Papillary Thyroid Carcinoma
Christopher Prichard, M.D.
December 4, 2003

In 1920, Dr. William Halstead, the first chairman of surgery at Johns Hopkins and the developer of the modern day American residency system, wrote the operative story of goiter in which he detailed the history of thyroid surgery up until his time and also describes his operation. And what became clear from Dr. Halstead’s treatment was that the history of the surgery of the thyroid gland really reflected and included some of the great developments of surgery in general and some of the greatest head and neck surgeons of the time. Dr. Halstead also contributed to the basic knowledge of the thyroid gland in demonstrating in the laboratory that postoperative tetany from a thyroidectomy was actually due to hypocalcemia. Now, the first great pioneer that Dr. Halstead spoke of was Theodore Bilroth, who, at the age of 31, assumed the chairmanship of surgery in Zurich and over the next seven years performed 20 cases of thyroidectomy with a mortality of 40%. Now of the eight deaths in these first 20 cases, seven were due to postoperative sepsis and one was due to intraoperative hemorrhage. Due to this, Dr. Bilroth actually stopped performing the operation for over 10 years. But developments in the technique of surgery allowed him to again perform thyroidectomies. One of these developments was the introduction of sterile operative techniques by Joseph Lister. The second was the development of the hemostat by Spencer Wells in 1872. Dr. Bilroth had moved to Vienna by the time he resumed performing thyroidectomies. He subsequently performed 48 cases with a mortality of about one-fifth of his previous series. Perhaps the greatest contributor to the development of thyroid surgery and an understanding of the thyroid gland was Dr. Emil Theodor Kocher. Dr. Kocher by 1883 reviewed his first 100 thyroidectomies and of these 100, 34 were total thyroidectomies. In follow-up, he saw a little 11-year-old girl on whom he had performed a thyroidectomy at the age of two. He noted that she was cretinoid and he was so horrified by this that he tried to recall the other 33 total thyroids. Of these, he got 18 of them back into the clinic and noted that 15 of them exhibited the symptoms and signs of myxedema. And this was some of the first real evidence of the importance of the physiologic function of the thyroid gland. For his work, Dr. Kocher was awarded the 1909 Nobel Prize in medicine and in the year of his death he reported his complete experience of thyroidectomy with a 0.5% mortality rate.

Moving into the modern ear, a man made disaster led to some insights in the development of papillary cancers. On April 26, 1986 in Chernobyl, Ukraine, the metal cladding responsible for containing the fission products of a nuclear reactor broke down. Subsequently, a fire developed that burned for 10 days. It released an estimated 50 million curies of radioactive isotopes into the atmosphere. The interesting thing about this in relation to thyroid cancer is that the majority of the radiation released was in the form of radioactive iodine, Iodine 131. If you look in the area near the Chernobyl plant over the 4 years prior to this disaster, there were 17 reported cases of thyroid cancer in children. If you look seven years after this incident, in 1993 there were 137 reported cases in children and almost all these cases were papillary cancers.

Embryology of the thyroid gland: The thyroid gland begins with a median outbudding of endoderm in week four of embryonic life and this outbudding, called the thyroid diverticulum, begins to descend in the midline attached by the thyroglossal duct, which disintegrates at week five, and it reaches its adult position by week seven of embryonic life. During its descent, it picks up several inpouchings of neural crest cells called the altima branchial bodies, which join the thyroid gland. The altima branchial bodies eventually become the parafollicular C cells that secrete calcitonin and the thyroid diverticulum forms into the follicular cells. These cells give rise to the different types of thyroid cancer. The C cells give rise to the medullary cancers and follicular cells give rise to the well-differentiated cancers as well as anaplastic cancers. If you look at thyroid cancers, it is noted that the incidence is on the rise. The ACS last year in their statistics reported 20,700 new cases a year with 1,300 deaths due to thyroid cancer. Thirty years ago there were about 8,000 new cases per year but the incidence of death has not increased significantly. At that time it was about 1,000 cases per year. If you look at an isolated thyroid nodule there is anywhere from 5% to 12% risk of development of cancer in an isolated nodule. Now, thyroid cancer in general is a variable disease and ranges from some of the best prognostic cancers that humans have to some of the most aggressive and deadly. We will see the 10-year survival rates show exc ellent survival rates for the well-differentiated cancers, papillary and follicular and terrible survival rates for anaplastic cancers.

In a study done in 1998, over 53,000 cases of thyroid cancer treated over a 10-year period in the U.S. were reviewed. This study found that between 77% and 81% in any given year were papillary thyroid cancers, the most common. The female to male ratio was 3:1, though the risk of dying from a papillary cancer is actually 2:1, males over females. The mean age of presentation in this study was 39 years and typically it presents in the third or fourth decade. These are indolent, slowly progressive tumors and there is an overall 10-year survival of 93%.

Most papillary cancers present as a clinically palpable asymptomatic nodule. Within a 40-year span, as many as 35% have recurrence after successful treatment. There is a high incidence of nodule metastasis: 35% of cases will have cervical node metastases, with the literature reporting this rate as high as 40 to 45%. Twenty percent of patients will have multiple tumors within the thyroid gland, 10% will extend beyond the capsule of the thyroid gland and 10% will have distant metastases. The risks of developing papillary thyroid cancer, aside from age and sex, include a history of ionizing radiation and the Chernobyl incident gave us some of the strongest evidence of how radiation plays a part in the development of papillary cancers. There is also a genetic predisposition. The papillary thyroid cancer proto-oncogene is a tyrosine kinase receptor that in its mutated form is constitutively active and that mutation is seen in up to three-quarters of radiation-associated thyroid cancers. In addition, there is an incidence as high as 10% correlation within families of papillary cancer.

The evaluation of a patient with papillary cancer begins with the physical exam and the mobility of the true vocal folds, as well as any cervical lymphadenopathy. Ultrasound examination is highly sensitive for thyroid nodules but not specific. It is useful in three major instances. The first is evaluation of the contra lateral lobe of the thyroid gland in which there is a unilateral palpable nodule. The second is for fine needle aspiration to obtain ultrasound guided fine needle aspiration. The third is in conjunction with scintigraphy studies. With ray and radioactive scintigraphy, if the nodule is hot it is very unlikely to be a cancer, with only about 4% of these actually being cancers. If it is cold, one in five thyroid nodules will end up being a cancer. You can correlate the ultrasound with the radionuclide scintigraphy: if an ultrasound shows a lesion of less than 4 cm that is cystic combined with a cold nodule, it is very unlikely to be cancer. There is a role for MRI in evaluation and demonstrating extrathyroidal extension. CT can do the same but it really should be avoided because the iodine load with the contrast will decrease the affinity for iodine and delay treatment with radioactive iodine. Chest x-ray should be obtained for a metastatic workup and laboratory evaluations include TSH, calcium and liver function tests for metastatic workup.

The hallmark of diagnosis of papillary cancers is fine needle aspiration. Dr. Mandell and Urken took a look retrospectively at 139 surgical cases that all had fine needle aspiration biopsies. Of these 139, they had 44 that were papillary thyroid carcinomas and they looked back to see what the FNA showed. In about 52% of the cases the FNA was read as papillary cancer and in another 43 it was read as suspicious and only 4.5% were outright false negatives. So, if you take the malignant and suspicious lesions, it gives a 96% diagnostic accuracy for papillary cancers. The role of frozen section was also evaluated in the study.

Now to review the pathologic characteristics of papillary thyroid carcinoma. Papillary cancer is interesting in that the diagnosis is cytologic and does not require a demonstration of vascular invasion or extracapsular spread to make a diagnosis of cancer. Typical characteristics of papillary carcinoma include a papillary type architecture with papilla surrounding fibrostromal cores. There is significant nuclear overlap as opposed to the well-lined cuboidal epithelium of a normal follicle and there is the hallmark “Orphan Annie” nuclei demonstrated at lower power here, which are nuclei with marginalized chromatin and central vacuoles. These tumors are typically unencapsulated. They have a predisposition for lymphatic spread and a pathologic hallmark is the psammoma body. These are seen in about 50% of papillary cancers. It’s a concentric lamilated structure seen at high power here and it is thought to result due to calcification of a necrotic papilla. The nuclear features allow the diagnosis of papillary cancer. This is an FNA section, which reveals nuclear grooves, which is a typical feature of papillary cancer. Again, you see the nuclear overlap and also the characteristic ground glass nuclei due to the dispersed chromatin pattern.

So if we review our patient’s pathology slide, she had some of the classic features of papillary cancer. She doesn’t have the overall papillary ultra structure due to the extensive nature of the thyroiditis, but at low power, you see a focus of papillary cancer in her gland bordered, below the black arrow, by areas of heavy lymphocytic infiltration characteristic of thyroiditis. Cellular features were very characteristic of papillary cancer; with exc ellent examples of “Orphan Annie” nuclei, nuclear grooves and ground glass nuclei.

Not all papillary cancer is the same. There are several histologic variants, which can affect prognosis. One is the tall cell variance seen in about one in 10 papillary cancers. It typically presents in elderly women and it has about a 1 in 4 mortality rate. We see an example to the right. Typical nuclear features of papillary cancers, but the cells typically are these high columnar epithelial cells. The diffuse sclerosing variant of papillary cancer is a much more aggressive variant. It is typically seen in young women. The most aggressive form is the columnar cell variant. It is quite rare and presents in elderly men, but has a 90% mortality rate. And then 1 out of 10 papillary cancers can actually be encapsulated and this actually provides a better prognosis. It was formerly thought to be a benign lesion referred to as a papillary adenoma. And finally, there is the follicular variant of papillary cancer, which displays follicular architecture but has the cytology typical of papillary carcinoma.

There are several staging systems for papillary cancer. The staging systems include the T&M staging system and the EORT (the European staging system). Two very similar systems, AMES and AGES out of the Lahey Clinic and the Mayo clinic is an acronym for age, metastasis, extracapsular spread and size of the tumor, while the G in AGES stands for grade. The Ohio State classification system typically relies on size and extrathyroidal spread. Now these factors with the Xs in this chart are factors that are used in determining the risk of a papillary cancer based on the staging system. While this is a busy slide, the important take home point is that the common denominator of all of these staging systems are four factors: age, size of the tumor, extrathyroidal spread and distant metastases. These are the most important prognostic factors in papillary cancer.

Looking at age as a prognostic factor, a review of 1,400 patients presented by Dr. Mazzaferri of Ohio State in 1994 revealed the effect of age on mortality. As you can see, the death rate at an age before 40 years is incredibly low, while at the age of 40 years, begins to rise linearly. So this demonstrates the significance of age at diagnosis on the prognosis. In females, a slightly older age of diagnosis is used. Higher risk lesions are considered females over 50 years, and males over 40 years. Extracapsular extension of the papillary cancer actually doubled the mortality of the lesion. As to tumor size, the mortality and recurrence rate begin to increase at lesions above 1.5 cm. Typically high risk tumors are considered tumors above 4 cm in size. An interesting thing about papillary cancer is that unilateral cervical nodal metastasis does not typically correlate with an increase in mortality, although mediastinal metastasis, bilateral cervical nodal metastasis and distant metastases do.

There is a phenomenon that applies to our patient described as papillary microcarcinoma. The exact definition has been debated, but it is typically accepted as a lesion smaller than 1 cm. A review was done at the Mayo Clinic of 535 cases of papillary microcarcinoma and these were the findings. There is a lot in common with our patient here. Twenty percent of these patients had multiple foci and 10% had bilateral lesions. One in five had associated extensive thyroiditis and one in two was associated with benign adenomas of the thyroid gland. These lesions had an exc ellent prognosis of 0.4% but, in this study, over 90% of these lesions were treated by bilateral lobectomy.

The treatment of papillary cancer is primarily surgical though there has been extensive debate as to the extent of surgery in various patients. In 1994, Dr. Mazzaferri also demonstrated that extensive surgery is an independent factor in looking at the cause specific mortality of papillary cancers. As you see here, there is an improved mortality in near total or total thyroidectomies as compared to those patients who underwent less than near total thyroidectomies. He updated this data in 2001, presenting over 1,500 patients and the findings held consistent. But, as I say, there is considerable debate as to how to treat the low risk papillary lesions, which constitute about 85% of papillary carcinomas. In 1999 a consortium of 17 institutions in the United States with specialists across multiple disciplines in the National Conference of Cancer Network tried to establish guidelines for the treatment of papillary carcinoma. The algorithm that they established is based on assessment of risk of the lesion. Three questions are asked. What is the age of the patient? How large is the tumor? And, what is the extent of spread as well as prior history of radiation, family history of disease or bilateral lesions? If the answer to any of these questions is “yes,” it is classified as a high-risk lesion. If the answer is “no,” it is classified as a low risk lesion.

The question them becomes, how do you treat the low risk lesions? There are several treatments with data to support them. One is near-total or total thyroidectomy with postoperative radioactive iodine ablation. This is the treatment that most practitioners in the U.S. seem to comply with. But there is data that suggests that in certain patients with close follow-up, a lobectomy plus isthmectomy is an acceptable treatment, and, if local recurrence occurs, then proceed with complete thyroidectomy. It is generally accepted that high-risk lesions should be treated with a total thyroidectomy and a selective neck dissection.

As to the postoperative management of the patient with papillary cancer, the primary hallmark is radioactive iodine with an iodine 131 whole body scan. That is what our patient underwent. Obtain a whole body scan about a week postoperatively, and observe if there is activity in terms of distant metastases. If there is activity isolated in the thyroid bed, you can treat and then follow-up six months later with a whole body scan, repeating this until you have a negative scan. Now the NCCN absolutely recommends iodine 131 and radioactive iodine ablation in high-risk patients. In low risk patients, it is at the discretion of the practitioner based on the patient’s characteristics.

Now Dr. Hay at the Mayo Clinic in 2002 reviewed all of the cases of thyroidectomy at the Mayo Clinic over a 50-year period. And what he found was in the first 10 years of the review lesions were primarily treated with lobectomy. Beginning in the second 10 years, the primary treatment was a near total or total thyroidectomy, and, at that point he did see significant improvement in mortality, but over successive decades there was periodic increases in the frequency of radioactive iodine ablation given to these patients and essentially the mortality remained the same. So he argues that radioactive iodine ablation should be much more selective in patients with papillary cancers.

Now, the Ohio State group has published data showing that total thyroidectomy with T4 suppression in conjunction with radioactive iodine does yield significant benefit in terms of local recurrence. And so they, in fact, strongly advocate the use of radioactive iodine.

With regard to further issues in postoperative management, patients should be followed with thyroglobulin levels. The thyroid follicle cell is the only cell in the body that secretes thyroglobulin. If you have two negative whole body scans in conjunction with a thyroglobulin level below 2, then it is nearly certain that the patient at that time does not have residual cancer. Suppression with thyroxin of TSH has been shown to provide benefit in terms of cause specific mortality as well as local recurrence. External radiation for unresectable lesions or if there is a significant amount of thyroid left over, has been shown to give improvements in cause specific mortality and local recurrence as well.

Our patient, based on NCCN guidelines, as a patient with papillary microcarcinoma, should not uniformly be treated with a total thyroidectomy, but should be counseled as to the options. After counseling, this patient elected to undergo completion thyroidectomy. The interesting fact in this patient is the pathology in the contralateral lobe revealed a papillary carcinoma of 1.6 cm that did not show up on the ultrasound. When you review her pathology slide, it becomes clear that the reason for this is that with the extensive thyroiditis in the gland, the carcinoma tends to just infiltrate linearly in between germinal centers of the thyroiditis. Her pathology again was typical cytologic characteristics of papillary cancer and there was no extracapsular extension. So, she underwent an iodine 131 whole body scan and it revealed uptake only in the thyroid bed. She underwent a dose of radioactive iodine and is scheduled for a follow-up whole body scan.

So, in summary, papillary thyroid carcinoma accounts for four out of five thyroid malignancies. It is a variable disease depending on factors of the patient as well as the histologic variant of the lesion. Age, size extracapsular spread and distant metastases are the major factors in prognosis for these lesions. The prognosis is, in general, exc ellent with over a ninety percent 10-year survival. Near total or total thyroidectomy is the treatment of choice amongst most practitioners in the U.S. though the ideal treatment is still hotly debated, with or without the use of radioactive iodine.

Case Presentation:

Y.H. is a 39-year-old female who presented to the Methodist Hospital ER with neck pain, a progressive sensation of choking and tightness in her neck. One week prior she presented to an outside hospital with similar symptoms, and a right thyroid nodule and thyromegaly were noted. At TMH her airway was determined to be stable, and she was subsequently referred to an endocrinologist for further work-up.

The patient was recently diagnosed with reflux and started on Nexium; otherwise, she had no significant medical history. She had no smoking history, does not drink alcohol, and has no history of neck irradiation. Review of systems was notable for occasional hoarseness and dysphagia.

Physical examination was notable for diffuse thyromegaly and a mildly tender thyroid gland with a palpable right thyroid nodule. There was no cervical lymphadenopathy. Flexible endoscopy revealed mobile true vocal folds bilaterally.

Laboratory studies revealed a normal CBC, Chem-7, and LFTs. Her TSH, T3, fT4 were normal as well. Thyroid peroxidase antibody was elevated at 194. Chest x-ray revealed no abnormalities.

A thyroid ultrasound was obtained, which revealed a dominant 2.8 x 1.8 cm right lobe nodule, as well as a hypoechoic 6mm left lobe nodule.

Fine needle aspiration biopsy was performed, which revealed a follicular neoplasm of the thyroid gland.

The patient was referred to the Otolaryngology clinic and the decision was made to perform a right thyroid lobectomy. The patient underwent right thyroid lobectomy with frozen section, which revealed a follicular adenoma.

Final pathology revealed a 2.2cm follicular adenoma, extensive thyroiditis, and a 4-5 mm focus of intraglandular papillary microcarcinoma.

Subsequently, the patient elected to undergo a completion thyroidectomy. Final pathology revealed a 1.6 cm papillary carcinoma without extracapsular extension.

The patient underwent post-operative I-131 scan which showed activity in the thyroid bed with no evidence of metastatic disease. She was admitted overnight and given I-131 sodium iodide orally.

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