Papillary thyroid cancer

Papillary thyroid cancer (papillary thyroid carcinoma,^[1] PTC) is the most common type of thyroid cancer,^[2] representing 75 percent to 85 percent of all thyroid cancer cases.^[1] It occurs more frequently in women and presents in the 20–55 year age group. It is also the predominant cancer type in children with thyroid cancer, and in patients with thyroid cancer who have had previous radiation to the head and neck.^[3] It is often well-differentiated, slow-growing, and localized, although it can metastasize.

Diagnosis

Papillary thyroid carcinoma is usually discovered on routine examination as an

Reduced expression of ATP5E is significantly associated with the diagnosis of papillary thyroid cancer and may serve as an early tumor marker of the disease.^[10] Serum microRNAs have shown good diagnostic performance for distinguishing patients with papillary thyroid cancer from patients with benign thyroid nodules and healthy controls, and are suggested as novel and minimally invasive diagnostic approach in clinical practice.^[11]

Pathology

Papillary thyroid cancer gets its name from the papillae among its cells, visible on microscopy. Features include:

• Characteristic
  psammoma bodies on light microscopy. The former is useful in identifying the follicular variant of papillary thyroid carcinomas.^[13]
• Lymphatic spread is more common than
  hematogenous
  spread
• Multifocality is common
• The so-called lateral aberrant thyroid is usually a lymph node metastasis from a papillary thyroid carcinoma.[14]
• Papillary microcarcinoma is a subset of papillary thyroid cancer defined as measuring less than or equal to 1 cm.^[15] The highest incidence of papillary thyroid microcarcinoma in an autopsy series was reported by Harach et al. in 1985, who found 36 of 101 consecutive autopsies to have an incidental microcarcinoma.^[16] Michael Pakdaman et al. report the highest incidence in a retrospective surgical series at 49.9 percent of 860 cases.^[17] Management strategies for incidental papillary microcarcinoma on ultrasound (and confirmed on FNAB) range from total thyroidectomy with radioactive iodine ablation to observation alone. Harach et al. suggest using the term "occult papillary tumor" to avoid giving patients distress over having cancer. It was Woolner et al. who first arbitrarily coined the term "occult papillary carcinoma" in 1960, to describe papillary carcinomas ≤ 1.5 cm in diameter.^[18]

Several variants are recognized, although classic papillary thyroid carcinoma is the most frequent: microscopic-follicular variant, diffuse-sclerosing variant, tall-cell variant, columnar-cell variant, hobnail variant, and others. The encapsulated-follicular variant, specifically when noninvasive, has been newly reclassified as the noninvasive follicular thyroid neoplasm with papillary-like nuclear features.^[19]

Although papillary carcinoma has a propensity to invade

• 
  Micrograph of papillary thyroid carcinoma demonstrating prominent papillae with fibrovascular cores. H&E stain.
• 
  Micrograph showing that the papillae in papillary thyroid carcinoma are composed of cuboidal cells. H&E stain.
• 
  Nuclear grooves (arrows indicate one of them)
• 
  Nuclear pseudoinclusions, which are invaginations of cytoplasm into the nucleus.^[23]
• 
  Micrograph (high power view) showing nuclear changes in papillary thyroid carcinoma (PTC), which include groove formation, optical clearing, eosinophilic inclusions and overlapping of nuclei. H&E stain.
• 
  Micrograph (high power view) of PTC demonstrating nuclear clearing and overlapping nuclei. H&E stain.
• 
  Micrograph of

  metastatic papillary thyroid carcinoma to a lymph node

  . H&E stain.
• 
  Micrograph of papillary thyroid carcinoma, tall cell variant - high magnification. H&E stain.
• 
  Micrograph of papillary thyroid carcinoma, tall cell variant - intermediate magnification. H&E stain.

Associated mutations

Mutations associated with papillary thyroid cancer are mainly two forms of chromosomal translocation and one form of point mutation. These alterations lead to activation of a common carcinogenic pathway—the MAPK/ERK pathway.

Chromosomal translocations involving the

Approximately a third to a half of papillary thyroid carcinomas harbor point mutations in the BRAF oncogene, also activating the MAPK/ERK pathway.^[1] In those cases the BRAF mutations found were V600E mutation. After performing a multivariate analysis, it was found that the absence of tumor capsule was the only parameter associated (P=0.0005) with BRAF V600E mutation.^[5] According to recent studies, papillary cancers carrying the common V600E mutation tend to have a more aggressive long-term course. BRAF mutations are frequent in papillary carcinoma and in undifferentiated cancers that have developed from papillary tumors.

Many more changes in gene expression are currently being investigated. Previous studies demonstrated the dysregulation of different

Mitochondrial mutations: MtDNA(mitochondrial) haplogroups, characterized by unique sets of non pathological mtDNA polymorphisms can modulate the pathogenesis of different diseases in specific populations because of its influence on the expression of genes related to ROS production and OXPHOS coupling efficiency and the regulation of apoptosis.[25] In Asian populations, haplogroup D4a is associated with an increased risk of thyroid cancer^[26] while in European populations, Haplogroup K is considered to be protective of Thyroid cancer.^[27]

Treatment

Surgery remains the mainstay of treatment for papillary thyroid cancer. The Revised 2009 American Thyroid Association guidelines for papillary thyroid cancer state that the initial procedure should be near-total or total thyroidectomy. Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologically or clinically involved cervical nodal metastasis.^[28]

• Minimal disease (diameter up to 1.0 centimeters) -
  isthmectomy
  may be sufficient. There is some discussion whether this is still preferable over total thyroidectomy for this group of patients.
• Gross disease (diameter over 1.0 centimeters) - total thyroidectomy, and central compartment lymph node removal is the therapy of choice. Additional lateral neck nodes can be removed at the same time if an ultrasound guided FNA and thyroglobulin TG cancer washing was positive on the pre-operative neck node ultrasound evaluation.

Arguments for total thyroidectomy are:^[29]

• Reduced risk of recurrence, if central compartment nodes are removed at the original surgery.
• 30-85% of papillary carcinoma is multifocal disease. Hemithyroidectomy may leave disease in the other lobe. However, multifocal disease in the remnant lobe may not necessarily become clinically significant or serve as a detriment to patient survival.
• Ease of monitoring with thyroglobulin (sensitivity for picking up recurrence is increased in presence of total thyroidectomy, and ablation of the remnant normal thyroid by low dose
  radioiodine
  131 after following a low iodine diet (LID).
• Ease of detection of metastatic disease by thyroid and neck node ultrasound.
• Post-operative complications at high-volume thyroid surgery centers with experienced surgeons are comparable to that of hemithyroidectomy.

Arguments for hemithyroidectomy:

• Most patients have low-risk cancer with an excellent prognosis, with similar survival outcomes in low-risk patients who undergo total thyroidectomy versus hemithyroidectomy.
• Less likelihood of patient requiring lifelong thyroid hormone replacement after surgery.

Thyroid total body scans are less reliable at finding recurrence than TG and ultrasound.

Papillary tumors tend to be more aggressive in patients over age 45. In such cases, it might be required to perform a more extensive resection including portions of the

After surgical thyroid removal, the patient waits around 4–6 weeks to then have radioiodine therapy. This therapy is intended to both detect and destroy any metastasis and residual tissue in the thyroid. The treatment may be repeated 6–12 months after initial treatment of metastatic disease where disease recurs or has not fully responded.^[30]

Patients are administered hormone replacement

After successful treatment, 35 percent of the patients may experience a recurrence within a 40-year span. Also, patients may experience a high incidence of nodule metastasis, with 35 percent cases of cervical node metastases. Approximately 20 percent of patients will develop multiple tumors within the thyroid gland.[31]

There is ongoing discussion regarding the best management regarding the optimal surgical procedure for papillary thyroid cancer. Prognosis of patients with papillary thyroid cancer is found to be dependent on the patient's age, the size of the tumor, presence of metastatic disease, and the presence of tumor invasion into adjacent tissues near the thyroid gland. Recent studies have examined a more conservative approach to surgery and have demonstrated that hemithyroidectomy may be acceptable for patients with low-risk papillary thyroid cancer with tumor size 1 cm to 4 cm with no presence of invasion to tissues surrounding the thyroid or metastasis. Studies examining large databases of patients with papillary thyroid cancer have concluded that there is no survival advantage for patients with stage I papillary thyroid cancer size 1–4 cm receiving total thyroidectomy versus hemithyroidectomy.^[32] In light of this data, choosing the optimal course of surgical and medical management of papillary thyroid cancer should involve shared decision making from patient, endocrinologists, and surgeons.

Prognosis

Depending on source, the overall

• AGES - Age, Grade, Extent of disease, Size
• AMES - Age, Metastasis, Extent of disease, Size
• MACIS - Metastasis, Age at presentation, Completeness of surgical resection, Invasion (extrathyroidal), Size[34] (this is a modification of the AGES system). It is probably the most reliable staging method available. Also known as the MAICS system.
• TNM staging
  - Tumor, node, metastasis. Remarkable about the TNM staging for (differentiated) thyroid carcinoma is that the scoring is different according to age.

MACIS

The MACIS system of estimating the prognosis of papillary thyroid cancer was developed by Clive S. Grant at the Mayo Clinic and was based on careful evaluation of a large group of patients. It is probably the most reliable staging method available.^[35]

It assigns scores to the main factors involved and uses the sum of this score to calculate the prognosis:

Most patients fall into the low-risk category (MACIS score less than 6.0) and are cured of the cancer at the time of surgery.^[35]

Children with multiple lung metastases and/or a miliary aspect still have an excellent long-term prognosis if given adequate treatment.^[36]

Stage

Based on overall

According to Surveillance, Epidemiology, and End Results (SEER), the incidence of papillary cancer has increased from 4.8 to 14.9 per 100,000 from 1975 to 2012. Females are more likely to get papillary cancer when compared to males with incidence ratio of 2.5 to 1 where most of the cancers are diagnosed between 40 and 50 years old in females. However, death rates from papillary cancer remains static from 2003 to 2012 at 0.5 per 100,000 men and women. There was an increased incidence of papillary cancer from 1910 to 1960 due to the use of ionising radiation in treating childhood head and neck cancers.^[39] The incidence decreased after radiation therapy was abandoned. Environmental exposures to radiation such as atomic bombings of Hiroshima and Nagasaki and Chernobyl disaster also causes an increase in childhood papillary thyroid cancer at 5 to 20 years after the exposure to radiation.^[40] Family history of thyroid cancer syndrome such as familial adenomatous polyposis, Carney complex, Multiple endocrine neoplasia type 2 (MEN-2), Werner syndrome, and Cowden syndrome increases the risk of getting papillary cancer.^[39]

References