Papillary thyroid cancer or papillary thyroid carcinoma is the most common type of thyroid cancer

Thyroid cancer

Thyroid neoplasm is a neoplasm or tumor of the thyroid. It can be a benign tumor such as thyroid adenoma, or it can be a malignant neoplasm , such as papillary, follicular, medullary or anaplastic thyroid cancer. Most patients are 25 to 65 years of age when first diagnosed; women are more affected...

, representing 75% to 85% of all thyroid cancer cases. It occurs more frequently in women and presents in the 30-40 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.

Markers

Thyroglobulin

Thyroglobulin

Thyroglobulin is a 660 kDa, dimeric protein produced by and used entirely within the thyroid gland. In earlier literature, Tg was referred to as colloid....

 can be used as a tumor marker

Tumor marker

A tumor marker is a substance found in the blood, urine, or body tissues that can be elevated in cancer, among other tissue types. There are many different tumor markers, each indicative of a particular disease process, and they are used in oncology to help detect the presence of cancer...

 for well-differentiated

Cellular differentiation

In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...

 papillary thyroid cancer. HBME-1 staining may be useful for differentiating papillary carcinomas from follicular carcinomas; in papillary lesions it tends to be positive.

Pathology

• Characteristic Orphan Annie eye nuclear inclusions (nuclei with uniform staining, which appear empty) and psammoma bodies on light microscopy. The former is useful in identifying the follicular variant of papillary thyroid carcinomas.

• Lymphatic spread is more common than hematogenous spread
• Multifocality is common
• The so-called Lateral Aberrant Thyroid is actually a lymph node metastasis from papillary thyroid carcinoma.
• Papillary microcarcinoma is a subset of papillary thyroid cancer defined as measuring less than or equal to 1 cm. The highest incidence of papillary thyroid microcarcinoma in autopsy series was reported by Harach et al. in 1985, who found 36 of 101 consecutive autopsies were found to have an incidental microcarcinoma. Michael Pakdaman et al. report the highest incidence in a retrospective surgical series at 49.9% of 860 cases. 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.

Although papillary carcinoma has a propensity to invade lymphatics, it is less likely to invade blood vessels.
These kinds of tumors are most commonly unencapsulated, and they have a high tendency to metastasize locally to lymph nodes, which may produce cystic structures near the thyroid that are difficult to diagnose because of the paucity of malignant tissue. Furthermore, papillary tumors may metastasize to the lungs and produce a few nodules or the lung fields may exhibit a snowflake

Snowflake

Snowflakes are conglomerations of frozen ice crystals which fall through the Earth's atmosphere. They begin as snow crystals which develop when microscopic supercooled cloud droplets freeze. Snowflakes come in a variety of sizes and shapes. Complex shapes emerge as the flake moves through...

 appearance throughout.

Other characteristics of the papillary carcinoma is that E.M. shows increased mitochondria, increased RER, as well as increased apical microvilli. Moreover, papillary carcinomas have an indolent growth, and 40% of cases spread out of the capsule.

Associated mutations

Mutation

Mutation

In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

s associated with papillary thyroid cancer are mainly two forms of chromosomal translocation

Chromosomal translocation

In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...

 and one form of point mutation

Point mutation

A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...

. These alterations lead to activation of a common carcinogenic

Carcinogenesis

Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...

 pathway - the MAPK/ERK pathway

MAPK/ERK pathway

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...

.

Chromosomal translocations involving the RET proto-oncogene

RET proto-oncogene

The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules....

 (encoding a tyrosine kinase receptor that plays essential roles in the development of neuroendocrine cell

Neuroendocrine cell

Neuroendocrine cells are cells that receive neuronal input and, as a consequence of this input, release message molecules to the blood. In this way they bring about an integration between the nervous system and the endocrine system, a process known as neuroendocrine integration...

s) located on chromosome 10q11 occur in approximately a fifth of papillary thyroid cancers. The fusion oncoproteins generated are termed RET/PTC proteins (ret/papillary thyroid carcinoma), and constitutively activate RET and the downstream MAPK/ERK pathway. The frequency of ret/PTC translocations is significantly higher in papillary cancers arising in children and after radiation exposure. The gene NTRK1 (encoding the TrkA receptor), located on chromosome 1q, is similarly translocated in approximately 5% to 10% of papillary thyroid cancers.

Approximately a third to a half of papillary thyroid carcinomas harbor point mutations in the BRAF oncogene

BRAF (gene)

Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene...

, also activating the MAPK/ERK pathway. 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. 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.

Diagnosis

Papillary thyroid carcinoma is usually discovered on routine examination as an asymptomatic

Asymptomatic

In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...

 thyroid nodule that appears as a neck mass. In some instances, the mass may have produced local symptoms. This mass is normally referred to a fine needle aspiration biopsy

Needle aspiration biopsy

Needle aspiration biopsy , may refer to fine needle aspiration cytology , fine needle aspiration biopsy and fine needle aspiration , is a diagnostic procedure sometimes used to investigate superficial lumps or masses...

 (FNA) for investigation. FNA accuracy is very high and it is a process widely used in these cases. Other investigation methods include ultrasound imaging and nuclear scan. The ultrasound is a useful test to distinguish solid from cystic lesions and to identify calcifications. The thyroid ultrasound is also very effective to discover microcarcinomas, which refer to very small carcinomas (<1 cm). A significant number of such carcinomas are malignant

Malignant

Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...

.

Papillary thyroid carcinomas are also discovered when a hard nodule is found in multinodular goiter, when enlarged cervical lymph nodes are detected, or when there are unidentified metastatic lesions elsewhere in the body. Expanding lesions found in the thyroid gland, especially if they are painful, should be examined as they may indicate the presence of papillary thyroid carcinoma. Other clinical signs that could indicate papillary thyroid are: fixation to the trachea, stony hardness, damage to recurrent laryngeal or cervical sympathetic nerves. Seventy five percent of the population will have these thyroid nodules, and the majority will always be benign.

Chest x rays are not commonly performed. In cases of metastasis, some other tests are run to obtain sufficient information before a surgery. Such tests include the ultrasound and MRI of the neck as well as the CAT scanning. Other options that have shown good results in identifying tumors or related outcomes are the use of Thallium201 chloride, which helps identify metastatic tumor; Gallium

Gallium

Gallium is a chemical element that has the symbol Ga and atomic number 31. Elemental gallium does not occur in nature, but as the gallium salt in trace amounts in bauxite and zinc ores. A soft silvery metallic poor metal, elemental gallium is a brittle solid at low temperatures. As it liquefies...

, which is helpful to visualize lymphomas; I-meatiodobenzylguanidine, which has proven useful in imaging MTC; Tc-MIBI, which has been effective in detecting deposits of metastatic thyroid cancer; PET scans, which are also helpful for the imaging of metastatic disease. Chia et al. report that TSHR mRNA measured with FNA enhances the preoperative detection of cancer in patients with thyroid nodules, reducing unnecessary surgeries, and immediate postoperative levels can predict residual/metastatic disease. Suspected lung metastases and/or miliary aspects at x-ray or CT can be diagnosed by cytology on a bronchoalveolar lavage

Bronchoalveolar lavage

Bronchoalveolar lavage is a medical procedure in which a bronchoscope is passed through the mouth or nose into the lungs and fluid is squirted into a small part of the lung and then recollected for examination. BAL is typically performed to diagnose lung disease...

 specimen.

Prognosis

Depending on source, the overall 5-year survival rate for papillary thyroid cancer is 96% or 97%, with a 10-year survival rate of 93%.

For a more specific prognosis for individual cases, there are at minimum 13 known scoring systems for prognosis; among the more often used are:

• 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 (this is a modification of the AGES system). It is probably the most reliable staging method available.
• TNM staging - Tumor, node, metastasis. Remarkable about the TNM staging for (differentiated) thyroid carcinoma is that the scoring is different according to age.

MAICS

The MAICS system of estimating the prognosis of papillary thyroid cancer was developed by the Mayo Clinic

Mayo Clinic

Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...

, and was based on careful evaluation of a large group of patients. It is probably the most reliable staging method available.

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

Factors		Score
Distant Metastasis: spread of the cancer to areas outside the neck	Yes	3
	No	0
Age at the time the tumor was discovered	Less than 39 years	3.1
	Over 40 years	0.08 x age
Invasion into surrounding areas of the neck as seen by the naked eye	Yes	1
	No	0
Completeness of surgical resection (or removal) of the tumor	Incomplete	1
	Complete	0
Size of the tumor		0.3 x size in cm

Sum of MAICS Score	20 yr Survival
< 6.0	99%
6.0 - 6.99	89%
7.0 - 7.99	56%
> 8.0	24%

Most patients fall into the low risk category (MAICS score less than 6.0) and are cured of the cancer at the time of surgery.

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

Overall stage

By overall cancer staging

Cancer staging

The stage of a cancer is a description of the extent the cancer has spread. The stage often takes into account the size of a tumor, how deeply it has penetrated, whether it has invaded adjacent organs, how many lymph nodes it has metastasized to , and whether it has spread to distant organs...

 into stages I to IV, papillary thyroid cancer has a 5-year survival rate of 100% for stages I and II, 93% for stage III and 51% for stage IV.

Treatment

Surgical treatment:

• Minimal disease (diameter up to 1.0 centimeters) - hemithyroidectomy (or unilateral lobectomy) and 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
  Thyroidectomy
  A thyroidectomy is an operation that involves the surgical removal of all or part of the thyroid gland. Surgeons often perform a thyroidectomy when a patient has thyroid cancer or some other condition of the thyroid gland...
  
  , 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 thyrobulin TG cancer washing was positive on the pre-operative neck node ultrasound evaluation.

Arguments for total thyroidectomy are:

• Reduced risk of recurrence, if central compartment nodes are removed at the original surgery.
• Papillary carcinoma is a multifocal disease (hemithyroidectomy may leave disease in the other lobe)
• Ease of monitoring with thyroglobulin (sensitivity for picking up recurrence is increased in presence of total thyroidectomy, and ablation of 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.

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 trachea

Vertebrate trachea

In tetrapod anatomy the trachea, or windpipe, is a tube that connects the pharynx or larynx to the lungs, allowing the passage of air. It is lined with pseudostratified ciliated columnar epithelium cells with goblet cells that produce mucus...

. Also, the sternocleidomastoid muscle

Sternocleidomastoid muscle

In human anatomy, the sternocleidomastoid muscle , also known as sternomastoid and commonly abbreviated as SCM, is a paired muscle in the superficial layers of the anterior portion of the neck...

, jugular vein

Jugular vein

The jugular veins are veins that bring deoxygenated blood from the head back to the heart via the superior vena cava.-Internal and external:There are two sets of jugular veins: external and internal....

, and accessory nerve are to be removed if such procedure allows apparently complete tumor resection. If a significant amount of residual tumor is left in the neck

Neck

The neck is the part of the body, on many terrestrial or secondarily aquatic vertebrates, that distinguishes the head from the torso or trunk. The adjective signifying "of the neck" is cervical .-Boner anatomy: The cervical spine:The cervical portion of the human spine comprises seven boney...

, external radiotherapy has been indicated and has proven useful especially in those cases when residual tumor does not take up radioiodine.

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

Metastasis

Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...

 and residual tissue in the thyroid. The treatment may be repeated 6–12 months after initial treatment of metastatic disease where disease

Disease

A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...

 recurs or has not fully responded.

Patients are administered hormone replacement levothyroxine

Levothyroxine

Levothyroxine, also L-thyroxine, synthetic T4, or 3,5,3',5'-tetraiodo-L-thyronine, is a synthetic form of thyroxine , used as a hormone replacement for patients with thyroid problems. The natural hormone is chemically in the chiral L-form, as is the pharmaceutical agent...

 for life after surgery, especially after total thyroidectomy. Chemotherapy

Chemotherapy

Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 with cisplatin

Cisplatin

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...

 or doxorubicin

Doxorubicin

Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....

 has proven limited efficacy, however, it could be helpful for patients with bone metastases

Bone Metastases

Bone metastases, or metastatic bone disease, is a class of cancer metastases that results from primary tumor invasion to bone. Bone-originating cancers like osteosarcoma, chondrosarcoma, and Ewing's sarcoma are rare...

 to improve their quality of life

Quality of life

The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...

. Patients are also prescribed levothyroxine and radioiodine after surgery. Levothyroxine influences growth and maturation of tissues and it is involved in normal growth, metabolism

Metabolism

Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

, and development. In case of metastases, patients are prescribed antineoplastic agents which inhibit cell growth

Cell growth

The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...

and proliferation and help in palliating symptoms in progressive disease.

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