AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Papillary carcinoma is the more common well-differentiated cancer of the thyroid. Papillary/follicular carcinoma must be considered a variant of the papillary thyroid carcinoma (mixed form). Despite its well-differentiated characteristics, papillary carcinoma may be overtly or minimally invasive. In fact, these tumors may spread easily to other organs. Papillary carcinoma appears as an irregular solid or cystic mass in a normal thyroid parenchyma.

As with most tumors, the cause of thyroid cancers is unknown; however, that thyroid cancers are more often found in patients with a history of low- or high-dose external irradiation (40-50 Gy) is well known. The life expectancy of patients with this cancer is related to their age. The prognosis is better for younger patients than for patients who are older than 45 years. Of patients with papillary cancers, 10-15% present with lymph node or lung metastases. Some years ago, lymph node metastases were thought to be aberrant (supernumerary) thyroids because of their well-differentiated aspect.

Pathophysiology

Papillary thyroid carcinoma seems closely related to the activation of trk and ret proto-oncogenes, both acting by amplifying and rearranging mechanisms. The trk proto-oncogene codes for tyrosine kinase receptors; the ret shows a paracentric inversion of chromosomes 10 and 11 in 30-35% of the cases. However, the met proto-oncogene is overexpressed and/or amplified in 3 of 4 patients.

In addition, evidence suggests that some molecules that physiologically regulate the growth of the thyrocytes, such as interleukin-1 and interleukin-8, or other cytokines (ie, insulinlike growth factor-1, transforming growth factor-beta, epidermal growth factor) could play a role in the pathogenesis of this cancer.

Frequency

United States

Approximately 70% of the thyroid cancers are of the papillary type.

International

Thyroid cancers are quite rare, accounting for only 1.5% of all cancers in adults and 3% of all cancers in children. The highest incidence of thyroid carcinomas in the world is found among female Chinese residents of Hawaii. During the last few years, the frequency of papillary cancer has increased, but this increase in frequency is related to an improvement in diagnostic techniques and the information campaign about this carcinoma. Of all thyroid cancers, 74-80% of cases are papillary cancer.

Mortality/Morbidity

In contrast to other cancers, thyroid cancer is almost always curable. Most thyroid cancers grow slowly and are associated with a very favorable prognosis. The mean survival rate after 10 years is higher than 90% and is 100% in very young patients with minimal nonmetastatic disease.

• Metastases are still frequent and are due to invasion of the lymphatics and spread to the lymph nodes. Vascular involvement is even more rare, occurring in fewer than 10% of cases. In most patients (35-50%), metastases are found at diagnosis. Distant spread (ie, to lungs or bones) is very uncommon. Worldwide, autopsy reviews show a high incidence of microscopic foci of thyroid carcinoma.
• Differing from medullary thyroid carcinoma, papillary thyroid cancer is not a part of multiple endocrine neoplasia syndromes.
• The mean mortality rate is 1.5% for females and 1.4% for males.

Race

This cancer occurs more frequently in whites than in blacks.

Sex

The female-to-male ratio is near 3:1 and is related to the patient's age.

• In patients younger than 19 years, the female-to-male ratio is 3.2:1.
• In patients aged 20-45 years, the female-to-male ratio is 3.6:1.
• In patients older than 45 years, the female-to-male ratio is 2.8:1.

Age

Thyroid carcinoma is common in persons of all age groups, with a mean age of 49 years and an age range of 15-84 years. In the younger population, papillary thyroid carcinoma tends to occur more frequently than follicular carcinoma, with a peak in patients aged 30-50 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Numerous cases of papillary thyroid cancer are subclinical.
• The most common presentation of thyroid cancer is an asymptomatic thyroid mass or a nodule that can be felt in the neck.
• Record a thorough medical history to identify any risk factors or symptoms.
• For any patient with a thyroid lump that has developed recently, obtain a history regarding every prior exposure to ionizing radiation and the lifetime duration of the radiation exposure.
• Consider a family history of thyroid cancer.
• Some patients have persistent cough, difficulty breathing, or difficulty swallowing.
• Pain is seldom an early warning sign of thyroid cancer.
• Other symptoms (eg, pain, stridor, vocal cord paralysis, hemoptysis, rapid enlargement) are rare. These symptoms can be caused by less serious problems.
• At the time of diagnosis, 10-15% of patients have distant metastases to the bones and lungs and, initially, are evaluated for pulmonary or osteoarticular symptoms (eg, pathologic fracture, spontaneous fracture).

Physical

• Palpate the patient's neck to evaluate the size and firmness of the thyroid and to check for any thyroid nodules. The principal sign of thyroid carcinoma is a palpable, firm, and nontender nodule in the thyroid area. This mass is painless.
• Some patients have a tight or full feeling in the neck, hoarseness, or signs of tracheal or esophageal compression.
• With thyroid palpation, a usually solitary nodule that has a hard consistency, an average size of less than 5 cm, and ill-defined borders can be felt. This nodule is fixed in respect to surrounding tissues and moves with the trachea at swallowing.
• Usually, signs of hyperthyroidism or hypothyroidism are not observed.

Causes

• Everyone is susceptible to thyroid cancer, but the thyroid is particularly sensitive to the effects of ionizing radiation. Exposure to ionizing radiation results in a 30% risk for thyroid cancer.
• A history of exposure of the head and neck to x-ray beams, especially during childhood, has been recognized as an important contributing factor for the development of thyroid cancer. For example, 7% of individuals exposed to the atomic bomb in Japan developed thyroid cancers.
• From 1920-1960, therapeutic irradiation of body areas was used to treat tumors and benign conditions (eg, acne; excessive facial hair; tuberculosis in the neck; fungus diseases of the scalp; sore throats; chronic coughs; enlargement of the thymus, tonsils, and adenoids). Approximately 10% of individuals who were treated with irradiation developed thyroid cancer after a latency period of 30 years.
• Patients who need radiotherapy for certain types of cancer of the head and neck area also may have an increased risk of developing thyroid cancer.
• Exposure to diagnostic x-rays does not increase the risk of developing thyroid cancers. Several reports have shown a relationship between iodine deficiency and the incidence of thyroid carcinomas.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Metastatic cancer
Leukemias

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Thyroid function
• • Perform a complete assessment of thyroid function in any patient with thyroid lumps.
  • Not all available tests are specific for papillary cancer of the thyroid. Higher-than-normal levels of thyroxine (reference range is 4.5-12.5 mcg/dL), triiodothyronine (reference range is 100-200 ng/dL), and thyroid-stimulating hormone (TSH) (reference range is 0.2-4.7 mIU/dL) may indicate thyroid cancer.
  • Evaluate serum levels of thyroglobulin, calcium, and calcitonin.
  • Determining the serum level of carcinoembryonic antigen (CEA) may be helpful (reference range is <3 ng/dL). However, the implications of the presence of CEA are not specific because CEA levels are high in several cancers, and numerous healthy people may have small amounts of CEA, especially pregnant women and persons who are heavy smokers.
• TSH suppression test
• • Cancer is autonomous and does not require TSH for growth, whereas benign lesions do require TSH. When exogenous thyroid hormone feeds back to the pituitary to decrease the production of TSH, thyroid nodules that continue to enlarge are likely to be malignant. However, 15-20% of malignant nodules are suppressible.
  • Preoperatively, the test is useful for patients with nontoxic solitary benign nodules and for women with repeated nondiagnostic test results. Postoperatively, the test is useful for monitoring papillary thyroid cancer cases.

Imaging Studies

• Chest radiography, CT scanning, and MRI: These tests are not usually used in the initial workup of a thyroid nodule, except in patients with clear metastatic disease at presentation. These tests are second-level diagnostic tools and are useful in preoperative patient assessment.
• Echography
• • This imaging study must be performed first in any patient with possible thyroid malignancy. Echography is noninvasive and inexpensive, and it represents the most sensitive procedure for identifying thyroid lesions and for determining the diameters of a nodule (2-3 mm).
  • Echography is also useful for localizing lesions when a nodule is difficult to palpate or is deeply seated. Echography images can help determine if a lesion is solid or cystic and can help detect the presence of calcifications.
  • The accuracy rate of echography in categorizing nodules as solid, cystic, or mixed is near 90%. It may be used to help direct a fine-needle aspiration biopsy (FNAB).
  • Pulsed and power Doppler echography may provide important information about the vascular pattern and the velocimetric parameters. Such information can be useful preoperatively to reach a correct differential diagnosis of malignant or benign thyroid lesion.
• Scintigraphy
• • Before FNAB, thyroid scintigraphy (or thyroid scanning) performed with technetium Tc 99m pertechnetate (99mTc) or radioactive iodine (iodine I 131 or iodine I 123) was the initial diagnostic procedure of choice for a thyroid evaluation.
  • The procedure is not as sensitive or specific as FNAB for distinguishing benign nodules from malignant nodules.
  • The scintigraphy procedure performed with 99mTc has a high error rate because 99mTc is trapped as iodide but is not organified in the thyroid.
  • The 99mTc has a short half-life and cannot help determine the functionality of a thyroid nodule. Radioactive iodine is trapped and organified in the thyroid and can help determine functionality of a thyroid nodule. Iodine-containing compounds and seafood interfere with any tests using radioactive iodine.
  • Scintigraphic images of the thyroid are acquired 20-40 minutes after intravenous administration of the radionuclide.
  • In more than 90% of cases, clearly benign nodules appear as hot nodules because they are hyperfunctioning and have a high captation rate of radionuclide and, physiologically, of iodine. Malignant nodules usually appear as cold nodules because they are not functioning.
  • Findings from thyroid scanning are helpful and specific in evaluating the preoperative and immediate postoperative periods for localization of cancer or residual thyroid tissue and in observing for tumor recurrence or metastasis. Thyroid scanning can also be useful for diagnosing benign lesions (by FNAB) or solid lesions (by echography).

Procedures

• FNAB is considered the best first-line diagnostic procedure for a thyroid nodule; the FNAB is a safe and minimally invasive procedure.
• • Local anesthesia is administered at the puncture site, and the aspiration biopsy needle is guided into the mass. Hold the nodule with the fingers of the left hand while introducing a needle through the skin into the thyroid nodule with the right hand.
  • After aspiration with a needle, 21- or 23-gauge, the material is deposited on a glass slide, fixed with alcohol-acetone, and then stained according to the Papanicolaou test protocol.
  • The accuracy of FNAB results is better than any other test for uninodular lesions. The sensitivity of the procedure is near 80%, the specificity is near 100%, and errors can be diminished using ultrasonographic guidance.
  • False-negative and false-positive results occur less than 6% of the time.
  • A thyroid biopsy can also be performed using the classic Tru-Cut or Vim-Silverman needles, but the FNAB technique is preferable. Patients comply best with FNAB.
  • A pathologist may experience difficulty distinguishing some benign cellular adenomas from their malignant counterparts.
• Perform indirect or fiberoptic laryngoscopy to evaluate airway and vocal cord mobility and to have preoperative documentation of any unrelated abnormalities.

Histologic Findings

Papillary thyroid carcinoma usually appears as a grossly firm mass that is irregular and not encapsulated. Microscopically, it is multifocal, and a net invasion of the lymphatics may be demonstrated. Complete or partial papillary architecture with some follicles is present. Otherwise, in some patients, the tumor may lack any papillary pattern. The thyrocytes are large and show an abnormal nucleus and cytoplasm with several mitoses. In some cases, the thyrocytes may have the so-called "Orphan Annie eyes," ie, large round cells with a dense nucleus and clear cytoplasm. Another typical feature of this cancer is the presence of the psammoma bodies, probably the remnants of dead papillae.

Immunohistochemistry findings usually have a CEA-negative, calcitonin-negative, thyroglobulin-positive, and keratin-positive pattern.

Definitive diagnosis is often not possible with samples obtained from the FNAB because findings cannot accurately distinguish between benign and malignant lesions.

Staging

The staging of well-differentiated thyroid cancers is related to age for the first and second stages, but it is not related to age for the third and fourth stages. In the staging protocol, T is tumor, N is node, and M is metastasis.

• Younger than 45 years
• • Stage I - Any T, any N, M0 (cancer in thyroid only)
  • Stage II - Any T, any N, M1 (cancer spread to distant organs)
• Older than 45 years
• • Stage I - T1, N0, M0 (cancer only in thyroid, may be found in one or both lobes)
  • Stage II - T2, N0, M0 and T3, N0, M0 (cancer only in thyroid and >1.5 cm)
  • Stage III - T4, N0, M0 and any T, N1, M0 (cancer spread outside thyroid but not outside of neck)
  • Stage IV - Any T, any N, M1 (cancer spread to other parts of body)

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Approximately 4-6 weeks after surgical thyroid removal, patients must have radioiodine therapy to detect and destroy any metastasis and residual tissue in the thyroid. Administer therapy until radioiodine uptake is completely absent.
• When a large, unresectable tumor is present and the uptake of radioiodine is limited, when intractable bone pain exists, or if resection is not feasible, external beam radiation may be performed to control local tumor growth, including, but not limited to, the neck, lungs, mediastinum, bone, and CNS (stage T4).
• Administer the thyroid hormone replacement levothyroxine to patients for life, especially after total thyroidectomy. Treatment consists of administering levothyroxine at 2.5-3.5 mcg/kg/d.
• Chemotherapy with cisplatin or doxorubicin has limited efficacy, producing occasional objective responses (generally for short durations). Because of the high toxicity of chemotherapy with cisplatin or doxorubicin, chemotherapy may be considered in symptomatic patients with recurrent or advancing disease. However, chemotherapy could improve the quality of life in patients with bone metastases, but a standard protocol for chemotherapeutic management has not been developed for these patients.

Surgical Care

Surgery is the definitive management of thyroid cancer, and various types of operations may be performed.

• Lobectomy with isthmectomy: This procedure is the minimal operation for a potentially malignant thyroid nodule.
• Subtotal thyroidectomy
• • This is a near-total thyroidectomy, which is preferable, if feasible, because total thyroidectomy does not improve long-term prognosis and the incidence of complications (eg, hypoparathyroidism, superior and/or recurrent laryngeal nerve injury) is lower with subtotal thyroidectomy.
  • Patients younger than 40 years who have papillary thyroid carcinoma nodules that are smaller than 1 cm, well-defined, minimally invasive, and isolated may be treated with hemithyroidectomy and isthmectomy. An important consideration is that approximately 10% of patients who have had total thyroidectomy develop recurrence in the contralateral lobe, and residual tissue has the potential to dedifferentiate to anaplastic cancer.
• Total thyroidectomy
• • Perform a total thyroidectomy (removal of all thyroid tissue but preserving the contralateral parathyroid glands) in patients who are older than 40 years with papillary carcinoma and in any patient with bilateral disease. In addition, recommend total thyroidectomy to any patient with a thyroid nodule and a history of irradiation.
  • Some studies show lower recurrence rates and increased survival rates in patients who have undergone a total thyroidectomy.
  • This surgical procedure also facilitates earlier detection and treatment of recurrent or metastatic carcinoma. This surgical option is mandatory in patients with papillary carcinoma discovered based on postoperative histology findings (ie, if a very well-differentiated tumor is discovered) after a one-sided lobectomy, with or without isthmectomy.
  • When the primary tumor spreads outside the thyroid and involves adjacent vital organs (eg, larynx, trachea, esophagus), preserve these organs at the first surgical approach. However, the surrounding soft tissues, including the muscles and involved areas of the trachea and/or esophagus, may be sacrificed if they are directly involved with the differentiated thyroid carcinoma and local resection is feasible.
• Video-assisted thyroidectomy: This is rarely used to treat thyroid cancer.

Consultations

• Schedule elderly patients for an assessment by a cardiologist because of the high risk of subclinical hypothyroidism episodes.
• Consult an otolaryngologist, especially in thyroid patients who have voice disturbances.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The most useful drugs for the treatment of papillary thyroid carcinomas after surgery are levothyroxine and radioiodine. For metastases, palliation with antineoplastic agents (eg, cisplatin, doxorubicin) may be useful.

Drug Category: Thyroid products

Useful to prevent hypothyroidism and to stop TSH stimulation.

Drug Category: Antithyroid agents

Reduce serum thyroid hormone levels.

Drug Category: Antineoplastic agents

Inhibit cell growth and proliferation. May be helpful in palliating symptoms in progressive disease.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• In patients with papillary thyroid carcinoma, systematic psychotherapeutic intervention may be very helpful.

Further Outpatient Care

• Perform a postoperative scintiscan of the neck 4-6 weeks after thyroid hormone replacement therapy is completed. At this time, a scan of the neck can help demonstrate if thyroid tissue is still present. If thyroid tissue is present, a dose of radioactive iodine is administered to destroy residual tissue. The patient is then placed back on thyroid hormone replacement (levothyroxine) therapy.
• Repeat the scintiscan 6-12 months after ablation and, thereafter, every 2 years. Before the scan, levothyroxine must be withdrawn for approximately 4-6 weeks to maximize thyrotropin stimulation of the eventual remaining thyroid tissue.
• Radioactive iodine may ablate the metastatic tissue in the lungs and bone. These metastases appear to be more amenable to radioiodine therapy than the metastases of papillary carcinoma.
• Evaluate thyroglobulin serum levels every 6-12 months for at least 5 years. Consider a level greater than 20 ng/mL, after TSH suppression, to be abnormal. A recurrence of thyroid cancer can be detected if a rise in the thyroglobulin level occurs.
• Perform thyroid hormone suppression tests in all patients who underwent total thyroidectomy and in all patients who have had radioactive ablation of any remaining thyroid tissue. Individualize the degree of suppression to avoid complications, such as subclinical hyperthyroidism.
• • A recent meta-analysis of clinical data from several studies including a large number of subjects demonstrated that an undetectable serum thyroglobulin finding during thyroid hormone suppression of TSH is often misleading.
  • Accordingly, the authors propose a new surveillance guideline for patients who have undergone total or near-total thyroidectomy and radioactive iodine ablation and have no clinical evidence of residual tumor with a serum thyroglobulin level less than 1 mcg/L during thyroid hormone suppression of TSH.
• A patient who has had a thyroidectomy without parathyroid preservation requires vitamin D and calcium supplementation for life.

Deterrence/Prevention

• No known preventative methods exist.

Complications

• If neglected, any thyroid cancer may exhibit symptoms because of compression and/or infiltration of the cancer mass into the surrounding tissues, and the cancer may metastasize to lung and bone.
• Surgical treatment of thyroid cancer may cause some complications, partially because of the variable anatomy of the neck. These possible complications include the following:
• • Hypothyroidism
  • Dysphagia due to damage of the upper laryngeal nerve
  • Vocal cord paralysis due to damage of recurrent laryngeal nerve
  • Hypoparathyroidism due to parathyroid gland ablation
• Radioiodine administration may have several consequences, including the following:
• • Radiation thyroiditis and transient thyrotoxicosis in patients with simple lobectomy
  • Sialoadenitis because radioiodine is taken up by the salivary glands
  • Nausea, anorexia, and headache (uncommon)
  • Pulmonary fibrosis in patients with large lung metastases
  • Brain edema in patients with brain metastases (may be prevented by glucocorticoid therapy)
  • Permanent sterility and transient oligospermia or menstrual irregularities
  • Teratogenesis and spontaneous abortions
  • A small increase in the risk for leukemias or breast and bladder carcinomas
• Metastases, in descending order of frequency, are most common in the neck lymph nodes and lung, followed by the bone, brain, liver, and other sites. Metastatic potential seems to be a function of the primary tumor size. Metastases in the absence of thyroid pathology in the physical examination findings are rare in patients with microscopic papillary carcinoma (occult carcinomas).

Prognosis

• The prognosis of papillary thyroid cancer is related to age, sex, and stage. In general, if cancer is not extending beyond the capsule of the gland, life expectancy is minimally affected. Prognosis is better in female patients and in patients younger than 40 years. The survival rate is at least 95% with appropriate treatments.

Patient Education

• Patients who discover a neck deformity or thyroid lumps or have a history of prior exposure to ionizing radiation must consult their physician.
• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The main medical and legal problems related to papillary thyroid cancer are vocal cord paralysis due to damage of the recurrent laryngeal nerve, damage of the parathyroid glands leading to temporary or permanent hypoparathyroidism, and toxic adverse effects of radioiodine administration. Always obtain informed consent for diagnostic procedures and treatments, explaining the procedures and their possible complications.

Special Concerns

• Because radioiodine treatment may cause either teratogenesis or spontaneous abortions, patients should delay pregnancy for at least 1 year after radioiodine treatment.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Sep 6, 2006