------------------------------------------------------------------------------- TITLE: TUMORS OF THE THYROID GLAND SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: October 21, 1992 RESIDENT PHYSICIAN: Daniel P. Slaughter, M.D. FACULTY: Karen H. Calhoun, M.D.:w DATABASE ADMINISTRATOR: Melinda McCracken, M.S. ------------------------------------------------------------------------------- "This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." INTRODUCTION: Malignant neoplasms of the thyroid include papillary carcinoma, follicular carcinoma, Hurthle cell carcinoma, medullary carcinoma, anaplastic carcinoma, thyroid lymphoma, sarcomas, and metastatic carcinoma. Papillary and follicular carcinomas are considered well differentiated tumors with an overall good prognosis. Medullary and anaplastic are less differentiated and tend to be aggressive. In this paper I will review the characteristics of these different tumors with regard to their epidemiology, histology, prognosis, operative treatment, and postoperative care. INITIAL HISTORY: 70-90% of patients with well differentiated carcinoma of the thyroid present with a thyroid nodule. The patients history may provide an index of suspicion for malignancy. Useful information to obtain includes: age, sex, radiation, and family history. Malignancy rates as high as 60% have been reported for ages less than 25 and greater than 60. Over 70% of the patients with this disease are woman. Woman have a better prognosis when compared to men with the same pathological entity. Although woman constitute the vast majority of thyroid cancer victims, men with a solitary nodule are more likely to have carcinoma than a woman with a solitary nodule(3x). Tumors arising as a result of radiation exposure tend to be larger and multicentric and have a higher rate of local recurrence than other tumors. They often show lymphocytic infiltration or Hashimotos disease. The carcinoma may present up to 30 years after radiation exposure and is more common in women. Family history can be indicative of an MEN syndrome. PHYSICAL EXAM: Thyroid nodules are common and occur in 4% of the population. It is difficult on physical examination to differentiate between an adenoma and the nodule of an adenomatous goiter.15 - 20% of nodules are cystic. If the gland appears otherwise normal the nodule is most likely an adenoma or carcinoma. It is difficult to determine by physical exam the difference between a malignant and benign nodule. Regional metastasis, local fixation or invasion of surrounding tissue(hoarseness), rapid growth, tracheal deviation, and hardness are obvious clues to a malignant process. Tenderness is more often found in thyroiditis than in malignancy. FINE NEEDLE ASPIRATION BIOPSY: The gold standard diagnostic technique. The diagnostic accuracy depends on tumor type and the experience of the cytopathologist. Medullary carcinoma and anaplastic carcinoma are easily recognized and approach 90% accuracy. Papillary carcinoma can be accurately diagnosed in 80% and follicular carcinoma in 40% of cases. If all thyroid nodules are considered, a diagnosis of benign will return in 60-75% of nodules aspirated. The false negative rate is 8-10% so patients need to be followed closely. About 5% of nodules will be diagnosed definitely malignant by FNA. 10% of these will be false positives. Roughly 20% of cases will be left with a diagnosis of "suspicious". These patients will have a 20-40% incidence of malignancy on final path. The primary downfall of FNA is the inability to reliably differentiate follicular and Hurthle cell adenomas from there malignant counterpart. Microscopically these carcinomas resemble adenoma closely, with the diagnosis made by evidence of invasion of the capsule, adjacent glands, lymphatics, or blood vessels. Papillary carcinoma, on the other hand, has characteristic fronds of epithelium in an uniform pattern making FNA quite useful. There are few complications from this procedure. There has been one case of reported seeding of the needle tract with malignancy. PREOPERATIVE THYROID SCANNING: Radionuclide scintigraphy is the best method of detecting active thyroid tissue, but nodules less than 1cm are not detected. Most cold nodules are benign but as many as 20% may be malignant. Hyperfunctioning nodules make up only about 5% of nodules and are almost never malignant. Some authors contend that with the reliability of FNA that the less specific radionuclide test is not useful. Arguments to the contrary point out that scanning can identify other nodules that are not palpable. The most commonly used agent is technetium 99m pertechnetate for initial scanning. I-131 is used for total body scanning for metastatic disease. Note that thyroid nodules at the periphery of the gland are not well visualized with standard AP and lateral views and require oblique views. ULTRASONOGRAPHY: This study can accurately differentiate solid from cystic lesions, measure nodule size to the millimeter, and detect tiny nodules in the remainder of what is felt to be normal gland. Proponents of routine use of this study point out that multinodular disease and purely cystic lesions less than 4cm are more frequently benign. Opponents of routine use point out that little information is gained over that in FNA which is recommended by all in routine diagnostic workup. Ultrasound can be of assistance in FNA of difficult or small nodules. CT SCAN/MRI Recent studies document the usefulness of CT and MRI to demonstrate sites of infiltration of extensive, hard tumors that are difficult to evaluate clinically. CT is particularly useful in assessing clinically occult cervical nodal involvement for staging. LABORATORY STUDIES: TFT'S are useful preoperatively to rule out hypo or hyperthyroidism. Thyroglobulin level is used postop to detect residual or recurrent carcinoma (see postop care). Calcitonin, especially if provoked with pentagastrin or calcium, can serve as a useful early detection device for patients who have family members with MEN syndromes. WELL DIFFERENTIATED THYROID CARCINOMAS-PAPILLARY AND FOLLICULAR: Papillary and predominately papillary(mixed papillary and follicular) tumors are the most common thyroid malignancy(>70%).Among patients with radiation exposure, papillary accounts for 85% of cases. The peak onset is in the 3 & 4th decades with F:M of 3:1. Papillary carcinoma arises as an irregular, solid or cystic mass that arises from follicular epithelium. Microscopically, uniform fronds of epithelium with rounded calcific deposits(psammoma bodies) are characteristic. Cells are large with fine granular cytoplasm and large pale nuclei giving an "orphan Annie" appearance. Prognosis is directly related to size of the tumor (<1.5cm). Tumors that invade or extend beyond the thyroid capsule have a worsened prognosis. These have a high local recurrence rate and eventual high mortality. Ten year survival rates are estimated at 80-90%. Cervical metastasis are present in 50% of occult and small tumors and with over 75% of palpable thyroid cancers. Levels II,III,IV,and VI are most commonly involved. The presence of nodal metastasis to these cervical areas causes a higher recurrence rate but not a higher mortality rate. Nodal metastasis does harbor a higher chance of progressive disease with eventual distant metastasis. Extracapsular spread does not carry the same ominous prognosis as that for squamous cell carcinoma. Distant metastasis is <1% initially but 5-10% eventually in late stages. The low incidence of distant metastasis is related to the lack of vascular invasion in early stages. Lung and bone are the most common sites. Management: Considerable controversy exits when discussing the management of well differentiated thyroid carcinomas. Proponents of conservative surgical therapy relate the low rate of clinical tumor recurrence(5-24%) despite findings of tumor foci in up to 88% of contralateral lobes and in cervical lymph nodes. They also site some studies showing hypoparathyroidism as high as 40% and recurrent laryngeal nerve injury as high as 21% in patients undergoing total thyroidectomy. Proponents of total thyroidectomy site several large studies that show that in experienced hands the incidence of recurrent nerve injury and permanent hypoparathyroidism are quite low(2.2 an 2.8%). More importantly, these studies show that patients with total thyroidectomy followed by radioiodine therapy and thyroid suppression, have a significantly lower recurrence rate and lower mortality when tumors are greater than 1.5cm. One must remember that it is also desirable to reduce the amount of normal gland tissue that will take up radioiodine. Based on the these studies and the above natural history and epidemiology of papillary carcinoma, the following recommendations are made: Papillary carcinomas that are well circumscribed, isolated, and less than 1cm in a young patient(20-40) without a history of radiation exposure can be treated with hemithyroidectomy and isthmusthectomy. All others should be treated with total thyroidectomy, central neck dissection and ipsilateral functional neck dissection (node picking in levels II,III, and IV). I-131 is taken up well by papillary thyroid carcinoma and should be used postoperatively. Uptake is enhanced by high TSH levels; thus patients should be off of thyroid replacement and on a low iodine diet for at least one week prior to therapy. The usual dose is 50-150 mCi and is given 6wks post surgery. Cumulative dose can not exceed 300-400mCi and doses can be repeated q6mo's. Thyroid hormone suppression is given based on evidence that the carcinoma responds to TSH. Recurrence and mortality rates have been shown to be lower in patients receiving suppression. In addition to the usual cancer follow up, patients should receive annual CXR, annual thyroglobulin levels Thyroglobulin is not useful as a screen for initial diagnosis of thyroid cancer but is quite useful in follow up of well differentiated carcinoma. A high serum thyroglobulin level that had previously been low following total thyroidectomy especially if gradually increased with TSH stimulation is virtually indicative of recurrence. A value of greater than 10ng/ml is often associated with recurrence even if scan is negative. Serum level of thyroglobulin is especially important in those patients who have metastases that does not concentrate I -131 as they would otherwise not be detected until much more advanced. FOLLICULAR CARCINOMA: Follicular carcinoma comprises about 15% of all thyroid carcinomas and is considered more malignant than papillary carcinoma. It occurs in a slightly older age group than papillary and is also less common in children. It occurs only rarely after radiation therapy. Microscopically it resembles its benign counterpart as mentioned previously. It is usually encapsulated and consists of highly cellular follicles and microfollicles with compact, dark staining nuclei. Diagnosis of malignancy is made by evidence of invasion as stated previously. Mortality is related to the degree of vascular invasion. Age is a very important factor in terms of prognosis. Patients over 40 have a more aggressive disease and typically the tumor does not concentrate iodine as well as in younger patients. Vascular invasion is characteristic for follicular carcinoma and therefore distant metastasis is more common. Distant metastasis may occur in a small primary. Lung, bone, brain,liver, bladder, and skin are sites of distant mets. Lyph node involvement is far less common than in papillary carcinoma(8-13%). Surgical therapy is similar to papillary carcinoma. It must be kept in mind that frozen section may be unreliable in making definitive diagnosis at the time of surgery. Most feel that definitive surgical therapy should await final diagnosis. Patients with minimally invasive tumors, less than 1cm, who are less than 40 years old may be treated with ipsilateral hemithyroidectomy and isthmusthectomy. All others should undergo total thyroidectomy and central neck dissection(with functional neck ipsilateral if enlarged nodes felt). Postoperative therapy with I-131 at 6wks and suppression therapy are as in papillary carcinoma. HURTHLE CELL VARIANT: Hurthle cell carcinoma, a variant of follicular carcinoma, occurs in an even older age group(mean=55) with clear cut female to male predominance. Roughly 30% of patients with Hurthle cell carcinomas have coexistent thyroid disease. In one study, coexistent well differentiated carcinoma was found in 40% of patients. 7-39% of patients have a history of radiation therapy. When some or all of the cells present in a follicular neoplasm are noted to be oxyphilic, it is termed a Hurthle cell neoplasm. Although they do not appear more invasive or less differentiated, this variant carries a less favorable prognosis. Hurthle cell neoplasms differ in their biologic behavior from regular follicular carcinoma. While lymph node involvement is rare in follicular carcinoma, it is present in up to 50% of patients with Hurthle cell carcinoma. In addition, Hurthle cell carcinoma does not usually trap iodine, therefore negating the diagnostic and therapeutic effects of iodine. There is some controversy in the literature regarding the malignant potential of Hurthle cell neoplasms. The difficulty lies in the ability to accurately assess malignant potential on histologic grounds. Currently there is no specific immunohistochemical markers, or features on electron microscopy that permit one to differentiate benign from malignant disease. Traditional methods of describing cellular atypia have also not been proven useful. Only the presence of DNA aneuploidy has been associated with increasing risk of recurrence, distant mets, and death. The problem is that some tumors judged to be histopathologically benign are aneuploid. At present, the diagnosis and prognosis is still based on clinical findings in the patient and the histopathology. In the absence of invasion of the capsule, lymph nodes, distant mets, or vascular invasion the lesion is considered benign. Only when one is quite sure based on serial section of the lesion on final path can one be satisfied with simple hemithyroidectomy and isthmusthectomy with central neck dissection. One must carefully examine the remaining lobe for coexistent disease. All other lesions should be treated with total thyroidectomy and neck dissection as described above. Patients should receive suppression therapy as in follicular carcinoma. If metastasis can be detected on I-131, attempt at radioiodine treatment can be made. Metastasis that do not uptake radioiodine should be treated with local excision and external beam therapy. MEDULLARY CARCINOMA: Medullary cancer accounts for about 5-10% of all thyroid cancer. It originates from the parafollicular cells or C cells of the thyroid. There are four clinical settings: 1) Sporadic- accounts for 80% of cases. They are unilateral and there are no associated endocrinopathies. Peak onset 4th-6th decades and F:M of 3:2. One third will present with intractable diarrhea. Diarrhea is caused by increased gastrointestinal secretion and hypermotility due to calcitonin, prostaglandins, serotonin, or VIP by the tumor. 2) and 3) are those associated with MEN II-A (Sipple syndrome) and MEN II-B. Sipple syndrome has bilateral medullary carcinoma or C cell hyperplasia, pheochromocytoma or medullary hyperplasia, hyperparathyroidism, and is autosomal dominant. MEN II-B also has medullary carcinoma and pheochromocytoma but only rarely will have hyperparathyroidism. Instead it has an unusual phenotype characterized by mucosal ganglioneuromas (especially of the tarsus and anterior tongue), Marfanoid habitus, and hyperplastic corneal nerves. Inheritance is AD or sporadic. They both peak at 3rd decade and F:M 1:1. Detection of pheochromocytoma is best by the epinephrine/norepinephrine ratio in the urine. Pheo. must be detected preop to remove the risk of intraoperative hypertensive crises. 4) Inherited medullary carcinoma without associated edocrinopathies. This form of medullary carcinoma is the least aggressive. Medullary carcinoma is an ill defined, nonencapsulated, hard, invasive mass. It usually originates in the upper central lobe of the thyroid. It is composed of columns of epithelial cells in a dense stroma that stains for amyloid and collagen. Stains for calcitonin are positive and thyroglobulin are negative. Immunoassay of calcitonin serves as a marker for C cell hyperplasia(predecessor of med. carcinoma) or medullary carcinoma. Residual disease or recurrence can be detected by this immunoassay. A significant increases of basal or provoked calcitonin level above 1000pg/ml confirms the presence of medullary carcinoma. Regional metastases occurs early in the course of the disease. Distant mets occur late in the disease and are to the liver, bone, brain, and adrenal medulla. Overall prognosis lies between the well differentiated carcinomas and anaplastic carcinoma. Poor prognostic factors include age >50, male, metastases, and MEN II-B. Overall 10 year survival rates are 90% when all the disease is confined to the gland, 70% with cervical mets, 20% with distant mets. After assessment and treatment of associated endocrinopathies with the assistance of an endocrinologist, all patients should receive total thyroidectomy, central neck dissection, and ipsilateral functional neck dissection in zones II,III,and IV. Hyperparathyriodism is usually mild and the main goal relative to the parathyroids during total thyriodectomy for medullary carcinoma is preservation of parathyroid tissue. Grossly enlarged parathyroid tissue is removed. If no viable parathyroid tissue is seen following total thyroidectomy then autotransplantation is performed. Distant mets do not uptake radioiodine and should be treated with external beam. In addition to the usual follow up exams, basal and provoked levels of calcitonin should return to normal within 6 months of treatment. Calcitonin should be checked q6mo to detect recurrence. ANAPLASTIC CARCINOMA: Anaplastic carcinomas comprise less than 10% of all thyroid malignancies. They are subdivided into spindle, giant cell, and small cell types with the former two being the most malignant. They often derive from more differentiated thyroid cancer or goiter or may follow radiation exposure. Peak age is 7th decade and F:M is 1:2. The most common complaint is of a growing neck mass. They invade adjacent structures and metastasize extensively to cervical nodes and distant sites. Tracheal invasion is present in 25% at time of presentation. Regional nodes are involved in 90% and lung in 50% at time of diagnosis. Most are inoperable at time of diagnosis. Even with aggressive therapy protocols such as hyperfractionated radiation therapy/chemo/ and surgery survival at 3 years is less than 12%. LYMPHOMA/SARCOMA/METASTATIC: Primary lymphoma of the thyroid is usually non-Hodgkin's type. It has a peak in the 6th decade with F:M 6:1. Lymphocytic thyroiditis and antithyroid antibodies are common. If the lymphoma is confined to the thyroid, the 5 year survival with XRT is 75-85%. With cervical mets the 5 year survival is 35%. Distant mets less than 5%. Primary sarcomas are quite rare. Angio and fibrosarcomas are the most common. The prognosis is uniformly very poor. The most common metastatic disease to the thyroid is SCCA of the head and neck. These are treated in accordance with the principles of treatment for SCCA(see other grand rounds). SURGICAL MANAGEMENT OF LARYNGOTRACHEAL INVASION: The relatively benign nature of well differentiated thyroid cancer has led some to the misconception that it is better to leave some local disease rather than remove local vital structures. In patients who eventually die of thyroid cancer, local recurrence with invasion of vital structures has been shown to be the cause of death most often. Well differentiated thyroid cancer with distant metastases should still undergo local complete control because most of these patients will still die of local disease and I-131 treatment depends on eradication of local tumor. Thyroid carcinoma that invades the airway can in most instances be treated with partial laryngectomy or partial tracheal resection. Total laryngectomy and circumferential tracheal resection may be required in patients with extensive disease. Full thickness cartilage resection is necessary even when there is no evidence of intraluminal involvement. The sternocleidomastoid myoperiosteal flap provides long term airway stability and has a low complication rate when used to reconstruct the defect. A complete discussion of this technique is beyond the scope of this talk. The reader is referred to the articles by Freidman et al in the bibliography. CHEMOTHERAPY: Chemotherapy is not part of the recommended therapy for well differentiated thyroid cancer. Some patients appear to respond to Doxorubicin, cisplatin, and VP16 but not predictably. Currently only giant cell anaplastic carcinoma is routinely treated with chemotherapy. It is believed that combination therapy for anaplastic carcinoma may assist in local control. -------------------------------------------------------------------------- BIBLIOGRAPHY 1. Cummings CW, et al, Otolaryngology and Head and Neck Surgery, 2nd ed., Mosby Year Book 2. Block BL, Speigel JC, Chami RG, The Treatment of Papillary and Follicular Carcinoma of the Thyroid, Otolaryngology Clinics-Disorders of the Thyroid and Parathyroid 3. Freidman MF, Pacella BL, Total vs Subtotal Thyroidectomy, Otolaryngology Clinics- Disorders of the Thyroid and Parathyroid 4. Auguste LJ, Attie JN, Completion Thyroidectomy for Initially Misdiagnosed Thyroid Cancer, Otolaryngology Clinics-Disorders of the Thyroid and Parathyroid 5. McLeod MK, Thompson NW, Hurthle Cell Neoplasms of the Thyroid, Otolaryngology Clinics- Disorders of the Thyroid and parathyroid 6. Block, MA, Surgical Treatment of Medullary Carcinoma of the Thyriod, Otolaryngology Clinics- Disorders of the Thyriod and Parathyroid 7. Freidman MF, Sugical Management of Thyroid Cancer with Laryngotracheal Invasion, Otolaryngology Clinics- Disorders of the Thyroid and Parathyroid 8. Hales MS, Hsu FSF: Needle tract implantation of papillary carcinoma of the thyroid following aspiration biopsy, Acta Cytol 34:801, 1990 9. Ashcraft MW, Van Herle AJ: Management of Thyroid Nodules. Head and Neck Surgery 3: 297-322,1981 10.Crow JP: Recurrent Occult Medullary Carcinoma detected by MR. Am J Roent 152: 1255, 1989 11.Takashima S et al, CT evaluation of anaplatic thyroid carcinoma, Am J Roent 154: 1079,1990. 12.Robbins, Pathological Basis of Disease, Fourth edition ---------------------------------END---------------------------------------