Thyroid, Papillary Carcinoma, Early Treatment & Management

Updated: Apr 06, 2016
  • Author: Eric J Lentsch, MD; Chief Editor: Arlen D Meyers, MD, MBA  more...
  • Print
Treatment

Medical Therapy

Adjuvant therapy

Thyroid-stimulating hormone (TSH) suppression therapy using administration of thyroid hormone has been employed for many years; however, the recurrence and survival rates among TSH-suppressed and TSH-nonsuppressed postoperative patients with low-risk papillary thyroid carcinoma are similar. Most centers do not administer thyroid hormone to suppress TSH in euthyroid patients with low-risk papillary thyroid carcinoma. [31]

Iodine-131 can be used to ablate the remaining thyroid gland in patients with a near-total thyroidectomy and in high-risk patients with persistent disease. If uptake of iodine-131 is inadequate, external beam radiation can be used.

Research indicates that in patients with low-risk papillary thyroid cancer, lithium increases the efficacy of thyroid remnant ablation and may therefore be preferable to using higher doses of iodine-131. [32]

A study by Suman et al indicated that in patients with papillary thyroid carcinoma with high-risk features, the timing of postthyroidectomy radioiodine therapy does not affect overall survival time. The study included 9706 high-risk patients, with some undergoing early radioiodine therapy (3 mo or less postoperatively), and others undergoing delayed radioiodine treatment (3-12 mo postthyroidectomy). Median survival time was 74.7 months, with adjusted Cox multivariable analysis showing no additional survival benefit to the earlier postoperative therapy. Propensity-matched patients also demonstrated no timing-based survival benefit. [33]

Surgical resection of any involved structures from local extrathyroidal spread is also used in adjuvant therapy.

Next:

Surgical Therapy

Thyroidectomy, surgical technique

Conventional thyroidectomy

Thyroidectomy dates to around 1170; however, in the early centuries it remained a rarely performed procedure because of its high morbidity and mortality. The danger of the operation usually came from uncontrolled bleeding and sepsis. However, in the last century, advances in general anesthesia, antisepsis, and hemostasis have paved the way for safe thyroid surgery.

At the forefront of these developments was Theodor Kocher, who performed thousands of thyroidectomies and, through development of specific surgical technique, was able to decrease the mortality of the procedure to less than 1%. Today, we continue to use his time-honored technique for thyroidectomy. This technique involves a midline cervical incision, usually 4-8 cm in length; careful ligation of the thyroid vasculature; identification and preservation of the parathyroid glands; identification and preservation of the recurrent laryngeal nerve; mobilization and removal of the gland; and meticulous hemostasis and closure. In the hands of an experienced surgeon, conventional thyroidectomy is an extremely safe and effective procedure.

Minimally invasive endoscopic thyroidectomy

Over the last several years, novel endoscopic approaches to thyroidectomy have been developed because of a growing desire for the establishment of less-invasive approaches throughout the surgical community. Minimally invasive procedures involve smaller neck incisions compared with conventional thyroidectomy and, as such, tend to demonstrate improved cosmesis, reduced postoperative pain, and shortened hospital stays.

Minimally invasive thyroid surgery can be performed in various ways. True “endoscopic” techniques create a working space within the neck using CO 2 insufflation, with both axillary and neck approaches as starting points for dissection. This technique, however, has resulted in severe hypercarbia and massive cervical subcutaneous emphysema. A more popular technique is the video-assisted technique, which was developed, refined, and popularized in Italy and Japan; it was subsequently established in the United States.

Perhaps the biggest proponent of this technique is Paolo Miccoli, who published his experience with over 550 minimally invasive video-assisted thyroidectomies between 1998 and 2003. [34] The procedure requires a small central neck incision and uses external retraction without neck insufflation. This approach combines a mini incision (1-2 cm) and an approach that is familiar to head and neck surgeons. More importantly, this technique allows treatment of both small benign nodules and small thyroid malignancies. Miccoli showed that patients treated with minimally invasive thyroidectomy demonstrated significantly lower postoperative pain, reduced postoperative distress, and improved cosmesis compared with patients undergoing conventional thyroidectomy procedures.

Other issues regarding the development of minimally invasive techniques for thyroid surgery include their safety, morbidity, and ease of performance when compared with conventional open techniques. Complications rates for recurrent laryngeal nerve palsy and hypoparathyroidism have been similar to those found in open procedures. Operative times appear to be equivalent, after a moderate learning curve is taken into consideration.

Although the indications for minimally invasive thyroidectomy procedures have become standardized for thyroid nodules, some controversy still exists regarding their appropriateness for known thyroid cancer. Several studies have attempted to clarify the growing role for these procedures in thyroid cancer.

In a 2006 report, Takami and Ikeda noted that patients with benign follicular adenomas, low-risk papillary carcinomas less than 10 mm, and oxyphilic cell tumors less than 4 cm could be managed with endoscopic thyroidectomy. [35] In 2005, Caliceti et al examined 15 patients with papillary thyroid carcinoma (none >2 cm) who underwent minimally invasive total thyroidectomy. [36] Although follow-up was limited, they found that results of this technique were similar to those obtained with open thyroidectomy, except that shorter hospital stays and smaller neck wounds were more common in the minimally invasive group.

These studies indicate that minimally invasive techniques are safe for some thyroid cancer patients, but what about the oncologic effectiveness of these procedures? A 5-year follow-up study comparing minimally invasive, video-assisted thyroidectomy with conventional open thyroidectomy showed no significant difference in oncologic effectiveness between the two techniques, although the minimally invasive procedure had better cosmetic results. [37]

Another study, by Miccoli et al, studied the completeness of thyroid resection when performed via a minimally invasive, video-assisted technique. A prospective study of patients with papillary thyroid carcinoma was performed by measuring iodine-131 thyroid bed uptake and serum thyroglobulin levels one month after either minimally invasive thyroidectomy or conventional thyroidectomy. The differences between the 2 techniques were not statistically significant. Several follow-up studies have reinforced these findings, hinting that it is a good surgical option in patients with small papillary thyroid carcinoma. However, long-term results must be evaluated before declaring it equivalent to conventional thyroidectomy. [38]

Because conventional endoscopic surgery has limitations with regard to the manipulation of tissues and the obtainment of adequate visualizations, the da Vinci S surgical robot system was developed. It avoids the use of a neck incision, instead reaching the thyroid via an approach from the axilla across the chest. However, despite offering better visualization and manipulation of tissues, the system has been associated with longer operating times, as well as a significant learning curve, and it comes with an increased cost. [39] Robotic surgery has been shown to be a safe and feasible alternative when compared with conventional open thyroid surgery, [40] but in comparison with conventional endoscopic procedures, it does not appear to have any advantage. The videos below demonstrate several aspects of minimally invasive thyroidectomy.

Minimally invasive thyroidectomy; incision and exposure.
Minimally invasive thyroidectomy; initial dissection.
Minimally invasive thyroidectomy; identification of the recurrent laryngeal nerve.
Minimally invasive thyroidectomy; superior pole release.
Minimally invasive thyroidectomy; division of isthmus and delivery.
Minimally invasive thyroidectomy closure.

Thyroidectomy, extent of surgery

Hemithyroidectomy

Patients with papillary carcinoma can be separated into low- and high-risk categories for mortality based on prognostic factors. These factors include age, distant metastatic disease, extrathyroidal invasion, and size of primary lesion. Some surgeons believe that hemithyroidectomy is the most appropriate treatment for low-risk papillary carcinoma that is macroscopically localized in one lobe or for patients with occult papillary thyroid cancers. This balances the risk of complications from a more involved surgery with the chance of recurrence. A study of 889 patients, 528 who underwent total thyroidectomy and 361 who underwent hemithyroidectomy, showed similar survival rates among both groups. Comparison of both groups showed no difference in local or regional recurrence. [41] This surgery may be a good choice for patients who may not be compliant with thyroid hormone replacement postoperatively.

Near-total thyroidectomy

A near-total thyroidectomy can be performed to decrease the risk of damage to the recurrent laryngeal nerve or parathyroid glands. Some thyroid tissue is left during the resection and subsequently can be ablated with iodine-131.

Total thyroidectomy

Total thyroidectomy remains the criterion standard treatment for papillary thyroid carcinoma. Total thyroidectomy is recommended if the primary tumor is 1.0 cm or greater, or if extrathyroidal extension or metastases is present. This surgical procedure removes all thyroid tissue so that postoperative iodine-131 is more effective in treating occult disease, eliminates the risk of leaving occult disease in the thyroid, and allows serum thyroglobulin levels to be more sensitive in detecting recurrent or persistent disease. Although the risk of surgical complication is higher than that of hemithyroidectomy or near-total thyroidectomy, most experts agree that the risk of recurrent disease is lower and the survival rate is higher after total thyroidectomy.

Neck disease

The thyroid gland has a rich lymphatic network. Papillary thyroid carcinoma readily enters the intrathyroidal lymphatics and spreads to lymph nodes in the anterior compartment of the neck.

Cervical lymph node involvement is common in papillary thyroid carcinoma, with positive adenopathy in 35% of cases and micrometastatic lymphatic deposits in up to 80% of cases. Up to 10% of patients with papillary thyroid carcinoma have a recurrence in the neck; however, prolonged survival is the norm even in the setting of extensive neck disease. In large longitudinal and case-control studies, positive neck disease had little impact on survival from papillary thyroid carcinoma after controlling for patient age, male sex, extent of disease, and tumor grade.

Elective neck dissection does not offer a benefit in the setting of small (< 1 cm) primary papillary cancers since the 5-year recurrence rates are extremely low in both undissected and dissected necks (< 0.5%). In the setting of multifocal disease within the thyroid, however, the odds of nodal recurrence are 6 times greater than those seen with a single foci of tumor. Performing elective central node dissection in the setting of larger (> 1 cm) and multifocal papillary thyroid carcinomas has several advantages. They are as follows:

  • Provides more tissue for accurate tumor staging
  • Decreases rate of local recurrence
  • Reduces likelihood of a more challenging reoperation that carries a higher risk of complications
  • Reduces local tumor load, which may increase radioactive iodine uptake in distant metastatic foci, if present
  • Renders more patients athyroglobulinemic, again by reducing local tumor load and thus allowing better surveillance
  • Addresses tumors with poor radioactive iodine uptake (papillary tall cell variant, Hürthle cell carcinoma)

Elective neck dissection results in higher rates of temporary recurrent nerve paresis and hypocalcemia; however, these risks may be reduced by injecting the thyroid with isosulfan blue or other tracer to clearly visualize the draining lymph nodes. Lateral neck dissections are reserved for palpable neck disease since subclinical disease usually responds to postoperative radioactive iodine.

Previous
Next:

Preoperative Details

Cervical lymph node involvement is seen in 20-50% of cases and may be coexistent even when the primary tumor is small and intrathyroidal. Preoperative ultrasonography is the first-line imaging modality used to identify suspicious cervical lymph nodes, but by itself, it identifies only half of the lymph nodes found at surgery. Malignancy in suspicious lymph nodes is confirmed via ultrasonographically guided fine-needle aspiration and/or by measuring thyroglobulin in the needle washout. Routine preoperative use of CT scanning, MRI, and PET scanning is not recommended, but these modalities may be beneficial in patients with large, rapidly growing, or retrosternal or invasive tumors. [22]

Previous
Next:

Intraoperative Details

The goals of surgical therapy are the removal of the primary tumor and of cancer that has extended beyond the thyroid capsule, as well as the removal of any involved cervical lymph nodes. Minimizing treatment-related morbidity is important, as is accurate staging of the disease, which can aid in prognostication. Surgery must facilitate postoperative treatment with radioactive iodine where appropriate, as this permits accurate, long-term surveillance for disease recurrence. As with most surgical procedures, operative therapy minimizes the risk of disease recurrence and metastatic spread. [22]

Determining the location of lesions in relationship to their surrounding structures is an intraoperative consideration that greatly affects outcome and quality of life. Strap muscles and the recurrent laryngeal nerve, trachea, esophagus, and larynx are often involved with lesions that have extrathyroidal extension. While the strap muscles can be resected with minimal morbidity and resection of the recurrent nerve can occur without change in symptoms, resection of the airway can result in significant morbidity or even mortality. A thorough assessment of the airway and anatomy is critical in decision making in such cases. [42]

Tumors extending to the infrahyoid strap muscles and perithyroid soft tissues can be managed by resection of the involved structure with minimal morbidity. If the malignancy is adherent to the recurrent laryngeal nerve but can be dissected free, then this should be the aim. If the nerve is infiltrated by carcinoma or is completely surrounded by cancer, total removal of the tumor should take priority, and it should be resected. [42]

Extension into the laryngotracheal axis predicts a poor outcome, and controversy exists over the management of airway invasion. Be that as it may, obtaining negative surgical margins remains the hallmark of adequate surgery. [42]

Previous
Next:

Postoperative Details

Postoperative staging is used to determine prognosis, make decisions regarding postoperative adjunctive therapy and follow-up, and enable accurate communication between health-care providers. AJCC/International Union Against Cancer Control (UICC) staging is recommended for all patients. [22]

Radioactive iodine ablation

It is recommended that all patients undergo radioactive iodine ablation if they have known distant metastases, gross extrathyroidal extension of the tumor (regardless of tumor size), or primary tumor size of greater than 4 cm even in if other higher-risk features are not present. [22]

Radioactive iodine ablation is also recommended for selected patients with thyroid cancers of 1-4 cm that are confined to the thyroid or who have documented lymph node metastases or other higher-risk features. It is not recommended for patients with unifocal cancer of less than 1 cm if higher-risk features are absent or for patients with multifocal cancer if all foci are below 1 cm. [22]

Radioactive iodine ablation can take place after thyroxine withdrawal or recombinant human TSH stimulation. It is recommended that the minimum activity (30-100 mCi) needed for successful remnant ablation be employed. In cases of suspected or documented residual microscopic disease or in the presence of more aggressive tumor histology, higher activities (100-200 mCi) can be used. In patients undergoing radioactive iodine remnant ablation, a low-iodine diet is recommended for 1-2 weeks, particularly if iodine intake is high. [22]

Posttherapy scanning is recommended for patients who have undergone radioactive iodine remnant ablation, with such scanning typically taking place 2-10 days after the therapeutic dose has been administered. [22]

Other therapies

TSH suppression is needed to treat patients with thyroid cancer to decrease recurrence risk. Papillary thyroid cancer, which expresses the TSH receptor on cell membranes, responds to TSH stimulation. It is recommended that TSH initially be suppressed to below 0.1 mU/L in high- and intermediate-risk thyroid cancer patients. TSH levels for low-risk patients can be maintained at 0.1-0.5 mU/L. [22]

In patients over age 45 years with grossly visible extrathyroidal extension, treatment of the primary tumor with external-beam irradiation should be considered. Chemotherapy has no routine adjunctive use in patients with papillary thyroid cancer. [22]

Previous
Next:

Follow-up

For long-term follow-up care, perform a physical examination and obtain a serum thyroglobulin level, using an immunometric assay that is calibrated against the CRM-457 standard, every 6-12 months. Every serum thyroglobulin measurement should include a quantitative thyroglobulin antibody assessment. In patients who have undergone less than total thyroidectomy and in persons who have had a total thyroidectomy but no radioactive iodine ablation, consider periodically measuring serum thyroglobulin and performing neck ultrasonography. [43]

To verify that the disease is absent, measure serum thyroglobulin after thyroxine withdrawal or recombinant human TSH stimulation about 12 months after ablation in low-risk patients who have undergone remnant ablation, demonstrated negative cervical ultrasonographic results, and been found to have undetectable TSH-suppressed thyroglobulin within the first year after treatment. [43]

Yearly clinical examination and thyroglobulin measurements on thyroid hormone replacement can be the primary means of following low-risk patients who have undergone remnant ablation, demonstrated negative cervical ultrasonographic results, and shown undetectable TSH-stimulated thyroglobulin. [43]

A diagnostic whole-body radioactive iodine scan (DxWBS) is used during follow-up when little or no normal thyroid tissue remains. If disease does not appear on DxWBS regardless of the activity of iodine-131 used, it may occasionally be revealed on a therapeutic whole body scan (RxWBS) performed after the administration of larger, therapeutic doses of iodine-131. [43]

Cervical ultrasonography should be performed 6-12 months after surgery to assess the thyroid bed and the central and lateral cervical nodal compartments. [43]

Serum TSH should be maintained at less than 0.1 mU/L indefinitely in patients with persistent disease. [22] In disease-free patients who are still considered to be at high risk, consider using TSH suppressive therapy to maintain their serum TSH levels at 0.1-0.5 mU/L for 5-10 years. [43]

Previous
Next:

Complications

Complications of resection of papillary thyroid carcinoma are those associated with thyroidectomy. Damage to the recurrent laryngeal nerve can lead to vocal cord paralysis and hoarseness. Damage to the external laryngeal branch of the superior laryngeal nerve may produce dysphonia because it denervates the cricothyroid muscle, which regulates pitch. Transection of the internal branch of the superior laryngeal nerve causes the mucosa of the piriform sinus and false vocal cords to become insensate, thereby placing the patient at an increased risk for chronic aspiration. Resection of the thyroid without reimplantation of parathyroidal tissue may result in hypocalcemia.

In addition to complications arising from surgery, cumulative, dose-related effects can result from radioactive iodine therapy, including the development of nasolacrimal duct obstruction, dental caries, salivary gland damage, and secondary malignancies. Sour candies, hydration, amifostine, and cholinergic agents have been used to prevent salivary gland damage . [22]

Previous
Next:

Outcome and Prognosis

In general, the prognosis for papillary carcinoma of the thyroid is excellent. A long-term survival rate of approximately 90% exists. One study showed a 1-year survival rate of 97.5%, a 5-year survival rate of 92.8%, a 10-year survival rate of 89.5%, and a 20-year survival rate of 83.9%.

Prognostic factors include tumor size, patient age, extrathyroidal spread, and histological variant. The presence of vascular invasion, even within the thyroid gland, is associated with more aggressive disease at diagnosis and has a higher incidence of tumor recurrence. About 30% of patients develop tumor recurrence. Two thirds of recurrences are within the first decade after therapy. Tumors recur outside of the neck in about 21% of those patients with recurrence. The most common site for distant metastasis is the lung. Mortality rates are lower when recurrences are detected early based on radioiodine scans rather than clinical signs. A long delay in initiating the previously described treatment results in more than 2 times the 30-year cancer mortality rate.

Quality of life and psychosocial issues

Despite the relatively favorable prognosis of papillary thyroid carcinoma, multiple studies have demonstrated that the quality of life among these patients is lower than would be expected, both in the initial year after diagnosis and long term.

Follow-up monitoring for thyroid cancer can have profound effects on patients' lives, as they are required to undergo levothyroxine withdrawal prior to whole-body scanning. This places the patient in the position of trying to maintain normal activity and function while experiencing the well-documented effects of hypothyroidism, including increased fatigue, memory loss, mood disturbances, decreased motor skills, and the many other effects of thyroid dysregulation. The impact of this experience on work performance, family relationships, and social life can be detrimental to the well-being of these patients.

Although the significant effects of levothyroxine withdrawal have been documented for some time, significant deficits in the health-related quality of life and psychometric functionality of patients while on maintenance levothyroxine have recently been reported. Although these deficits are less severe than those experienced during periods of levothyroxine withdrawal, they can be significant, as levothyroxine supplementation therapy typically continues for the remainder of a patient's life.

Previous
Next:

Future and Controversies

Controversy has emerged over changes in epidemiology. The incidence of thyroid cancer has increased rapidly since the beginning of the 21st century. The reasons for this are not completely understood, but increased detection and increased true incidence due to multiple factors are the prevailing theories.

Controversy also exists regarding the treatment of papillary thyroid carcinoma. Treatment with total or near-total thyroidectomy results in a higher surgical complication rate, but more conservative measures result in a higher rate of postoperative cancer recurrence. Determination of prognostic factors to classify patients with papillary carcinoma into high- or low-risk categories for mortality after surgery is ongoing. To date, these prognostic factors include age, histologic grade, extrathyroidal invasion, distant metastases, and sex. Classification into high- and low-risk categories can aid in the determination of the most appropriate type of resection.

While surgery is the cornerstone of treatment for papillary thyroid cancer, the extent of primary surgery needed in low-risk disease is also under debate. Some argue that because papillary thyroid cancer is commonly multifocal and bilateral, total thyroidectomy should be performed to remove all disease. Others favor hemithyroidectomy, because disease-specific survival rates are excellent and recurrence risk is low with this procedure, and because it may allow patients to avoid levothyroxine therapy. [44]

Much of current clinical research on papillary thyroid carcinoma is focused on finding better methods of detection and better prognostic indicators. Headway is being made in the identification of genetic markers in tumor cells that indicate prognosis in general, as well as in the tendency of the cancer to metastasize. Gene expression patterns have been found that can differentiate between benign thyroid tissue and papillary thyroid carcinomas, as well as between papillary and follicular carcinomas.

Although surgery can adequately treat most patients, targeted therapies are being clinically evaluated for individuals who develop progressive, metastatic spread of papillary thyroid carcinoma. For example, the tyrosine kinase inhibitors axitinib, sorafenib, and pazopanib have demonstrated efficacy in phase II trials. In the future, growth modulators, apoptosis modulators, immunomodulators, angiogenesis inhibitors, and gene therapy may aid patients who do not respond to traditional therapy. [45]

Previous