Well-Differentiated Thyroid Carcinoma

Papillary Carcinoma
Clinical features Papillary carcinoma is the most common thyroid malignancy, representing approximately 80%. Papillary carcinoma and follicular carcinoma make up the well-differentiated thyroid carcinomas. Women develop papillary cancer 3 times more frequently than men do, and the mean age at presentation is 34-40 years. Cases can occur familially, either alone or in association with Gardner syndrome (familial adenomatous polyposis). As noted above, radiation exposure, especially during childhood, is associated with the development of papillary thyroid carcinoma. Tumors typically appear after a latency period of about 10-20 years. In addition, an increased incidence of papillary cancer is hypothesized among patients with Hashimoto thyroiditis (chronic lymphocytic thyroiditis). Despite this possibility, the rate of malignancy for a given nodule in people with Hashimoto thyroiditis is similar to that of individuals with a normal gland. Papillary carcinoma is a slow-growing tumor that arises from the thyroxine (T4)- and thyroglobulinproducing follicular cells of the thyroid. The cells are TSH sensitive and take up iodine. They produce thyroglobulin in response to TSH stimulation. This feature has both diagnostic and therapeutic value for managing residual disease and recurrences after surgical excision (see Treatment and Prognosis below). Pathology On gross pathologic examination, papillary carcinomas are whitish invasive neoplasms with ill-defined margins. Under microscopy, the tumors are unencapsulated neoplasms that characteristically grow with papillae consisting of neoplastic epithelium overlying fibrovascular stalks. Very differentiated tumors can have a complex arborizing pattern. Nuclei have an empty ground-glass appearance with characteristic nuclear grooves and pseudoinclusions. Mitoses are rare. Another histologic feature is the presence of psammoma bodies, which occur in 50% of papillary carcinomas. Psammoma bodies are calcific concretions that have a circular laminated appearance. They are found in the stroma of the tumor. In addition, many papillary carcinomas contain areas that show a follicular growth pattern. However, when the nuclear features in follicular areas are the same as those in papillary areas, the tumor behaves like a classic papillary carcinoma and should be designated as such. Papillary carcinoma may be multicentric, with foci present in both the ipsilateral and contralateral lobes. Local invasion Tumors can grow directly through the thyroid capsule to invade surrounding structures. Growth into the trachea can occur, producing hemoptysis. Extensive involvement can cause airway obstruction. The recurrent laryngeal nerves can become involved because of their proximity in the tracheoesophageal groove. Patients present with a hoarse, breathy voice and, occasionally, dysphagia. Regional and metastatic disease Another common feature of papillary carcinoma is its propensity to spread to the cervical lymph nodes. Clinically evident lymph node metastases are present in approximately one third of patients at presentation. Microscopic metastases are present in one half. The most common site of lymph node involvement is in the central compartment (level 6) located medial to the carotid sheaths on both sides, with extension from the hyoid bone superiorly to the sternal notch inferiorly. The jugular lymph node chains (levels 2-4) are the next most common sites of cervical node involvement. Lymph nodes in the posterior triangle of the neck (level 5) may also develop metastases. This finding has important implications on the treatment algorithm for patients in this situation (see Treatment and Prognosis below and the images below). Approximately 5-10% of patients develop distant metastases. Distant spread of papillary carcinoma typically affects the lungs and bone.

Follicular Carcinoma Clinical features Follicular carcinoma is the second most common thyroid malignancy and represents about 10% of thyroid cancers. Follicular carcinoma represents an increased portion of thyroid cancers in regions where dietary intake of iodine is low. Similar to papillary carcinoma, follicular carcinoma occurs 3 times more frequently in women than in men. Patients with follicular carcinoma are typically older than those with papillary carcinoma at presents. The mean age range at diagnosis is late in the fourth to sixth decades. Like papillary carcinomas, follicular carcinomas arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulina feature that is exploited diagnostically and therapeutically (see Postoperative radioiodine scanning and ablation below). Pathology On gross pathology, the tumors appear as round, encapsulated, light brown neoplasms. Fibrosis, hemorrhage, and cystic changes are found in the lesions. Under microscopy, the tumors contain neoplastic follicular cells, which overall can have a solid, trabecular, or follicular growth pattern (that usually produces microfollicles). The follicular cells in these tumors do not have characteristic features like papillary carcinoma cells. Follicular carcinomas are differentiated from benign follicular adenomas by tumor capsule invasion and/or vascular invasion. For this reason, differentiating follicular adenomas from follicular carcinomas is extremely difficult with FNAB cytology and frozen section analysis. The tumors are divided into minimally invasive and widely invasive lesions depending on the histologic evidence of capsule and vascular invasion. Immunohistochemical staining for thyroglobulin and cytokeratins is nearly always positive. Local invasion Local invasion can occur as it does with papillary carcinoma, with the same presenting features (see Local invasion for Papillary Carcinoma, above). Cervical and distant metastases Unlike papillary carcinoma, cervical metastases from follicular carcinomas are uncommon. However, the rate of distant metastasis is significantly increased (approximately 20%). Lung and bone are the most common sites. Surgical treatment The extent of surgical therapy for well-differentiated neoplasms is controversial. Primary treatment for papillary and follicular carcinoma is surgical excision whenever possible. Total thyroidectomy has been the mainstay for treating well-differentiated thyroid carcinoma. In this procedure, all apparent thyroid tissue is surgically removed. Major complications in this procedure are recurrent laryngeal nerve injury and hypoparathyroidism from inadvertent damage or removal of the parathyroid glands. Complications associated with total thyroidectomy are discussed in the Technique of Thyroidectomy section below. After total thyroidectomy, patients undergo radioiodine scanning to detect regional or distant metastatic disease (see Postoperative radioiodine scanning and ablation below), followed by radioablation of any residual disease found. Over the years, modifications to total thyroidectomy have been proposed in an effort to reduce recurrent laryngeal nerve injury and hypoparathyroidism associated with total thyroidectomy. Subtotal thyroidectomy has been proffered as an alternative to total thyroidectomy. With subtotal thyroidectomy, a small portion of gross thyroid tissue opposite the side of malignancy is left in place to minimize the risk of injuring the recurrent laryngeal nerve and of inadvertently removing the parathyroid glands on that side. Patients usually receive postoperative radioiodine treatment in an attempt to ablate the remaining thyroid tissue.

With improved stratification of patients into prognostic groups (see Prognostic factors below), some surgeons have proposed thyroid lobectomy with isthmectomy alone as definitive treatment for patients at low risk for recurrent or metastatic disease. This approach remains to be substantiated as a feasible alternative to total thyroidectomy. Using the Surveillance, Epidemiology, and End Results (SEER) database, one study compared the overall survival (OS) and cause-specific survival (CSS) of 23,605 subjects with papillary or follicular thyroid cancer treated with local excision, lobectomy, near-total thyroidectomy, or total thyroidectomy. The 10-year OS and CSS results concluded that total thyroidectomy resulted in improved survival over other techniques; poorer outcomes were associated with age, stage T3/T4 disease, positive nodes, and tumor size.[3] According to a 2009 study by Asari et al, of 207 patients with follicular thyroid carcinoma, the 127 patients with minimum growth had no lymph node metastases. The authors state that thyroidectomy is still recommended for all patients with follicular thyroid carcinoma, although patients with widely invasive disease may need more aggressive surgical treatment. Patients with minimal disease invasion have an excellent prognosis with limited need for nodal surgery.[4] Management of the neck The neck must be thoroughly examined for lymphatic metastases. Ultrasonography of the neck with particular attention to the central compartment (level 6) is an effective diagnostic approach. FNAB of suspicious lymph nodes can be performed. Cervical metastases discovered preoperatively or intraoperatively should be removed by means of en bloc lymphatic dissection of the respective cervical compartment (selective neck dissection) while sparing the nonlymphatic structures. Excision of single nodes, known as berry picking, is inadequate therapy for metastatic disease. Elective neck dissection (removal of clinically benign neck lymphatic tissue) in a well-differentiated carcinoma is not indicated because postoperative radioiodine treatment effectively treats microscopic lymphatic metastases. Postoperative radioiodine scanning and ablation Because differentiated thyroid tissue and well-differentiated thyroid carcinomas are TSH sensitive and because they take up iodine, radioiodine preferentially targets residual normal or malignant tissue after thyroidectomy. Therefore, radioiodine can be given in diagnostic doses to detect residual normal or neoplastic tissue in the body and in therapeutic doses to ablate this tissue. After thyroidectomy, use of radioiodine scanning and ablation has become commonplace for diagnosing and treating residual thyroid tissue, as well as regional and distant metastases from well-differentiated thyroid carcinomas. Pretherapeutic iodine-uptake scanning is controversial because of its cost and because of concerns about131 I-induced tumor stunning, which may decrease the effectiveness of radioiodine treatment. After thyroidectomy, patients are given thyroid replacement therapy with T4 (Synthroid) or triiodothyronine (T3, Cytomel).131 I or123 I scanning is performed when the patient is in a hypothyroid state (TSH >30-50). Approximately 4-6 weeks after thyroidectomy, hypothyroid can be induced by discontinuing replacement (T4 for 4 weeks or T3 for 2 weeks) to obtain high serum TSH levels. A diagnostic dose of131 I or123 I is given initially. Whole-body scanning is performed to detect any tissue taking up radioiodine. If any normal thyroid remnant or metastatic disease is detected, a therapeutic dose of131 I is administered to ablate the tissue. Posttreatment scanning should also be performed because it may reveal metastatic disease not otherwise noted. The role of recombinant human TSH (Thyrogen) in remnant ablation continues to evolve. Thyrogen is approved for postsurgical remnant ablation in Europe but not the United States. Barbaro et al found equivalent results in postsurgical remnant ablation when they compared traditional T4 withdrawal with the discontinuation of T4 1 day before TSH stimulation. Thyrogen stimulation avoids the discomfort of patients having to discontinue thyroid replacement and is especially useful in those unable to tolerate hypothyroidism or to generate a high TSH level. If a treatment dose of131 I is required, diagnostic thyroid scanning is repeated while the patient is in the hypothyroid state about 6 months after initial treatment. Again, if the diagnostic scan is positive, an additional therapeutic dose is given. This process is repeated until the diagnostic scan is negative.

A promising new development for follow-up thyroid scanning is the use of recombinant human TSH as opposed to withdrawing T4 to increase autogenous TSH levels. This approach avoids the discomfort of having to discontinue thyroid replacement therapy for these scans. Thyroid suppression After thyroidectomy and radioiodine ablation, patients with well-differentiated thyroid carcinoma are maintained on thyroid-suppression suppression. Patients take T4 in daily doses sufficient to suppress TSH production by the pituitary. Low TSH levels in the bloodstream reduce tumoral growth rates and reduce recurrence rates of well-differentiated thyroid carcinomas. The extent to which TSH should be suppressed is controversial. Most authors recommend reducing TSH levels to 0.1 mU/L. This level provides adequate thyroid suppression while avoiding deleterious cardiac and bone effects of profound thyroid suppression. Follow-up care Patients are regularly monitored every 6-12 months with serial radioiodine scanning and serum thyroglobulin measurements after surgery and radioiodine therapy. Thyroglobulin is a useful marker of tumor recurrence because well-differentiated thyroid cancers synthesize thyroglobulin. However, it is useful only after total thyroid ablation. Serum thyroglobulin is measured at the time of follow-up thyroid scanning, during the withdrawal of thyroid hormone or the administration of recombinant TSH. Serum antithyroglobulin antibodies are measured in addition to thyroglobulin because their presence invalidates the assay. Thyroglobulin antibody levels should be obtained with each thyroglobulin measurement. Rising thyroglobulin level after thyroid ablation suggests recurrence. Ultrasonography of the neck can also be used to detect regional recurrences. Management of recurrence Recurrences are best treated with surgical excision if the disease is clinically evident and surgically accessible. Nonlocalized recurrences detected on the basis of elevated thyroglobulin levels are treated with 131 I. On occasion, recurrent tumors do not concentrate iodine. Positron emission tomography (PET) may be helpful in localizing disease in such circumstances. When surgical excision of recurrent disease is not feasible, external-beam radiation therapy may be useful. Chemotherapy, usually with doxorubicin, is reserved for tumors that do no respond to other treatments and for palliative care. Response rates of 35-40% are reported, though complete responses to chemotherapy are rare. Prognostic factors The long-term disease-free survival with aggressive treatment and management is nearly 90% overall. A variety of factors are associated with prognosis, as listed below. y Age: The patient's age at diagnosis is one of the most important prognostic features of welldifferentiated thyroid carcinoma. Cancer-related death is most likely to occur if the patient is >40 years at the time of diagnosis. Recurrences are most common in patients whose disease is diagnosed when they were < 20 years or >60 years. Sex: Men are twice as likely as women to die from thyroid cancer. Size: The size of the primary tumor is related to survival. Patients with primary tumors >4 cm have increased recurrence and cancer-related mortality rates. Histology: Overall, papillary carcinoma is associated a 30-year cancer-related death rate of 6%. Follicular carcinoma has a 30-year cancer-related death rate of 15%. Local invasion: Invasion of surrounding tissues outside of thyroid indicates biologic aggressiveness and significantly worsens the patient's prognosis. Lymph node metastasis: Lymph node metastasis does not appear to be as important in the outcome of well-differentiated thyroid carcinomas as in the outcome of most other solid tumors. Distant metastasis: Distant metastasis at initial examination is associated with a 68.1-fold increase in the rate of disease-specific death.

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Background

Hrthle cell carcinoma of the thyroid gland is an unusual and relatively rare type of differentiated thyroid cancer. Hrthle cell cancer accounts for only about 3-10% of all differentiated thyroid cancers; therefore, few institutions have extensive experience with Hrthle cell neoplasms. According to the World Health Organization (WHO), these neoplasms are considered a variant of follicular carcinoma of the thyroid and are referred to as follicular carcinoma, oxyphilic type.

A monomorphous cell population of Hrthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant granular cytoplasm with well- defined cell borders. The nuclei are enlarged and have a central prominent macronucleolus.

Some investigators believe that this condition is distinct from other follicular cell neoplasms. Hrthle cells are observed in both neoplastic and nonneoplastic conditions of the thyroid gland (eg, Hashimoto thyroiditis, nodular and toxic goiter). Oncocytic cells in the thyroid are often called Hrthle cells, and oncocytic change is defined as cellular enlargement characterized by an abundant eosinophilic granular cytoplasm as a result of accumulation of altered mitochondria. This is a phenomenon of metaplasia that occurs in inflammatory disorders, such as thyroiditis, or other situations that result in cellular stress. The proliferation of oncocytes gives rise to hyperplastic and neoplastic nodules.[1] The cytological features for Hrthle cell neoplasms are hypercellularity with a predominance of Hrthle cells (usually >75%), few or no lymphocytes, and scanty or absent colloid. In 1898, Askanasy described Hrthle cells; however, they are mistakenly named for the German physiologist who actually described the interfollicular C-cell. [2] Hrthle cells are large and polygonal in shape, with indistinct cell borders. They have a large pleomorphic hyperchromatic nucleus, a prominent nucleolus, and intensely pink, fine, granular cytoplasm with hematoxylin-eosin staining. Hrthle cells are also found in other tissues, such as the salivary gland, parathyroid gland, esophagus, pharynx, larynx, trachea, kidney, pituitary, and liver. Controversy exists about the origin of Hrthle cells, which generally are thought to derive from the follicular epithelium. A Hrthle cell neoplasm is defined generally as an encapsulated thyroid lesion consisting of at least 75% of Hrthle cells. Distinguishing a benign neoplasm from a malignant neoplasm based on cytologic analysis of fine-needle aspiration (FNA) biopsy is not possible. Features such as pleomorphism, anaplasia, hyperchromatism, and atypia are also observed in benign follicular adenomas; therefore, definitive differentiation of Hrthle cell carcinoma from Hrthle-cell adenoma is based on vascular invasion and/or capsular invasion, as well as on permanent histologic sections or extrathyroidal tumor spread and lymph node and systemic metastases. In the literature, the incidence of malignancy in Hrthle-cell neoplasms is variable, ranging from 1367%. Overall, only about 33% of Hrthle cell tumors demonstrate signs of that invasive growth that indicates malignancy and the possibility of metastasizing. On balance, Hrthle cell tumors may be considered to be more likely to metastasize than follicular tumors. The likelihood of nodal metastases is greater in Hrthle cell tumors than in follicular tumors; it is, however, not as great as with papillary tumors. Permissive histologic interpretation may result in the designation of some non-neoplastic Hrthle cell lesions as malignant tumors. Obviously, this factor has a major impact in interpreting the natural history of this disease and adds to the controversy about the aggressiveness of Hrthle cell carcinoma. This leads to reported overall mortality rates ranging from 9-28%. Tumor size is an important feature for biological behavior. A 1988 study found that a Hrthle tumor that is 4 cm or larger has an 80% chance of histologic evidence of malignancy.[3] In another study by Pisanu et al, [4] in a series of 23 patients, the mean tumor size was significantly greater for carcinomas than adenomas (3.1 cm vs 1.9 cm).

In another study done at Memorial Sloan-Kettering Cancer center,[5]outcomes of 56 patients with Hrthle cell cancer were analyzed. In this study, recurrence was a significant predictor of tumorrelated mortality, and the most significant predictor of outcome was extent of invasion. In addition, tumor size, extrathyroidal disease extension, and initial nodal or distant metastasis were found to be associated with an adverse outcome. Hrthle cell cancer has the highest incidence of metastasis among the differentiated thyroid cancers. Metastatic disease is reported at the time of initial diagnosis in 10-20% of patients and in 34% of the patients overall. Metastasis usually occurs hematogenously, but lymph node metastasis is also not uncommon and more frequently involves the regional lymph nodes. Some studies suggest that lymph node metastases at initial diagnosis may not be an unfavorable prognostic factor. The lungs, bones, and central nervous system are the most prevalent sites of metastases.