| Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Hürthle Cell Thyroid Carcinoma J.G. is a 60-year-old Hispanic female that was originally referred to the otolaryngology clinic at Ben Taub by her primary care physician after being diagnosed with a left thyroid nodule. She was asymptomatic and denied any dysphasia, dyspnea, hoarseness, or weight loss and she had no other significant past medical history. A thyroid scan ordered by her primary care physician revealed a large cold nodule in the left thyroid lobe. She underwent an ultrasound, which showed an 8.6 x 5.4 cm heterogeneous solid mass in the left thyroid lobe. A fine needle aspiration biopsy was performed and revealed Hürthle cells but was indeterminate for malignancy. She underwent a left thyroid lobectomy. Frozen section analysis revealed a Hürthle cell neoplasm, but malignancy could not be confirmed. Final pathology was consistent with Hürthle cell carcinoma and vascular and capsular invasion present. The maximum diameter of the tumor was 7.5 cm and she was staged at a T3,N0M0. A completion thyroidectomy was performed 10 days after original surgery and she did well postoperatively. She will undergo radioactive iodine scan and possible ablation of any residual thyroid tissue. The objective of this talk to introduce Hürthle cell carcinoma. I will review the pathology and the unique findings of Hürthle cell neoplasms, also look at the role of fine needle aspiration and frozen section analysis in the workup of thyroid nodules specific to the Hürthle cells. I will also briefly talk about the surgical management. I will address prognosis and staging, and I would like to briefly discuss radioactive iodine therapy as it applies to Hürthle cell carcinoma as well as the role of external beam radiotherapy. The instance of thyroid carcinoma in the United States in 2003 was estimated by the American Cancer Society to be about 22,000 new cases. This represents 1% of all new cancers and 2% of all cancer deaths. Hürthle cell carcinoma is uncommon and represents only 3 to 10% of all differentiated thyroid carcinomas. The World Health Organization recognizes Hürthle cell carcinoma as a sub-type of follicular carcinoma; however, as time goes by and as molecular studies increase, Hürthle cell carcinoma will be likely recognized as its own separate entity. Other names that might be seen historically are Askanazy carcinoma, oxyphil tumor and oncocytoma. Hürthle cell neoplasm is not characterized just by the presence of Hürthle cells. The tumor needs to be composed of greater than 75% Hürthle cells. There are few to no lymphocytes which can be see in conditions like Hashimoto’s thyroiditis where Hürthle cells may be present. Hürthle cell carcinoma demonstrates vascular and/or capsular invasion which differentiates this from a Hürthle cell adenoma. The incidence of metastases is higher than in other differentiated thyroid carcinomas, with the most common sites of metastasis being lung, bone, and the central nervous system. This picture shows capsular invasion of a Hürthle cell neoplasm. Hürthle cells can also be seen in tissues outside of the thyroid gland including the pituitary gland, salivary gland, pharynx, esophagus, trachea, larynx, kidney, and liver and as mentioned previously it can also be found in chronic thyroiditis such as Hashimoto’s thyroiditis and multinodular goiter. In these conditions lymphocytes are present, and there will not be a capsule as can be seen in a neoplasm. Historically, Hürthle cells are named after a German histologist, Karl W. Hürthle; however, he was most likely describing parafollicular cells or C-cells. Dr. Askanazy is actually thought to be the first to describe what we now call Hürthle cells. In 1907 Langhans reviewed the first series of patients with Hürthle cell tumors and two of these patients died of metastatic disease. This time he did not describe capsular invasion, and it is unclear whether these were adenomas or carcinomas. This is an electron micrograph showing the characteristic mitochondria that give Hürthle cells their unique appearance. Hürthle cells represent 0.4 to 10% of all thyroid tumors. They generally occur between the fifth and the seventh decade with a mean age in the sixth decade. Hürthle cell neoplasms are more common in females, but Hürthle cell carcinomas are more frequent in males. This is consistent among most series and the incidence of carcinoma increases with age. On clinical presentation, Dr. Watson from Mayo looked at a large series of patients over a 25 year time span. All patients with Hürthle cell carcinoma had a palpable thyroid anomaly. Hoarseness, pain, palpable lymphadenopathy, and vocal cord paralysis were all uncommon findings. A history of non-malignant thyroid disease occurred in approximately one-third of patients. Dyspnea and dysphasia can also occur in this series. All patients that had dyspnea and dysphasia were found to have carcinoma. Patients are generally euthyroid, and a history of previous radiation to the head and neck is an important predisposition for likelihood of carcinoma rather than an adenoma. On gross pathology the lesions are generally circumscribed and encapsulated, having a brownish color. There maybe spontaneous infarction but is not specific for benign and malignant lesions. Also previous FNA can give an area of infarction. It has been shown that carcinomas generally show more necrosis, scarring, and hemorrhage. On cytology, the cells are characterized as large polygonal cells. They are poorly cohesive. The eosinophilic and granular cytoplasm that can be seen is due to the high mitochondrial count characteristic of Hürthle cells. You can see they have prominent chromatin, the nuclei are similar in size, and nuclear atypia can be seen in both benign and malignant tumors. This is a Hürthle cell carcinoma that is metastatic to a lymph node. Cytologic features suggesting malignancy include an increased nuclear to cytoplasm ratio, the presence of columnar rather than polygonal cells, and increased mitotic rate. Most importantly, malignancy needs to be confirmed by histologic section looking for capsular vascular invasion. This chart shows how to differentiate aspirates that have Hürthle cell carcinomas. Generally, a tumor is going to be solitary where Hashimoto's thyroiditis and multinodular goiter are going to be either diffuse or have multiple nodules. The Hürthle cells are generally not very cohesive compared to the thyroiditis and te multinodular thyroid goiter. The nuclei are uniform size in Hürthle cell neoplasms, colloid is generally absent, and lymphocytes are rare. These can help differentiate a patient that might have a chronic thyroid condition compared to a thyroid Hürthle cell neoplasm. It has also been demonstrated that the number of Hürthle cells do not correlate with malignancy. This picture shows capsular invasion and vascular invasion. Both define a Hürthle cell carcinoma. Dr. Wartovsky out of Michigan reviewed 179 patients that had either follicular or Hürthle cell suspicious FNAs and divided them into two groups. The groups were categorized by the amount of colloid with lesions suspicious of carcinoma having less colloid and degree of cellularity. They divided them into Group I (lesions suggestive of carcinoma by degree of cellularity or colloid content) and Group II (inconclusive biopsy). By evaluating for the amount of colloid and cellularity, actually 85% in Group I had malignant tumors. Cellularity and colloid content are helpful in predicting malignancy, however, FNA remains limited in definitive diagnosis. Dahl and others in 2002 looked at 116 patients who were diagnosed with a Hürthle cell neoplasm. This is a retrospective review over a 10-year period. Forty-nine patients were found to have carcinoma and 67 patients were found to just have benign Hürthle cell neoplasm. Patients with thyroiditis and multinodular goiter were excluded. Frozen section analysis at the time of the original operation diagnosed 20% with carcinoma. There was 100% correlation with final pathology. However, the vast majority of frozen sections were indeterminate and for these patients either a decision was made to do a complete thyroidectomy at that time or to bring them back later after results of the final pathology. Notably, six of the patients actually had a papillary thyroid carcinoma. Size correlated with malignancy with the carcinomas having a larger size than the benign lesions. Staging for Hürthle cell carcinoma is the same as other well demonstrated carcinomas. The TNM system is most commonly used with size being a criteria. Our patient had a 7.5 cm thyroid carcinoma, but it did not have any extensions. As a result, she was staged as a T3. Lymph node disease is a little different than squamous cell carcinoma. It is either N0 or N1 with an N1A being disease limited to ipsilateral nodes and N1B being bilateral, midline, contralateral, or mediastinal involved lymph nodes. Metastases staging is the same for most other carcinomas. Staging is further divided by age, with patients under 45 years of age having a much better prognosis with metastases defining a Stage II disease. Patients 45 years or older have a stage 1 for very small lesions, less than 1 cm, stage 2 between 1 and 4 cm, and then stage 3 for larger lesions and lesions with lymph node involvement, and then stage 4 with metastatic disease. Overall mortality for Hürthle cell carcinoma is actually greater than both papillary and follicular thyroid carcinoma. This is due to the higher incidence of pulmonary lymphatic metastases and the poor uptake of radioactive iodine. Poorer survival correlates with patients age. The male sex has poor survival and larger tumor size. The presence of lymph node disease, unlike papillary thyroid carcinoma, results in increased local recurrence, metastases, and mortality. Grant looked at DNA histograms of 50 patients and found that the majority of patients with Hürthle cell carcinoma had aneuploid DNA histograms. Aneuploidy was a significant positive predictor for mortality. Aneuploidy also predicted increased recurrence although this was not significant in this series.. In regards to surgical management, most advocate initial thyroid lobectomy and completion thyroidectomy if Hürthle cell carcinoma is identified on permanent pathology. Completion thyroidectomy also increases the efficacy of radioactive iodine scanning therapy if needed later. Cervical nodal metastases is generally treated with a modified radical neck dissection. Level I cervical involvement is uncommon and does not routinely need to be addressed. Seguina reported recurrence in three patients with a Hürthle cell adenoma and, interestingly, two of these were subcutaneous implantations. It is import avoid tumor spillage during resection. Adjuvant therapy is not as effective for Hurthle cell carcinoma as for other well differentiated thyroid carcinomas. Generally doses are given that range between 30 and 150 millicuries. Other arguments for radioactive iodine therapy is to ablate any remaining thyroid tissue. This will increase efficacy of future treatmentsand increases sensitivity of future thyroid scans. But unfortunately, Hürthle cell carcinomas generally do not uptake radioactive iodine and even if they do, uptake usually decreases with subsequent recurrences. Potential side effects of radioactive iodine therapy include bone marrow suppression, pulmonary fibrosis and lymphoma. Doses are cumulative over successive treatments. Thyroid hormone suppression has been shown to decrease cancer related deaths in patients with papillary thyroid carcinoma. It has also been shown to lower tumor recurrence in patients with both papillary and follicular thyroid carcinoma. Also patients with Hürthle cell carcinoma generally should have thyroid hormone suppression therapy. Risks of suppression include cardiovascular incidents, including arrhythmias, and decrease bone mineral density. One author made recommendations of keeping a TSH in the range of 0.01 to 0.1 in patients that have been deemed in the high risk category, and then TSH range of 0.1 to 0.4 in patients with lower risk to decrease incidence of side effects. External beam radiotherapy can be helpful for Hurthle cell carcinoma since radioactive iodine treatments are not as efficacious. Phillips and others in 1993 looked at 94 patients with well differentiated thyroid carcinoma. 56 patients were treated with radioactive iodine alone; and 38 of these patients had additional course of radiation therapy, 55 Gy over 5.5 weeks. There was no difference in survival despite the fact that the patients who were treated with radiation therapy generally had more advanced disease. Treatment with radioactive iodine resulted in a 21% local recurrence, but with the addition of radiation therapy this decreased to 3%. The authors concluded radiation therapy was very effective for well-differentiated thyroid carcinoma. And these authors recommended adjuvant radiation therapy if the patient has macroscopic or microscopic residual disease deemed at the time of the original surgery or if extracapsular extension from cervical lymph node disease was identified. O’Connell and others out of England looked at 113 patients with well-differentiated thyroid carcinoma. All patients received radiation therapy and it was 60 Gy over a six-week period. Seventy-four patients also received radioactive iodine. An 81% local control rate was appreciated if there was either probable or definite microscopic residual disease. Residual disease was defined as tracheal involvement needing tracheal shave, strap muscle involvement, or other possibility of residual microscopic tumor left behind. There was only a 37% local control rate in patients with macroscopic residual disease. This would be disease involving the carotid sheath or the pharynx or esophagus that was unresectable at time of initial operation. The majority of the patients with macroscopic disease did not have a response. These authors felt indications for radiation therapy would be failure to concentrate iodine, poorly differentiated tumors, inoperable tumors, tumors with multiple local recurrences, and then palliative relief in progressive symptoms including stridor, dysphasia, or hemoptysis. They also point out the fact that radioactive iodine, if it is to be given, should be given prior to radiation therapy since radiation therapy may cause a decrease in radioactive iodine uptake. Putt and others in 2003 looked at 18 patients with Hürthle cell carcinoma and radiotherapy. This is the only series that specifically looks at only Hürthle cell carcinoma and external beam radiation. The overall five-year survival in these patients was 66.7%. They did conclude that Hürthle cell carcinoma is a radiosensitive tumor. Five of the patients received radiation therapy as adjuvant therapy for local disease. Four out of five patients had local regional control. Three out of five, however, died of metastatic disease. The mean survival was approximately 38 months. Seven patients received radiation therapy for salvage. All these patients had recurrent neck disease, between one and four recurrences. There was fair local regional control rate of three of the seven patients and these died of metastases. Four of the seven developed recurrence, and the median survival in this group was 34 months. Six patients received palliative radiation therapy in multiple sites for distant metastases. Most of these were bony metastases, and all of them received pain relief for at least 12 months. With these results they concluded Hürthle cell carcinoma is a radiosensitive tumor and radiotherapy is a viable option, especially in patients with distant metastases and pain for palliation. These authors recommend radiation therapy for unresectable recurrent disease, symptomatic distant metastases, and large invasive tumors. They also looked at DNA aneuploidy since this carries a worse prognosis and recommended radiation therapy. Potential side effects include mucositis and xerostomia. With thyroid cancer, damage to the spinal cord is a significant issue. With new techniques this is becoming less of a problem. Importantly, patients should not be considered cured once they are diagnosed with Hürthle cell carcinoma. The mean interval of recurrence is almost five years from their initial diagnosis, and there are many instances of recurrences greater than 15 years out from treatment. Patients need to be followed for a lifetime with a high index of suspicion for recurrence. Serum thyroglobulin is probably the most common way of following these patients. All patients should have evaluation for anti-thyroglobulin antibodies and is present in about one out of every five adults. This, of course, will make thyroglobulin a poor way to monitir for recurrence. Also, all normal thyroid tissue should be removed or ablated so you can follow the thyroglobulin more accurately. It is important to remember an undetectable level or very low level does not necessarily prove the absence of carcinoma. So if patients are symptomatic and they have a normal thyroglobulin instead of a high index of suspicion, they could have recurrence of the tumor. Radioactive iodine scans are probably not helpful since Hurthle cell carcinomas do not uptake radioactive iodine. Because of the problems with radioactive iodine alternate imaging modalities have been evaluated in patients with recurrent disease detected by an elevated thyroglobulin. A high-resolution ultrasound can be used to look for neck recurrence. CT scan, MRI, and PET scanning have also all been used to help look for recurrence of metastatic disease. Octreotide scan is a good option if tumor location is difficult. In conclusion, Hürthle cell carcinoma is and uncommon malignancy and is currently considered a variant of follicular cell carcinoma. Capsular or vascular invasion differentiates an adenoma from a malignancy. Overall mortality is greater than both papillary and follicular carcinomas. The eosinophilic and granular cytoplasm is due to the increased amount of mitochondria. Surgical management is total thyroidectomy. It is important to remember that Hürthle cell neoplasms concentrate iodine poorly. Alternative imaging modalities will be developed, and some are available now. External beam radiation therapy may be of especially beneficial in patients with Hurthle cell malignancies since iodine is poorly absorbed. And it is important to remember that recurrences may occur many years later, and careful surveillance is required. Case Presentation She underwent a thyroid scan that revealed a large cold nodule in the left thyroid lobe. Ultrasound was subsequently performed and revealed an 8.6 X 4.3 X 5.4 cm heterogeneous solid mass in the left thyroid lobe. No suspicious cervical lymphadenopathy was present. Fine needle aspiration revealed Hürthle cells and was interpreted as inconclusive for malignancy. She underwent a left thyroid lobectomy with intraoperative frozen section consultation that revealed a follicular neoplasm with Hürthle cells. Permanent sections demonstrated focal capsular and vascular invasion, and she was diagnosed with Hürthle cell thyroid carcinoma. The maximum dimension of the tumor was 7.5 cm and all margins were clear. She underwent completion thyroidectomy 10 days later. There was no carcinoma identified in the right thyroid lobe. Her final pathologic staging was a T3N0M0 Hürthle cell thyroid carcinoma. She is to undergo a radioactive iodine scan and possible ablation of any remaining thyroid tissue. Bibliography: Ambu R, Riva A, Lai ML, Loffredo F, Riva FT, Tandler B. Scanning electron microscopy of the interior of cells in Hurthle cell tumors. Ultrastruct Pathol 2000;24:211-219. Arganini M, Behar R, Wu TC, Straus F 2nd, McCormick M, DeGroot LJ, Kaplan EL. Hurthle cell tumors: A twenty-five-year experience. Surgery 1986;100:1108-1115. 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Increasing the effectiveness of radioactive iodine therapy in the treatment of thyroid cancer using Trichostatin A, a histone deacetylase inhibitor. Surgery 2002;132:984-990. BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2005
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