Course of the Disease

Clinical signs

Most frequently the tumor is discovered accidentally by the patient or physician as a lump in the neck or may be a fortuitous finding at ultrasound of the neck. It may appear as a gradually enlarging, painful mass with associated symptoms of hoarseness, dysphagia or dysphonia, or there may be difficulty in breathing. Occasionally a patient arrives with metastatic nodules in the neck, pulmonary symptoms from metastases, or a pathologic fracture of the spine or hip. Usually there are no symptoms of hyper- or hypothyroidism, but in rare instances the tumor can produce enough hormone to cause hyperthyroidism (208, 209). (See also Chapter 13)

Upon examination of the neck, carcinoma of the thyroid characteristically appears as an asymmetrical lump in the gland. If it is still within the confines of the gland, it will move with the gland when the patient swallows and may be moveable within the gland. If it has invaded the trachea or neighboring structures, it may be fixed; this is a useful sign. Lymph nodes containing metastases may be found in the supraclavicular triangles, in the carotid chain, along the thyroid isthmus, and rarely in the axillary nodes. A sentinel or "Delphic" node above the isthmus may be present. Although carcinoma of the thyroid is typically firm or hard, rapidly growing lesions may sometimes be soft or even fluctuant. Lesions may undergo necrosis and discharge through sinuses that developed in the skin of the neck. Patients with thyroid cancer are also prone to develop other cancers, the risk being about double the average. Among these cancers is an excess incidence of leukemia, perhaps related to 131I therapy (210-212).

Age at diagnosis has an important bearing on the patient's subsequent course. The adverse effect of age on the prognosis increases gradually with each decade (213). For practical assessment purposes, it is clear that patients diagnosed before age 45 have a much better prognosis than those detected later (214). Age is also directly related to the incidence of undifferentiated tumors and to overall mortality (215). Pregnancy does not seem to worsen the course of established or previously treated thyroid cancer (216). Overall, women have a better prognosis than men with cancer (217). Other characteristics of the tumor, including (as would be expected) extraglandular extension, gross invasion of the tumor capsule, and increasing size also carry a worsened prognosis (217).

Papillary Carcinoma- course of disease

Papillary carcinoma has a peak incidence in the third and fourth decades (218). It occurs three times more frequently in women than in men, and accounts for 60-70% of all thyroid cancers in adults and about 70% of those found in children. The disease tends to remain localized in the thyroid gland and in time metastasizes locally to the cervical or upper mediastinal nodes. The lesions are multicentric in 20% or more of patients, especially in children. Although long thought to be evidence of "intra-glandular metastasis", it has been demonstrated by molecular genetic techniques that multiple foci often originate from separate oncogenic events, and are biochemically distinct (218b). Using rigid pathologic criteria, perhaps two-thirds of predominantly papillary thyroid cancers are found to have follicular elements. The natural history of these tumors is similar to that of pure papillary lesions(218a). The metastases may conform to either histologic pattern. At present, the mixed tumors are lumped together with all other papillary cancers.

This tumor tends to be indolent and may exist for decades without killing the host. In a Mayo Clinic series of papillary tumors that were detected because of lymph node metastasis or found incidentally during surgery of the thyroid gland, all the patients were unaffected by the tumors over several decades (218).

The frequent occurrence of occult or minimal incidentally found thyroid cancers, usually papillary and under 0.5 cm in size, is described above. However, the term occult has been used in a variety of ways, including reference to tumors with malignant nodes but no obvious primary, or in reference to any tumor under 1.5 cm in diameter. Mayo Clinic reports of papillary tumors under 1.5 cm in diameter, treated with conservative subtotal thyroidectomy and node dissection, have stressed their nonlethal nature, but a 1980 follow-up report on 820 patients treated by this group notes that 6 patients eventually died after spread of tumor from such "occult" primaries (219). Patients with appropriately treated Clinical Class I or II lesions have 96-100% survival even after 15-30 years. Survival lowers to 87% for Class III and 35% for Class IV lesions at 15 years.

While the disease may be aggressive in children, it is distinctly less aggressive in young adults, as compared to patients over age 40 (220). Young patients tend to have small primary lesions and extensive adenopathy, but even with local invasion survival is good. When papillary cancer occurs in persons over the age of 45, it may show, on microscopic examination, areas of undifferentiation, and pursue a highly malignant clinical course. The lesions tend to be larger and more infiltrative, and to have fewer local metastases (221). It is possible that persons dying in older age actually have had their disease since youth, and that it has simply evolved into a more malignant phase (222, 223).

Papillary carcinoma tends to metastasize locally to lymph nodes, and occasionally produces cystic structures near the thyroid that are difficult to diagnose because of the paucity of malignant tissue. The presence of nodal metastasis correlates with recurrence (222-224) but has little effect on mortality in patients under age 45. In some studies, cervical adenopathy even seems to confer a protective effect on young people (225). In patients over 45, the presence of nodes is associated with greater recurrence rates and more deaths (256, 257) (Fig. 18-3a,3b). The tumors often metastasize elsewhere, especially to lung or bones.

Papillary tumors may metastasize to the lungs and produce a few nodules, or the lung fields may have a snowflake appearance throughout. These tumors are amazingly well tolerated and may allow relatively normal physical activity for 10-30 years. At times the pulmonary metastases are active in forming thyroid hormone, and may even function as the sole source of hormone supply after thyroidectomy. The metastases may progress gradually to obstructive and restrictive pulmonary disease. They also may develop arteriovenous shunts, with hypoxia or cyanosis. Such shunts become more prominent during pregnancy, perhaps as an effect of the increased supply of estrogens.

The tall cell variant of papillary carcinoma comprises about 10% of total cases, and as noted by several authors appears to be more aggressive than other forms of the disease (258, 259). .

The usual net extra mortality in papillary cancer is not great when compared to that of a control population - perhaps 10-20% over 20-30 years (260-262). Mortality is rare in patients diagnosed before age 40, and is much greater in the patients found to be in clinical stages III and IV (Tables 18-4 and 18-5) at initial diagnosis (Fig. 18-14). About one-half of patients ultimately dying from this lesion do so because of local invasion. Frazell and Duffy (263) have noted that papillary carcinoma is not always so benign; they reported 35 patients with "invasive papillary carcinoma," which had a very malignant course.

We found that risk of death from cancer was increased by extrathyroidal invasion (6 fold) or metastasis (47 fold), age over 45 years (32 fold) and size over 3 cm (6 fold). Thyroiditis, multifocality and the presence of neck nodes had no effect on disease-induced mortality.

P.P., 41-Year-Old Man: Long-Term Survival with Papillary Cancer

This man was first seen at age 41. At age 14, while living in Yugoslavia, he had developed a mass in his neck. Tracheostomy was required because of dyspnea, and a biopsy of the mass was performed. A diagnosis of papillary thyroid carcinoma was made, and he was treated with radiotherapy to the neck. Because of an abnormal chest x-ray film, presumed to be due to tuberculosis, he was given streptomycin and isoniazid for 2 months, but this therapy was discontinued when no improvement occurred. Extracts of calf thymus were injected. He was evaluated for hemoptysis at age 18, and chest x-ray films again showed the infiltrates without evidence of change. The patient was not given thyroid hormone replacement therapy at any time. At age 39 he developed fatigue, substernal chest pain, occasional cough without production of sputum, and occasional hemoptysis. A thyroid scintiscan at another hospital revealed poor visualization of the thyroid and uptake of 4%, and 131I uptake in the mediastinum.

Physical examination disclosed hyperpigmentation of the skin in the area of radiotherapy in the neck and supraclavicular areas. There was no evidence of a mass or lymph-adenopathy. The tracheostomy site was well healed. The lungs were clear, BP was 100/70, pulse 68, and respiration 16/min, and there was no cyanosis. Routine complete blood count, urinalysis, and blood chemistry test results were normal. Chest x-ray films showed multiple nodular densities throughout both lungs and a prominent left hilum. The results of a radiographic skeletal survey and a technetium pyrophosphate bone scan were normal. The FTI was 8.4 and TSH was 4.1 µU/ml. A whole body 131I scan showed multiple areas of abnormal uptake in the area of the thyroid, and satellite areas of focal uptake around the thyroid bed. There was also focal activity in the mediastinum, in both hila, and in the lung fields. A 72-hour chest uptake was 8.9%. The serum TG level was 81 ng/ml.

The patient was treated multiple times with RAI and remained well while taking replacement T4 for ten years. At age 51, the tumor grew more rapidly, failed to accumulate 131I, and caused the patient's death.

This patient developed thyroid carcinoma at age 14 and probably had lymph node and lung metastases at that time. He lived a normal life during the ensuing 27 years, without suppressive thyroxine treatment, and with only intermittent episodes of hemoptysis. The tumor responded at first to 131I but later was uncontrolled. The common benign course of metastatic papillary thyroid carcinoma over many years is clearly shown, as is the equally typical later exacerbation and death.

Follicular Carcinoma

Follicular carcinoma has a peak incidence in the fifth decade of life in the United States and accounts for about one-quarter of all thyroid carcinomas (264-266). In past decades, follicular carcinomas comprised up to 50% of thyroid malignancies in Europe. The high incidence may partly be explained by iodine deficiency, but, more likely, was due to histological miss-classification at a time when the follicular variant of papillary thyroid carcinoma was not recognized as papillary but rather was classified as follicular. It is a slowly growing tumor and frequently is recognized as a nodule in the thyroid gland before metastases appear. Variation in the cellular pattern ranges from an almost normal-appearing structure to anaplastic tissue that forms no follicles or colloid. The insular variant of follicular tumor tends to be more aggressive(266a). The tumor is three times as common in women as in men. At operation one-half to two-thirds of these tumors are resectable. Tumors that are small and well circumscribed (not surprisingly) tend to be less lethal than those actively infiltrating local structures at the initial operation. Local adenopathy, which is uncommon, does not appear to carry a greater risk, but extensive invasion of the tumor capsule and thyroid tissue increases mortality (267). Local direct invasion of strap muscles and trachea is characteristic of the more aggressive tumors (268). Resectability depends on this feature, and death may be caused by local invasion and airway obstruction. The "minimally invasive" variant has a far better prognosis than the highly invasive variant.

Poorly differentiated follicular carcinoma is usually reported to have a more aggressive and lethal course than well-differentiated tumors.  A recent study correlated the clinical outcome and survival of 40 PDFC patients with histological architecture, cytological characteristics, and expression of various markers of cell proliferation and differentiation (cyclin A, cyclin B1, cyclin D1, cyclin E, Ki67, thyroperoxidase, galectin 3, dual oxidase [Duox], vascular endothelial growth factor, epidermal growth factor receptor, and p53). At 5 years, the overall survival rate was 63% and the metastasis-free survival rate was 57%. An older age at the time of diagnosis and a larger tumor size were associated with an increased risk of distant metastases and of cancer-related death. Polymorph architecture was associated with a reduced risk of metastases, whereas a high expression of Duox was associated with a reduced risk of death. No other histological features or expression of any other marker had a prognostic significance. PDFC had a more aggressive behavior than well-differentiated carcinomas but prognosis is related to the same indicators as in patients with well-differentiated carcinomas. (Pulcrano M, Boukheris H, Talbot M, Caillou B, Dupuy C, Virion A, De Vathaire F, Schlumberger M. Poorly Differentiated Follicular Thyroid Carcinoma: Prognostic Factors and Relevance of Histological Classification. Thyroid. 2007 Jul;17(7):639-646).

Follicular carcinomas tend to invade locally and metastasize distantly, rather than to local nodes, and are especially prone to metastasize to bone or lung. In a Massachusetts General Hospital series (269), one-half had metastasized at the time the diagnosis was originally established. Bony metastases are usually osteolytic, rarely osteoblastic, and the alkaline phosphatase level is rarely elevated. The tumor and metastases often retain an ability to accumulate and hold iodide, and are therefore sometimes susceptible to treatment with RAI. Indeed, some metastatic tumors synthesize thyroid hormone in normal or even excessive amounts. RAI therapy, as discussed below, improves survival in these patients (270).

Occasionally the primary lesion of a follicular tumor appears to be entirely benign, but distant metastases are found. Invasion of vessels or the capsule, apart from the metastasis, is the only reliable criterion of malignancy. This variant has been called the benign metastasizing struma or malignant adenoma. It has a more prolonged course than do other varieties of follicular tumor, and is the type that has offered the best opportunity for the therapeutic use of 131I.

The net extra mortality attributable to follicular cancer in the 10 - 15 years after diagnosis is 30 - 50% (271-273). Of the patients dying from the lesion, three-fourths do so from the effect of distant metastases and the remainder from locally invasive disease.

Hurthle Cell Tumors

Hurthle cell tumors are histologically distinct from other follicular tumors, but they pursue a similar course. They tend to invade and metastasize locally and have a strong propensity to recur after surgery. The course tends to be prolonged. These carcinomas often do not accumulate 131I. However, in a large survey, Caplan et al (274) found that 4.4% of Hurthle cell neoplasms were hot on scan and 8.9% were warm. Serum TG levels may be normal or elevated. Cheung et al recently studied the presence of ret/PTC gene rearrangements in Hurthle cell tumors and found that many expressed ret/PTC, and also had other evidence of a papillary cancer origin, including focal nuclear hypochromasia, grooves, and nuclear inclusions. Tumors with the ret/PTC gene rearrangement tended to have lymph node metastases, rather than hematogenous spread. Thus Hurthle cell tumors can be classified into Hurthle cell adenomas, Hurthle cell carcinomas, and Hurthle cell papillary thyroid carcinoma (275).

Insular Tumors

A subset of thyroid carcinomas which give a histologic picture of islands of cells -- thus "insular" -- has been identified (276). These tumors often look like anaplastic cancers, but sometimes are able to concentrate 131I and thus are amenable to this excellent treatment. Whether these are properly considered a variety of follicular cancer is uncertain. The important message is that the histology in this instance does not reliably predict the utility of 131I treatment, suggesting that all patients with thyroid cancer should at some point be studied to determine whether 131I treatment is possible.

Undifferentiated Tumors

Undifferentiated tumors occur predominantly in persons over 50 years of age and constitute an increasing proportion of lesions in each subsequent age decade. Of great interest is the pathologic evidence that such tumors arise, in perhaps half of the cases, in a long-standing benign lesion or in differentiated carcinoma (277). Although 131I therapy for differentiated cancers has been blamed for this dedifferentiation, current evidence is against this hypothesis. Spindle cell, and most giant-cell carcinomas of the thyroid grow rapidly and are very invasive. Local invasion may cause difficulty in breathing or swallowing, and tracheotomy is frequently required. These tumors metastasize to lymph nodes both locally and widely, but not characteristically to bone. Pulmonary metastases are frequent. Some patients present with a tender mass suggesting thyroiditis, and occasionally thyroid destruction induces hyperthyroidism (278). The outlook in this particular group of tumors is poor. By the time the diagnosis is made, the disease has spread in most patients beyond the area that can be attacked surgically, and they die within 6 months to 1 year. A few, perhaps 10%, of these tumors are entirely resectable when first discovered. There is nothing characteristic about the growth pattern of these tumors; their behavior is similar to that of any highly malignant tumor elsewhere in the body. The course of the epidermoid carcinoma and sarcoma of the thyroid is essentially the same. Small-cell anaplastic carcinomas are also found, but probably most tumors so classified in the past are actually lymphomas or lymphosarcomas.

Malignant Lymphomas

Lymphomas of the thyroid gland represent less than 5% of primary thyroid neoplasms (279-282). Unlike most other thyroid neoplasms, lymphomas usually appear as rapidly enlarging masses and local symptoms are common. Many patients note pain, hoarseness, dysphagia, and dyspnea or stridor. Hoarseness is often present in the absence of vocal cord paralysis. Rarely, patients may have the superior vena cava syndrome. The mean age at occurrence is 62 years. Primary lymphomas of the thyroid are two to three times more common in women than in men.

The incidence of hypothyroidism at the time of appearance is variable, ranging from 0 to 60% (283, 284). The co-occurrence of pathologic lymphocytic thyroiditis has ranged from 30 to 87%. These figures may underestimate the true incidence, as some patients have only had a biopsy examination and in others the entire gland has been replaced by the lymphoma. The frequent presence of thyroiditis has naturally led to the suggestion that the lymphoma might derive from preexisting thyroiditis.

The co-occurrence of thyroiditis may create difficulties in the proper interpretation of fine needle aspiration cytology. The clinical appearance must be carefully considered in accepting a diagnosis by fine needle aspiration of thyroiditis only or thyroiditis with lymphoma. An excisional or large needle biopsy may be necessary to make the correct diagnosis.

The majority of thyroid lymphomas are diffuse, large-cell lymphomas (formerly classified as diffuse histiocytic or reticulum cell lymphomas), diffuse mixed small and large cell lymphomas (formerly called diffuse mixed lymphocytic-histiocytic), or diffuse small cleaved-cell lymphomas (formerly classified as diffuse poorly differentiated lymphocytic). Although older series include reports of Burkitt's lymphoma, none were reported in larger, more recent series. Areas of diffuse large-cell lymphomas may have features similar to those characteristic of Burkitt's lymphoma or the Reed-Sternberg cells of Hodgkin's lymphoma.

Metastatic Carcinomas to the Thyroid

Melanomas, breast tumors, pulmonary tumors, gastric, pancreatic, and intestinal carcinomas, renal carcinomas, lymphomas, carcinomas of the cervix, and tumors of the head and neck may metastasize to the thyroid. Sometimes the first indication of one of these tumors may be the appearance of a lump in the neck. Unless there is evidence for a primary site elsewhere, these tumors are easily mistaken for expanding tumors that have their origin in the thyroid gland. Usually by the time metastases appear in the thyroid, other metastases have occurred and the primary lesion may be discerned.

Cancer in Aberrant Thyroid Tissue

Thyroid tumors occasionally arise in lingual thyroids, along the thyroglossal duct (285), in substernal goiters, and even in struma ovarii.

Second Primary Tumors
A recent review of over 39,000 individuals from combined registries found a 31% increased risk of developing a second primary cancer. Increases were found in tumors of colon, salivary gland,  pharynx, stomach, skin, breast, salivary glands, and lymphoma and leukemia, as well as a reciprocal increase in thyroid cancers after other primary tumors (284a). While it is logical to consider the role of RAI in many of these tumors, the authors suggest that these relationships are also related to shared risk factors, including genetic factors. Brown et al (284b) studied records on  over 30,000 patients, and reached essentially the same conclusions.