appraisal. J Clin Oncol 2001 19 2616 2625 11352953 
Khafif A Khafif RA Attie JN  Hürthle cell carcinoma: A malignancy of low-grade potentia Head Neck 1999 21 506 511 10449665 10.1002/(SICI)1097-0347(199909)21:6<506::AID-HED2>3.0.CO;2-M 
Sanders LE Silverman M  Follicular and Hürthle cell carcinoma: predicting outcome and directing therapy. Surgery 1998 124 967 974 9854570 10.1067/msy.1998.92000 
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 1996 120 1000 1004 8957486 
Bhattacharyya N  Survival and prognosis in Hürthle cell carcinoma of the thyroid gland. Arch Otolaryngol Head Neck Surg 2003 129 207 210 12578450 10.1016/S0194-5998(03)01257-9 
Stojadinovic A Hoos A Ghossein RA Urist MJ Leung DH Spiro RH Shah JP Brennan MF Singh B Shaha AR  Hürthle cell carcinoma: a 60-year experience. Ann Surg Oncol 2002 9 197 203 11888879 10.1245/aso.2002.9.2.197 
McIvor NP Freeman JL Rosen I Bedard YC  Value of fine-needle aspiration in the diagnosis of Hürthle cell neoplasms. Head Neck 1993 15 335 341 8360056 
Udelsman R Westra WH Donovan PI Sohn TA Cameron JL  Randomized prospective evaluation of frozen-section analysis for follicular neoplasms of the thyroid. Ann Surg 2001 233 716 722 11323510 10.1097/00000658-200105000-00016 
Arganini M Behar R Wu TC Straus F McCormick M DeGroot LJ Kaplan EL  Hürthle cell tumours: a twenty-five-year experience. Surgery 1986 100 1108 1115 3787466 
Beasley NJ Walfish PG Witterick I Freeman JL  Cause of death in patients with well-differentiated thyroid carcinoma. Laryngoscope 2001 111 989 991 11404609 
Grebe SK Hay ID  Follicular thyroid cancer. Endocrinal Metab Clin North Am 1995 24 761 801 
Berho M Suster S  The oncocytic variant of papillary carcinoma of the thyroid: a clinicopathologic study of 15 cases. Hum Pathol 1997 28 47 53 9013831 10.1016/S0046-8177(97)90278-1 
Tan RK Finley RK 3rdDriscoll D Bakamjian V Hicks WL JrShedd DP  Anaplastic carcinoma of the thyroid: a 24-year experience. Head Neck 1995 17 41 47 7883548 
Hadar T Mor C Shvero J Levy R Segal K  Anaplastic carcinoma of the thyroid, Eur J Surg Oncol 1993 19 511 516 8270035 
Junor EJ Paul J Reed NS  Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy. Eur J Surg Oncol 1992 18 83 88 1582515 
Tyler DS Winchester DJ Caraway NP Hickey RC Evans DB  Indeterminate fine-needle aspiration biopsy of the thyroid: identification of subgroups at high risk for invasive carcinoma. Surgery 1994 116 1054 1060 7985087 
Gundry SR Burney RE Thompson NW Lloyd R  Total thyroidectomy for Hürthle cell neoplasm of the thyroid: Arch Surg 1983 118 529 532 6838358 
Caplan RH Abellera RM Kisken WA  Hürthle cell neoplasms of the thyroid gland: reassessment of functional capacity: Thyroid 1994 4 243 248 7833658 
Thompson NW Dunn EL Batsakis JG Nishiyama RH  Hürthle cell lesions of the thyroid gland: Surg Gynecol Obstet 1974 139 555 560 4479589 
McLeod MK Thompson NW  Hürthle cell neoplasms of the thyroid: Otolaryngol Clin North Am 1990 23 441 452 2195433 
Rosen IB Luk S Katz I  Hürthle cell tumour behaviour: dilemma and resolution. Surgery 1985 98 777 783 4049249 
Mazzaferri EL  Thyroid remnant 131I ablation for papillary and follicular thyroid carcinoma: Thyroid 1997 7 265 271 9133698 
Miccoli P Antonelli A Spinelli C Ferdeghini M Fallahi P Baschieri L  Completion total thyroidectomy in children with thyroid cancer secondary to the Chernobyl accident. Arch Surg 1998 133 89 93 9438766 10.1001/archsurg.133.1.89 
Vassilopoulou-Sellin R Klein MJ Smith TH  Pulmonary metastases in children and young adults with differentiated thyroid cancer. Cancer 1993 71 1348 1352 8435810 
Wartofsky L Sherman SI Gopal J Schlumberger M Hay ID  The use of radioactive iodine in patients with papillary and follicular thyroid cancer. J Clin Endocrinol Metab 1998 83 4195 4199 9851751 10.1210/jc.83.12.4195 
Sugg SL Ezzat S Rosen IB Freeman JL Asa SL  Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab 1998 83 4116 4122 9814501 10.1210/jc.83.11.4116 
Lopez-Penabad L Chiu AC Hoff AO Schultz P Gaztambide S Ordonez NG Sherman SI  Prognostic factors in patients with Hürthle cell neoplasms of the thyroid. Cancer 2003 97 1186 94 12599224 10.1002/cncr.11176 
Schlumberger M Challeton C De Vathaire F Travagli JP Gardet P Lumbroso JD Francese C Fontaine F Ricard M Parmentier C  Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med 1996 37 598 605 8691248 
Vini L Hyer SL Marshall J A'Hern R Harmer C  Long-term results in elderly patients with differentiated thyroid carcinoma. Cancer 2003 97 2736 2742 12767085 10.1002/cncr.11410

