Issues in Managing Hurthle Cell Carcinoma of Thyroid: A Case Report

A 61-year-old woman noticed a right neck lump in October 2001. Fine needle aspiration showed follicular neoplasm, adenoma versus carcinoma. The ultrasound scan showed a solid mass of maximum dimension of 3.7 cm. She had a right thyroid lobectomy and isthmectomy in January 2002 (first surgery). The tissue specimen showed a 4.5 cm Hurthle cell carcinoma (HCC) with vascular invasion. There were no capsular invasion, extra-thyroidal extension, or margin involvement. A completion left lobectomy (second surgery) was performed two weeks later. Therefore the pathological stage is II (T3N0M0). She received adjuvant radioactive iodine ablation for residual thyroid tissue. By 2003, she developed local recurrence, which was resected (third surgery), followed by adjuvant external beam radiotherapy. Unfortunately, she developed further recurrence in the left main bronchus, as identified by Indium-111 Octreotide (Curium, Missouri, USA) and positron emission tomography-computed tomography PET-CT imaging in 2006. She underwent a left pneumonectomy (fourth surgery) in July 2006. In November 2007 she was found to have mediastinal recurrence which was treated with high-dose external beam radiotherapy. She initially responded but developed more local recurrence and a lung metastasis by 2011. She was treated with brivanib with ixabepilone, under a phase I clinical trial with mixed response. Her treatment was discontinued secondary to toxicity and she succumbed to her disease in 2012. This case report illustrates the natural history and clinical decision making for patients diagnosed with HCC of the thyroid. Specifically, we highlight the clinical issues surrounding the histopathological diagnosis, extent of surgical resection, radioiodine diagnostic imaging/ablative treatment, as well as external beam radiotherapy.


Introduction
Hurthle cell carcinoma (HCC) of the thyroid, also called oncocytic carcinoma, is a rare form of differentiated thyroid cancer. Preoperative clinical, cytological, and genetic studies have not been shown to reliably discriminate between benign and malignant variants of Hurthle cell neoplasms (HCN) [1]. Therefore, histopathological analysis remains the gold standard for diagnosis; although, it may be apparent preoperatively if there is evidence of metastasis.  She had a right thyroid lobectomy and isthmectomy in January 2002 (first surgery) because the frozen section could not tell if the tumor was benign or malignant. The tissue specimen showed a 4.5 cm Hurthle cell carcinoma (HCC) with vascular invasion. There were no capsular invasion, extra-thyroidal extension, or resection margin involvement. A completion left lobectomy (second surgery) was performed two weeks later. The pathological stage was II: T3N0M0 due to the maximum tumor dimension of 4.5 cm (TNM 1997 Staging). The histological type was HCC and was confirmed with another pathologist in a tertiary center.
As there was a significant amount of residual thyroid tissue by a radioactive Iodine-123 scan, ablation with 100 milliCurie of Iodine-131 was given in April 2002. Unfortunately by January 2003, a doctor felt a 0.6 cm lump in the right neck scar. There was no nodal or distant recurrence with a non-contrast computerized tomography (CT) scan. The Iodine-123 scan did not show any uptake of the radio-isotope in the neck or the rest of the body. The local recurrence in the right neck was locally excised in  In April 2012 she participated in a phase I trial of target therapy (brivanib) with a new chemotherapy (ixabepilone). She was admitted due to bladder infection and febrile neutropenia. A CT scan in May 2012 showed that the right middle lobe lesion had been reduced to 1.1 x 0.7 cm. The mediastinal mass was stable in appearance. She declined further treatment due to treatment toxicities.
By November 2012, the CT scan showed that the right middle lobe mass had grown to 1.9 x 2.4 cm and the mediastinal mass around the aortopulmonary window to 7.3 x 5 cm. There were also a new 3 x 2.5 cm right peribronchial mass and a 4 x 4.9 cm infra-carinal mass. She died of progressive disease by early December 2012.

Discussion
The case report illustrates the decision-making process in HCC. HCC is a less common type of differentiated thyroid cancer. It has distinct adverse features: higher rate of regional lymph node metastases, recurrences and cause-specific mortality, all shown in this case [3]. Four management issues will be addressed below.
The first issue is about the difficulty to separate HCC from other benign or malignant thyroid neoplasms preoperatively or even by frozen section like our case. Hurthle cells (HC), or oncocytes, are large cells found in the thyroid gland and elsewhere, and are characterized by abundant, granular, eosinophilic cytoplasm which is a consequence of the accumulation of altered mitochondria. Pathological differential diagnoses include medullary carcinoma and papillary thyroid carcinoma. Workup typically involves a fine needle aspiration biopsy (FNAB). The Bethesda system for reporting thyroid cytopathology classifies HCC in the diagnostic category of "follicular neoplasm or suspicious for a follicular neoplasm" [2]. Histological features of capsular and vascular invasion have been used for many years as a sign of malignancy. Our case has vascular invasion in the final pathology report. Since it is undesirable to over-treat benign HCN, there is growing research in genetic profiling. The genetic abnormalities identified in HCN include aneuploidy, H-ras mutations and allelic alterations and include alterations in mitochondrial DNA (or genes) [4]. The cellular proliferation index (Ki67) was found to be higher in HCC. It may help as a diagnostic marker of malignancy in HCN cytology. However, larger studies are needed to validate these findings and, until then, testing for genetic alterations in HCC tumors remains primarily investigational [4].
The second issue is about the extent of surgical resection. Our case had completion thyroidectomy very soon after the pathology report came back as HCC. An ipsilateral neck lymphadenectomy is recommended for clinically/ radiologically/ biopsy-proven lymphadenopathy. Like our case, all patients should have a radioiodine scan three to four months after surgery. The iodine-123 scan was a diagnostic scan to see any residual thyroid tissue. Since there was a lot of residual thyroid tissue, she had I-131 ablation with 100 mCi, followed by a whole body scan nine days later.
The third management issue is on imaging and the role of radio-iodine diagnostic scan and treatment. The 2016 National Comprehensive Cancer Network (NCCN) guidelines recommended consideration of radio-iodine therapy based on pathological findings and postoperative serum thyroglobulin levels [5]. Except for low-risk cases, remnant thyroid could be ablated with iodine-131 to facilitate the use of serum thyroglobulin for surveillance. This will ablate the residual thyroid tissue, identify and treat known metastases. The current recommendation advocates its use in HCC patients with tumors >2 cm or those with nodal and distant metastases.
In patients with a negative radioiodine scan and rising serum thyroglobulin, PET/CT can be ordered. A meta-analysis of seven trials showed an improved detection rate of recurrence/metastasis by either thyroxine withdrawal [6] or recombinant thyroid stimulating hormone (rTSH) injection. Our patient underwent the PET/CT while on thyroxine.
The last issue is on the role of external beam radiotherapy. Our center employed this for gross postoperative residual disease and in this case for adjuvant and salvage treatments. In the modern era, our center also arranges radiofrequency ablation or stereotactic body radiotherapy for limited small lung metastases. Other salvage treatments include ethanol ablation, radioiodine ablation, external radiotherapy, radioisotope and systemic treatment. Our patient had external radiotherapy and systemic treatment.

Conclusions
The reported case illustrates the management of this rare cancer. The patient presented with a neck mass, which was investigated with an ultrasound scan. We tried to establish the pathological diagnosis by a fine needle aspiration biopsy and a frozen section of the resected tissue, both of which could not confirm malignancy. The detailed examination found vascular invasion and concluded with the diagnosis of HCC. We performed radioactive iodine ablation, multiple surgeries, external radiotherapy and finally enrolled her into a clinical trial of systemic therapies due to lack of options. Despite our impeccable follow-ups, assessment, and treatments, she suffered multiple recurrences in different locations. Sadly, we lost her after 11 years of the cancer battle. The discussed strategic diagnosis and treatment plans could be used