M a n a g e m e n t o f R e c u r re n t C e r v i c a l P a p i l l a r y T h y ro i d Cancer Rachna M. Goyal, MDa,b,*, Jacqueline Jonklaas, Kenneth D. Burman, MDa
b MD, PhD ,
KEYWORDS Papillary thyroid cancer Cervical lymph nodes Ethanol injection Radioactive iodine Cervical re-operation KEY POINTS Thyroid cancer is the most common endocrine malignancy, and its incidence and prevalence are on the rise. Papillary thyroid cancer has been shown to metastasize and recur in the locoregional lymph nodes of the neck. Options for treatment of recurrent cervical papillary thyroid cancer include observation, surgery, radioactive iodine ablation, or percutaneous ethanol injection.
INTRODUCTION
Thyroid cancer is the most common endocrine malignancy, and its incidence and prevalence are on the rise. According to the American Cancer Society, the projected incidence of thyroid cancer for 2013 was 60,220 new cases (45,310 in women and 14,910 in men), with 1850 deaths from thyroid cancer (1040 women and 810 men).1 Fortunately, most of these patients achieve good disease-specific outcomes if treated appropriately at the time of diagnosis. However, up to 30% of patients experience persistent disease or recurrences, often limited to cervical lymph nodes.2 The management of these recurrent lymph nodes remains controversial, and the current guidelines do not clearly outline the best options. The existing literature consists of retrospective studies with small sample sizes; no prospective, large randomized trials are available that delineate the various treatment modalities. Currently, there are several approaches to patients with recurrent papillary thyroid cancer (PTC) in their cervical lymph nodes, including observation, radioactive iodine therapy, ethanol a Division of Endocrinology, Washington Hospital Center, 110 Irving Street Northwest, Washington, DC 20010, USA; b Division of Endocrinology, Georgetown University Hospital, 4000 Reservoir Road Northwest, Building D Room 232, Washington, DC 20007, USA * Corresponding author. Division of Endocrinology, Washington Hospital Center, 110 Irving Street Northwest, Washington, DC 20010. E-mail address: [email protected]
Endocrinol Metab Clin N Am 43 (2014) 565–572 http://dx.doi.org/10.1016/j.ecl.2014.02.014 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
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Goyal et al
injection, and surgery. The management approach should be a joint decision between the health care team and the patient. BACKGROUND
The incidence of well-differentiated thyroid cancer continues to rise; in particular, the mortality rate of older men with differentiated thyroid cancer is increasing at an alarming rate. There are several risk factors associated with PTC. These include female gender (3 times more common in women), previous exposure to ionizing radiation, and rare hereditary conditions (eg, Cowden syndrome). Approximately 5% of patients with PTC will have familial PTC; the exact genetic cause has not yet been determined. Although mortality from thyroid cancer is low, the recurrence rate is 25% to 35%, making risk stratification a priority. Prognostic factors such as age less than 15 years or greater than or equal to 45 years, male gender, tumor size greater than 4 cm, follicular histology or tall and columnar cell variants, multifocality, initial local tumor invasion, and regional lymph node metastasis are associated with increased risk of recurrence.3 Prediction of nodal metastases can also be determined based on several of the previously mentioned features, and additionally the genotype – BRAF-positive tumors are associated with higher rates of metastases, and therefore should not be solely observed but treated with more aggressive options.4 Several risk factors for recurrence also include older age, follicular variant PTC, cervical lymph node involvement, T4 tumors, and stage greater than 4A.5 Often, it may be difficult to distinguish between persistent and recurrent disease, and many of the patients thought to have recurrences may actually have had residual microscopic disease. According to the American Thyroid Association (ATA) revised guidelines on the management and treatment of differentiated thyroid cancer from 2009, the initial surgical option for those with a tumor size of greater than 1 cm, is a near-total or total thyroidectomy. Thyroid lobectomy should be reserved for those with low-risk disease, micropapillary carcinoma, unifocality, absence of lymph nodes, and no personal history of head and neck irradiation. All patients with fine-needle aspiration proven differentiated thyroid cancer should be staged preoperatively and undergo a neck ultrasound with node mapping evaluating the contralateral lobe and lymph nodes for the presence of disease.6 In the presence of metastatic disease in the central or lateral neck, regional lymph node dissection is often indicated.7 However, performing prophylactic lymph node dissection at the time of thyroidectomy is controversial, and surgical expertise is warranted. However, it allows pathologic identification of metastases and leads to up-staging in patients over the age of 45. This can help guide further treatment options, including utility and dose of radioactive iodine.8 The thyroid gland has a rich lymphatic supply, allowing the possibility of thyroid cancer to spread to local lymph nodes in the central and lateral compartments of the neck. The lymph nodes of the neck are divided into 6 levels (Fig. 1). Level 1 is split into 2 sublevels: sublevel 1A (submental) and sublevel 2B (submandibular). Level 2 is upper jugular; level 3 is midjugular, and level 4 is lower jugular. Level 5 comprises the posterior triangle nodes including the supraclavicular nodes and spinal accessory nodes. The anterior compartment lymph nodes are located in level 6 and include the pretracheal and paratracheal lymph nodes, precricoid nodes, and perithyroidal lymph nodes. Neck ultrasound is the imaging modality of choice to monitor well-differentiated thyroid cancer after total thyroidectomy. Certain sonographic features can help determine whether a lymph node is malignant or normal. Worrisome features for the presence of thyroid cancer include shape (taller than wide), irregular margins, lack of an echogenic hilus, the presence of calcifications, and enhanced perinodularvascularity.9
Recurrent Cervical PTC
Fig. 1. Anatomic scheme of neck with lymph node compartments. (From Smith PW, Salomone LJ, Hanks JB. Thyroid. In: Sabiston DC, Townsend CM. Sabiston textbook of surgery: the biological basis of modern surgical practice. 19th edition. Philadelphia: Elsevier Saunders; 2012; with permission.)
Head and neck cancers tend to metastasize to specific lymph node clusters. Thyroid cancer in particular spreads to lymph nodes in the lower third of the neck in 67% of cases, the middle third in 20% of cases, and the superior third in13% of cases. This is in contrast to benign lymph nodes, which are more commonly seen the superior and middle thirds of the neck.10 Flat, oval-shaped lymph nodes are considered benign, whereas round lymph nodes are often concerning for malignancy.11 The type of border surrounding the lymph node and its correlation with cancer are somewhat controversial. In general, benign-appearing lymph nodes tend to have sharp borders, and cancerous nodes tend to have ill-defined borders on ultrasound.12 The hilum of a normal lymph node appears as an eccentric, echogenic intranodal structure that is continuous with the adjacent perinodal fat. In malignant lymph nodes, this hilum frequently becomes obliterated. Metastatic lymph nodes also exhibit peripheral vascular patterns, unlike benign lymph nodes.9 Cervical lymph node calcification is uncommonly found, but it can signify thyroid cancer infiltration.13 Although ultrasound is the imaging modality of choice of thyroid cancer, computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) can be useful in monitoring patients with thyroid cancer and for preoperative
567
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planning. These alternated imaging modalities may be useful in the assessment of large, rapidly growing, retrosternal, or invasive tumors to characterize the involvement of extrathyroidal.6 Fluorodeoxyglucose PET has been known to show metastases in 131 I scan-negative thyroid cancer patients with a high accuracy, which is thought to be related to increased glucose metabolism in poorly differentiated carcinoma.14 The preoperative use of PET remains controversial and has not been thoroughly evaluated. It can be useful in patients with a high tumor stage and less nodal disease than expected or in those with indeterminate nodes on CT or MRI.15 Before reviewing the management options for cervical recurrent well-differentiated thyroid cancer, several questions remain unanswered. How often do cervical lymph nodes grow and cause significant local disease? Do local cervical metastases lead to distant metastases? Does removal of these metastatic cervical lymph nodes improve morbidity and mortality? There are no controlled studies evaluating these questions, but the various treatment options will be discussed.16 SURGERY
The frequency of locoregional recurrence is anywhere from 5% to 20% in PTC, and more than one-third of reoperations for persistent or recurrent disease are related to insufficient initial thyroid surgery.17 If a recurrence is easily palpable or visualized on radiography, excision should be strongly considered, because even small lymph node metastases are commonly more extensive than would appear clinically or on imaging.18 In a study done by Travagli and colleagues in France, 54 patients with persistent or recurrent disease in the neck after surgery for thyroid cancer were enrolled to undergo a combination protocol of radioiodine and probe-guided surgery. Interestingly, in 14 patients, lymph node metastases were not initially visualized by the surgical probe or postoperative 131I whole-body scan, but were found upon histologic dissection. This argues for neck dissection for recurrent thyroid cancer as a means to detect hidden metastases. However, the clinical significance of these smaller metastases in long-term outcomes and prognosis remains controversial. Al-Saif and colleagues19 retrospectively analyzed 95 patients with a neck dissection for recurrent or persistent PTC in the cervical lymph nodes. This cohort of patients underwent lymphadenectomies, and complete biochemical remission was initially achieved in only 17% of the patients with an undetectable serum thyroglobulin level after 1 cervical neck dissection. After 2 or 3 reoperations, 27% achieved biochemical remission. In those patients who did not reach biochemical remission, there was a significant reduction in serum thyroglobulin levels after both the first and second reoperation, and none of the patients developed detectable distant metastases or died from PTC during a 60-month average follow-up. The efficacy of first reoperation was subsequently observed by Yim and colleagues,20 who noted that 51% of patients attained biochemical remission with a stimulated thyroglobulin level of less than 1 ng/mL. Those with stimulated thyroglobulin levels greater than 5 ng/mL after the first reoperation had a higher chance of clinical recurrence (the estimated 5-year clinical recurrence-free survival rate was 94 vs 74). Additionally, Clayman and colleagues21 reported that 71% of patients had an undetectable unstimulated thyroglobulin levels (4 cm). For low-risk patients (unifocal or multifocal tumor burden
b MD, PhD ,
KEYWORDS Papillary thyroid cancer Cervical lymph nodes Ethanol injection Radioactive iodine Cervical re-operation KEY POINTS Thyroid cancer is the most common endocrine malignancy, and its incidence and prevalence are on the rise. Papillary thyroid cancer has been shown to metastasize and recur in the locoregional lymph nodes of the neck. Options for treatment of recurrent cervical papillary thyroid cancer include observation, surgery, radioactive iodine ablation, or percutaneous ethanol injection.
INTRODUCTION
Thyroid cancer is the most common endocrine malignancy, and its incidence and prevalence are on the rise. According to the American Cancer Society, the projected incidence of thyroid cancer for 2013 was 60,220 new cases (45,310 in women and 14,910 in men), with 1850 deaths from thyroid cancer (1040 women and 810 men).1 Fortunately, most of these patients achieve good disease-specific outcomes if treated appropriately at the time of diagnosis. However, up to 30% of patients experience persistent disease or recurrences, often limited to cervical lymph nodes.2 The management of these recurrent lymph nodes remains controversial, and the current guidelines do not clearly outline the best options. The existing literature consists of retrospective studies with small sample sizes; no prospective, large randomized trials are available that delineate the various treatment modalities. Currently, there are several approaches to patients with recurrent papillary thyroid cancer (PTC) in their cervical lymph nodes, including observation, radioactive iodine therapy, ethanol a Division of Endocrinology, Washington Hospital Center, 110 Irving Street Northwest, Washington, DC 20010, USA; b Division of Endocrinology, Georgetown University Hospital, 4000 Reservoir Road Northwest, Building D Room 232, Washington, DC 20007, USA * Corresponding author. Division of Endocrinology, Washington Hospital Center, 110 Irving Street Northwest, Washington, DC 20010. E-mail address: [email protected]
Endocrinol Metab Clin N Am 43 (2014) 565–572 http://dx.doi.org/10.1016/j.ecl.2014.02.014 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
566
Goyal et al
injection, and surgery. The management approach should be a joint decision between the health care team and the patient. BACKGROUND
The incidence of well-differentiated thyroid cancer continues to rise; in particular, the mortality rate of older men with differentiated thyroid cancer is increasing at an alarming rate. There are several risk factors associated with PTC. These include female gender (3 times more common in women), previous exposure to ionizing radiation, and rare hereditary conditions (eg, Cowden syndrome). Approximately 5% of patients with PTC will have familial PTC; the exact genetic cause has not yet been determined. Although mortality from thyroid cancer is low, the recurrence rate is 25% to 35%, making risk stratification a priority. Prognostic factors such as age less than 15 years or greater than or equal to 45 years, male gender, tumor size greater than 4 cm, follicular histology or tall and columnar cell variants, multifocality, initial local tumor invasion, and regional lymph node metastasis are associated with increased risk of recurrence.3 Prediction of nodal metastases can also be determined based on several of the previously mentioned features, and additionally the genotype – BRAF-positive tumors are associated with higher rates of metastases, and therefore should not be solely observed but treated with more aggressive options.4 Several risk factors for recurrence also include older age, follicular variant PTC, cervical lymph node involvement, T4 tumors, and stage greater than 4A.5 Often, it may be difficult to distinguish between persistent and recurrent disease, and many of the patients thought to have recurrences may actually have had residual microscopic disease. According to the American Thyroid Association (ATA) revised guidelines on the management and treatment of differentiated thyroid cancer from 2009, the initial surgical option for those with a tumor size of greater than 1 cm, is a near-total or total thyroidectomy. Thyroid lobectomy should be reserved for those with low-risk disease, micropapillary carcinoma, unifocality, absence of lymph nodes, and no personal history of head and neck irradiation. All patients with fine-needle aspiration proven differentiated thyroid cancer should be staged preoperatively and undergo a neck ultrasound with node mapping evaluating the contralateral lobe and lymph nodes for the presence of disease.6 In the presence of metastatic disease in the central or lateral neck, regional lymph node dissection is often indicated.7 However, performing prophylactic lymph node dissection at the time of thyroidectomy is controversial, and surgical expertise is warranted. However, it allows pathologic identification of metastases and leads to up-staging in patients over the age of 45. This can help guide further treatment options, including utility and dose of radioactive iodine.8 The thyroid gland has a rich lymphatic supply, allowing the possibility of thyroid cancer to spread to local lymph nodes in the central and lateral compartments of the neck. The lymph nodes of the neck are divided into 6 levels (Fig. 1). Level 1 is split into 2 sublevels: sublevel 1A (submental) and sublevel 2B (submandibular). Level 2 is upper jugular; level 3 is midjugular, and level 4 is lower jugular. Level 5 comprises the posterior triangle nodes including the supraclavicular nodes and spinal accessory nodes. The anterior compartment lymph nodes are located in level 6 and include the pretracheal and paratracheal lymph nodes, precricoid nodes, and perithyroidal lymph nodes. Neck ultrasound is the imaging modality of choice to monitor well-differentiated thyroid cancer after total thyroidectomy. Certain sonographic features can help determine whether a lymph node is malignant or normal. Worrisome features for the presence of thyroid cancer include shape (taller than wide), irregular margins, lack of an echogenic hilus, the presence of calcifications, and enhanced perinodularvascularity.9
Recurrent Cervical PTC
Fig. 1. Anatomic scheme of neck with lymph node compartments. (From Smith PW, Salomone LJ, Hanks JB. Thyroid. In: Sabiston DC, Townsend CM. Sabiston textbook of surgery: the biological basis of modern surgical practice. 19th edition. Philadelphia: Elsevier Saunders; 2012; with permission.)
Head and neck cancers tend to metastasize to specific lymph node clusters. Thyroid cancer in particular spreads to lymph nodes in the lower third of the neck in 67% of cases, the middle third in 20% of cases, and the superior third in13% of cases. This is in contrast to benign lymph nodes, which are more commonly seen the superior and middle thirds of the neck.10 Flat, oval-shaped lymph nodes are considered benign, whereas round lymph nodes are often concerning for malignancy.11 The type of border surrounding the lymph node and its correlation with cancer are somewhat controversial. In general, benign-appearing lymph nodes tend to have sharp borders, and cancerous nodes tend to have ill-defined borders on ultrasound.12 The hilum of a normal lymph node appears as an eccentric, echogenic intranodal structure that is continuous with the adjacent perinodal fat. In malignant lymph nodes, this hilum frequently becomes obliterated. Metastatic lymph nodes also exhibit peripheral vascular patterns, unlike benign lymph nodes.9 Cervical lymph node calcification is uncommonly found, but it can signify thyroid cancer infiltration.13 Although ultrasound is the imaging modality of choice of thyroid cancer, computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) can be useful in monitoring patients with thyroid cancer and for preoperative
567
568
Goyal et al
planning. These alternated imaging modalities may be useful in the assessment of large, rapidly growing, retrosternal, or invasive tumors to characterize the involvement of extrathyroidal.6 Fluorodeoxyglucose PET has been known to show metastases in 131 I scan-negative thyroid cancer patients with a high accuracy, which is thought to be related to increased glucose metabolism in poorly differentiated carcinoma.14 The preoperative use of PET remains controversial and has not been thoroughly evaluated. It can be useful in patients with a high tumor stage and less nodal disease than expected or in those with indeterminate nodes on CT or MRI.15 Before reviewing the management options for cervical recurrent well-differentiated thyroid cancer, several questions remain unanswered. How often do cervical lymph nodes grow and cause significant local disease? Do local cervical metastases lead to distant metastases? Does removal of these metastatic cervical lymph nodes improve morbidity and mortality? There are no controlled studies evaluating these questions, but the various treatment options will be discussed.16 SURGERY
The frequency of locoregional recurrence is anywhere from 5% to 20% in PTC, and more than one-third of reoperations for persistent or recurrent disease are related to insufficient initial thyroid surgery.17 If a recurrence is easily palpable or visualized on radiography, excision should be strongly considered, because even small lymph node metastases are commonly more extensive than would appear clinically or on imaging.18 In a study done by Travagli and colleagues in France, 54 patients with persistent or recurrent disease in the neck after surgery for thyroid cancer were enrolled to undergo a combination protocol of radioiodine and probe-guided surgery. Interestingly, in 14 patients, lymph node metastases were not initially visualized by the surgical probe or postoperative 131I whole-body scan, but were found upon histologic dissection. This argues for neck dissection for recurrent thyroid cancer as a means to detect hidden metastases. However, the clinical significance of these smaller metastases in long-term outcomes and prognosis remains controversial. Al-Saif and colleagues19 retrospectively analyzed 95 patients with a neck dissection for recurrent or persistent PTC in the cervical lymph nodes. This cohort of patients underwent lymphadenectomies, and complete biochemical remission was initially achieved in only 17% of the patients with an undetectable serum thyroglobulin level after 1 cervical neck dissection. After 2 or 3 reoperations, 27% achieved biochemical remission. In those patients who did not reach biochemical remission, there was a significant reduction in serum thyroglobulin levels after both the first and second reoperation, and none of the patients developed detectable distant metastases or died from PTC during a 60-month average follow-up. The efficacy of first reoperation was subsequently observed by Yim and colleagues,20 who noted that 51% of patients attained biochemical remission with a stimulated thyroglobulin level of less than 1 ng/mL. Those with stimulated thyroglobulin levels greater than 5 ng/mL after the first reoperation had a higher chance of clinical recurrence (the estimated 5-year clinical recurrence-free survival rate was 94 vs 74). Additionally, Clayman and colleagues21 reported that 71% of patients had an undetectable unstimulated thyroglobulin levels (4 cm). For low-risk patients (unifocal or multifocal tumor burden
