ASHOK R. SHAHA, MD, FACS SNEHAL G. PATEL, MD, MS, FRCS
Diseases of the thyroid gland represent a common medical and surgical problem. A variety of inflammatory lesions and neoplasms are noted by endocri-nologists and surgeons interested in thyroid pathology. Various pathologic conditions include Hashimoto's thyroiditis, nodular goiter, solitary thyroid nodule, adenomas and thyroid cancer.
Although thyroid disease is extremely common, thyroid cancer is relatively uncommon and forms less than 2 percent of all human cancers. Approximately 19,500 new patients with thyroid cancer will be seen in the United States during the year 2001, while approximately 1,300 patients will die of thyroid cancer.1 The prevalence of nodular goiter has decreased considerably in the United States due to the routine use of iodized salt. However, it is still quite prevalent in other parts of the world, particularly in certain European countries around the Alps, and in Asia near the Himalayas. The routine use of ultrasonography has shown a very high incidence of occult thyroid lesions in the general population, although the incidence of clinically palpable thyroid nodularity is only approximately 5 percent.2,3 The prevalence of malignancy in solitary thyroid nodules ranges between 5 and 20 percent, while the incidence of thyroid cancer in multi-nodular goiter is less than 5 percent.2,3 Even though the incidence and mortality rate of thyroid cancer is not very high, this subject has generated considerable discussion and controversies. Major controversial issues are related to the diagnostic work-up and the extent of thyroidectomy.
Various groups of physicians are involved in the management of thyroid disease, including family practitioners, internists, endocrinologists, radiotherapists, nuclear medicine physicians, general surgeons, otolaryngologists, surgical oncologists, head and neck surgeons and endocrine surgeons. Even though thyroid surgery appears to be one of the safest surgical procedures, the morbidity and complications of thyroid surgery can be devastating to the patient in relation to voice dysfunction and permanent hypoparathyroidism.
It is interesting to note that Samuel Gross, in 1866, stated, "Thyroid surgery is horrid butchery. No honest and sensible surgeon would ever engage in thyroid surgery."4 On the other hand, toward the turn of the twentieth century, the first surgeon ever to win the Nobel Prize was Theodore Kocher for his contributions to the understanding of thyroid physiology, as well as for perfecting the technique of thy-roidectomy. In his hands, the mortality rate from thyroidectomy was less than 1 percent.4
The thyroid gland develops from the pharyngeal pouch, starting at the base of the tongue in the region of the foramen cecum, during the fourth week of gestation. As the thyroid gland descends to the lower neck, it brings with it a tract called the thy-roglossal duct. An undescended thyroid gland, though rare, is occasionally seen as a lingual thyroid. A more common anomaly of the thyroglossal tract is the thyroglossal duct cyst, commonly presenting as a midline cervical mass in children. This is one of the most common midline neck masses in children, the treatment of which is generally complete surgical excision (Sistrunk operation), where the cyst is removed in its entirety, along with a central portion of the hyoid bone. The thyroglossal duct track is invaginated by the hyoid or is intimately adherent to the hyoid bone. In the latter instance, the central portion of the hyoid and the core of the tissue of the base of the tongue should be removed to secure complete removal of the thyroglossal duct tract to avoid recurrences. The lingual thyroid is a rare condition where a patient may present with an enlargement of thyroid tissue on the base of the tongue. It is important, whenever a lingual thyroid is suspected, to determine the presence or absence of normal thyroid in the neck, prior to any surgical undertaking, since surgical excision may precipitate hypothy-roidism. Most patients with a lingual thyroid, however, can be treated conservatively.
The three important structures surrounding the thyroid gland are the recurrent laryngeal nerves, the superior laryngeal nerves, and the parathyroid glands (Figures 14-1 to 14-3). Any surgeon undertaking a surgical procedure on the thyroid must be quite familiar with the normal anatomy and variations of these important structures surrounding the thyroid gland to reduce complications and morbidity.
The superior laryngeal nerve runs parallel to the vagus nerve at the base of the skull, and then turns medially to divide into external and internal branches. The external branch supplies the cricoarytenoid muscle, which makes the vocal cord tight.5 This nerve is popularly called the "singer's nerve," since injury to this nerve will lead to the lack of ability to raise the voice or sing at high pitch. The true incidence of injury to the superior laryngeal nerve is unclear in the literature, although this complication can be devastating, especially for a professional singer.
The recurrent laryngeal nerve supplies all the intrinsic muscles of the larynx—with the exception of the cricoarytenoid muscle. During thyroid surgery, the nerve may be injured near its entry into the larynx, close to the cricoid cartilage, or where the nerve crosses the inferior thyroid artery.6 The nerve may be injured below the thyroid gland in the superior mediastinum near the trachea, but the most common site of injury is the area of Berry's ligament, or where the nerve crosses the inferior thyroid artery.5 Berry's ligament is thickened, pre-tracheal fascia that suspends
Figure 14-1. Schematic representation of the lateral and superior aspects of the thyroid gland, showing the superior laryngeal nerve running parallel to the vessels.
Figure 14-2. Exposure of the tracheoesophageal groove, depicting the recurrent laryngeal nerve and its relation to the branches of the inferior thyroid artery.
Figure 14-2. Exposure of the tracheoesophageal groove, depicting the recurrent laryngeal nerve and its relation to the branches of the inferior thyroid artery.
the thyroid gland from the trachea and the cricoid cartilage. Several capsular veins course through this ligament, which makes surgical resection tedious and carries a high risk of injury to the recurrent laryngeal nerve. Occasionally the recurrent laryngeal nerve may divide into two or three branches external to the cricoid cartilage, and this should be kept in mind to avoid injury to any of these branches.
The parathyroid glands are generally located on the posterior surface of the thyroid gland, each weighing approximately 35 mg. Identification and preservation of the parathyroid glands and their blood supply is extremely critical in thyroid surgery— especially in patients undergoing total thyroidectomy. The blood supply to the parathyroids generally comes from the inferior thyroid artery, however in some instances there are small branches exclusively supplying the superior parathyroid gland from the superior thyroid artery.7 Some of the anteriorly placed parathyroid glands may receive their blood supply directly from the thyroid gland and these glands are at high risk of injury during total thyroidectomy. An understanding of the anatomy of the parathyroid glands, as well as their blood supply, is essential for the surgeon contemplating thyroid surgery.
examination followed by a fine-needle aspiration biopsy (Table 14-1).
The three main indications for surgery on the thyroid gland are suspicion of malignancy, compression symptoms, and cosmesis. There continues to be considerable controversy regarding the optimal work-up of a thyroid mass. The most appropriate, cost-effective, and accurate initial test available today is a fine-needle aspiration biopsy. The accuracy, sensitivity and positive-predictive value of this method exceeds 90 percent.9
Certain clinical features need to be carefully looked for in every patient with a thyroid mass as these masses are commonly associated with malignancy (Table 14-2). Age is an important factor, since benign thyroid disease is more common in middle-aged individuals and thyroid cancer is more prevalent among the young and the elderly. A young child presenting with a thyroid mass has a greater than 40 percent chance of having thyroid cancer. Every effort should be made to rule out thyroid cancer in young individuals. Similarly, in older patients, a thyroid mass is more likely to be neoplastic rather than a benign nodular goiter. Thyroid disease is more common in women, but thyroid cancer, per se, is more common in men
When a patient presents with a solitary thyroid nodule or a diffuse enlargement of the thyroid, a variety of diagnostic studies can be employed.8-12 Although an extensive work-up can be performed (including various imaging studies), probably the most cost-effective approach is a good history and physical
Radiography of neck/chest
Thyroid function tests
Fine-needle aspiration cytology
Table 14-2. CLINICAL FEATURES INDICATIVE OF A MALIGNANT THYROID NODULE
Age (very young or old) Sex (male)
Presence of distant (pulmonary) metastases
Neck node metastases
Vocal cord paralysis
History of irradiation to the neck
Clinical characteristics: hard, fixed nodule
Sudden change in size of thyroid nodule Residence of the individual Pressure effects
(Figure 14-4). The overall incidence of colloid goiter has decreased in the United States due to the routine use of iodized salt over the past half century.
A history of radiation to the neck is also an important factor in the genesis of thyroid cancer. Radiation was commonly used in years gone by for benign diseases such as acne, enlarged tonsil, adenoids, enlarged thymus, or skin infections. The common dose of external radiation used by the dermatologists was generally between 800 and 1,200 cGy. There is a very high incidence of thyroid cancer in individuals presenting with a thyroid mass in the setting of previous exposure to radiation. A majority of these tumors are multifocal and involve both lobes of the thyroid, and the most common histopathology is papillary carcinoma. The Chernobyl nuclear accident in 1986 exposed certain regions of Belarus, the Ukraine, and Russia to environmental radiation and since 1990 there has been an upsurge in the incidence of thyroid cancer (up to a 30-fold increase) in these areas.
Other clinical features such as vocal cord paralysis, the presence of lymph node metastasis, or a hard
Figure 14-4. Incidence of thyroid cancer and mortality in the United States, 1974 to 1996.
Figure 14-5. A large substernal goiter with tracheal deviation.
and fixed thyroid mass are highly suggestive of thyroid cancer (Figures 14-5 and 14-6). Other symptoms may be related to the presence of distant disease such as pulmonary metastases (Figure 14-7). A family history of medullary carcinoma of the thyroid or multiple endocrine neoplasia, type I or II, should prompt appropriate evaluation.
Most patients presenting with thyroid cancer or solitary thyroid nodule are euthyroid and blood tests
Figure 14-4. Incidence of thyroid cancer and mortality in the United States, 1974 to 1996.
done as a routine do not aid the differential diagnosis of a solitary thyroid nodule. However, thyroid antibody estimation is helpful in young women with diffuse goiter or for the diagnosis of Hashimoto's thyroiditis.
Although various imaging studies have been used in the evaluation of a thyroid mass, none can routinely confirm the diagnosis of malignancy.
A thyroid ultrasound examination is commonly performed as the initial evaluation of a thyroid mass to rule out a solid versus a cystic mass, and to confirm whether a clinically solitary nodule is indeed a single thyroid nodule as opposed to a dominant nodule within a multinodular goiter.13,14 Between 15 and 20 percent of solitary thyroid nodules are malignant, while the corresponding rate is less than 5 percent in cystic thyroid nodules. The incidence of malignancy may be slightly higher in cysts that recur after initial aspiration or thyroid masses that are more than 3.0
cm in size. Ultrasonography is also helpful in the evaluation of incidentally-noted thyroid nodules, the so-called incidentalomas of the thyroid picked up on a CT or MRI scan of the neck done for other reasons. Since most of these incidentalomas are clinically non-palpable, ultrasound-guided fine-needle aspiration biopsy may be performed in an effort to get tissue diagnosis.13 Another indication for thyroid ultrasonography is to monitor the size of the thyroid mass in patients who are managed conservatively, eg, pregnant women. For patients undergoing ipsi-lateral thyroid lobectomy it may be helpful to monitor the contralateral lobe and to rule out local recurrence in the thyroid bed during follow-up.
Thyroid scintigraphy using technetium 99m or iodine-123 may be used to evaluate the hormonal secretory status of a thyroid nodule. A cold nodule represents nonfunctioning thyroid tissue (Figure 14-8) while a hot nodule is indicative of functioning or hyperfunctioning tissue. The incidence of malignancy in a cold thyroid nodule ranges between 15 and 20 percent, while the incidence of malignancy in a hot thyroid nodule is generally less than 5 percent.10 A thyroid scan is also helpful in distinguishing a solitary thyroid nodule from a thyroid nodule that is part of a multinodular pathology.
Not all patients with differentiated thyroid cancer have radioiodine avid tumors and it is not uncommon for a patient with elevated serum thyroglobulin (TG) to have a negative radioactive iodine (RAI) scan. In these patients, the residual or recurrent tumor may be too small to be resolved on the scan. Alternatively, the tumor cells may have lost their iodine-concentrating ability in spite of being able to secrete detectable levels of TG. When these patients are treated empirically with high-dose RAI, post-treatment scans often demonstrate uptake in micrometastatic deposits.
Another alternative for imaging differentiated thyroid cancer that has lost its iodine-trapping ability is to employ one of the newer imaging modalities such as thallium-201 total body scan or 18FDG-PET scan. Thallium-201 has been in clinical use for evaluation of myocardial function and has been reported to be sensitive in imaging differentiated thyroid tumors. Less well-differentiated thyroid carcinomas that do not concentrate RAI may be better imaged with a 18FDG-PET scan. The role of these modalities is currently under investigation and needs to be better defined before recommending their use in routine clinical practice.
Computed Tomography (CT) Scan
A CT scan is not routinely recommended in patients with thyroid masses, especially those with a clinically solitary thyroid nodule. However, it may be of great help in evaluating large tumors (Figure 14-9), especially those with substernal extension, or in patients with lymphoma or anaplastic thyroid can
cer. In patients with recurrent thyroid masses or recurrent thyroid cancer, a CT scan may be indicated to evaluate the extent of the disease and its relation to the airway. In patients with anaplastic thyroid cancer and recurrent thyroid cancer who present with airway problems, it can define the presence and extent of endo-luminal pathology. Features such as the position of the trachea, involvement of either the tracheal wall or esophageal lumen, and the status of the tracheoesophageal grooves can be assessed quite reliably. Other issues such as minimal invasion of the laryngotracheal cartilage or pharyngoesophageal musculature are more difficult to interpret and are most often resolved only at surgical exploration.
Magnetic Resonance Imaging (MRI)
An MRI scan is rarely used for the routine evaluation of thyroid nodules. However, with the frequent use of MRI for investigating other head and neck conditions, including neurologic problems, an "incidentaloma of the thyroid" may be picked up (Figure 14-10). Further investigation of such incidentalomas may be performed by an ultrasound-guided needle biopsy. However, most of these incidentally discovered thyroid nodules are less than 1.0 cm in greatest dimension and, if non-palpable, they can be kept under observation with close follow-up (Figure 14-11).
Fine-needle aspiration biopsy is probably the most important and cost-effective diagnostic study currently available for evaluation of a solitary thyroid
Figure 14-11. Suggested algorithm for the management of thyroid incidentalomas.
Table 14-4. INTERPRETATION OF FINE-NEEDLE ASPIRATION BIOPSY OF THE THYROID
Figure 14-11. Suggested algorithm for the management of thyroid incidentalomas.
nodule. The fear of needle-track implantation that was generated in the mid-1950s is no longer a consideration today. While the technique of fine-needle aspiration biopsy is familiar to most surgeons, endocrinologists and pathologists, one needs to be aware of certain pitfalls of the procedure (Table 14-3).
A number 22, 23, or 25 guage needle is generally used for thyroid mass aspiration and the smears are preserved in 95 percent alcohol. The results of fine-needle aspiration biopsy are usually interpreted as definite malignant pathology (such as papillary carcinoma, medullary carcinoma or anaplastic carcinoma) or clearly benign (such as thyroid cyst, colloid goiter, or Hashimoto's thyroiditis) (Table 14-4). The intermediate gray area of "suspicious" pathology includes findings that may be consistent with a follicular or Hurthle cell neoplasm. Most of these patients are recommended to undergo surgical intervention as the distinction between a benign follicular neoplasm and a malignant follicular tumor is generally possible only after removal of the entire thyroid mass and evaluating the tumor for capsular and vascular invasion. In the indeterminate group, where there may have been a technical problem or difficulties in interpretation, the investigation can be easily and safely repeated.
Papillary Cellular smears Colloid goiter Technical
Medullary Follicular Colloid cyst problems
Anaplastic neoplasm Thyroiditis Degenerative Hurthle cell nodule lesion Hemorrhagic
Patients who have an unequivocally benign needle aspiration result with no clinical suspicion of a malignant process could be observed. Whether or not suppressive therapy is indicated in these patients remains controversial. The likelihood that the thyroid nodule will disappear on suppressive therapy is small, but if the nodule exists in the background of a multinodular goiter, it may decrease in overall size. It is important to appreciate that while the diagnosis of malignancy is easy and reliable on fine-needle aspiration biopsy, a negative result cannot rule out malignancy. With the more widespread use of fine-needle aspiration biopsy, there has been a 50 percent reduction in the number of patients undergoing routine thyroidectomy, while the prevalence of malignancy has doubled in these specimens—most likely due to the selection associated with this approach.
Although a variety of histologic types of tumors can occur in the thyroid (Table 14-5), an overwhelming majority of malignant thyroid tumors are well-differentiated tumors (Figure 14-12), and include papillary, follicular, mixed, and Hurthle cell tumors. The Hurthle cell tumors of the thyroid are an independent group consisting of oncocytic cells (also know as oxyphil or Askanazy cells). In the recent WHO classification, although Hurthle cell tumors are included as a variant of follicular tumors, the behavior of
Table 14-3. PITFALLS IN NEEDLE ASPIRATION BIOPSY OF THE THYROID
Adequacy of specimen—quantitative and qualitative Accuracy of specimen—nonhomogeneity of needle placement Accuracy of cytopathologic interpretation Cysts—difficulties with degenerative nodules Follicular lesions—benign versus malignant Hurthle cell lesions—benign versus malignant Lymphocytic lesions—lymphocytic thyroiditis versus lymphoma
Table 14-5. PATHOLOGIC TYPES OF THYROID CANCER
Papillary carcinoma Follicular carcinoma Mixed
Hürthle cell carcinoma
Medullary carcinoma Anaplastic carcinoma Lymphoma
Metastatic tumors to the thyroid approximately 30 percent. It is interesting to note that thyroid cancer represents a spectrum of diseases ranging from the most common and favorable papillary thyroid cancer to the highly lethal anaplastic or giant and spindle cell thyroid cancer.
In the group of differentiated thyroid cancers, Rosai and colleagues recently observed variants of differentiated thyroid cancer such as tall cell (Figure 14-13), scirrhous, trabecular, and insular varieties, which represent more aggressive forms of differentiated thyroid cancer commonly grouped as poorly-differentiated thyroid tumors.16 These are more likely to present with extra-thyroidal extension of the disease and generally affect elderly male patients.
Medullary thyroid cancer (MTC) is a tumor of the thyroid originating from the parafollicular C cells, which produce calcitonin. MTC may present either as a sporadic or familial form. The familial variety is transmitted as an autosomal dominant inheritance and may occur as a part of multiple endocrine neoplasia, types I/II. Recently, molecular studies have revealed the presence of the RET proto-oncogene mutation in MTC. Screening of siblings and family members is now performed for RET mutation and if the family members are RET-positive they are considered candidates for prophylactic total thyroidectomy, which may be performed as early as age 5 or 6. Most of these young individuals are found to have C-cell hyperpla-sia or early medullary carcinoma.
Hurthle cell tumors is quite distinct and, overall, the prognosis of Hurthle cell cancer is much poorer than papillary or follicular thyroid cancers. Papillary carcinoma has a better outcome in comparison to follic-ular thyroid cancer.
Hundahl and colleagues have recently reported the data from the NCDB (National Cancer DataBase) on thyroid cancer in the United States.15 In their report of 53,865 cases, 78 percent were papillary thyroid cancer, 13 percent were follicular cancer while medullary and anaplastic thyroid cancer comprised 3 percent and 2 percent respectively. Papillary thyroid carcinoma is the most common histologic type, with a high incidence of multicentricity and lymph node metastasis. On the other hand, follicular thyroid cancer has a high likelihood of hematoge-nous spread with prevalence of distant metastasis of
Anaplastic thyroid cancer comes in different forms, the most common being giant and spindle cell anaplastic thyroid cancer. Most of these tumors grow rapidly and have a very high likelihood of lymph node and distant metastasis. Accurate pathologic diagnosis of anaplastic thyroid cancer is critical to rule out either small cell anaplastic thyroid cancer or a lymphoma of the thyroid, as these are managed very differently and have a more favorable clinical course.
Metastatic tumors to the thyroid are quite rare, but occasionally a primary tumor of the lung, breast or kidney, or a melanoma may metastasize to the thyroid, presenting a diagnostic dilemma in differentiation from a solitary thyroid nodule.
Treatment Goals and Treatment Alternatives—The Role of Multidisciplinary Treatment
The goals of treatment in the management of thyroid tumors are to cure the disease while minimizing the complications of thyroid surgery and side effects of adjuvant therapeutic modalities. The mainstay of treatment in thyroid cancers is complete surgical extirpation of the primary tumor. The extent of surgery should be tailored to the biologic aggressiveness of the disease.
Adjuvant therapeutic options available include radioactive iodine and external beam radiation therapy. In the low risk patient, surgical removal of all gross tumor is generally quite satisfactory. However, in the more aggressive forms of thyroid cancer or in the high risk group, a combined modality approach using surgery followed by radioactive iodine is indicated. After a total thyroidectomy, radioactive iodine dosimetry is used to document any evidence of residual thyroid tissue, and ablative treatment can then kill any residual normal or abnormal thyroid remnant tissue. Radioactive iodine scans also facilitate documentation of distant metastasis, most commonly pulmonary metastasis, which can be controlled satisfactorily in the early stages when the gross disease may not be evident on a routine chest radiograph.
The role of chemotherapy in the management of thyroid cancer is extremely limited, and is restricted to treatment of high-grade, poorly-differentiated or anaplastic cancers. External beam radiation therapy also has limited application in the management of thyroid cancer.17 Experience in the United States with postoperative external radiation therapy is limited, but it has been routinely used in France, where improved local control of disease has been reported with this approach. External beam radiation therapy may be utilized when gross residual tumor remains or when an aggressive tumor exhibits extra-thyroidal extension at surgery. The most common indication for postoperative external radiation therapy is a high-grade tumor in a high risk patient, especially when the tumor is adherent to the esophageal or tracheal wall. Primary external beam radiation therapy, along with chemotherapy, is utilized in the management of anaplastic thyroid cancer.
The treatment plan for differentiated thyroid cancer can be rationally formulated by taking into account prognostic factors and assigning risk groups. Before considering any definitive treatment procedure in the management of thyroid cancer, it is extremely important to understand the factors that impact prognosis in this disease. Our understanding of thyroid cancer has improved considerably over the last 2 decades, with the definition of patient-related factors (eg, age and sex) and tumor-related factors (eg, size of the tumor, grade of the tumor, extra-thyroidal extension of the primary tumor, and the presence or absence of distant metastasis) as prognostic factors of importance. The Mayo Clinic1819 based their classification system (AGES) on prognostic factors of age, grade of the tumor, extra-thyroidal extension, and size of the tumor, while the Lahey Clinic used age, distant metastasis, extra-thyroidal extension, and size (AMES).2021 Both institutions divided their patients into low and high risk groups based on their respective prognosticators. Outcomes in the low risk group were uniformly excellent, with a long-term mortality of less than 2 percent. Conversely, mortality in the high risk group was as high as 46 percent. A similar experience was reported from the European Organization for Reseach and Treatment of Cancer (EORTC),22 the University of Chicago, and Memorial Sloan-Kettering Cancer Center. Shaha and colleagues from Memorial Sloan-Kettering Cancer Center
Table 14-6. RISK GROUPS IN THYROID CANCER
Low risk patients/low risk tumors Low risk patient/high risk tumor High risk patient/low risk tumor High risk patient/high risk tumor
Patient Factors Age, Gender
Tumor Factors Grade, Size, Extrathyroidal extension,
Distant metastasis divided their patients into low, intermediate, and high risk groups23 (Tables 14-6 and 14-7). The significant prognostic factors in their series were grade of the tumor, age, distant metastasis, extra-thyroidal extension, and size of the tumor (GAMES).24 Their low risk group included low risk patients (below the age of 45) with low risk tumors, while the high risk group included high risk patients (above the age of 45) with high risk tumors. The intermediate risk group included two separate categories: young patients with more aggressive tumors and older patients with less aggressive tumors. The reported long-term survival in the low-risk group was 99 percent, while the intermediate risk group was 85 percent and the high risk group was 57 percent24 (Figure 14-14).
Hay and colleagues, in a recent report from the Mayo Clinic, described the prognostic factors of importance as MACIS (distant metastasis, age, completeness of resection, extra-thyroidal tumor invasion, and size of the tumor).25 They emphasize completeness of resection as a major prognostic factor. This is especially vital in patients who present with extra-thyroidal tumor extension. Thus, the experience of several different institutions based on a large number of patients followed for a long period of time essentially point to the fact that a relatively uniform set of prognostic factors can be used to reliably classify patients with differentiated thyroid cancer into well-defined risk groups.
Based on the excellent outcome in the low risk group, a lobectomy and isthmusectomy is quite satisfactory if the disease is confined to only one lobe. The decision to subject a patient to total thyroidectomy should be based on gross intraoperative findings, prognostic factors and risk-group analysis rather than
the fact that the patient has thyroid cancer (Table 14-8). The role of radioactive iodine dosimetry and ablation remains undefined in the low risk group, since the overall outcome is excellent and routine use of these modalities may represent overtreatment.
However, in patients with high risk tumors, appropriate surgical aggressiveness is crucial, as is consideration of adjuvant radioactive iodine therapy. If the patient is likely to require radioactive iodine therapy, it is important to proceed with total thyroidectomy to facilitate dosimetry and treatment at a later date. It is also vital to review the pathology to rule out areas of poorly-differentiated thyroid cancer within the specimen, a situation that is not uncommon in elderly patients or in patients who present with extra-thy-roidal extension. These patients are at high risk for local recurrence and should be considered for adjuvant external beam radiation therapy. Table 14-9 presents the common indications for employing external beam radiation therapy in thyroid cancer.
Patients with certain histologic subtypes such as tall cell, insular, scirrhous, solid trabecular, and those
Table 14-7. RISK-GROUP DEFINITIONS IN DIFFERENTIATED CARCINOMA OF THE THYROID
Low Risk Intermediate Risk High Risk
Age (years) Distant metastasis Tumor Size
Histology and grade
5-Year survival 20-year survival
<45 M+ T3, T4 (>4 cm) Follicular and/or high-grade 96% 85%
>45 M+ T3, T4 (>4 cm) Follicular and/or high-grade 72% 57%
Multicentricity of thyroid cancer, varying between 30 and 70% The incidence of local recurrence in the opposite thyroid lobe may be 5 to 15% High incidence of mortality in patients with local recurrence To facilitate the routine use of radioactive iodine dosimetry and ablation
Follow-up with thyroglobulin, which is difficult in presence of normal thyroid tissue Theoretical consideration of anaplastic transformation of residual thyroid tissue High incidence of complications in reoperative thyroid surgery Minimal complications of total thyroidectomy in experienced hands with undifferentiated areas respond relatively poorly and generally do not show avidity for radioactive iodine. The role of external radiation therapy, especially in this category, still remains to be defined.
Other prognostic factors including DNA ploidy, adenylate cyclase receptor, epidermal growth factor (EGF) receptor, vascular endothelial growth factor (VEGF), telomerase content, and cathepsin have been examined in various reports over the years. The role of the tumor suppressor gene p53 has also been studied extensively and a higher expression has been reported in poorly-differentiated or anaplastic thyroid cancers. Techniques such as comparative genomic hybridization have been used to screen for genomic aberrations, and a more detailed molecular and genetic understanding of the spectrum of thyroid tumors can be expected over the next few years.
Considerable controversy exists regarding the extent of thyroidectomy in patients presenting with a differentiated thyroid cancer in a solitary nodule. There are strong proponents of routine total thyroidectomy, an approach that is mainly based on the premise of being able to treat multicentric microscopic disease in the opposite lobe. The incidence of microscopic thyroid cancer in the opposite lobe has been reported to range between 30 and 80 percent. However, the clinical significance of this "laboratory cancer" remains unclear, as the incidence of recurrence in the opposite lobe after ipsilateral lobectomy is only 5 to 7 percent. In the absence of level I evidence for the advantage of such an approach, as discussed above, a rational risk-group based approach should be used to determine the extent of thyroidectomy. Another argument used to promote routine total thyroidectomy is that it allows for radioactive iodine dosimetry and ablation, as well as the use of serum thyroglobulin as a tumor marker in the follow-up of patients. However, in low risk-group patients these are of minimal value and are generally not necessary.
A detailed description of the technique of thy-roidectomy is beyond the scope of this book, but a few technical considerations will be discussed. The most commonly used incision for thyroid operations is the low "collar" incision. An appropriate transverse skin crease is chosen and the incision should preferably be marked out with the patient sitting up before induction of anesthesia. This is especially important in women as anatomic orientation changes when the patient is supine with the neck hyperextended. The usual extent of the incision is from the anterior border of one sternocleidomastoid muscle to that of the other, and this provides adequate exposure for safe conduct of the operation. Smaller incisions may be adequate in patients with thin necks and a centrally situated nodule, but surgical exposure should never be compromised for the questionable benefit of better cosmesis associated with small incisions. Obviously, larger tumors may need more extensive exposure and the horizontal incision can be extended laterally if neck dissection becomes unexpectedly necessary. Superior and inferior flaps are developed in a sub-platysmal plane and held apart with a self-retaining retractor. Certain maneuvers such as dividing the fascia over the sternocleidomastoid muscle and lateral to it, and dividing one or both strap muscles can provide extra exposure when required. Division of the ster-nothyroid muscle close to the thyroid cartilage facili-
Table 14-9. INDICATIONS FOR EXTERNAL RADIATION THERAPY
Anaplastic thyroid cancer
Medullary thyroid cancer with extensive nodal or mediastinal disease
Residual medullary thyroid cancer
High risk differentiated thyroid cancer patient with high risk tumor
Patient with extrathyroidal extension and microscopic residual tumor
Gross residual tumor
Poorly-differentiated thyroid cancer invading central compartment
Selected patients with distant metastasis, such as bone or brain tates safe mobilization of the superior thyroid pole and allows accurate identification of the superior laryngeal nerve. Mobilization of the thyroid lobe generally proceeds from the lateral to medial direction after identification of the recurrent laryngeal nerve caudad to the inferior cornu of the thyroid cartilage in the tracheoesophageal groove. Once the middle and inferior thyroid veins and the superior thyroid pedicle have been divided, the lobe can be rotated medially to expose its posterolateral surface. If the parathyroid glands are identified, they are dissected off the thyroid to preserve their blood supply. Routine division of the inferior thyroid artery lateral to the recurrent nerve is not only unhelpful in mobilization of the thyroid lobe, but can also devascularize both parathyroid glands on that side. Instead, the branches of the inferior thyroid artery are divided medial to and between the parathyroid and thyroid glands. The areolar tissue containing the parathyroid gland can then be swept away laterally along with the inferior thyroid artery. It should be noted that the recurrent nerve is intimately related to the inferior parathyroid gland and great care is essential in this dissection. Obviously, the presence of gross tumor or abnormal lymph nodes in the tracheoesophageal groove may make it impossible to accomplish this part of the procedure without compromising complete tumor excision and placing the recurrent nerve at risk. If the parathyroid gland is devascularized, it should be autotransplanted into the sternocleidomas-toid muscle. As described under the Anatomy section, it is well recognized that the recurrent laryngeal nerve is at highest risk of injury in the region of Berry's ligament. Meticulous and careful dissection using a fine microclamp is vital if complete excision of all thyroid tissue is to be safely accomplished without injuring the recurrent nerve. It is also crucial to recognize that the recurrent nerve may be at risk if the region of the Berry's ligament is dissected medial to the superior pole of a low-lying thyroid gland without demonstrating the entire course of the nerve.
Management of Locally Invasive Differentiated Thyroid Cancer
Unlike poorly-differentiated or anaplastic carcinoma, well-differentiated thyroid carcinoma is only rarely locally invasive. Although the presence of extra-thyroidal extension is a significant predictor of treatment failure and outcome, this finding should not be automatically construed as a sign of unre-sectability. Extended resections may be necessary to achieve palliation, but if complete excision of all gross tumor is achieved, the presence of extra-thy-roidal extension has been shown to have no adverse impact on prognosis in younger patients.26 The most commonly involved structures that need resection include the infrahyoid strap muscles, the recurrent laryngeal nerve, the cartilage of the laryngotracheal complex or the pharyngoesophageal musculature. The majority of tumors adherent to the larynx or trachea can be grossly resected by conservative measures such as "shaving" the cartilage. However, in the presence of obvious cartilage or endo-luminal invasion, partial or even circumferential sleeve resection of the trachea is justifiable. Tumors adherent to the pharyngoesophageal wall can be adequately resected by excising the involved muscle up to the submucosal layer. Other structures such as the strap muscles or the internal jugular vein can be sacrificed without much consequence if they are involved. Obviously, total thyroidectomy must be performed in these patients even if the opposite lobe is grossly normal to facilitate monitoring and treatment with radioactive iodine. As these tumors are more likely to be of poorer differentiation, they may not concentrate radioactive iodine and external beam radiation must be considered when appropriate.
Elective neck dissection is not recommended in the management of differentiated thyroid cancer, but clinically or radiologically demonstrable nodes must be appropriately addressed. Although the incidence of regional nodal metastases is highest in young patients, this finding is of no prognostic significance if the neck is managed appropriately.27 Suspicious nodes encountered during thyroidectomy can be sampled and submitted for frozen-section evaluation, but there is no merit in the so-called berry picking procedure. Central compartment dissection including the tracheoesophageal groove lymph nodes is the preferred operation and is carried out taking precau tions to preserve the recurrent laryngeal nerve and the parathyroids with their vascular supply. For lateral compartment nodal disease, a comprehensive neck dissection including levels II to V becomes necessary. Level I can be safely spared if there are no clinically abnormal nodes in the region. A type III modified neck dissection preserving the internal jugular vein, the sternocleidomastoid muscle and the spinal accessory nerve is preferred if there is no evidence of extra-thyroidal or extra-nodal extension of disease. Although not essential, we prefer to stage neck dissections for patients with bilateral lymphatic metastases a few days apart to increase the safety of an otherwise long and tedious operation. Every effort must be made to preserve the recurrent laryngeal nerve, even in patients with bulky disease in the tra-cheoesophageal groove. It is often possible to dissect the nerve free of the nodes without leaving gross residual disease; although tedious, this is a worthwhile endeavor as preservation of laryngeal function significantly impacts the patient's quality of life after surgery. In contrast, preservation of the parathyroid glands, especially their vascular supply, may be impossible under these circumstances and if a normal parathyroid gland is identified, autotransplantation must be considered. Patients with bulky nodal disease are at high risk for pulmonary micrometas-tases, and should be evaluated with a postoperative radioactive iodine scan followed by ablative therapy if indicated. In contrast to young patients, the presence of regional nodal metastases does predict a higher rate of neck failure in older patients in whom comprehensive neck dissection should be followed by adjuvant radioactive iodine therapy.
Even though thyroid surgery is considered to be one of the safest surgical procedures in modern practice, a variety of complications can occur. The most important complications directly related to the surgical procedure include injury to the recurrent laryn-geal nerve, the superior laryngeal nerve, and the parathyroid glands.
The recurrent laryngeal nerve is a branch of the vagus; on the right side it loops around the subcla-vian artery, while on the left side it originates in the mediastinum and curves around the arch of the aorta, supplying all the intrinsic muscles of the larynx with the exception of the cricoarytenoid muscle. Injury to the recurrent laryngeal nerve may occur in the para-tracheal area, in the region where it crosses the inferior thyroid artery, or in the vicinity of the ligament of Berry.6 The recurrent laryngeal nerve may cross the inferior thyroid artery either superficial or deep to it, or it may indeed course between the branches of the artery. The inferior parathyroid gland is also commonly located in intimate relation to these two important structures. The recurrent laryngeal nerve then proceeds close to Berry's ligament to enter the larynx at the level of the cricoid cartilage. Most injuries to the recurrent laryngeal nerve probably occur in this area near Berry's ligament, where there are often tiny veins passing through. If one of these veins is injured during dissection of this region, the recurrent laryngeal nerve may be traumatized during efforts to attain hemostasis. It is also known that the recurrent laryngeal nerve can branch into tiny filaments before entering the larynx, and injury to any of these has the potential for altering laryngeal function. Generally, traction injury to the recurrent laryngeal nerve will improve over a period of 3 to 4 weeks. Transection of the recurrent laryngeal nerve, however, obviously leads to permanent paralysis of the vocal cord, but the final resting position of the paralyzed vocal cord may vary over a period of time. In a majority of young individuals, the paralyzed vocal cord may come to rest in the median or paramedian position where the opposite cord may be able to compensate for the ipsilateral paralyzed one. If adequate compensation occurs, the quality of voice may be acceptable under most circumstances, but never does return to normal. Laryngoplasty with vocal cord medialization may be undertaken in selected patients to improve the quality of the voice.
Injury to the superior laryngeal nerve leads to an inability to raise the voice to a high pitch, resulting in difficulty with yelling, screaming or singing. On routine examination of the larynx, the findings are often very subtle, but careful comparison of the vocal cords shows bowing on the affected side. Special investigations such as videostroboscopy or voice analysis may be better able to help define the problem. There is no effective treatment for injury to the superior laryngeal nerve except for voice training and speech therapy.
One of the most distressing complications of total thyroidectomy is permanent hypoparathyroidism which may result from total removal of all four parathyroid glands or from damage to their blood supply. During the surgery, if the parathyroid gland is identified and if the blood supply is thought to be compromised, a biopsy of a sliver of tissue should be sent for frozen-section analysis to confirm the presence of parathyroid tissue. The compromised gland can then be minced into small pieces and implanted into a pocket created within the strap muscles or the sternomastoid muscle.7 The minced parathyroid will pick up blood supply from the surrounding musculature and, over a period of a few weeks, will regain its normal function. For thyroid surgery, it is not necessary to autotransplant the parathyroid into the forearm, which is the usual practice in patients undergoing parathyroidectomy for secondary hyperparathyroidism due to renal failure.
The vocal cord function should be evaluated after surgery, and the status of the vocal cords should be documented in the patient's chart. In patients undergoing total thyroidectomy and para-tracheal nodal dissection, it is important to check calcium levels 24 and 48 hours after surgery to be certain that normal levels are maintained. Routine postoperative supplementation of calcium has been advocated by some authors in all patients undergoing thyroidectomy. We prefer to observe the patient clinically and monitor the blood for serum calcium, reserving calcium supplementation for symptomatic patients and those with a significant downward trend in serum calcium levels. Asymptomatic patients are followed with serial calcium levels and close clinical observation. If the parathyroid glands have been preserved in situ, calcium supplements can generally be eliminated within 3 to 4 weeks after the surgical procedure.
Another dreaded complication of thyroid surgery is postoperative hematoma28 which usually occurs between 6 to 24 hours after surgery, leading to increased central compartment pressure and airway distress. It has traditionally been a routine practice to keep a tracheostomy tray by the bedside in the event that the patient develops airway distress. An emergent tracheostomy is rarely indicated in modern practice, since the patient can easily be re-intubated if necessary, prior to exploration. If a wound hematoma is noted, it is generally best to bring the patient back to the operating room, explore the wound, achieve hemostasis, and place a drain. Most of these patients are then ready to be discharged from the hospital within 24 to 48 hours.
There appears to be recent interest in outpatient thyroidectomies, or else discharging the patient within 23 hours after the surgical procedure. There also seems to be some interest in thyroidectomy under local anesthesia. Obviously, the surgeon must be quite familiar with the technique of local anesthesia and the patient must be cooperative. We feel more comfortable performing these surgical procedures under general anesthesia. Drains are not commonly used in patients undergoing routine thy-roidectomy. However, drains are indicated if there is excessive bleeding, or a subtotal thyroidectomy has been performed for Grave's disease (where there is an increased chance of bleeding from the cut surface of the thyroid), or in patients with a large dead space after removal of colloid goiter or substernal goiter. With judicious selection, the author has been able to avoid the use of drains in approximately 70 percent of patients undergoing thyroidectomy.
Clearly, safe and successful thyroidectomy requires meticulous and careful dissection, reinforcing Halsted's statement that the "technique of thyroidectomy reveals the triumph of surgical procedure."
The use of radioactive iodine (RAI) in the diagnosis and management of differentiated thyroid cancer (DTC) is based on the physiologic property of the thyroid follicular cell to trap and retain iodine. Undifferentiated tumors and medullary carcinomas therefore are not amenable to this form of treatment. DTC is reported to take up approximately 0.5 percent of the administered dose of RAI per gram of tissue with a biologic half-life of about 4 days.29 In radiobiologic terms, this delivers approximately five times the absorbed dose of external beam radiation therapy. Also, because of this differential uptake in functioning cells, tumor tissue, including distant metastases, receives a several hundredfold higher dose compared to normal tissue.
Table 14-10 presents some common indications for considering RAI in the management of patients with thyroid cancer. A dose of 3 to 5 mCi of RAI is used for a diagnostic scan that is usually performed 4 to 6 weeks after total thyroidectomy. After a well-executed total thyroidectomy, less than 1 to 2 percent of the diagnostic dose of RAI is generally concentrated in the region of the thyroid bed. Older patients, those with Hürthle cell or poorly-differentiated tumors, and those with bone metastases generally do not benefit from RAI therapy because these tumors do not effectively concentrate RAI. If the RAI scan demonstrates a significant thyroid remnant, 75 to 150 mCi of RAI is administered to ablate this tissue before any further RAI imaging or treatment can proceed.
Patients scheduled for RAI scan, dosimetry or treatment are generally required to be off their supplemental thyroxine for at least 4 to 6 weeks to allow a hypothyroid state to develop. The resultant elevation of serum TSH to around 40 mU/ml creates optimal conditions for any functioning thyroid tissue to concentrate RAI. However, the symptoms of hypothyroidism can be debilitating, and until recently patients either had to endure them, or were switched over to exogenous T3 from their usual dose of thyroxine for 2 to 4 weeks. Exogenous T3 would then have to be discontinued and followed about 2 weeks later by RAI scan and/or therapy. A recent advance has been the use of recombinant human TSH which can be administered exogenously to elevate the patient's serum TSH level with the aim of increasing the RAI-concentrating ability of thyroid tissue. The experience with recombinant human TSH is, however, not mature and initial reports seem to suggest that the traditional hypothyroid approach may be more effective. Other precautions that are important in patients undergoing RAI evaluation or
Table 14-10. INDICATIONS FOR RADIOACTIVE IODINE THERAPY
Ablation of remnant thyroid tissue following total thyroidectomy Gross or microscopic residual disease after surgical resection Adjuvant therapy of bulky cervical nodal metastases to evaluate for pulmonary micrometastases Management of the patient presenting with clinically apparent distant metastases Treatment of distant metastases, especially pulmonary disease therapy include avoidance of iodine-containing food or medication and radiographic contrast.
If imaging does demonstrate the presence of RAI-avid tumor, the appropriate dose for safe and effective treatment needs to be calculated. The therapeutic dose of RAI has usually empirically varied between 100 to 200 mCi depending upon the extent of local and metastatic disease. Dosimetry studies based on the estimated tumor volume and the radio-biologic characteristics of RAI have been reported with some correlation of response rates. However, on a practical basis we prefer to use dosimetry to assess and deliver the maximum tolerable dose of RAI. RAI therapy can be repeated at intervals of 6 to 12 months until there is no longer any demonstrable evidence of functioning disease.
Complications of RAI include thyroiditis that usually resolves within 2 to 3 weeks. Parotitis may also occur but is self-limiting. More serious side effects like bone marrow depression and pulmonary fibrosis are generally associated only with high cumulative doses of RAI.
Following total thyroidectomy and RAI therapy, serial measurements of serum thyroglobulin (TG) can be used to monitor patients for development of recurrent disease. While elevated serum Tg levels in patients receiving thyroxine-suppressive therapy are a relatively reliable indicator of recurrent disease, low or borderline levels do not necessarily exclude recurrence. Skeletal and pulmonary metastases are associated with the highest Tg levels while patients with lymphatic metastases generally have lower levels. Borderline patients should be investigated by taking the patient off exogenous thyroxine to induce hypothyroidism as discussed above. It should be noted that serum Tg estimation is reliable only in the absence of thyroglobulin antibodies.
The parathyroid glands are the smallest of the endocrine glands and yet their proper function in controlling calcium and phosphorus metabolism is vital in normal calcium homeostasis and is avoiding osteo-porosis.30 The routine use of serum multi-channel chemistry has made it possible to document hypercal-cemia in an increasing number of otherwise totally asymptomatic patients—individuals who require further endocrinologic evaluation to rule out primary hyperparathyroidism. The incidence of primary hyper-parathyroidism is 1 out of 700 individuals and occurs most commonly in women above the age of 45.
There is considerable interest in hyperparathy-roidism related to the multiple endocrine neoplasia (MEN) syndromes type I and II. MEN, type I, known as Wermer's syndrome, includes pancreatic, parathyroid and pituitary adenomas; MEN, type II, known as Sipple's syndrome, includes medullary carcinoma of the thyroid, pheochromocytoma, and hyperparathyroidism. MEN, type II is divided into MEN, type IIA and IIB, the latter of which includes mucosal neuromas.30 Most parathyroid tumors associated with the MEN syndromes are functional and only 1 percent are malignant.
Recent advances in management of hyper-parathyroidism relate to the development of more accurate localization studies and investigations such as the quick parathormone assay.31,32 Other advances include minimally invasive parathyroidectomy, minimal access surgery, the use of intraoperative gamma probes for localization, and endoscopic parathyroidectomy.33,34,35
The parathyroid glands develop during the sixth week of gestation, with the superior parathyroids originating from the fourth pharyngeal pouch along with the thyroid gland. They may come to rest behind the upper pole of the thyroid or may descend into the posterior mediastinum. The inferior parathyroid glands develop from the third pharyn-geal pouch along with the thymus, and may remain buried under the thymic capsule. Likewise, the superior parathyroid glands may also be buried under the thyroid capsule.
Approximately 10 percent of individuals have supernumerary parathyroid glands (ranging from five to eight), and approximately 2 to 3 percent of individuals have less than four parathyroid glands. The most common location of the superior parathyroid is on the posterior capsule of the superior pole of the thyroid. Anatomically, the superior parathyroid glands are generally superior and lateral to the
Table 14-11. ANATOMIC LOCATION OF PARATHYROID GLANDS
Superior Parathyroid Glands Inferior Parathyroid Glands
Superior thyroid pole Submanubrial space
Tracheoesophageal groove Thymic fat pad
Behind the esophagus In the thyroid crypt or capsule
Within the thyroid gland recurrent laryngeal nerve while the inferior parathyroid glands are inferior and medial to the nerve. Due to the more tortuous course of their embryologic descent, the inferior parathyroids are more variable in their location as compared with the superior glands (Table 14-11).
The parathyroids are generally oval or irregularly-shaped, tan-colored, small glands that measure between 4.0 to 5.0 mm x 1.0 to 3.0 mm in size. Each parathyroid gland weighs approximately 35 mg. The blood supply to the inferior parathyroid glands generally comes from the branches of the inferior thyroid artery. The superior parathyroid may receive its blood supply either from a branch of the inferior thyroid artery or, occasionally, from the posterior branch of the superior thyroid artery. The inferior thyroid artery branches to the parathyroid glands before dividing into multiple branches and supplying the thyroid gland (Table 14-12).
Although most patients with hyperparathyroidism present with hypercalcemia,36 a variety of disorders may cause hypercalcemia and should be ruled out in the differential diagnosis (Table 14-13). The most common symptoms include vague fatigue, weight loss, discomfort, forgetfulness, and renal stones. The classic symptoms of "bones, moans, groans and psychic overtones" are rarely encountered in modern
Table 14-12. BLOOD SUPPLY TO THE PARATHYROID GLANDS
Superior Parathyroid Glands Inferior Parathyroid Glands
Branch of inferior thyroid artery Branch of the inferior thyroid
Superior thyroid artery artery
Branches from the anastomotic From thyroid gland loop between superior and inferior thyroid artery
Table 14-13. CAUSES OF HYPERCALCEMIA
Metastatic cancer from lungs, kidneys, prostate, breast, etc.
Milk alkali syndrome
Thiazide diuretic therapy
Benign familial hypocalciuric hypercalcemia
Acute Addison's disease
Chronic or acute leukemia
Hyperthyroidism practice. The hallmarks of primary hyperparathy-roidism are high calcium, low phosphorus, and high parathormone serum levels.
Hyperparathyroidism is classified into three groups: primary hyperparathyroidism (which represents intrinsic derangement of the parathyroid gland), secondary hyperparathyroidism, (which refers to a reaction to hypocalcemia generally resulting from renal failure), and tertiary hyperparathy-roidism (which is the autonomous development of parathyroid hyperfunction generally subsequent to secondary hyperparathyroidism in patients with renal failure who may be on long-term dialysis). Evaluation of the intact parathyroid hormone level is extremely important in the diagnosis of primary hyperparathyroidism. Other diagnostic studies such as 24-hour urinary calcium, chloride-to-phosphorus ratio, and urinary cyclic AMP are rarely utilized since the advent of bone densitometry, which is used for assessing the need for surgery in patients with asymptomatic hyperparathyroidism so as to prevent future osteoporosis (Table 14-14).
Bone densitometry is typically performed on the lumbar spine and neck of the femur or distal radius.
The most common pathologic find
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