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Prognostic factors in papillary thyroid carcinoma and implications of large nodal metastasis
Prognostic factors in papillary thyroid carcinoma and implications of large nodal metastasis Ashok R. Shaha, MD, New York, NY
From the Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, NY
SUGITANI ET AL1 HAVE PRESENTED AN EXPERIENCE of 604 patients who underwent definitive surgery for papillary thyroid carcinoma. The authors have excluded microcarcinoma and tumors less than 1 cm in size. The information provided in this manuscript is quite interesting that in younger patients, the most important risk factor was the presence of distant metastasis, whereas in patients older than age 50, the important prognostic factors included distant metastasis (risk ratio 6.7), extrathyroidal invasion (risk ratio 2.4), and large nodal metastasis (more than 3 cm, risk ratio 5.3). They have divided their patients into 106 patients at high risk (17%) and 498 at low risk (83%). The 10-year survival rate was 69% in the high-risk group and 99% in the low-risk group. Interestingly, only 3 patients in the low-risk group died; 2 of whom had poorly differentiated thyroid carcinoma. The authors have also concluded that among postoperative factors, recurrence within the first 3 years after initial surgery was the most important risk factor for cancer-related death. In the high-risk group, the patients who were disease-free for more than 3 years showed an excellent outcome with a 96% 10-year survival rate, almost similar to the low-risk group. Sugitani et al1 provide important information and a step ahead of previous understanding of the prognostic factors in papillary carcinoma of the thyroid.2-8 Understanding the biology of thyroid cancer has improved considerably over the last 2 decades with the clinical definition of prognostic factors and risk group analysis. Several publications Accepted for publication August 28, 2003. Reprint requests: Ashok R. Shaha, MD, Memorial SloanKettering Cancer Center, 1275 York Ave, New York, NY 10021. Surgery 2004;135:237-9. 0039-6060/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.surg.2003.08.023
in the literature, from major institutions, have defined the risk groups on the basis of retrospective clinical review. The most important prognostic factors include age, grade of the tumor, extrathyroidal extension, presence or absence of distant metastasis, size of the tumor, and sex of the patient. Interestingly, most of the studies have concluded that lymph node metastases have no prognostic bearing in papillary thyroid cancer. There is clearly a very high incidence of clinical and microscopic incidence of lymph node metastases in papillary thyroid cancer, especially in young individuals. Most of these patients do remarkably well because of their age, being younger than 45, rather than presence or absence of lymph node metastasis. Elective lymph node dissection is not advised in papillary thyroid carcinoma. However, more than 50% of the patients do present with clinically apparent lymph node metastasis that will generally require a modified neck dissection. The old ‘‘berry-picking’’ operation has essentially been abandoned because of the high incidence of regional recurrence requiring multiple surgical procedures. Hughes et al9 did a comparative, matched-pair analysis and concluded that the presence of lymph node metastasis in patients over age 45 had some impact on the overall prognosis. Interestingly, the authors in this article in Surgery have looked at large lymph node metastasis suggesting a high incidence of locoregional recurrence and distant metastasis. This information is important with regard to the addition of adjuvant therapy. Most such patients will benefit from radioactive iodine ablation, because there may be subclinical metastatic disease to the lungs, which can be controlled more easily with radioactive iodine ablation than can macroscopic disease in the lungs. Among all prognostic factors the presence of extrathyroidal extension and invasion of the surrounding structures is considered to be most SURGERY 237
238 Shaha
important from a surgical standpoint during initial operative procedure. If the recurrent laryngeal nerve is paralyzed before operation with extrathyroidal invasion of the tumor, an adequate, aggressive surgical procedure is essential to remove all gross tumors. The chances of local recurrence are extremely high if the entire gross tumor is not removed. However, the authors have considered extrathyroidal invasion involving only the recurrent laryngeal nerve, trachea, or esophagus. However, the surrounding soft tissues and strap muscles may also harbor extrathyroidal invasion with high incidence of local recurrence. For younger patients, the presence of 5 or more lymph node metastases was an important prognostic factor for recurrence; whereas in older patients, the presence of lymph node metastases greater than 3 cm in size was an important prognostic factor. On the basis of this information the authors have developed a novel classification system for patients with papillary thyroid carcinoma. They have defined the highrisk group as patients of any age with distant metastasis, patients 50 years or older with 3 cm or larger nodal metastasis, or extrathyroidal extension as the high-risk group. All other patients were classified in the low-risk group. The 10-year diseasespecific survival rate in the low-risk group was 99%, whereas in the high-risk group it was 69%. The similar risk group definitions have been reported from the Mayo Clinic,3,4 Lahey Clinic,2 and Memorial Sloan-Kettering Cancer Center,5,8 where the survival rate in the low-risk group exceeds 99%. The authors have reported 3 deaths in the low-risk group. Interestingly, 2 of these patients were 69 and 72 years old. Generally, these patients would be considered as an intermediate-risk group in Memorial Sloan-Kettering Cancer Center’s definition of risk group analysis.8 Two of these patients had poorly differentiated components of thyroid carcinoma and anaplastic transformation in the end. Clearly, these patients are not at low risk, and we would strongly use grade and differentiation of the tumor as an additional important prognostic factor and place these patients in the high-risk group. The authors reviewed their high-risk group in a more critical fashion in relation to the followup period; recurrence within the first 3 years after surgery proved to be an important predicting factor in relation to disease-specific death of patients in the high-risk group. The high-risk group of patients with distant metastases at the time of initial surgery had a 10-year, disease-specific survival rate of 33%; whereas patients in the high-risk group without distant metastasis but with recurrence within the first 3 years had a 10-year survival rate of 48%.
Surgery February 2004
However, in the high-risk group, patients with neither distant metastasis nor recurrence within 3 years after primary surgery showed an excellent, 10-year disease-specific survival rate of 96%. The authors have used the philosophy of thyroid lobectomy if the tumor was macroscopically localized in one lobe. Multifocality of the papillary thyroid cancer had no prognostic implication in their study, and the development of recurrent thyroid cancer in the remnant thyroid lobe was considerably less than the reports in the literature. The authors believe that larger lymph node deposits have a definite adverse influence on prognosis because of the large size of the lymph node metastases concurrent with extranodal invasion and hematogenous metastasis. The authors reported 15 distant metastases in 60 patients with large nodal metastasis at presentation and another 6 patients had developed distant metastasis during the follow-up. Although 12 patients in this group of 60 died of distant metastasis, the patients with large nodal metastases showed an increasing incidence of local recurrence in the neck with involvement of the surrounding soft tissues of the neck, including the carotid artery. These patients underwent pathologic dedifferentiation from well-differentiated papillary thyroid carcinoma to poorly or undifferentiated carcinoma along with nodal recurrences. The authors also tried to separate tumor adhesion from tumor invasion. Tumors that were ‘‘adherent’’ to the surrounding structures could be easily shaved off with good locoregional control; however, in the 69 patients grouped as the ‘‘invasion’’ group, 16% died of papillary thyroid carcinoma. In addition, extrathyroidal invasion was a prognostic factor predicting disease-specific death in the older patient group. Shaha et al5,8 grouped patients with thyroid cancer into a low-risk group in whom the tumor presents in patients younger than age 45 with a tumor less than 4 cm and good histologic category; the high-risk group included patients over age 45 with larger tumors and extrathyroidal extension or less well-differentiated histologic variety. They also identified a separate intermediate-risk group in whom an aggressive tumor may be seen in younger patients or a good tumor may be seen in older patients. There were survival differences among low-, intermediate-, and high-risk groups of 99%, 87%, and 57%, respectively. The information provided by the authors and the data from Memorial SloanKettering Cancer Center help identify patients at good risk and poor risk for thyroid cancer where the critical decisions may be made for adjuvant
Shaha 239
Surgery Volume 135, Number 2
therapy. The authors have shown a high incidence of distant metastases, and local and regional recurrence in patients with nodal metastasis of more than 3 cm or more than 5 lymph node metastases. Clearly, these patients will be benefited with adjuvant radioactive iodine ablation. Thyroglobulin continues to be an important prognostic marker in patients who have undergone total thyroidectomy and ablation of the residual thyroid tissue. With recent advances in management of thyroid cancer with recombinant thyroid-stimulating hormone, the radioactive iodine dosimetry can be performed without making individuals hypothyroid, clearly a major advance in the follow-up of patients with thyroid cancer. This is an interesting manuscript with a more critical analysis of existing prognostic factors and definition of the low- and high-risk group patients. It is essential to define patients with thyroid cancer into risk groups depending on their prognostic factors and understanding the biology of the thyroid cancer. The Mayo Clinic recently defined their prognostic factors as metastasis, age, completeness of resection, invasion, and size (MACIS), where completeness of resection of tumor was an important prognostic factor.4 Clearly this is an important prognostic factor in patients with extrathyroidal invasion where every attempt should be made to remove all gross tumor to avoid local recurrence in the thyroid bed. The presence of local recurrence in the thyroid bed is a very difficult problem, because the tumor may involve vital structures or may recur in critical areas where all gross tumor may not be able to be removed. Even though there are a large number of papers in the literature on prognostic factors of thyroid cancer,
the authors have defined a new outlook toward the low- and high-risk groups of patients with papillary thyroid cancer.
REFERENCES 1. Sugitani, I Kasai N, Fujimoto Y, Yanagisawa A. A novel classification system for patients with PTC: addition of the new variables of large (3 cm or greater) nodal metastases and reclassification during the follow-up period. Surgery 2004;135:139-48. 2. Cady B, Rossi R. An expanded view of risk group definition in differentiated thyroid carcinoma. Surgery 1988;104: 947-53. 3. Hay ID, Grant CS, Taylor WF, McConahey WM. Ipsilateral lobectomy versus bilateral lober resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic score system. Surgery 1987;102:1088-95. 4. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114:1050-8. 5. Shaha AR, Shah JP, Loree TR. Risk group stratification and prognostic factors in papillary carcinoma of thyroid. Ann Surg Oncol 1996;3:534-8. 6. Pasieka JL, Zedenius J, Auer G, Grimelius L, Hoog A, Lundell G, et al. Addition of nuclear DNA content to the AMES risk-group classification for papillary thyroid cancer. Surgery 1992;112:1154-60. 7. Shaha AR, Shah JP, Loree TR. Low-risk differentiated thyroid cancer. The need for selective treatment. Ann Surg Oncol 1997;4:328-33. 8. Shaha AR, Loree TR, Shah JP. Intermediate risk group for differentiated carcinoma of thyroid. Surgery 1994;116: 1036-41. 9. Hughes CJ, Shaha AR, Shah JP, Loree TR. Impact of lymph node metastasis in differentiated carcinoma of the thyroid—a matched pair analysis. Head Neck 1996;18: 127-32.
From the Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, NY
SUGITANI ET AL1 HAVE PRESENTED AN EXPERIENCE of 604 patients who underwent definitive surgery for papillary thyroid carcinoma. The authors have excluded microcarcinoma and tumors less than 1 cm in size. The information provided in this manuscript is quite interesting that in younger patients, the most important risk factor was the presence of distant metastasis, whereas in patients older than age 50, the important prognostic factors included distant metastasis (risk ratio 6.7), extrathyroidal invasion (risk ratio 2.4), and large nodal metastasis (more than 3 cm, risk ratio 5.3). They have divided their patients into 106 patients at high risk (17%) and 498 at low risk (83%). The 10-year survival rate was 69% in the high-risk group and 99% in the low-risk group. Interestingly, only 3 patients in the low-risk group died; 2 of whom had poorly differentiated thyroid carcinoma. The authors have also concluded that among postoperative factors, recurrence within the first 3 years after initial surgery was the most important risk factor for cancer-related death. In the high-risk group, the patients who were disease-free for more than 3 years showed an excellent outcome with a 96% 10-year survival rate, almost similar to the low-risk group. Sugitani et al1 provide important information and a step ahead of previous understanding of the prognostic factors in papillary carcinoma of the thyroid.2-8 Understanding the biology of thyroid cancer has improved considerably over the last 2 decades with the clinical definition of prognostic factors and risk group analysis. Several publications Accepted for publication August 28, 2003. Reprint requests: Ashok R. Shaha, MD, Memorial SloanKettering Cancer Center, 1275 York Ave, New York, NY 10021. Surgery 2004;135:237-9. 0039-6060/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.surg.2003.08.023
in the literature, from major institutions, have defined the risk groups on the basis of retrospective clinical review. The most important prognostic factors include age, grade of the tumor, extrathyroidal extension, presence or absence of distant metastasis, size of the tumor, and sex of the patient. Interestingly, most of the studies have concluded that lymph node metastases have no prognostic bearing in papillary thyroid cancer. There is clearly a very high incidence of clinical and microscopic incidence of lymph node metastases in papillary thyroid cancer, especially in young individuals. Most of these patients do remarkably well because of their age, being younger than 45, rather than presence or absence of lymph node metastasis. Elective lymph node dissection is not advised in papillary thyroid carcinoma. However, more than 50% of the patients do present with clinically apparent lymph node metastasis that will generally require a modified neck dissection. The old ‘‘berry-picking’’ operation has essentially been abandoned because of the high incidence of regional recurrence requiring multiple surgical procedures. Hughes et al9 did a comparative, matched-pair analysis and concluded that the presence of lymph node metastasis in patients over age 45 had some impact on the overall prognosis. Interestingly, the authors in this article in Surgery have looked at large lymph node metastasis suggesting a high incidence of locoregional recurrence and distant metastasis. This information is important with regard to the addition of adjuvant therapy. Most such patients will benefit from radioactive iodine ablation, because there may be subclinical metastatic disease to the lungs, which can be controlled more easily with radioactive iodine ablation than can macroscopic disease in the lungs. Among all prognostic factors the presence of extrathyroidal extension and invasion of the surrounding structures is considered to be most SURGERY 237
238 Shaha
important from a surgical standpoint during initial operative procedure. If the recurrent laryngeal nerve is paralyzed before operation with extrathyroidal invasion of the tumor, an adequate, aggressive surgical procedure is essential to remove all gross tumors. The chances of local recurrence are extremely high if the entire gross tumor is not removed. However, the authors have considered extrathyroidal invasion involving only the recurrent laryngeal nerve, trachea, or esophagus. However, the surrounding soft tissues and strap muscles may also harbor extrathyroidal invasion with high incidence of local recurrence. For younger patients, the presence of 5 or more lymph node metastases was an important prognostic factor for recurrence; whereas in older patients, the presence of lymph node metastases greater than 3 cm in size was an important prognostic factor. On the basis of this information the authors have developed a novel classification system for patients with papillary thyroid carcinoma. They have defined the highrisk group as patients of any age with distant metastasis, patients 50 years or older with 3 cm or larger nodal metastasis, or extrathyroidal extension as the high-risk group. All other patients were classified in the low-risk group. The 10-year diseasespecific survival rate in the low-risk group was 99%, whereas in the high-risk group it was 69%. The similar risk group definitions have been reported from the Mayo Clinic,3,4 Lahey Clinic,2 and Memorial Sloan-Kettering Cancer Center,5,8 where the survival rate in the low-risk group exceeds 99%. The authors have reported 3 deaths in the low-risk group. Interestingly, 2 of these patients were 69 and 72 years old. Generally, these patients would be considered as an intermediate-risk group in Memorial Sloan-Kettering Cancer Center’s definition of risk group analysis.8 Two of these patients had poorly differentiated components of thyroid carcinoma and anaplastic transformation in the end. Clearly, these patients are not at low risk, and we would strongly use grade and differentiation of the tumor as an additional important prognostic factor and place these patients in the high-risk group. The authors reviewed their high-risk group in a more critical fashion in relation to the followup period; recurrence within the first 3 years after surgery proved to be an important predicting factor in relation to disease-specific death of patients in the high-risk group. The high-risk group of patients with distant metastases at the time of initial surgery had a 10-year, disease-specific survival rate of 33%; whereas patients in the high-risk group without distant metastasis but with recurrence within the first 3 years had a 10-year survival rate of 48%.
Surgery February 2004
However, in the high-risk group, patients with neither distant metastasis nor recurrence within 3 years after primary surgery showed an excellent, 10-year disease-specific survival rate of 96%. The authors have used the philosophy of thyroid lobectomy if the tumor was macroscopically localized in one lobe. Multifocality of the papillary thyroid cancer had no prognostic implication in their study, and the development of recurrent thyroid cancer in the remnant thyroid lobe was considerably less than the reports in the literature. The authors believe that larger lymph node deposits have a definite adverse influence on prognosis because of the large size of the lymph node metastases concurrent with extranodal invasion and hematogenous metastasis. The authors reported 15 distant metastases in 60 patients with large nodal metastasis at presentation and another 6 patients had developed distant metastasis during the follow-up. Although 12 patients in this group of 60 died of distant metastasis, the patients with large nodal metastases showed an increasing incidence of local recurrence in the neck with involvement of the surrounding soft tissues of the neck, including the carotid artery. These patients underwent pathologic dedifferentiation from well-differentiated papillary thyroid carcinoma to poorly or undifferentiated carcinoma along with nodal recurrences. The authors also tried to separate tumor adhesion from tumor invasion. Tumors that were ‘‘adherent’’ to the surrounding structures could be easily shaved off with good locoregional control; however, in the 69 patients grouped as the ‘‘invasion’’ group, 16% died of papillary thyroid carcinoma. In addition, extrathyroidal invasion was a prognostic factor predicting disease-specific death in the older patient group. Shaha et al5,8 grouped patients with thyroid cancer into a low-risk group in whom the tumor presents in patients younger than age 45 with a tumor less than 4 cm and good histologic category; the high-risk group included patients over age 45 with larger tumors and extrathyroidal extension or less well-differentiated histologic variety. They also identified a separate intermediate-risk group in whom an aggressive tumor may be seen in younger patients or a good tumor may be seen in older patients. There were survival differences among low-, intermediate-, and high-risk groups of 99%, 87%, and 57%, respectively. The information provided by the authors and the data from Memorial SloanKettering Cancer Center help identify patients at good risk and poor risk for thyroid cancer where the critical decisions may be made for adjuvant
Shaha 239
Surgery Volume 135, Number 2
therapy. The authors have shown a high incidence of distant metastases, and local and regional recurrence in patients with nodal metastasis of more than 3 cm or more than 5 lymph node metastases. Clearly, these patients will be benefited with adjuvant radioactive iodine ablation. Thyroglobulin continues to be an important prognostic marker in patients who have undergone total thyroidectomy and ablation of the residual thyroid tissue. With recent advances in management of thyroid cancer with recombinant thyroid-stimulating hormone, the radioactive iodine dosimetry can be performed without making individuals hypothyroid, clearly a major advance in the follow-up of patients with thyroid cancer. This is an interesting manuscript with a more critical analysis of existing prognostic factors and definition of the low- and high-risk group patients. It is essential to define patients with thyroid cancer into risk groups depending on their prognostic factors and understanding the biology of the thyroid cancer. The Mayo Clinic recently defined their prognostic factors as metastasis, age, completeness of resection, invasion, and size (MACIS), where completeness of resection of tumor was an important prognostic factor.4 Clearly this is an important prognostic factor in patients with extrathyroidal invasion where every attempt should be made to remove all gross tumor to avoid local recurrence in the thyroid bed. The presence of local recurrence in the thyroid bed is a very difficult problem, because the tumor may involve vital structures or may recur in critical areas where all gross tumor may not be able to be removed. Even though there are a large number of papers in the literature on prognostic factors of thyroid cancer,
the authors have defined a new outlook toward the low- and high-risk groups of patients with papillary thyroid cancer.
REFERENCES 1. Sugitani, I Kasai N, Fujimoto Y, Yanagisawa A. A novel classification system for patients with PTC: addition of the new variables of large (3 cm or greater) nodal metastases and reclassification during the follow-up period. Surgery 2004;135:139-48. 2. Cady B, Rossi R. An expanded view of risk group definition in differentiated thyroid carcinoma. Surgery 1988;104: 947-53. 3. Hay ID, Grant CS, Taylor WF, McConahey WM. Ipsilateral lobectomy versus bilateral lober resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic score system. Surgery 1987;102:1088-95. 4. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114:1050-8. 5. Shaha AR, Shah JP, Loree TR. Risk group stratification and prognostic factors in papillary carcinoma of thyroid. Ann Surg Oncol 1996;3:534-8. 6. Pasieka JL, Zedenius J, Auer G, Grimelius L, Hoog A, Lundell G, et al. Addition of nuclear DNA content to the AMES risk-group classification for papillary thyroid cancer. Surgery 1992;112:1154-60. 7. Shaha AR, Shah JP, Loree TR. Low-risk differentiated thyroid cancer. The need for selective treatment. Ann Surg Oncol 1997;4:328-33. 8. Shaha AR, Loree TR, Shah JP. Intermediate risk group for differentiated carcinoma of thyroid. Surgery 1994;116: 1036-41. 9. Hughes CJ, Shaha AR, Shah JP, Loree TR. Impact of lymph node metastasis in differentiated carcinoma of the thyroid—a matched pair analysis. Head Neck 1996;18: 127-32.