Poorly Differentiated Thyroid Cancer

Often can be diagnosed on needle biopsy of a suspicious thyroid nodule.

• Low threshold for expedited second opinion pathology review from a high volume academic medical center.

Imaging

• Ultrasound and CT Neck to rule out local invasion to nearby structures, regional metastasis (spread to the lymph nodes of the neck), and determine ability to remove surgically.
  • Low threshold to biopsy (FNA) any suspicious appearing lymph nodes in the neck.
  • If the cancer is considered unresectable, core needle biopsy with gene sequencing / molecular analysis should be considered to identify possible targets for neo-adjuvant therapy (treatment prior to surgery – with goal to shrink cancer until it can be resected).
    • In this event, the patient should be referred to medical oncologist specializing in the treatment of Head and Neck cancers at a high volume academic medical center.
• Consider whole-body PET scan given high risk for distant metastases.
  While identifying distant metastases will unlikely change initial treatment (surgery if possible) to control the cancer in the neck, it will provide information for long term prognosis.

Examination of the vocal cords with flexible fiberoptic camera to ensure no compromised function prior to surgery.

• If there is suspicion that the cancer is affecting the recurrent laryngeal nerve (controls movement of the vocal cords and voice) based on symptoms, imaging, and/or fiberoptic camera exam, there is an increased likelihood that the nerve will need to be sacrificed (cut in order to remove all the cancer) during the surgery.

Due to the rarity of this cancer and challenges related to making the pathology diagnosis, consensus guidelines for management do not exist.

Treatment of choice is surgery, generally erring on the aggressive side due to the aggressive nature of the cancer.

• Extent of surgery is determined based on imaging prior to surgery, biopsy results of lymph nodes in the neck (if indicated / performed) prior to surgery, as well as intraoperative findings (suspicious appearing lymph node sent for frozen biopsy during the surgery).
• At minimum a total thyroidectomy should be performed.
  • Low threshold for concurrent central and lateral neck dissections if lymph nodes in these compartments are biopsy proven for spread of cancer or are suspicious appearing on imaging prior to surgery.
  • Aggressive surgery can achieve good locoregional control (removal of all cancer in the neck).

For all types of thyroid cancer, surgical outcomes / cure rates are the highest and complication rates are the lowest when surgery is performed by a high-volume surgeon (> 50 thyroid cancer surgeries per year).

To read more about Thyroid and Neck Dissection surgeries including what to expect, as well as details regarding recovery and risks:

• Hemithyroidectomy.
• Total Thyroidectomy.
• Central Neck Dissection.
• Lateral Neck Dissection.

Again, there is a lack of consensus guidelines for recommend treatment following surgery due to the rarity of PDTC.

Due to the accumulated effects of multiple DNA alterations causing loss of normal thyroid cell function, PDTC cells frequently due not absorb iodine and therefore do not respond to radioactive iodine (RAI) or are not visible on Whole-body Iodine Scans (WBS).

• If regional (in the neck) or distant (outside of the neck) residual cancer exists based on suspicious imaging findings or elevated tumor marker levels (thyroglobulin) in the blood following surgery, a diagnostic WBS can be considered to determine definitively if tumor cells are iodine avid (still absorb iodine).
  • It the cancer remains iodine avid, higher doses of RAI (> 150 mCi) can be considered.

Role for external beam radiation therapy (EBRT) is controversial.

• Considered if there is a high risk for recurrence in the neck (based on poor pathological features or aggressive DNA alterations on gene sequencing – see below in ‘Staging & Prognosis’) or gross residual / unresectable disease.
• The results of EBRT in these above situations are inconclusive, but trend towards no significant survival improvement.

Gene sequencing and/or molecular analysis should be performed on the removed tumor.

• Helps to understand overall prognosis (seen below in ‘Staging & Prognosis’).
• Can identify potential targets for systemic therapies (medication given that effects the entire body) if there is unresectable residual disease in the neck and / or distant metastatic (outside the neck) disease is identified.
  • Routine systemic therapy is not currently indicated following surgery unless there is unresectable disease in the neck and / or distant metastatic disease is identified.

No official staging guidelines exist for PDTC.

Overall 5-year survival rate is reported at 66% (how many patients have not died from thyroid cancer 5 years following treatment).

• Majority of patients die of distant metastases (85%).
• 15% die from cancer in the neck invading critical structures (trachea, larynx, esophagus, carotid artery, etc.).

Poor prognosis is based on several factors:

• Patient demographics:
  • Age > 45 years.
• Findings on pathology report:
  • Tumors size > 4.0 cm.
  • Extrathyroidal extension (invasion of the cancer through the capsule of the thyroid and into nearby structures, aka ETE).
  • High mitotic rate (> 3 / 10 HPF; nuclei of many cells are dividing causing rapid growth of the tumor).
  • Tumor necrosis (cells growing so fast that areas of the tumor don’t have enough blood supply to survive and will subsequently die / necrose).
• Presence of distant metastases (spread of cancer outside of the neck) typically diagnosed on whole-body PET scan.
• Gene Sequencing / Molecular Analysis Results:
  • Main DNA alteration causing PDTC:
    • BRAF V600E – 27% of patients.
      • Higher rates of regional metastases (spreads via the lymphatic system to lymph nodes).
    • RAS mutations – 24% of patients.
      • Higher rates of distant metastases (spreads via the blood system).
    • TERT promoter mutation represent the most common (40%) additional DNA alteration that will trigger the change from WDTC to PDTC.
      • Presents with significantly higher rates of distant metastases and higher mortality rates.
  • Worse survival rates with DNA mutations TERT, MED12, RBM10, TP53, ATM, and EIFAX, as well as gain in Chromosome 1q copy number alterations and loss of 22q expression.

Predominantly Imaging:

• Ultrasound and/or CT of the Neck with contrast to assess for recurrence of cancer in the neck.
• Whole-Body PET scans to rule out distant metastatic spread beyond the neck.
• Frequency of imaging depends on overall prognosis, if known cancer is present, and how the known cancer is behaving (stable or growing).

Tumor Marker Levels

• Some PDTC cells maintain enough normal thyroid function to produce thyroglobulin (Tg), a protein made only by thyroid cells in the body and which can be measured in the blood.
  • 6 weeks after a total thyroidectomy, Tg levels can give an accurate measurement of how much thyroid tissue remains in the body, both normal and cancer cells.
    • It takes 6 weeks for Tg made previously by the thyroid to filter out of the blood.
  • If there are no thyroid cells (both normal and cancerous) in the body following surgery, the Tg level will be very low (< 1.0) or even undetectable (< 0.10).
  • If cancer cells remain in the body following treatment, Tg levels will often be elevated (> 1.0).
  • If Tg levels rise following surgery, it may be an indication that thyroid cancer cells are present or growing in the body.
    • Type and frequency of imaging may be influenced by a rise in Tg levels during surveillance.
• Not all PDTC cells will produce Tg due to a significant loss in normal thyroid cell function.
  • If Tg levels are very low or undetectable 6 weeks following surgery, an initial whole body PET scan should still be considered to rule out distant metastatic disease more completely.
  • PDTC that do not produce Tg are considered more aggressively behaving.

Surveillance should be performed for at least 5 years following treatment.

• If there are no obvious signs of cancer recurrence at 5 years, patients can be considered clinically cured.
• If there are suspicious signs for possible recurrence based on imaging results and/or tumor marker levels at 5 years, indefinite surveillance should be considered.

Treatment for recurrent cancer in the neck or distant spread of cancer.

• Recurrence in the neck (aka locoregional) should be treated surgically if possible.
  • If not possible because the cancer is unresectable or the patient is too ill to tolerate surgery, EBRT and/or systemic therapy can be considered with the goal of palliative treatment (non-curative, but rather to slow the growth, prevent invasion into nearby structures, or spread beyond the neck).
• Distant Metastases
  • Once PDTC has spread beyond the neck, cure is no longer possible.
    • Treatment should be focused on extending life, preserving quality of life, and/or palliation.
  • Surgical resection of a focal distant metastasis if possible is preferred if not too morbid (unfortunately this is not often possible).
  • Focal external beam radiation to an isolated site of disease can be considered if possible.
  • Gene sequencing and/or molecular analysis should be performed to identify any possible targets for systemic therapies.
    • These treatments are not curative, and their side effects can limit their use in some patients.
  • To explore these treatment options as a patient, you should be seen by a Head and Neck Cancer Medical Oncologist who specializes in the treatment of advanced thyroid cancers (typically practicing at an academic university hospital).
• If at any time the cancer is considered not curable, the patient / family / treatment team should collectively consider:
  • Palliate tracheotomy to prevent future airway compromise (cancer directly invading the larynx and/or trachea effecting the patient’s ability to breathe).
  • Feeding tube placement to allow for adequate nutrition and administration of medications if the cancer invades the pharynx or esophagus.
  • Establish goals of treatment and advance directives / end of life care plan.