eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > Head & Neck Surgery

Thyroid, Papillary Carcinoma, Early

Author: Eric J Lentsch, MD, Assistant Professor of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina
Coauthor(s): M Boyd Gillespie, MD, MS, FACS, Associate Professor, Department of Otolaryngology, Associate Member of College of Graduate Studies, Medical University of South Carolina; Director, Medical University of South Carolina Snoring Clinics; Surgical Consultant, Medical University of South Carolina Sleep Disorders Center; John C Goddard, MD, Staff Physician, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina; Christina ST Wilhoit, EMT, BA, CCRP, Program Coordinator for Head and Neck Surgery Clinical Trials, Department of Otolaryngology, Hollings Cancer Center, Medical University of South Carolina; Zoran Rumboldt, MD, Associate Professor, Department of Radiology, Medical University of South Carolina; Rana S Hoda, MD, FIAC, Professor of Pathology, Attending Pathologist and Director of Cytopathology, University of Rochester Medical Center; Allen O Mitchell, MD, Chairman, Department of Otolaryngology-Head and Neck Surgery, Naval Medical Center, Portsmouth; Kenneth M Spicer, MD, PhD, Professor of Radiology with Tenure, Director of Nuclear Medicine Residency, Medical Director of Radiology Informatics, Medical University of South Carolina
Contributor Information and Disclosures

Updated: Apr 24, 2009

Introduction

Much attention has been generated regarding the topic of thyroid neoplasia and papillary thyroid carcinoma. This attention can be attributed to the frequency of benign thyroid nodules and the clinical difficulty in distinguishing these nodules from malignant thyroid lesions.

Problem

Thyroid nodules are found in up to 7% of the population. Only 4-6.5% of these nodules are malignant. Malignant tumors of the thyroid account for only about 1% of all cancers and only 0.4% of cancer-related deaths. The prognosis for papillary thyroid carcinoma is favorable; however, controversy exists regarding management of this cancer. Surgery is the primary mode of therapy for treatment, but the most appropriate type of resection for this disease is controversial.

Frequency

Papillary thyroid carcinoma accounts for about 80% of all thyroid carcinomas in the United States. The incidence of thyroid cancer increased from 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002—a 2.4-fold increase. Virtually the entire increase is attributable to an increase in the incidence of papillary thyroid cancer, which increased from 2.7 to 7.7 per 100,000—a 2.9-fold increase. Between 1988 (the first year SEER collected data on tumor size) and 2002, 49% of the increase consisted of cancers measuring 1 cm or smaller. These trends, combined with the known existence of a substantial reservoir of subclinical cancer and stable overall mortality, suggest that increasing incidence reflects increased detection of subclinical disease, not an increase in the true occurrence of thyroid cancer.

The tumor most often occurs in individuals aged 20-50 years. In adults, the female-to-male ratio of clinically diagnosed papillary carcinoma of the thyroid is 3:1; In children, the tumor is distributed by sex nearly equally. Although this condition is more common in females, they have a better overall prognosis. Papillary thyroid carcinoma occurs more often in whites than in blacks.

Etiology

The etiology of papillary carcinoma is yet to be elucidated, but a number of associations have been made.

  • Molecular
    • Activation of receptor tyrosine kinases (RET/PTC, TRK, MET), whether by rearrangement or gene amplification, appears to be specific for the transformation of thyroid follicular cells into papillary thyroid carcinomas. These rearrangements produce chimeric proteins with tyrosine kinase activities that contribute to the development of the malignant phenotype. Approximately 40% of adults with sporadic papillary carcinoma have RET gene rearrangement, and about 15% have NTRK1 rearrangement. This rearrangement is higher (60%) in children. Somatic point mutation in the BRAF gene may be the most common mutation among papillary thyroid cancers, varying from 29-69 % in different series. This gene encodes a serine/threonine kinase acting on the RAS-RAF-MEK-MAPK signaling pathway. BRAF mutations seem to be much less common in childhood thyroid carcinomas.
    • A 10-fold increased risk of thyroid cancer in relatives of patients with thyroid cancer suggests a genetic basis for susceptibility to these tumors. A correlation between papillary thyroid carcinoma and human leukocyte antigen (HLA)-DR7 has also been observed. Also, a parallel incidence has been described for this tumor in monozygotic twins.
  • Iodine excess
    • Papillary thyroid cancer has been induced in animals with the administration of excess iodine. In Vienna, Austria during a period when iodide intake was low in the population, papillary carcinoma accounted for only 25% of all thyroid cancers instead of the expected 80%.
    • In areas where goiters are endemic, the addition of iodine in the diet has increased the proportion of papillary carcinomas relative to follicular thyroid cancer. However, these cancers are less aggressive and have a better prognosis for long-term survival.
  • Radiation
    • External radiation to the neck increases the incidence of papillary carcinoma of the thyroid later in life. Irradiation during childhood has been associated with the greatest risk for acquiring papillary thyroid cancer. As many as 9% of children irradiated for conditions such as tonsillar hypertrophy, thymic enlargement, and acne have developed thyroid cancer over a period of 20 years. Of the survivors of the atomic bomb explosion in Japan, 6.7% developed papillary thyroid cancers.
    • This percentage is much higher than what is expected in the general population. More recently, data have become available from studies of over 4000 people who developed thyroid cancer after the Chernobyl nuclear accident in 1986.1 They revealed that radiation exposure during childhood carries an increased risk of thyroid cancer and that the risk is radiation dose dependent. The youngest children are most sensitive to radiation-induced carcinogenesis, and the minimal latent period for thyroid cancer development after exposure is as short as 4 years. The vast majority of these cancers are papillary carcinomas. On the molecular level, chromosomal rearrangements (such as RET/PTC) are more common than point mutations of BRAF and other genes. Radiation exposure only increases the risk of developing thyroid cancer; it does not affect the prognosis or the aggressiveness of the tumor. However, treatment with radioactive iodine has not been shown to increase the incidence of thyroidcancers.

Pathophysiology

Gross description

Papillary carcinomas can range in size from microscopic, clinically undetectable lesions to masses up to 10 cm in diameter. The average tumor size at diagnosis is 2.3 cm. As many as 75% of these tumors are multifocal in the thyroid gland. On gross examination, most are pale and firm; less than 10% of papillary carcinomas are truly encapsulated. The larger nodules are usually unencapsulated and locally invasive. Penetration of the capsule of the thyroid gland occurs in about 40% of cases.

Microscopic description

The most common types of thyroid carcinoma are the well-differentiated types, which include papillary and follicular thyroid carcinoma. Both papillary and follicular carcinomas arise from the endodermally derived follicular cell that synthesizes thyroxine and thyroglobulin. This is in contrast to medullary thyroid carcinoma, which is derived from the neuroendocrine calcitonin-producing parafollicular C cells of the thyroid.

Papillary tumors may have a pure papillary histopathology, but more than one half contain an admixture of follicular elements. Long-term follow-up care of patients with these mixed tumors shows that, regardless of the precise proportions, all neoplasms containing some papillary areas have identical biological behavior; therefore, these tumors are classified under papillary and not follicular carcinoma.

The histopathological diagnosis of follicular variant of papillary thyroid carcinoma (FVPCA) can be difficult. Lloyd (2004) examined interobserver variation by 10 experienced thyroid pathologists in the diagnosis of FVPCA in 87 tumors.2 A concordant diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency of 39%. Diagnostic criteria used to diagnose FVPCA, including pseudoinclusions, nuclear grooves, and powdery nuclei, are clearly not uniformly recognized even by experts; immunohistochemical markers may provide more objective diagnostic criteria.

However, as shown by Papotti (2005) and Sahoo (2001), the immunohistochemical expression of cytokeratin 19, galectin-3 and HBME-1, 3 malignancy-related markers in thyroid papillary carcinoma, including its follicular variant, is assuming increasing importance but should be used with caution.3,4

Thus, genetic alterations in papillary carcinoma of thyroid may hold the ultimate key to diagnosis. Three genetic alterations, including BRAF point mutations, RET/PTC rearrangements, or RAS point mutations, have been recognized in this regard. In a study by Adeniran (2006), these alterations have been shown to be associated with distinct microscopic, clinical, and biologic features of thyroid papillary carcinomas.5 BRAF mutations were associated with older age, taller cell appearance, and more advanced tumor stage at presentation. RET/PTC rearrangements presented at a younger age, showed typical papillary histology, and were associated with a high rate of lymph node metastases. Tumors with RAS mutations were exclusively of FVPCA type.

The identification of these alterations may lead to the increasing use of genetic studies in the diagnosis and in predicting the prognosis of papillary thyroid carcinoma. In addition, these involved genes may also serve as targets for cancer chemotherapy in patients in which standard thyroid cancer treatment is not effective.

The histological features of papillary carcinoma of the thyroid include branching papillae composed of a central fibrovascular core and a single or stratified lining of cuboidal to columnar cells. Tumor cells may form colloid-containing follicles, and foci of squamous metaplasia are frequently found. Nuclear atypia is also an important diagnostic feature.

In more than half of these tumors, the nuclei have a characteristic ground-glass appearance; laminated calcific spherules known as psammoma bodies are also often found within the histological framework. In fact, the presence of psammoma bodies is virtually diagnostic for papillary carcinoma because they are rarely found in other lesions.

Papillary thyroid carcinomas typically invade the lymphatics and spread to other sites within the thyroid gland, as well as to the regional lymph nodes. Lymph node metastases have been reported in the range of 46-90% of cases of papillary carcinoma. Vascular invasion is uncommon; however, if it does occur, the spread of tumor is usually to the lungs and bones. Direct extension into the soft tissues of the neck occurs in approximately 25% of cases.

Variants

The variants of papillary thyroid carcinoma include the following:

  • Encapsulated tumors: About 10% of papillary carcinomas are completely surrounded by a dense fibrous capsule. The prognosis for patients with such tumors is better than the prognosis for patients with unencapsulated papillary carcinoma.
  • Diffuse sclerosing variant: Occurring at a younger age, the diffuse sclerosing variant constitutes 2% of papillary carcinomas and may cause a diffuse goiter without palpable nodules that can be mistaken for goitrous autoimmune thyroiditis. Diffuse involvement of one or both lobes occurs with dense sclerosis, patchy lymphocytic infiltration, and abundant psammoma bodies. Prognosis for individuals with the diffuse sclerosing variant is less favorable than that for individuals with typical papillary thyroid carcinoma.
  • Oxyphilic (Hürthle) cell type: The oxyphilic (Hürthle) cell type variant has typical papillary architecture but may be more aggressive than usual papillary carcinoma.
  • Follicular variant: The follicular variant has a purely follicular architectural pattern but may be recognized by the typical cellular features of papillary carcinoma.
  • Tall-cell carcinoma: Tall-cell carcinoma is a more aggressive form of thyroid carcinoma that differs from the usual form by showing tall columnar cells. The frequency of more aggressive behavior is higher, but the carcinoma resembles papillary carcinoma in other morphologic and clinical aspects.
  • Columnar cell carcinoma: Columnar cell carcinoma is a distinctly more aggressive form of papillary thyroid carcinoma that occurs more often in older men and is associated with a poor prognosis.

Presentation

The mainstays of the preoperative diagnosis of papillary carcinoma are a thorough history and physical examination, including an assessment of risk factors, along with ancillary tests such as cervical ultrasonography and aspiration cytology.

The most common presentation of thyroid cancer is a nontender palpable nodule. However, a diagnostic dilemma is present as this is the presentation of most benign thyroid conditions. A palpable nodule occurs in up to 7% of the general female population. A single nodule has a 5-12% malignancy rate, while multiple nodules have a 3% malignancy rate in the general population.

Papillary carcinoma may also present as a nodule with enlarged cervical lymph nodes or cervical lymphadenopathy in the absence of a palpable thyroid nodule. Benign thyroid tissue can be found in the neck anywhere medial to the sternocleidomastoid muscle. Any thyroid tissue lateral to the sternocleidomastoid muscle should be considered malignant.

Unlike follicular thyroid carcinoma, distant metastases of papillary thyroid carcinoma are rarely observed at the time of presentation. When distant metastases are present at the time malignancy is discovered, the primary tumor is almost invariably large and easily palpable.

Indications

Symptoms of dysphagia, odynophagia, or shortness of breath may lead to the discovery of a thyroid mass during physical examination or ultrasound. Presence of a mass in the thyroid requires further investigation, especially in patients at high risk for carcinoma. A positive fine-needle aspiration finding is an indication for surgical removal of the mass. Some clinicians assert that a history of neck irradiation and a thyroid mass is in itself an indication for surgical excision.

Relevant Anatomy

Knowledge of the anatomy of the infrahyoid neck and thyroid region aids in the identification and preservation of structures (eg, recurrent laryngeal nerve, superior laryngeal nerve, superior thyroid artery, inferior thyroid artery). The isthmus of the thyroid usually overlies the third tracheal ring, although this middle portion of the gland may be absent altogether in some individuals. The thyroid gland consists of a superior pole that may extend as far as the oblique line of the thyroid cartilage, and an inferior pole that may extend as far as the sixth tracheal ring.

The external branch of the superior laryngeal nerve innervates the cricothyroid muscle near the superior pole. The left recurrent laryngeal nerve lies in the tracheoesophageal groove, while the right recurrent laryngeal nerve approaches the thyroid gland from a more lateral position. The superior thyroid artery is the first branch of the external carotid artery and often accompanies the external laryngeal branch of the superior laryngeal nerve near the superior pole of the thyroid as it runs superficially toward the isthmus. The inferior thyroid artery arises from the thyrocervical trunk, which comes off of the subclavian artery. This artery runs in the tracheoesophageal groove and sends branches to the posterior aspect of the lateral thyroid lobe. The inferior thyroid artery has a longitudinal branch that anastomoses with the superior thyroid artery near the superior pole.

Contraindications

Surgical excision of papillary thyroid carcinoma has no absolute contraindications. Even people with distant metastasis would benefit from surgical removal of the primary disease, neck dissection, and ablation with iodine-131.

A total thyroidectomy may be contraindicated in people with disease limited to only one lobe of the thyroid who are likely to be noncompliant with thyroid replacement therapy. These individuals may be better suited for a hemithyroidectomy.

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References
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Further Reading

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Keywords

papillary carcinoma, thyroid carcinoma, thyroid carcinomas, papillary carcinomas, thyroid cancer, thyroid neoplasia, thyroid neoplasias, papillary and follicular carcinoma, thyroid tumor, thyroid tumors, diffuse sclerosing variant, Hürthle cell, oxyphilic cell, tall-cell carcinoma, columnar cell carcinoma, thyroid mass, thyroid masses, hemithyroidectomy, near-total thyroidectomy, thyroidectomy, modified radical neck dissection, ipsilateral radical neck dissection, psammoma bodies

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Contributor Information and Disclosures

Author

Eric J Lentsch, MD, Assistant Professor of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina
Disclosure: Nothing to disclose.

Coauthor(s)

M Boyd Gillespie, MD, MS, FACS, Associate Professor, Department of Otolaryngology, Associate Member of College of Graduate Studies, Medical University of South Carolina; Director, Medical University of South Carolina Snoring Clinics; Surgical Consultant, Medical University of South Carolina Sleep Disorders Center
M Boyd Gillespie, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Academy of Sleep Medicine, American College of Surgeons, American Head and Neck Society, American Medical Association, Johns Hopkins Medical and Surgical Association, Phi Beta Kappa, and South Carolina Medical Association
Disclosure: Nothing to disclose.

John C Goddard, MD, Staff Physician, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina
John C Goddard, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Medical Association, and South Carolina Medical Association
Disclosure: Nothing to disclose.

Christina ST Wilhoit, EMT, BA, CCRP, Program Coordinator for Head and Neck Surgery Clinical Trials, Department of Otolaryngology, Hollings Cancer Center, Medical University of South Carolina
Disclosure: Nothing to disclose.

Zoran Rumboldt, MD, Associate Professor, Department of Radiology, Medical University of South Carolina
Zoran Rumboldt, MD is a member of the following medical societies: American College of Radiology, American Roentgen Ray Society, American Society of Neuroradiology, and Radiological Society of North America
Disclosure: Bracco Grant/research funds Other; Bracco Honoraria Consulting

Rana S Hoda, MD, FIAC, Professor of Pathology, Attending Pathologist and Director of Cytopathology, University of Rochester Medical Center
Rana S Hoda, MD, FIAC is a member of the following medical societies: American Society for Clinical Pathology, American Society of Cytopathology, College of American Pathologists, College of American Pathologists, International Academy of Cytology, South Carolina Medical Association, and United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.

Allen O Mitchell, MD, Chairman, Department of Otolaryngology-Head and Neck Surgery, Naval Medical Center, Portsmouth
Allen O Mitchell, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, and American Medical Association
Disclosure: Nothing to disclose.

Kenneth M Spicer, MD, PhD, Professor of Radiology with Tenure, Director of Nuclear Medicine Residency, Medical Director of Radiology Informatics, Medical University of South Carolina
Kenneth M Spicer, MD, PhD is a member of the following medical societies: American College of Nuclear Medicine, American College of Nuclear Physicians, American College of Radiology, Association of University Radiologists, Radiological Society of North America, Society of Nuclear Medicine, and South Carolina Medical Association
Disclosure: Nothing to disclose.

Medical Editor

David J Terris, MD, FACS, Porubsky Professor and Chairman, Department of Otolaryngology, Medical College of Georgia
David J Terris, MD, FACS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Association for the Advancement of Science, American Bronchoesophagological Association, American College of Surgeons, American Head and Neck Society, Federation of American Societies for Experimental Biology, International Association of Endocrine Surgeons, Phi Beta Kappa, Radiation Research Society, Society of University Otolaryngologists-Head and Neck Surgeons, and Triological Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Nader Sadeghi, MD, FRCS(C), Associate Professor of Surgery, Director of Head and Neck Surgery, Division of Otolaryngology, George Washington University
Nader Sadeghi, MD, FRCS(C) is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society, Federation of Medical Specialists in Quebec, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

CME Editor

Christopher L Slack, MD, Otolaryngology-Facial Plastic Surgery, Private Practice, Associated Coastal ENT; Medical Director, Treasure Coast Sleep Disorders
Christopher L Slack, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck Society
Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation unstricted gift unknown

 
 
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