Papillary thyroid cancer (PTC) is the most common type of thyroid cancer accounting for approximately 80% of all thyroid cancers.3,7 It has a bimodal frequency, with the peak incidence being in the third and sixth decades, and it affects women more commonly than men (3:1). In patients over 60 years of age, papillary thyroid cancer accounts for only 50% of all thyroid carcinomas.8 A history of radiation exposure increases the risk of PTC.14 The prevalence of occult papillary thyroid cancer, based on autopsy results, is estimated to be about 6-9% in patients over 80 years of age, which is similar to patients who are <50 years of age.15

The most common presenting complaint of patients with PTC is a lump in the neck.3 Patients may also complain of lymphadenopathy, hoarseness, neck discomfort or pain, cough, or dysphagia. In a case-control study of 56 lethal cases of PTC, hoarseness and vocal cord paralysis secondary to locally invasive thyroid cancer were found to predict death from papillary carcinoma.16 Tollefsen et al also noted a 20% incidence of recurrent laryngeal nerve paralysis in those dying from PTC.17 Papillary thyroid cancer spreads via the lymphatics to the regional lymph nodes, and bilateral involvement is present in approximately one-third of the cases. In the Mayo Clinic series,18 10% of the patients presented with only cervical lymphadenopathy. Occasionally patients may present with distant metastasis involving the lungs, bones, brain, and soft tissues.

Papillary thyroid cancer is generally associated with a low mortality rate in patients younger than age 40. However, in older patients the mortality rate is higher. In the Mayo Clinic series, five of the six patients in the intrathyroid papillary carcinoma group (lesion >1.5 cm and confined within the thyroid capsule) who died were more than 60 years of age. In addition, in two of the five older patients who died, there was marked Hurthle-cell transformation. In an autopsy series, 525 papillary tumors were detected (12% of the autopsies), but only three were fatal and all three subjects were older than 60 years of age and had distant metastases.19 In a retrospective case-matched control study, age was one of the variables that significantly affected prognosis.16 The mean age for the lethal PTC group, 59.1 years, was significantly higher than the mean age of 42.4 years for the nonlethal PTC group.

Follicular thyroid cancer (FTC) is the second most common tumor of the thyroid gland and constitutes approximately 15% of all thyroid cancers. Follicular thyroid cancer tends to be more common in areas of iodine deficiency.3 The peak incidence is in the sixth decade of life. Woolner et al found that 76% of FTCs were found in adults between the ages of 40 and 69 years.18 Like PTC, FTC is more common in women than men (3:1). Differentiation of FTC from follicular adenoma requires invasion of the capsule, adjacent thyroid tissue, or blood vessels.

The most common presenting complaint of patients with FTC is an asymptomatic neck mass. In a retrospective analysis of follicular thyroid cancer conducted by the Mayo Clinic, 85% of the patients had a neck mass: 53% of patients noted the mass themselves, in 32% the primary care provider noted the mass, and in 15% another family member noted the lesion.20 Cervical lymph node involvement (4-6%) is less common compared to PTC, but distant metastasis is more frequent.

Follicular thyroid cancer is associated with a higher mortality than PTC because of its tendency to metastasize. In the Mayo Clinic multivariate analysis of 100 patients with follicular thyroid cancer, age greater than 50 years, marked vascular invasion, and distant metastatic disease were independent predictors of thyroid cancer-related death.20 The 20-year survival rate was approximately 95% for patients less than age 50 and about 50% for patients older than age 50. In patients over 50 years of age who had either marked vascular invasion or metastatic disease at the time of diagnosis, the cumulative thyroid cancer mortality was 53% at 5 years and 92% at 20 years; in patients who were less than 50 years of age with no vascular invasion or metastatic disease, the 5-year mortality rate was 1% and the 20-year mortality rate was 14%. Ladurner et al reported a worse prognosis in patients older than 50 years of age at the time of diagnosis of follicular thyroid cancer, and Crile et al reported a worse prognosis for patients older than 60 years of age.21,22

The increased mortality in older patients with FTC may be related to the greater frequency of extraglandular recurrences; intraglandular recurrences are more common in younger patients. Cady et al found that 67% of recurrences in older patients were extraglandular while only 12% of recurrences were extraglandular in younger patients.13

Medullary thyroid cancer (MTC) constitutes approximately 2-5% of all thyroid malignancies, but it is responsible for up to 13.4% of all deaths from thyroid cancer.23 It is a well-differentiated type of tumor that arises from the parafollicular (C cells) of the thyroid gland, and therefore it is categorized as a neuroendocrine tumor. In 70-80% of patients, medullary thyroid cancer occurs sporadically, but in about 20% of patients there is a family history of medullary carcinoma. Medullary thyroid cancer is inherited in an autosomal dominant pattern with virtually 100% penetrance. A germline mutation in the RET protooncogene, which encodes a transmembrane tyrosine kinase receptor, predisposes individuals to develop hereditary MTC. In the sporadic form, the tumor occurs as a result of a mutation involving only the somatic cells.

Medullary thyroid cancer is considered to be less aggressive than anaplastic thyroid cancer, but more lethal than papillary and follicular carcinomas. Sporadic forms of MTC are more common in older patients (mean age at presentation about 47 years), while the hereditary forms of MTC are more common in younger patients.23 The prevalence of MTC is about the same in both males and females. The parafollicular cells secrete calcitonin. Serum calcitonin is greatly elevated in almost all patients with MTC.3 In addition, there appears to be a direct correlation of calcitonin level and the extent of thyroid involvement by medullary carcinoma. Serum histamine, serotonin, prolactin, vasoactive intestinal polypeptide, and prostaglandin levels can also be elevated in patients with MTC. In some cases, Cushing’s syndrome may develop as a result of ectopic adrenocorticotrophic hormone (ACTH) secretion from the tumor.3

While most patients with MTC typically present with a palpable nodule in the upper part of the thyroid lobe, some patients may present with systemic symptoms associated with distant metastases. In the retrospective review of 104 patients with MTC by Kebebew et al, 74.2% of the patients in the sporadic group presented with a thyroid mass, 15.5% had local symptoms (dysphagia, dyspnea, or hoarseness ), and 10.3% had systemic symptoms (bone pain, flushing, and/or diarrhea) attributable to the cancer.23 All of the patients with sporadic MTC who presented with systemic symptoms had distant metastases at the time of presentation.

Older age at diagnosis is associated with a worse prognosis. Kebebew et al followed patients with MTC for a mean time of 8.6 years.23 Age and stage of disease at diagnosis were independent predictors of survival. The 5-year survival rates by stage were 100% (stage I), 90% (stage II), 86.5 % (stage III), and 55.5% (stage IV). Patients who were less than 45 years of age, female, and with MTC confined to the thyroid had the best overall prognosis (100% at 10 years).23 Saad et al reported similar findings; patients younger than 40 years old at the time of diagnosis of MTC had a significantly better survival rate than those who were older.24 In addition, women had a better prognosis than men, who were 1.9 times more likely to die of MTC than women. Scopsi et al reported a worse prognosis in patients with sporadic MTC who had extrathyroid tumor invasion, distant metastases, or age greater than 60 years at the time of diagnosis.25

Anaplastic thyroid cancer (ATC) accounts for only 1-2% of all thyroid cancers.14 It is a very aggressive, highly malignant tumor that is most commonly seen in older people. The peak incidence of ATC is the seventh decade of life and more than two thirds of all ATC affects people over the age of 65 years.3 Women are more commonly affected than men (approximately 1.5:1).

Unlike PTC and FTC, the most frequent presenting complaint in patients with ATC is a rapidly growing mass with tightness in the neck.26 Patients may also complain of dysphagia, hoarseness, dyspnea, neck pain, sore throat, and cough. Anaplastic thyroid cancer can be seen in several contexts: 1) a patient with differentiated thyroid carcinoma whose disease suddenly becomes fulminant after an interval of several years; 2) a patient with a longstanding goiter that suddenly grows at a rapid rate; 3) a patient without previous thyroid disease who develops a rapidly growing neck mass; 4) a patient whose pathological sections reveal a focus of anaplastic carcinoma in the thyroid specimen; and 5) a patient with widespread metastases whose biopsy of an accessible metastasis suggests an anaplastic cancer. In a retrospective analysis of 84 patients with ATC, 21% had a history of differentiated thyroid cancer, 37% had a longstanding goiter with sudden rapid growth, 30% had no previous thyroid disease, and 6% had widespread metastatic disease.26

Examination of the neck usually reveals a fixed, large, firm mass that usually makes it difficult to detect neck nodes clinically. Hemorrhage and necrosis within the tumor may result in soft, fluctuant masses. Large axillary nodes are sometimes seen. Rarely, patients with massive tumor extension into the mediastinum may present with superior vena cava syndrome. Most patients with anaplastic carcinomas present with stage IV disease. In the review of Aldinger et al, 78 of 84 (93%) patients presented with stage III and stage IV disease.26

Age at diagnosis of anaplastic thyroid cancer is a strong predictor of prognosis. In a cohort of 516 patients with anaplastic thyroid cancer, on multivariate analysis, Kebebew et al noted that patients who were less than 60 years and those who had intrathyroidal tumor survived longer.27 There was a 28% difference in mortality between patients who were less than 60 years of age and patients who were 60 years of age and older. They also reported a 45% difference in mortality at one-year follow-up between patients who had distant metastasis and patients who had intrathyroidal ATC.

Anaplastic thyroid carcinoma has a grave prognosis and is reputed to be the most aggressive of all cancers.28,29 Aldinger et al reported a five-year survival rate of only 7.1% (six survivors) with a mean survival period of 6.2 months from the time of tissue diagnosis and 11.8 months from the time of onset of symptoms.26 They found that the long-term survivors had a very small focus of anaplastic cells. Tolfensen et al also reported that eight patients with a minute focus of anaplastic cells had a mean survival of nine years.17 In Lin et al’s retrospective review of thyroid carcinomas in aging patients, thirty-two (82.1%) patients died of anaplastic thyroid cancer during the follow-up period of up to ten years.9 Seventy-five percent of these patients had distant metastases to the lung, bone, mediastinum, and peritoneum at the time of diagnosis.

In summary, anaplastic carcinomas are much more common in older patients, and are likely to develop in a site of well-differentiated thyroid carcinoma in nearly half of the patients. The patient has an increased chance of survival if the anaplastic carcinoma exists in only a small area, but in a bulky and clinically aggressive tumor, even a small focus of anaplastic cells leads to a rapidly fatal course.

Primary thyroid lymphoma is a relatively rare thyroid malignancy, accounting for only 0.6% to 5% of all thyroid cancers.30 The peak incidence of thyroid lymphoma is between 50 and 80 years of age, and it occurs three times more frequently in women than men. Almost all patients with thyroid lymphoma have Hashimoto’s thyroiditis with or without hypothyroidism.31

Rapid enlargement of the thyroid gland is the presenting feature in about 70% cases.32,33 Patients may present with shortness of breath and difficulty swallowing related to infiltration of the trachea and esophagus by the cancer. Hoarseness may be a consequence of recurrent laryngeal nerve palsy. Obstructive symptoms are more common in patients with invasive, inoperable cancers.34 The diagnosis of primary thyroid lymphoma may be difficult to make by fine-needle aspiration biopsy alone because of coexisting lymphocytic thyroiditis, so that excisional biopsy may be necessary to make the diagnosis. On palpation, the lymphoma feels like a hard, smooth, rubbery mass. The cut surface is characteristically smooth, white, and homogenous.31 Unlike papillary and follicular thyroid cancers, thyroid lymphoma does not concentrate iodine.

In the older literature, patients with primary thyroid lymphoma were reported to have a grave prognosis, especially if the cancer extended beyond the thyroid capsule.34 In a retrospective review of forty-six cases of primary thyroid lymphoma by Woolner et al, survival ranged from 15% in patients with extracapsular invasion or regional lymph node involvement of the cancer who were followed for 5 to 13 years to 75% in patients with noninvasive cancer who were followed for 2 to 25 years. In more recent studies, the reported five-year survival has ranged from 53% to nearly 100%.31,35 The combination of the diagnostic use of fine needle biopsy and treatment with both chemotherapy and external radiation has dramatically altered the prognosis of thyroid lymphoma.

The treatment of thyroid lymphoma is unique in that surgical resection is no longer a routine part of therapy.31,36 In a review of 62 patients treated at the Mayo Clinic, complete remission was obtained in 88% of patients who underwent diagnostic biopsy plus adjuvant therapy compared to 85% for patients in whom debulking plus adjuvant therapy was used.35 In addition, there was no difference in survival between the two groups. In Matsuzuka et al’s review of 119 Japanese patients with thyroid lymphoma, radiation combined with six cycles of CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) chemotherapy resulted in a survival rate of 100% at 8 years.31