- Tumor Histology
- Numerous histologic variants of PTC have been described based on architectural or cellular features
- Acknowledgement of the tumor subtype is important:
- As it can contribute to the risk stratification of individual tumors
- The classic subtype of PTC and the follicular subtype of PTC (FVPTC) are associated with very favorable outcomes
- More concerning histologic subtypes include:
- Tall cell, hobnail subtype, and, perhaps to a lesser extent, columnar cell:
- These tumors tend to present at an older age and with more advanced disease than is seen in classic PTC
- Tall cell, hobnail subtype, and, perhaps to a lesser extent, columnar cell:
- These more aggressive histologic subtypes:
- Also are associated with worse recurrence-free and disease-specific survival rates
- Tumor Size
- Primary tumor size is closely associated with the outcome of PTC, including both 10-year recurrence and cancer-specific mortality rates
- Cancer-specific mortality rates increase incrementally from 2% for tumors 8 cm
- Furthermore, larger tumors are associated with a higher rate of locoregional and distant metastases
- Multifocality
- Patients with PTC have a 32% to 45% chance of cancer elsewhere in the ipsilateral or contralateral lobe
- Tumor multifocality is also found frequently in papillary thyroid microcarcinomas (PMCs)
- Multifocal disease increases the risk of recurrence, particularly in patients who have had a lobectomy
- With the current trend to performing lobectomy for the majority of low-risk cancers, some have raised concerns about the potential for increased recurrence rates
- Indeed, some patients may develop recurrence in the remaining contralateral lobe, necessitating completion thyroidectomy at a later date:
- Fortunately, it is the minority (7% at 10 years of follow-up) of patients who will require such an intervention
- A large, long-term follow-up study of patients undergoing lobectomy for PTC:
- 14.6% of whom had multifocal disease, demonstrated a recurrence-free 20-year survival rate of 95% in the opposite lobe, 91% for lymph node (LN) recurrence, and a disease-specific survival rate of 97.8%
- Predictors of recurrence or worse disease-specific survival were:
- Age
- Primary tumor > 4 cm
- Clinically apparent LNs
- Suggesting that properly selected patients will have an excellent prognosis after lobectomy of PTC
- The implications of tumor multifocality on survival are controversial:
- Some studies have determined that multifocal disease does not increase the risk of disease-specific mortality
- However, when distinguishing unilateral multifocal from bilateral disease, other studies have demonstrated that survival was lower for bilateral tumors
- Extrathyroidal Extension
- Extrathyroidal extension (ETE) of tumor beyond the thyroid capsule into the perithyroidal soft tissues and adjacent structures:
- May be seen in up to 40% of surgical specimens and is an important prognostic factor in PTC
- The specific extent of ETE should be described on the surgical pathology report
- Minimal ETE is defined as:
- Microscopic visualization of tumor into the immediate perithyroidal soft tissues
- In contrast, extensive ETE is described as:
- Gross tumor extension into subcutaneous soft tissues, larynx, trachea, esophagus, or the recurrent laryngeal nerve (RLN)
- The prognostic implications of ETE in differentiated thyroid cancer is controversial, which may stem largely from a failure to distinguish between these distinct degrees of tumor spread
- It is generally accepted that tumor extension into the surrounding tissues:
- Which is visible intraoperatively or on preoperative imaging:
- Is associated with a worse prognosis
- Which is visible intraoperatively or on preoperative imaging:
- The implications of minimal ETE on outcomes, however, is less clear:
- Some retrospective studies have demonstrated that minimal ETE is associated with higher rates of LN metastases
- Other studies found recurrence rates in those with minimal ETE were dependent on primary tumor size
- In contrast others have found that minimal ETE is not associated with increased recurrence or decreased survival
- A recent systematic review and meta-analysis of the effects of minimal ETE on survival and recurrence demonstrated:
- No influence of minimal ETE on disease-related mortality but did indicate an increased risk of recurrence in patients with minimal ETE
- The absolute recurrence risk increase for patients with lymph node negative disease was from 2.2% to 3.5% and for patients with lymph node positive disease the increase was from 6.2% to 7%:
- Suggesting that the effects of minimal ETE on absolute risk for disease recurrence was small
- Indeed, the 8th edition of The American Joint Committee on Cancer/The Tumor, Node, and Metastases (AJCC/TNM) cancer staging system removed the minimal ETE definition and its influence on overall tumor stage
- This omission is an acknowledgment of the negligible effects of minimal ETE on tumor-associated mortality
- Extrathyroidal extension (ETE) of tumor beyond the thyroid capsule into the perithyroidal soft tissues and adjacent structures:
- Lymph Node Metastases
- The incidence rates of cervical LN metastases identified at the time of initial surgery in patients with PTC varies widely, depending on the mode of nodal detection
- Prophylactic LN dissections yield high rates of LN micrometastases (up to 65%)
- Whereas gross nodal involvement detected by preoperative US or during surgery occurs in a smaller, but still substantial, percentage (20%) of patients
- The manner of discovery is important as it is related to the prognostic significance of nodal involvement:
- Those nodes incidentally identified on surgical pathology with microscopic tumor deposits:
- Do not significantly alter risk of recurrence
- Prophylactic nodal dissection, therefore, is not recommended as it does not lower recurrence-free survival and risks upstaging patients:
- Resulting in unnecessary additional treatment
- Those nodes incidentally identified on surgical pathology with microscopic tumor deposits:
- In contrast, grossly abnormal nodes:
- Are associated with a worse recurrence-free survival:
- Removal of these nodes is thus considered therapeutic
- Are associated with a worse recurrence-free survival:
- The number of involved nodes:
- Is also related to the recurrence risk
- Even with microscopic nodal deposits:
- More than five involved nodes:
- Carries a higher risk of recurrence compared with lower numbers of diseased nodes:
- 7% to 21% and 3% to 8%
- Carries a higher risk of recurrence compared with lower numbers of diseased nodes:
- More than five involved nodes:
- The effects of LN metastases on survival is less clear:
- There are conflicting reports regarding cancer-specific mortality in the presence of nodal involvement
- An analysis of the Surveillance, Epidemiology, and End Results (SEER) database:
- Determined that nodal metastases were associated with increased mortality only in those patients over the age of 45 years:
- However, a more recent study of patients from the SEER database and the National Cancer Database (NCDB) of patients under the age of 45 years:
- Found that increasing numbers of nodal metastases were associated with decreasing overall survival up to six nodes, after which more metastatic nodes conferred no additional mortality risk
- However, a more recent study of patients from the SEER database and the National Cancer Database (NCDB) of patients under the age of 45 years:
- Determined that nodal metastases were associated with increased mortality only in those patients over the age of 45 years:
- Distant Metastases
- Although distant metastases are uncommon in PTC:
- They are present in approximately 5% of patients at the time of initial diagnosis:
- Another 2.5% to 5% will develop distant metastases after initial therapy
- They are present in approximately 5% of patients at the time of initial diagnosis:
- The most common sites of involvement are:
- Lung (50%) and bone (25%):
- Followed by both lung and bone (20%) and other tumor sites (5%)
- One study found a 50% survival rate of 3.5 years:
- However, subsets of patients have better survival rates, especially postpubertal children, those with microscopic metastases, and patients with iodine-avid tumors
- Additional prognostic information about distant metastases may be gained by performing 2-[18F]fluoro-2-deoxy-D- glucose-positron emission tomography (18FDG-PET) /computed tomography (CT) scanning:
- One study found an inverse relationship between survival and degree of 18FDG-PET avidity of the most active lesion as well as the number of (18FDG-PET)–avid lesions
- Patients with a positive 18FDG-PET scan had a 7.28-fold increased risk of dying from thyroid cancer compared with patients who had a negative scan
- Lung (50%) and bone (25%):
- Although distant metastases are uncommon in PTC:
- Oncogenes
- The MAPK (mitogen-activated protein kinase) pathway:
- Is an intracellular signaling cascade that results in:
- Cell growth
- Proliferation
- Apoptosis
- A mutation in one of these signaling components in the MAPK pathway is responsible for the majority of PTCs:
- These mutations are almost always mutually exclusive:
- Suggesting that a single molecular alteration is sufficient to drive oncogenesis
- Detection of these mutations may be used to:
- Identify malignancy on fine-needle aspiration (FNA)
- To prognosticate for patients with thyroid cancer
- To guide the systemic agent used in radioiodine-refractory disease
- These mutations are almost always mutually exclusive:
- Is an intracellular signaling cascade that results in:
- The MAPK (mitogen-activated protein kinase) pathway:
- BRAF
- BRAF is a serine / threonine kinase in the MAPK signaling pathway:
- That regulates cellular differentiation, proliferation, and survival
- The BRAF V600E pathogenic variant:
- Is the most common oncogene in sporadic PTC:
- With an incidence of 36% to 69%
- The presence of BRAF V600E is associated with:
- Higher risk clinic-pathologic features, including:
- LN metastases
- ETE
- Recurrence
- Age-associated mortality
- Is the most common oncogene in sporadic PTC:
- BRAF is a serine / threonine kinase in the MAPK signaling pathway:
- The independent prognostic utility of a BRAF mutation remains in question, however
- With such a high prevalence of this pathogenic variant and the excellent outcomes in the majority of thyroid cancer patients, the specificity of BRAF for prognostication is limited:
- Further, because BRAF is often associated with high-risk clinical features, it is difficult to discern what component of the poor outcomes seen with this pathogenic variant are due to the mutation itself, independent of the pathologic elements
- Indeed several studies attempting to determine whether BRAF serves as an independent predictor of recurrence have produced mixed results
- The identification of a BRAF mutation instead may provide:
- Direction for the management of radioiodine refractory tumors:
- A recent clinical trial aimed at redifferentiating noniodine-avid tumors:
- Used a BRAF-inhibitor, dabrafenib:
- 60% of patients exhibited new iodine uptake on diagnostic whole-body scans
- After treatment with 5GBq of 88I at 3 months of follow-up, two patients had partial responses and four had stable disease
- An ongoing trial is examining the effect of dabrafenib alone or in combination with a MEK inhibitor, trametinib:
- In progressive, iodine-refractory, BRAF-mutated tumors (clinicaltrials.gov, NCT01723202)
- Used a BRAF-inhibitor, dabrafenib:
- A recent clinical trial aimed at redifferentiating noniodine-avid tumors:
- Direction for the management of radioiodine refractory tumors:
- TERT
- Newly described in thyroid cancers, telomerase reverse transcriptase (TERT) promoter mutations:
- Are found in low frequency in lower risk PTC (9%)
- Increasing in frequency in more advanced PTC (51%):
- PDTC (40%)
- ATC (54% to 73%)
- Telomerase is responsible for adding tandem repeats of the TTAAGGG sequence to the end of chromosomes:
- To maintain genome stability
- Whereas these enzymes are highly expressed in germline and stem cells, expression is reduced or even repressed in somatic cells
- The loss of telomeres during somatic cell division:
- Results in cells entering senescence
- Reactivation of telomerase leads to immortalization:
- By way of unrestricted proliferation and inactivation of replicative senescence
- Newly described in thyroid cancers, telomerase reverse transcriptase (TERT) promoter mutations:
- Although there are conflicting reports regarding the effect of a TERT mutation on prognosis in PTC:
- A recent meta-analysis demonstrated that the presence of coexisting BRAF and TERT mutations was associated with a more aggressive clinical course and another study demonstrated higher mortality rates
- Further study is needed to determine the feasibility of pharmacologic therapy targeting TERT mutations
- Age at Diagnosis
- Age at the time of tumor diagnosis is one of the most important contributing factors to prognosis:
- There is a trend of worsening cause-specific survival for each decade starting at age 60 compared with younger patients (less than 20 years old)
- An analysis of the NCDB revealed an incremental increase in 10-year mortality:
- By 30% to 50% per 5 year increment beginning at age 35 years
- A recent study determined that the age-associated increasing risk of mortality was associated with BRAF mutational status:
- This multi-institutional study found that age is a strong, continuous, and independent mortality risk factor in patients with a BRAF V600E mutation but not in those with wild-type BRAF
- Older patients are also more likely to harbor more aggressive histologic subtypes
- In patients with distant metastases:
- Those over the age of 40 years are less likely to demonstrate iodine avidity in their lung metastases
- Children and adolescents:
- Are more likely to have a more advanced tumor stage at the time of diagnosis
- Up to 80% harbor nodal involvement and 15% to 20% develop pulmonary metastases rates that are nearly double those seen in adults
- Despite the extent of disease at the time of diagnosis, children generally have excellent outcomes
- In one systematic review of pediatric patients with pulmonary metastases, a complete response to radioactive iodine (RAI) therapy was seen in up to 50% and disease-specific mortality was 2.7%
- Are more likely to have a more advanced tumor stage at the time of diagnosis
Rodrigo Arrangoiz MS, MD, FACS, FSSO 