Effect of Patient Variables on Prognosis

• Age at the time of tumor diagnosis:
  • Is one of the more important contributing factors to prognosis
  • After the age of 40:
    • Recurrence and mortality rates increase significantly
  • The recurrence and mortality rates of PTC in patients beyond the age of 60 years become even more steep
  • Children and adolescents (less than 20 years of age) are more likely to have more advanced tumor stage at the time of diagnosis:
    • One large study found that:
      • 64% of children had cervical lymph node metastases at the time of diagnosis
      • 23% had distant metastases at the time of diagnosis
    • In contrast, studies of adults have found that:
      • Up to 40% have lymph node metastases and only 5% present with distant metastases
    • Likewise, the pediatric recurrence rates over 20 to 30 years:
      • Are nearly twice those of adults
        • 40% versus 20%, respectively
    • Despite the extent of disease at the time of diagnosis, children generally have excellent survival rates:
      • One large study found a 2% cause-specific mortality rate after 40 years of follow-up
    • Most authorities suggest children with PTC should be treated with total thyroidectomy and radioiodine, although others prefer surgery alone
      • Differentiated thyroid cancer has a more aggressive presentation in prepubertal children, and rigorous initial surgical and ¹³¹I treatment followed by thyrotropin suppression has resulted in favorable outcomes
    • Thyroid cancer mortality increases progressively with advancing age, without a specific age cutoff that stratifies mortality risk:
  • This was illustrated in an analysis of 53,581 patients in the Surveillance, Epidemiology, and End Results (SEER) database, in which the five-year survival rate decreased with increasing age at diagnosis (stratified in five-year categories from 20 to 84 years)
  • There was a continuum of disease-specific mortality with increasing age:
    • Survival remained above 90% for patients less than 65 years at diagnosis

• Primary tumor size is closely associated with the outcome of PTC:
  • The prognosis is poorer in patients who have large tumors:
    • In one series, as an example, 20-year cancer-related mortality rates were:
      • 6%, 16%, and 50% for patients whose primary tumor diameters were 2 to 3.9 cm, 4 to 6.9 cm, or 7 cm or larger, respectively
  • A retrospective study of 52,173 patients with PTC found that:
    • 10-year cumulative recurrence rates:
      • Increased incrementally from 5% for tumors less than 1 cm to 25% for tumors greater than 8 cm
    • 10-year cumulative cancer-specific mortality rates:
      • Increased incrementally from 2% for tumors less than 1 cm to 19% for tumors greater than 8 cm
    • This study demonstrated that primary tumor size is closely associated with disease outcome, including both 10-year tumor recurrence and cancer-specific mortality rates, and with higher rates of locoregional and distant metastases

• Tumor multifocality may affect prognosis:
  • Patients with PTC in one thyroid lobe:
    • Have nearly a 45% chance of cancer in the contralateral lobe
  • This is one of the reasons why recurrence rates are often higher in patients treated with hemithyroidectomy:
    • One study found that tumor multifocality:
      • Was associated with a higher risk of persistent or recurrent disease, even in patients treated with total thyroidectomy
  • Tumor multifocality is also found in papillary thyroid microcarcinomas (PTMC):
    • One study of PTMC found that the only factors significantly influencing recurrence rates were:
      • The number of histologic foci (p < 0.002) and the extent of initial thyroid surgery (p < 0.01)
    • Another study of PTMC found that recurrent locoregional disease was more likely in patients:
      • With cervical lymph node metastases at the time of presentation
      • Multifocal disease
      • In those not treated with remnant ablation

• Microscopic extension of tumor outside the thyroid bed:
  • Identified by central lymph node compartment (level VI) dissection is found in as many as 30% of patients:
    • As compared to patients without extracapsular spread, extracapsular spread is associated with a:
      • Higher risk of persistent or recurrent disease
      • An increased likelihood of cervical lymph node metastases
      • Reduced survival
• Macroscopic extrathyroidal PTC visualized at surgery:
  • Is found in up to 9% of patients:
    • Invasion into the surrounding musculature, esophagus, or trachea:
      • Has been associated with:
        • Higher recurrence rates
        • Reduced survival:
          • It may benefit from external beam radiotherapy after aggressive surgery
• Soft-tissue invasion increases the risk of death fivefold:
  • It can also cause substantial morbidity if there is involvement of the:
    • Trachea, esophagus, recurrent laryngeal nerves, or the spinal cord
  • It is important to note that it is gross soft-tissue invasion (usually described as extrathyroidal extension) identified on clinical examination, intraoperatively, or on imaging:
    • That conveys an increased risk of mortality
  • Extrathyroidal extension that is only identified on histopathologic examination:
    • Is not a major factor for mortality, as reflected in the changes in the eighth edition American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system:
      • Where minor extrathyroidal extension no longer upstages a patient to stage III

• Lymph Node Metastases:
  • Cervical lymph node metastases may be found at the time of initial surgery in as many as 53% of patients with PTC:
    • However, the incidence rates vary widely, depending on the mode of nodal detection:
      • Prophylactic central lymph node dissections yield high rates of lymph node micrometastases:
        • 53% to 65%
      • Macrometastases (i.e., when lymph node metastases are detected by preoperative ultrasound or during surgery):
        • Occur in a smaller but still substantial percentage:
          • Typically between 30% to 40%, of patients
  • The importance of neck ultrasonography on the management of PTC:
    • Was highlighted by a study in which patients with preoperative positive lateral neck lymph nodes on ultrasound had significantly worse lymph node recurrence-free survival as compared to patients without preoperatively detectable lateral lymph node metastases
    • Patients who did not have preoperatively detected lymph node metastases on cervical ultrasonography:
      • Received no benefit in terms of recurrence-free survival when prophylactic neck dissection was performed
  • Other studies have confirmed that lymph node macrometastases detected by ultrasonography are associated with lower recurrence-free survival rates for PTMC
  • The number of grossly involved lymph node metastases:
    • Is inversely related to recurrence-free survival
  • The impact of lymph node metastases on cancer-specific survival is less clear:
    • Several studies have not been able to demonstrate an increase in mortality rates for patients with lymph node metastases, whereas other studies have shown reduced survival
    • The disparity among studies regarding the effect of lymph node metastases on mortality may be explained through an analysis of the SEER database:
      • In which patient age at the time of lymph node surgery was investigated:
        • Those over age 45 years with lymph node involvement had a 46% increased risk of death as compared with similarly aged patients without lymph node metastases
        • In contrast, there was no effect on survival in patients less than age 45 years with lymph node metastases (p < 0.001)

• Molecular characteristics:
  • The most common oncogene in sporadic PTC is:
    • BRAF
  • BRAF prevalence varies with the geographic locale being sampled:
    • But pooled analyses have found that approximately 39% of PTCs have this mutation
  • Although the clinical significance of BRAF has been debated:
    • Most studies have found that this tumor mutation is associated with adverse clinicopathologic characteristics of PTC, including:
      • Rapid tumor progression and tumor recurrence:
        • In older age patients
      • Lymph node metastases
      • Extrathyroidal invasion
      • Advanced tumor stages
      • It also has been associated with treatment failure
  • The BRAF mutation:
    • Has even been found with PTC recurrence in patients with what would have been otherwise regarded as low-risk tumors
  • Another study found that patients with BRAF-positive tumors have a higher overall mortality rate:
    • However, several studies have not confirmed a correlation between the BRAF mutation and a worse clinical outcome:
      • Indeed, with such a high rate of BRAF positivity (up to nearly 40%) and an overall excellent outcome for the majority of patients with PTC:
        • Not all patients with BRAF do poorly
  • Moreover, not all patients with aggressive tumors have the BRAF mutation:
    • Suggesting other factors play a role in determining tumor phenotype
  • Further study is needed to identify patients at highest risk for poor outcomes among those with a BRAF mutation
• Other mutations that have been associated with papillary thyroid carcinomas include:
  • RET / PTC rearrangements
  • PAX8 / PPARγ rearrangements
  • RAS point mutations
• Numerous rearrangements of the RET receptor tyrosine kinase gene have been associated with papillary thyroid carcinomas:
  • The most common being RET / PTC1 and RET / PTC3
    • The prevalence of this genetic alteration is variable, depending on the study, the sensitivity of the detection methods, and geographic variability:
      • Estimates range from 20% to 50%
  • RET / PTC3 was the most prevalent mutation among children exposed to radiation after the Chernobyl accident
  • The clinical implications of a RET / PTC rearrangement in a tumor are unclear:
    • There is evidence that a favorable prognosis may be found in the presence of this mutation in some cases, whereas others have found no association with patient outcomes
  • The RAS mutation may be found in:
    • PTC, FTCs, and follicular adenomas (FAs) with unclear prognostic implications
  • The PAX8 / PPARγ fusion oncogene is found in about:
    • 36% of FTC
    • 11% of FAs
    • 13% of FVPTC
    • 2% of Hürthle cell carcinomas
    • It has not been described in classic PTC
  • The presence of this molecular marker in follicular adenoma, a benign tumor:
    • Raises the question the role of PAX8 / PPARγ in tumor develpment
    • The usefulness of this mutation as a predictor of clinical outcomes is also disputed:
      • One study found that tumors with PAX8 / PPARγ rearrangement are more likely to have multifocal capsular and vascular invasion:
        • Whereas others have not been able to reproduce these findings
• In addition to the traditional histopathologic risk factors:
  • Specific molecular profiles (eg, BRAF, telomerase reverse transcriptase [TERT]) may be used to predict risk of:
    • Extrathyroidal extension
    • Lymph node metastases
    • Even distant metastases
• While these observations need further validation, it is likely that the specific molecular profile of the primary tumor:
  • May have significant prognostic value that could be incorporated into stratification systems
• In a cohort of low-risk patients with intrathyroidal papillary thyroid cancer (less than 4 cm, N0, M0; 33% with BRAF mutation):
  • The overall risk of having structural disease recurrence:
    • Over five years of follow-up was:
      • 3%
  • However, BRAF V600E mutated tumors had a recurrence rate of:
    • 8% (8 of 106) compared with only 1% (2 of 213) in BRAF-negative tumors
  • Furthermore, in multivariate analysis:
    • The only clinicopathologically significant predictor of persistent disease after five years of follow-up:
      • Was the presence of mutated BRAF V600E
• TERT mutations have been described in:
  • 7% to 22% of papillary thyroid cancers
  • 14% to 17% of follicular thyroid cancers
• TERT mutations are associated with a:
  • Significantly higher prevalence of aggressive thyroid cancer
• In the largest reported series (332 papillary and 70 follicular thyroid cancers followed on average for eight years):
  • TERT mutation was an independent predictor of persistent disease (odds ratio [OR] 4.68, 95% CI 1.54-14.27) and mortality (hazard ratio [HR] 10.35, 95% CI 2.01-53.24):
    • For well-differentiated thyroid cancer
• Expression of vascular endothelial growth factor (VEGF, a potent stimulator of endothelial cell proliferation) in thyroid cancer specimens:
  • May help predict the presence of metastases:
    • As an example, in a retrospective study of 19 patients with papillary thyroid cancer:
      • A high level of immunostaining for VEGF correlated with:
        • A high risk of metastatic disease
    • In a second report, elevated preoperative serum VEGF-C concentrations:
      • Were an independent risk factor for nodal metastases and advanced tumor stages
• A broader genetic analysis may provide more accurate tumor prognostication:
  • Specifically, a growing body of data suggest that a more aggressive clinical course can be expected in tumors that carry:
    • BRAF V600E in combination with other driver oncogenic mutations such as:
      • PIK3CA
      • TP53
      • AKT1
      • RET / PTC mutation
    • TERT mutations:
      • Isolated or
      • In combination with BRAF
    • TP53 mutations
• These results, although pending confirmation in other studies:
  • Suggest that specific molecular profiles may eventually prove to be a useful adjunct to risk stratification
• Whether the presence of BRAF independently predicts mortality is uncertain:
  • Although in a retrospective analysis, the presence of a BRAF V600E mutation was associated with thyroid cancer mortality:
    • Overall mortality 5.3% versus 1.1% in BRAF V600E-positive versus mutation-negative patients):
      • The association was no longer significant after adjusting for clinical and histopathologic features, including:
        • Lymph node metastases
        • Extrathyroidal invasion
        • Distant metastasis
  • However, BRAF V600E mutation does appear to have a significant interaction with important clinicopathologic risk factors:
    • As the risk of mortality was higher in BRAF mutated versus BRAF wild-type tumors:
      • In the setting of lymph node metastases, distant metastases, and age greater than 45 years at diagnosis

• Distant metastases:
  • Although distant metastases are uncommon in PTC:
    • They are present in approximately 5% of patients at the time of initial presentation:
      • And another 2.5% to 5% will develop distant metastases after initial therapy
  • The most common sites of involvement are:
    • Lung (50%)
    • Bone (25%)
    • Followed by both lung and bone (20%)
    • Other tumor sites (5%):
      • Liver
      • Adrenal
      • Brain
  • The presence of distant metastases portends a poor prognosis:
    • 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
    • Patients with iodine-avid tumors
  • In addition, the ability to achieve a negative posttreatment diagnostic whole-body radioiodine scan (RxWBS) after radioiodine therapy:
    • Was associated with a 92% overall 10-year survival rate:
      • As compared with a 19% rate for patients who did not have a negative RxWBS
  • Additional prognostic information about distant metastases may be gained by performing FDG-PET/CT scanning:
    • One study found an inverse relationship between survival and degree of FDG-PET avidity of the most active lesion as well as the number of FDG-PET avid lesions
    • Patients with a positive FDG-PET scan had a 7.28-fold increased risk of dying from thyroid cancer as compared with patients who had a negative scan
  • The rate of survival in patients with distant metastases is variable:
    • Depending upon the site of metastases
  • Among patients with small pulmonary metastases but no other metastases outside of the neck:
    • The 10-year survival rate is:
      • 30% to 50%
    • Even higher survival rates have been reported in patients whose pulmonary metastases:
      • Were detected only by radioiodine imaging
  • Conversely, the median survival of patients with brain metastases:
    • Is only approximately one year
  • In multivariate analysis:
    • Fluorodeoxyglucose (FDG) positivity was the most powerful predictor of death in a large cohort of patients with metastatic disease:
      • Patients with large-volume, intense FDG uptake had a three-year, disease-specific survival:
        • Less than 50% from the time of the positron emission tomography (PET) scan
        • This may be due in part to lower radioiodine avidity in papillary thyroid cancers demonstrating a high FDG uptake

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