Geeta Lal,Thomas O'Dorisio,
Ross McDougall,
Ronald J. Weigel
SUMMARY OF KEY POINTS
|
Thyroid Cancer Incidence
Types
Presentation and Diagnosis
Treatment
Adrenocortical Cancer Incidence
Clinical Features
Diagnosis
Treatment
Malignant Pheochromocytoma Incidence
Diagnosis
Biochemical
Imaging
Treatment
Parathyroid Carcinoma Incidence
Diagnosis
Imaging
Treatment
Carcinoid Tumors Incidence
Diagnosis
Imaging Techniques
Special Diagnostic Techniques
Treatment
Pancreatic Islet Cell Tumors Incidence
Diagnosis
Imaging Techniques
Special Diagnostic Techniques
Treatment
|
INTRODUCTION
Cancers of the endocrine glands are uncommon. Endocrine tumors—both benign and malignant—although infrequent, present challenges in diagnosis and treatment. Cancers of the thyroid usually do not alter thyroid function, but abnormal hormone secretion can cause the earliest symptoms or signs in cancers of these others endocrine glands. Abnormal plasma levels of these hormones can be useful in monitoring the effects of therapy, and specific inhibitors of hormone biosynthesis or activity can palliate symptoms significantly without having any effect on tumor growth. Diagnosing and treating endocrine cancers requires oncologists, endocrinologists, surgeons, and other subspecialists to work together. This chapter provides a practical guide to the diagnosis and management of endocrine tumors.
THYROID CANCER
Thyroid cancer is the most common tumor of the endocrine system. The biologic behavior of the different histologic types of thyroid neoplasms varies greatly. Approximately 33,550 new cases of thyroid cancer will be diagnosed in 2007, and about 1530 patients will die from thyroid cancer.[1] Recently published studies indicate that the incidence of this malignancy is increasing, from 3.6 per 100,000 to 8.7 per 100,000 in 2002. However, the mortality rate remains unchanged at 0.5 per 100,000 population. This increase in incidence has been attributed largely to the increased detection of small cancers.[2] In general, thyroid tumors do not exhibit aggressive growth characteristics. Papillary cancer, the most common type in the United States, has an excellent prognosis.
Etiology
External radiation to the cervical region has been found to be a cause of thyroid cancer. This association has been recognized in patients who had thymic irradiation in childhood, in patients who had irradiation for acne in teenage years, and in patients with cancer such as Hodgkin's disease who received neck irradiation. [3] [4] [5] [6] The incidence of thyroid cancer is increased in children who received irradiation to the scalp.[7] Reports from Israel of children who received scalp irradiation to treat ringworm have shown an increase in thyroid cancer compared with siblings and age-matched nonirradiated control subjects.[8] Retrospective phantom studies demonstrate that radiation doses as low as 0.09 Gy could be incriminated as the cause of cancer in these children. In addition, children exposed to radioactive fallout from Chernobyl have shown an increase in thyroid cancer. [9] [10] The radiation doses that originally were blamed were in the range of 1 to 10 Gy, but based on the evidence in patients with Hodgkin's disease, doses as high as 40 Gy are potentially carcinogenic.[11] In laboratory animals, combining radiation with increased thyroid-stimulating hormone (TSH) increases the potential risk.[12] [13] The lag time from radiation exposure to diagnosis of cancer usually is 10 to 20 years; however, periods from 5 to 50 years have been reported. Epidemiologic studies show that between 7% and 9% of patients who received 5 to 10 Gy external radiation develop thyroid cancer.[14] About 20% have a palpable abnormality; therefore, about one third of these nodules are cancers. Patients now are rarely given external radiation to the neck for benign disease, so this association should become uncommon. Patients treated for cancer usually are followed closely, and careful palpation of the neck and measurement of TSH annually is advisable. Radiation to the thyroid from internal sources and diagnostic or therapeutic doses of iodine 131 (131I) have not been associated with an increased incidence of thyroid cancer. However, the recent epidemics of childhood thyroid cancers in Belarus and the Ukraine have a clear connection with the massive release of radionuclides, including radioisotopes of iodine, from the Chernobyl reactor.[15] Almost all of these patients were children at the time of exposure, and there was internal radiation to the thyroid from 131I and other shorter-lived radionuclides of iodine,[16]as well as exposure to external radiation and probably internal radiation from 137Cs. The etiology of these cancers probably is multifactorial, but the data must cause us to reconsider the risks from internal radiation.
There is increasing evidence of genetic alterations in some thyroid cancers, especially in Chernobyl survivors. [17] [18] Approximately 70% of cancers in children following radiation from this nuclear disaster carried RET and papillary thyroid cancer (RET/PTC) rearrangements, the most common of which were RET/PTC1 and RET/PTC3. The latter was associated with a distinct solid growth type and appeared to be more aggressive.[19] A family history of thyroid cancer also is a risk factor for development of this tumor, particularly medullary thyroid cancer. This tumor occurs commonly within the spectrum of multiple endocrine neoplasia (MEN) syndromes 2A and 2B, and familial medullary thyroid cancer syndrome, all characterized by inherited mutations in the RET proto-oncogene.[20] Familial nonmedullary thyroid cancer (FNMTC) is now recognized as a true phenomenon, with several families reported in the literature. Several candidate gene loci for FNMTC have been explored. Bignell and colleagues[21] studied a large Canadian family with 18 cases of nontoxic multinodular goiter and 2 cases of papillary thyroid cancer and noted linkage to MNG1 on 14 q. However, detailed analysis of 37 FNMTC families showed that MNG1 does not account for most cases of this disorder. Linkage analysis in a French family with multinodular goiter and papillary thyroid cancer with oxiphilia revealed TCOon 19p13[22] to be a potential candidate gene in a small number of families. Another group noted linkage to FPTC/PRN on 1q21[23] in a large three-generation pedigree with papillary renal neoplasia, thyroid nodules, and papillary thyroid cancer. There is an association of nonmedullary thyroid cancer and Gardner's syndrome, Cowden's syndrome, and Werner's (adult progeroid) syndrome. [24] [25] Some studies also indicate that individuals with familial nonmedullary thyroid cancer have a worse overall prognosis. [26] [27]
Because of varied incidences of thyroid cancer in different ethnic groups, the role of an environmental factor or factors must be considered. A higher incidence of papillary cancer is found in regions with high dietary iodine intake such as the Pacific rim and Iceland.[28] In contrast, follicular cancer is more prevalent in iodine-deficient countries.
Classification and Prognosis
The most common thyroid cancers are papillary carcinoma and mixed papillary and follicular carcinomas ( Table 75-1 ; Fig. 75-1 A and B), the latter of which are also classified as papillary carcinomas.Occult cancers, now classified as papillary microcarcinoma, are less than 1 cm in size and have been reported in 10% to 30% of autopsy series. These tumors usually were identified at surgery for benign thyroid disease but are being identified more frequently due to the widespread use of ultrasound. They generally are believed to have a better prognosis than larger tumors; however, other studies indicate that these tumors may be more aggressive than previously appreciated. [29] [30]
Table 75-1 -- Histologic Classification of Thyroid Cancers and Their Incidence
|
Tumor Histology |
Incidence (%) |
|
Differentiated carcinomas |
81-87 |
|
Papillary |
|
|
Follicular variant of papillary |
|
|
Follicular and Hurthle cell |
|
|
Medullary |
6-8 |
|
Anaplastic |
5 |
|
Lymphoma |
1-5 |
|
Metastatic |
<1 |
|
Figure 75-1 Histologic patterns of thyroid cancer. A, Papillary carcinoma. B, Pure follicular carcinoma. C, Anaplastic carcinoma. D, Medullary carcinoma. |
Death from papillary cancer is rare, and in most reports nodal metastasis does not adversely influence prognosis.[31] Recent series, however, have demonstrated a slightly lower survival rate with locoregional nodal metastases. [32] [33] The prognosis in intrathyroidal papillary carcinoma depends on the age of the patient and size of the tumor; when the cancer is less than 5 cm in diameter, the prognosis is excellent. [34] [35] Lymph node metastases can occur, but even in patients with nodal metastases only a small percentage of patients die of thyroid cancer.[36] The situation in older patients with larger, more aggressive papillary cancers is different. In patients with local invasion and cancers that cannot be totally resected, the recurrence rate and mortality rate are higher.[34] Death can result from local invasion and extensive metastases; nevertheless, the overall death rate from papillary cancer is low (<10%).[37]
In summary, the prognosis for papillary cancer is better in younger patients and in those with cancers smaller than 2 cm that are intrathyroidal and have no evidence of distant spread. The presence of metastases to lymph nodes has not been a negative prognostic factor in most series, although some series have reported increased recurrence and mortality rates for node-positive patients. Based on simple criteria such as the age of the patient, the size of the primary cancer, and whether local invasion or distant metastases are found, it is possible to determine the prognosis at presentation. Scoring systems such as AGES (age, grade of cancer, extrathyroidal spread, and size) and MACIS (metastases, age, complete excision, invasion, and size) are examples of these approaches.[38] The TNM system also stresses the importance of age at time of presentation. In patients under 45 years of age, those without distant metastases are all stage I, and those with distant metastases are stage II.
Pure follicular carcinoma carries a poorer prognosis. [39] [40] Even when the disease appears confined to the thyroid gland, 5% to 15% of patients ultimately die of cancer, although survival is measured in decades. Lymph node metastases are seen less frequently than with papillary cancers of similar size. Approximately 50% of follicular cancers demonstrate intrathyroidal spread.[41] Follicular cancers cannot be distinguished from follicular adenomas based on fine-needle aspiration biopsies, because the diagnosis is based on the identification of vascular or capsular invasion. Prognosis in follicular carcinomadepends on the patient's age, the size of the cancer, and the amount of capsular and vascular invasion.[42] Minimally invasive tumors are grossly encapsulated but have evidence of microscopic invasion of the tumor capsule and/or invasion into small or medium-sized vessels in or immediately outside the tumor capsule. In contrast, widely invasive tumors are characterized by large vessel invasion and/or broad capsular invasion. Even though exact definitions are variable among pathologists, widely invasive tumors have a worse prognosis.[43]
The incidence of anaplastic carcinoma appears to be decreasing. and this type now represents less than 3% of thyroid malignancies in the United States[44] ( Fig. 75-1C ). This apparent decrease may be secondary to improvement in the techniques available to differentiate thyroid lymphoma and medullary carcinoma ( Fig. 75-1D ) from true anaplastic thyroid cancer. A proportion of patients with anaplastic cancers are immigrants from countries where goiter is common, and the anaplastic cancer probably has arisen from a more differentiated cancer that went undiagnosed for many years. In some cases there is a spectrum from papillary to anaplastic cancer, indicating that anaplastic cancers arise from more differentiated lesions,[45] and earlier diagnosis of the latter also plays a role in the reduced incidence. Anaplastic carcinomas usually occur in persons older than 60 years. These carcinomas are highly malignant and typically cause death within 6 months, either by local invasion or by distant metastases. Cure of anaplastic carcinoma is rare.[46]
Hürthle cell tumors of the thyroid are derived from the follicular cell.[47] Both carcinomas and adenomas of Hürthle cell origin have been described. Hürthle cell cancers often are classified with follicular cancer. As with follicular cancer, the differentiation of Hürthle cell adenoma from carcinoma is based on vascular features, or capsular invasion in the latter. However, Hürthle cell cancers seldom concentrate iodine, and their prognosis is worse, so a separate category is justified. Adenomas have an excellent prognosis with resection, and less than 2.5% are subsequently found to demonstrate malignant behavior. [48] [49] Large (>2 cm) malignant tumors have a recurrence rate of 21% to 59% after surgical resection.[50]
Because of differences in the biology and behavior of thyroid cancers, determinging the prognosis of an individual patient may be difficult. Byar and associates[51] examined the impact of several variables on survival. Age, gender, cell type, clinical extent of cancer, lymph node status, and number of metastatic sites had prognostic significance, but not all were independent variables. However, a prognostic index that mirrored actual data was developed. Thus, in the “best” group (i.e., young patients with small localized differentiated tumors), the 5-year survival rate was approximately 95%, whereas in the “worst” group, which contained many patients with anaplastic carcinoma, the 5-year survival rate was less than 5%. These data agree with those from many other large series. To achieve uniformity in assessing the results of therapy, it is important that a single tumor, node, metastasis (TNM)[52] and clinical staging system be used. Tables 75-2 and 75-3 [2] [3] outline the most recent iteration of the TNM staging system for thyroid cancer. This system takes into account not only the effect of histologic type (papillary/follicular, medullary, anaplastic) on staging but also the negative prognostic effect of advancing age on stage and prognosis in differentiated thyroid neoplasms.
Table 75-2 -- TNM Classification of Malignant Tumors of the Thyroid Gland
|
PRIMARY TUMOR (T STAGE) |
|
|
Tx |
Tumor cannot be assessed |
|
TO |
No clinical evidence of tumor |
|
T1 |
Tumor ≤2 cm limited to the thyroid |
|
T2 |
Tumor >2 cm and <4 cm limited to the thyroid |
|
T3 |
Tumor ≥4 cm limited to the thyroid or any tumor with minimal extrathyroid extension |
|
T4a |
Tumor of any size extending beyong the thyroid capsule to invade the subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve |
|
T4b |
Tumor that invades prevertebral fascia or encases carotid artery or mediastinal vessels |
|
Anaplastic carcinomas[*] |
|
|
T4a |
Intrathyroidal—surgically resectable |
|
T4b |
Extrathyroidal—surgically unresectable |
|
REGIONAL LYMPH NODES (N STAGE) |
|
|
Nx |
Regional nodes cannot be assessed |
|
NO |
No palpable nodes |
|
N1 |
Regional nodal metastases |
|
N1a |
Level VI nodes (pretracheal, paratracheal, prelaryngeal) |
|
N1b |
Metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal nodes |
|
DISTANT METASTASES (M STAGE) |
|
|
Mx |
Metastases cannot be assessed |
|
MO |
No evidence of distant metastases |
|
M1 |
Distant metastases present |
Adapted from Greene FL, Page DL, Fleming ID, et al (eds): AJCC Cancer Staging Manual, 6th ed. New York, Springer-Verlag, 2002.
|
* |
AII anaplastic carcinomas are considered T4 tumors. |
Table 75-3 -- Staging of Thyroid Cancer
|
Stage |
TNM |
|
Patients < age 45 years |
|
|
I |
Any T, any N, MO |
|
II |
AnyT, any N, Ml |
|
Patients ≥ age 45 years |
|
|
I |
T1, N0, M0 |
|
II |
T2, N0, M0 |
|
III |
T3, N0, M0 |
|
T1-3, Nla, MO |
|
|
IVA |
T4a, NO-la, MO |
|
T1-4a, Nib, MO |
|
|
IVB |
T4b, any N, MO |
|
IVC |
AnyT, any N, Ml |
|
MEDULLARY THYROID CANCER |
|
|
I |
T1, N0, M0 |
|
II |
T2-3, N0, M0 |
|
III |
T1-3, Nla, MO |
|
IVA |
T4a, NO-la, MO |
|
T1-4a, Nib, MO |
|
|
IVB |
T4b, any N, MO |
|
IVC |
AnyT, any N, Ml |
|
ANAPLASTIC CANCER |
|
|
IVA |
T4a, any N, MO |
|
IVB |
T4b, any N, MO |
|
IVC |
AnyT, any N, Ml |
From Greene FL, Page DL, Fleming ID, et al (eds): AJCC Cancer Staging Manual, 6th ed. New York, Springer-Verlag, 2002.
Primary lymphoma of the thyroid is not common. It usually occurs in an older woman with untreated Hashimoto's thyroiditis.[53] The condition characteristically presents as a rapidly growing thyroid mass with compressive symptoms and signs and sometimes causes pain. Diagnosis often can be made by fine-needle aspiration and immunophenotyping of the lymphocytic aspirate. Treatment usually consists of chemotherapy in addition to radiation therapy.
Diagnosis
Despite extensive experience with thyroid neoplasms, diagnostic recommendations continue to evolve.[54] In a patient presenting with a thyroid nodule, history and physical examination are important,because a history of radiation exposure to the head and neck or a family history of thyroid cancer should increase the clinician's suspicion of thyroid cancer. In younger patients, a solitary nodule is more likely to be cancerous. The solitary nodule is more likely than a multinodular goiter to be malignant, and a history of recent painless growth is suggestive of cancer. Malignant nodules tend to be harder, and fixation to the underlying structure is suggestive not only of cancer but also of a poorer prognosis. The presence of enlarged cervical nodes also increases the likelihood that a thyroid nodule is malignant. Table 75-4 categorizes the risk factors for a variety of clinical characteristics of thyroid nodules. Patients with nodules demonstrating high-risk characteristics should be referred for surgical resection.
Table 75-4 -- Risk Factors for Malignancy in Nodular Thyroid
|
|
Low RISK ⇆ HIGH RISK |
||||
|
Factor |
1 |
2 |
3 |
4 |
5 |
|
Age |
|||||
|
Elderly |
• |
||||
|
Child |
• |
||||
|
Sex |
|||||
|
Male |
• |
||||
|
Female |
• |
||||
|
Low-dose radiation in childhood |
• |
||||
|
Family history |
• |
||||
|
Cystic mass |
• |
||||
|
Solid mass |
• |
||||
|
Multiple masses |
• |
||||
|
Solitary mass |
• |
||||
|
Growing mass |
• |
||||
|
Stable mass |
• |
||||
|
Hot scan |
• |
||||
|
Cold scan |
• |
||||
|
Warm scan |
• |
||||
|
Fine-needle aspiration (-) |
• |
||||
|
Fine-needle aspiration (+) |
• |
||||
|
Associated cervical adenopathy |
• |
||||
|
Complete resolution in response to thyroid suppression |
• |
||||
|
Partial resolution in response to thyroid suppression |
• |
||||
|
No response to suppression |
• |
||||
Modified from Sessions RB, Diehi WL: Thyroid cancer and related nodularity. In Myers E, Suen J (eds): Cancer of the Head and Neck, 2nd ed. New York, Churchill Livingstone, 1981, p 766.
Laboratory Tests
Except for measurement of calcitonin in the diagnosis of medullary carcinoma, assessment of plasma levels of thyroid hormones has limited value in the diagnosis of thyroid cancer except in the rare patient who has a suppressed TSH and has a functioning nodule. Serum thyroglobulin (Tg) levels can be elevated in patients with cancer, but this test is not specific, and similar increases are seen in benign thyroid disorders. The American Thyroid Association guidelines do not recommend measurement of Tg preoperatively.[55] However, serum thyroglobulin is an important test in the follow-up of patients who have undergone thyroid resection for differentiated thyroid cancer. A level greater than 2 ng/mL with a suppressed TSH or 10 ng/mL while off thyroid hormone is a reliable indicator of locally recurrent or metastatic disease [56] [57] and could predict the need for ablative doses of 131I; undetectable values (<0.5 ng/mL), especially after TSH stimulation, greatly reduce the need for further imaging studies to detect presumptive metastases.[58]
In patients who are hyperthyroid with a nodule, scanning with 123I is advised; hyperfunctional or “hot” nodules rarely are malignant.[59] There is one exception to this rule: a functioning nodule in a child has a higher risk of being cancerous.[60] In contrast, patients with Graves’ disease can have a nonfunctioning nodule, which can be malignant and should be investigated by fine-needle aspiration.[61] In euthyroid patients, fine-needle aspiration is the best first test.[62] Although “hot” nodules rarely are malignant, approximately 10% to 20% of “cold” nodules are malignant. Thyroid radionuclide imaging, therefore, has limited efficacy in distinguishing reliably between benign and malignant abnormalities. Differentiated thyroid cancers will trap iodine but are less efficient at concentrating iodine than the normal thyroid gland. Therefore, iodine uptake in a thyroid cancer typically can be demonstrated only after all normal thyroid tissue has been ablated and the TSH level is allowed to rise. There can be biochemical, quantitative, and intracellular positional alterations in the sodium-iodide symporter (NIS) in thyroid cancer cells.[63] Ultrasonography may be useful in distinguishing among cysts, cystic tumors, and solid tumors of the thyroid.[62] Small cysts are unlikely to be cancerous, but all cysts should be aspirated and the aspirate examined cytologically. Aspiration of a benign cyst often will suffice forboth diagnosis and therapy, whereas fluid tends to reaccumulate in a cystic cancer. Because a malignant tumor of the thyroid may present as a solid, cystic, or mixed lesion, ultrasonography alone is not diagnostic.[64]
Needle biopsy, particularly fine-needle aspiration, is the diagnostic procedure of choice for thyroid nodules in euthyroid patients.[62] When the result of fine needle aspiration biopsy is clearly positive or clearly negative, the decision regarding surgery, or no surgery, can be made confidently. [65] [66] However, a negative fine-needle biopsy or cutting needle biopsy does not ensure that a thyroid mass is not malignant (false-negative rate, 1% to 5%), and clinical concern and careful follow-up will dictate the decision to proceed to resection. Fine-needle aspiration biopsy appears to be less reliable in patients with a history of radiation exposure to the head and neck or a family history of thyroid cancer, primarily due to the multifocal nature of the tumors present in these scenarios.[67] High-resolution ultrasound guidance to perform fine-needle aspiration accurately is being used routinely. Ultrasound alone can identify features of nodules that increase the a priori risk of malignancy such as fine stippled calcification and enlarged regional nodes, but a tissue diagnosis is strongly recommended prior to thyroidectomy. The common indications for ultrasound-guided fine-needle aspiration are for biopsy of nodules that are nonpalpable or difficult to palpate, for previously failed fine-needle aspiration, and for nodules incidentally identified during neck imaging for other reasons. Ultrasound-guided fine-needle aspiration has been shown to result in improved cancer diagnosis on significantly smaller nodules compared with fine-needle aspiration performed by palpation.[68]
Treatment
Treatment of thyroid cancer includes surgery, 131I radiation, and suppression with thyroid hormone. [39] [69] External-beam therapy also (rarely) has been employed.
Surgery of the Thyroid
Debate continues concerning the optimal surgical treatment of well-differentiated thyroid carcinoma. Preoperatively, the surgeon often cannot be certain whether a thyroid nodule is cancer, and must make a decision concerning the extent of operation based on clinical judgment. Young patients with small, well-encapsulated tumors that appear benign on frozen section, with a normal contralateral lobe, can be treated with lobectomy. A history of neck irradiation, the presence of contralateral disease, and cytologic or histologic findings suggestive of malignancy influence the decision to perform a total or near-total thyroidectomy. The location of the parathyroid glands and recurrent nerve also can influence the extent of lobectomy on the contralateral lobe. When a diagnosis of thyroid carcinoma is clear, a total or near-total thyroidectomy is preferred. [70] [71] [72] The rationale for this decision is based on several facts related to the biology of thyroid carcinoma. First, thyroid cancer often can be multicentric, and resection of the contralateral lobe often identifies malignancy. Second, a total thyroidectomy can be performed safely with a low morbidity rate. Patients with thyroid carcinoma will be treated with thyroid replacement postoperatively, regardless of whether an adequate, normal-functioning thyroid is left intact. Resection of the entire gland facilitates both the use of radioiodine postoperatively and the use of thyroglobulin levels as a tumor marker. Because papillary cancer often metastasizes to regional lymph nodes, if enlarged nodes are identified at thyroidectomy, a midneck dissection on the ipsilateral side is performed at resection. Follicular cancer rarely demonstrates lymph node metastases, and a midneck dissection is not routinely justified during thyroidectomy. Modified neck dissection is advocated only in instances of obvious nodal metastases involving the lateral cervical nodes.
Debate continues as to whether recurrence and fatality are influenced by the extent of surgery. [73] [74] A study by Van Nguyen and associates[75] showed that for low-risk patients total thyroidectomy gave results identical to those with lobectomy. Shaha and associates[76] reported 1038 patients with thyroid carcinoma, 465 of whom were in the low-risk group. The mean follow-up period was 20 years. Their study did demonstrate significant improvement in local recurrence with lobectomy compared with less extensive operations. However, results for lobectomy compared with those of total thyroidectomy failed to achieve significance, with local recurrence of 4% versus 1% (P = 0.1) and overall failure of 13% versus 8% (P = 0.06). However, these studies did demonstrate a trend for total thyroidectomy giving superior results when compared to lobectomy. Sanders and Cady[35] did not demonstrate a difference in survival comparing total thyroidectomy and lobectomy in low-risk patients. Of particular interest is the study by Wanebo and associates,[77] who examined extent of operation for low, intermediate-, and high-risk groups. Their work failed to demonstrate any difference in survival with extent of operation in all risk groups.
Other studies have demonstrated improved outcome with total thyroidectomy. Samaan and associates[78] examined 1599 patients with well-differentiated thyroid carcinoma and reported improvement in recurrence for total thyroidectomy compared to lesser operations. DeGroot and associates[34] demonstrated a decreased recurrence rate for total thyroidectomy compared with lobectomy and a significant improvement in mortality rate. Mazzaferri and Jhiang[33] reported their study of 1355 patients with a mean follow-up of 15.7 years. They reported significant improvements in recurrence rate (26% vs. 40%; P < 0.002) and mortality rate (6% vs. 9%; P = 0.02) comparing total thyroidectomy with lesser procedures. Loh and associates[79] reported their results in 700 patients with a mean follow-up period of 11.3 years. They demonstrated significant improvement in recurrence and mortality rates with total thyroidectomy or near-total thyroidectomy compared with lesser operations, particularly for advanced tumors. Given these reports, and the fact that accurate risk-stratification of patients preoperatively is not possible, it is recommended that all patients with differentiated thyroid cancers identified preoperatively undergo a near-total or total thyroidectomy, provided the procedure can be accomplished with minimal morbidity.
A thyroidectomy begins with the patient anesthetized in the supine position with the neck in extension ( Fig. 75-2 ). A Kocher collar incision is made, and dissection is carried out through the platysma. Superior and inferior flaps are raised by dissection in the avascular plane deep to the platysma muscle, superiorly to the level of the thyroid cartilage and inferiorly to the suprasternal notch. Strap muscles can be divided in the midline. It rarely is necessary to transect either the strap muscles or the sternocleidomastoid muscle. The thyroid lobe is exposed using blunt dissection. Occasionally, it is necessary to resect en bloc regions of muscle invaded by tumor. The thyroid lobe is reflected medially and the middle thyroid vessels are ligated. The isthmus can be divided between clamps and ligated early in the procedure; this often facilitates dissection, particularly for large goiters. Branches of the superior pole vessels are identified close to the superior pole and ligated individually to avoid injury to the external branch of the superior laryngeal nerve. Once the superior pole is mobilized, the recurrent nerve is identified by careful dissection in the region of the inferior thyroid artery. The parathyroid glands should be sought and left with their blood supply intact. The parathyroid glands usually can be identified within 1 cm of the crossing of the recurrent laryngeal nerve and the inferior thyroid artery. Occasionally, a parathyroid gland is devascularized; after confirmation of identity by frozen section, this gland can be reimplanted into the sternocleidomastoid muscle. The inferior thyroid pole also is mobilized by a combination of blunt dissection and ligation of the inferior thyroid vessels. The thyroid then is dissected off the trachea until the ligament of Berry is reached. This structure often contains small vessels, and the nerve is most vulnerable in this location. Once the ligament is carefully divided, the thyroid can easily be separated off the trachea. The contralateral lobe always should be exposed to examine for gross pathologic processes. A total thyroidectomy is completed by performing the contralateral lobectomy in a fashion identical to that used for the ipsilateral lobe. Occasionally, to preserve the blood supply to the parathyroid glands, it is reasonable to perform a subcapsular dissection of the contralateral lobe, leaving a small area of thyroid in the region of the parathyroid gland. This procedure is referred to as a near-total thyroidectomy.
|
Figure 75-2 Thyroidectomy. A, The patient is placed with the neck in extension. The thyroid is approached through a Kocher collar incision, which is commonly made approximately 2.0 cm superior to the sternal notch. B, The strap muscles are divided in the midline to expose the thyroid gland. C, The strap muscles are retracted laterally and the thyroid is retracted medially, exposing the structures of the midneck. The recurrent laryngeal nerve can be seen lying within the tracheosophageal groove. D, The superior pole vessels are individually clamped and ligated as they enter the thyroid gland. Inferior thyroid vessels, as well as the thyroidea ima vessels, are individually suture-ligated. E, The dissection is completed by dissection of the thyroid gland off the trachea. The isthmus is then transected and can be oversewn with a suture for hemostasis. |
Radiation Therapy
Metastatic cancer shown to accumulate 131I warrants treatment with 100 to 200 mCi of 131I. Radioiodine treatment is accomplished by discontinuing thyroid hormone replacement and allowing the patient to become hypothyroid, with resultant TSH stimulation of metastases to achieve increased uptake of 131I. A low-iodine diet is advised for 2 weeks prior to testing and treatment. Figure 75-3 shows an example of a radionuclide scan in a patient with pulmonary metastases from papillary thyroid carcinoma. Most authorities obtain a whole-body scan with a diagnostic dose of 131I, or 123I before treatment with 131I. That scan provides information about the quantity of residual thyroid tissue and the presence of local or distant metastases. The information helps in the selection of the appropriate therapeutic dose of 131I. Knowledge of normal and variants of normal distributions of iodine help ensure that interpretation of the scan does not produce a “false” positive. [69] [79] In Figure 75-4 a whole-body scan shows metastases in cervical lymph nodes. In contrast, Figure 75-5 shows uptake in the mediastinum indicating the thymus, not nodal metastasis.[80] Following administration of 131I, thyroid replacement therapy is restarted. This cycle can be repeated at 6- to 12-month intervals. Residual thyroid and locally invasive thyroid cancer can be eliminated, but success is related to extent of thyroidectomy. [81] [82] [83] Similarly, functioning metastases in lymph nodes can be eliminated [84] [85] [86]; however, when the nodes are palpable it is recommended that they be removed.[87] Small homogeneous pulmonary metastases can be cured, but in bulky distant lesions, especially in the skeleton, cure is uncommon. [88] [89] Recent data have failed to demonstrate an improved disease-specific survival or disease-free survival in patients with Stage I thyroid cancer treated with 131I. [36] [90]
|
Figure 75-3 I scan in a patient with metastatic papillary thyroid cancer demonstrating diffuse pulmonary metastases from papillary thyroid carcinoma. Anterior and posterior views are shown. |
|
Figure 75-4 A, Whole-body scan acquired 24 hours after administration of 2 mCi 123I. B, Spot view of the neck and chest. There are several areas of uptake indicative of residual thyroid and functioning metastases in cervical lymph nodes. C, Post-therapy scan made 7 days after administration of 150 mCi 131I. There is intense uptake in the region, but the resolution is not as good as with 123I. There is faint uptake in the liver on the post-treatment scan due to metabolism of radioiodinated thyroid hormones at that site. |
|
Figure 75-5 Whole-body scans of a patient who had total thyroidectomy and 131I for thyroid cancer (left). Spot views of the neck and chest (right). The lower panel has markers at the chin and mid-sternum to help anatomic interpretation. The patient was treated with a second dose of 131I because of an elevated Tg level. This post-treatment scan shows no uptake of 131I in the neck, but there is physiologic uptake in the salivary glands and uptake in the mediastinum. The mediastinal uptake is characteristic of the thymus and is a potential false positive finding. |
A number of controversial topics are related to radioiodine therapy:
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Park and associates[91] showed in a small number of patients that large diagnostic doses, especially 5 to 10 mCi, can “stun” the thyroid, and subsequent therapy is not trapped as expected. In a comparison of 300 diagnostic scans made with 2 mCi 131I and subsequent post-therapy whole-body scans, possible stunning was found in only 2%.[92] In two of the four patients, the follow-up scan was negative, so stunning probably had not occurred. |
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• |
Is it necessary to conduct a diagnostic whole-body scan? Because of the report of Park and associates, some physicians prescribe 131I therapy without a prior diagnostic scan. This practice could result in treating patients who do not require therapy, and, furthermore, it does not allow tailoring of the dose. For those concerned about stunning, 123I provides superior images and substantially less radiation to the residual thyroid, making stunning extremely unlikely. [93] [94] |
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• |
How should patients who have a negative diagnostic scan but have elevated thyroglobulin be treated? A small number of patients have been treated with large doses of 131I when the prior diagnostic scan was negative but serum thyroglobulin was elevated.[95] The rationale is that cells producing thyroglobulin can trap enough 131I to expect a therapeutic effect. These patients are then followed by serum Tg measurement and are re-treated when the thyroglobulin remains high. On the other hand, both high-resolution neck ultrasounds and positron emission tomographic (PET) scans, particularly when combined with CT scans, have shown utility in identifying sources of increased Tg in patients with biochemical evidence of recurrent or persistent disease but negative 131I scans. [96] [97] Figure 75-6 shows a PET scan that was performed to stage the extent of an anaplastic cancer and is presented to demonstrate the superb resolution. |
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Figure 75-6 PET scan of a 75-year-old woman with anaplastic cancer of the thyroid. Images were acquired 1 hour after intravenous injection of 15 mCi 18F-fluorodeoxyglucose (FDG). There is intense uptake of FDG in the undifferentiated cancer. |
Radioactive iodine treatment generally is well tolerated. Some patients develop swelling of the salivary glands, which can be reduced or prevented by having them suck lemon candy. A dry mouth can be a troubling aftermath. Leukemia has been reported to occur following 131I when given in repeated doses and at shorter intervals than is currently advised.[98] Although there have been reports of pulmonary fibrosis developing when uptake in pulmonary metastases was extensive, the risk of dying from pulmonary metastases is significantly greater. Radiation safety precautions are necessary. The patient should be kept isolated until the body load of 131I is reduced. This approach requires consultation among the patient, the family, and a nuclear medicine physician.
Some studies have examined the use of recombinant human TSH (rhTSH) as an alternative protocol in preparation for 131I treatment. Treatment with rhTSH has been shown to induce increased Tg and improved uptake of iodine in a manner similar to induction of hypothyroidism.[99] However, in a recent study of 127 patients in whom rhTSH and thyroid hormone withdrawal were compared, induction of hypothyroidism was found to be superior to rhTSH.[100] Patients treated under the rhTSH protocol do avoid the symptoms associated with hypothyroidism. We have used rhTSH in more than 160 patients and have found it can replace withdrawal scans provided both the scan and Tg are obtained. The average TSH is well above 100 IU/mL. RhTSH treatment was preferred by the patient over withdrawal of thyroid hormone in all but one patient.[101] In addition, improvement in the treatment protocol with rhTSH may result in improved efficacy.[102] Although 131I is the mainstay of radiation treatment of thyroid carcinoma, external-beam radiation also plays a role in the treatment of this disease. [103] [104] Persistent or recurrent thyroid cancer may fail to take up 131I, especially tumors that recur after multiple radioactive iodine treatments. Extremely bulky tumors may fail to be completely controlled with 131I, and the treatment of anaplastic thyroid cancer[105] almost always includes external-beam treatment. Radiation therapy also is useful for bony metastases not amenable to resection.[106] Treatment of the thyroid tumor bed involves both sides of the neck and the upper mediastinum. Minimal residual disease (positive surgical margins or small gross residual in an 131I-negative tumor) can be treated with 60 Gy, whereas larger amounts of disease will require doses of 65 to 70 Gy. Because the target volume wraps around the spinal cord and the tolerance of that structure is only 45 Gy, the dosimetry of thyroid bed irradiation is extraordinarily challenging. Figure 75-7 illustrates the type of complex radiation therapy performed for this disease.
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Figure 75-7 External beam radiation for thyroid carcinoma can be quite complex. On the left, the target for this bulky thyroid carcinoma is marked with a dashed line. The high-dose volume (95% dose line) encompasses this target while avoiding the spinal cord. The radiosensitive spinal cord is in the 60% isodose line, which permits delivery of doses up to 70 Gy with this plan. On the right is a superimposition of the six cross-firing fields that are used to create this dose distribution. The fields either avoid the spinal cord or include a lead block to shadow the spinal cord, protecting it from the high-dose radiation. The treatment planning and dosimetry of thyroid carcinoma treatment is one of the most complex challenges in radiation oncology. |
Use of Thyroid Preparations for Suppression of Thyroid-Stimulating Hormone
Differentiated thyroid cancers respond to TSH by growing, producing, and secreting Tg and by trapping more iodine. Conversely, suppression of TSH can slow or reverse growth and lower Tg. Some reports suggest that thyroxine suppression of TSH decreases recurrence after thyroid resection for differentiated carcinomas.[107] When using the strategy of TSH suppression, it is important to follow plasma TSH levels to ensure an adequate thyroxine dose. In patients who have been adequately treated by surgery or radioiodine and who have no clinical evidence of disease, a negative 131I scan, and undetectable Tg, it is debatable whether suppressed TSH adds any benefit, and side effects of long-term TSH suppression such as anxiety, bone loss, and arrhythmias have to be considered, particularly in older patients.
Postirradiation Tumors
The natural history of postirradiation thyroid carcinoma has been reviewed by Roundebush and DeGroot.[108] Patients tend to be younger (mean age, 28 years) and have a higher incidence of multifocal tumors. This study and others[109] have contributed to the development of treatment recommendations for persons known to have been exposed to ionizing radiation. When palpation of the neck is normal, the patient is followed by careful clinical examination at yearly intervals. The value of a thyroid scan has not been proved. When a discrete nodule is noted, fine-needle aspiration is indicated, and if the result is suspicious, the patient is referred to surgery. In the case of small benign nodules, clinical follow-up with or without thyroid hormone is appropriate. Shimaoka[110] noted that exogenous thyroid hormone caused shrinkage of the nodules in about 50% of cases. Some authorities recommend thyroidectomy for patients with a history of radiation exposure and a thyroid nodule, skipping fine-needle biopsy due to the high rate of false-negative biopsy in this setting.[111]
Schneider and associates,[112] reporting on a large surgical experience with postirradiation thyroid carcinoma, found results similar to those noted for spontaneous thyroid cancers. Because many thyroids have multifocal disease, the surgeon usually cannot perform lobectomy for an apparent single nodule, and in general, when there is preoperative suspicion of thyroid cancer, total or near-total thyroidectomy is advised. Schneider and associates[112] found that the likelihood of nodules developing in the remnant following subtotal thyroidectomy was 36%. The risks of total thyroidectomy (i.e., damage to the laryngeal nerve and hypoparathyroidism) must be balanced against the slow growth of papillary carcinoma and the potential for cure.
Chemotherapy
Cytotoxic drug treatment for metastatic thyroid cancer has not been evaluated extensively. The largest experience is with anaplastic carcinomas, which have high growth rates and a very poor prognosis. Doxorubicin is the most active single agent in both medullary and nonmedullary carcinomas of the thyroid. [105] [113] In a report from the Southwest Oncology Group, the combination of doxorubicin and cisplatin resulted in an objective response in 27% of 41 patients.[114] A similar trial reported by the Southeastern Cancer Study Group, however, failed to document this level of activity, with only two partial responses out of 22 subjects.[115] Novel therapies currently being investigated for the treatment of thyroid cancers refractory to other treatments include tyrosine kinase inhibitors targeting RET/PTC translocations[116] and angiogenesis inhibitors. [117] [118] A small phase II clinical trial has shown that treatment with rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist resulted in increased radioactive iodine uptake in 4 out of 10 patients with persistent thyroid cancer that was radioactive iodine scan negative at study initiation.[119]
MEDULLARY CARCINOMA OF THE THYROID
Medullary thyroid carcinoma (MTC) arises from the parafollicular C cells, which are part of the amine precursor uptake decarboxylation (APUD) system, rather than thyroid epithelial cells (see Fig. 75-1D). Medullary thyroid carcinoma accounts for 6% to 10% of all thyroid cancers. It can occur sporadically or in a familial form, either as part of multiple endocrine neoplasia type 2 (MEN-2) or as a familial MTC without MEN association. The gender distribution is approximately equal. The tumor is unilateral in most sporadic cases and bilateral and multifocal in familial cases. [120] [121] [122]
Diagnosis
Any thyroid nodule could be MTC ( Fig. 75-8 ); however, a family history of MTC, pheochromocytoma, hyperparathyroidism, or other manifestations of MEN-2 increases this likelihood. Plain film radiography of the neck may be useful. Keiser and associates[123] reported that tumor calcification was present in 35% of the patients in their series. Lymph nodes often are enlarged clinically and at surgery are involved pathologically in two thirds of patients.[124] Amyloid deposition between the spindle-shaped tumor cells is characteristic of MTC. The presence of calcitonin messenger RNA (mRNA) has been used to diagnose MTC when the histologic type is unclear.[125] The molecular diagnosis of MEN-2 is discussed later in this chapter. The parafollicular C cells secrete calcitonin, a peptide hormone that inhibits bone resorption. Calcitonin secretion is stimulated by calcium infusion. In patients with MTC, the basal calcitonin level is elevated above normal[126] and can be increased further with infusion of calcium and pentagastrin. The few cases of MTC that exhibit normal basal plasma calcitonin levels demonstrate an exaggerated response to calcium and pentagastrin. [126] [127] The excessive calcitonin secretion does not appear to exert any metabolic effect. In the familial form, the associated parathyroid hyperplasia is an independent manifestation of the MEN syndrome inasmuch as it may precede MTC. MTC tumors also may contain large quantities of histaminase[128] and dopa-decarboxylase,[129] neither of which produces any clinical syndrome. Serum histaminase is increased in many patients with metastatic disease, and its presence suggests metastases.[130] The diarrhea that occasionally accompanies the syndrome has been attributed in some studies to prostaglandin secretion,[131] but other investigators have not found this association.[132] Other compounds secreted by C-cells include carcinoembryonic antigen (CEA), corticotrophin, vasoactive intestinal peptide, and serotonin. MTC is one cancer in which it is possible to recognize the precancerous state. In the familial form, C-cell hyperplasia occurs prior to the development of carcinoma,[133] making it crucial for the physician to measure basal and stimulated calcitonin levels in all family members of a patient with MTC. Stimulation tests performed with calcium or pentagastrin predicted MTC in 12 members of one family, 11 of whom had no clinical evidence of disease. [134] [135] Similarly, Jones and Sisson[136] were able to identify eight children, whose disease was diagnosed by appropriate testing, who were members of a family with the MEN-2 syndrome. However, these stimulation tests were associated with unpleasant side effects that could potentially affect compliance with annual provocative testing in members of MTC families. Because mutations in the RET proto-oncogene have now been established in MEN-2, family members can be screened at birth, obviating yearly provocative testing and allowing affected members to be offered early thyroidectomy.[137]
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Figure 75-8 Diagnosis of a thyroid mass. |
Treatment
Treatment of MTC is surgical excision. Because the cancer often is multifocal, surgery should include total thyroidectomy with complete resection of nodes in the central neck, that is, between the carotid sheaths laterally and from the thyroid cartilage superiorly to the suprasternal notch inferiorly. This includes paratracheal and upper mediastinal lymph nodes as well. If the patient presents with palpable lymph node disease, an ipsilateral modified radical neck dissection is also performed. Since the rate of contralateral lymph node metastases in this setting is high, some authors advise a prophylactic contralateral lymph node dissection, whereas others advise following postoperative calcitonin levels. In the absence of palpable disease, prophylactic modified radical neck dissection is recommended for primary tumors larger than 1.5 cm. [138] [139] Deftos and Stein[140] have reported that 131I treatment is occasionally a useful adjunct to surgery when a calcitonin-secreting remnant is identified following total thyroidectomy; however, subsequent studies have failed to show any benefit from 131I.[122] The cancer per se does not trap iodine. Because pheochromocytomas occur in the MEN-2 syndrome, it is necessary to exclude their presence in MTC patients, as thyroid surgery in a case with an undetected pheochromocytoma could be disastrous. An identified pheochromocytoma should be removed first and the patient given time to recover before the MTC is excised.
The clinical course in cases with metastatic MTC is variable. Death due to lung, liver, or bone metastases may occur quite quickly. However, it is not uncommon for patients with MTC to be relatively asymptomatic, even with large tumor burden. Many patients may be debilitated by intractable diarrhea,[132131] which correlates with plasma calcitonin levels of greater than 20 ng/mL and which may be palliated by cytoreductive surgery[141] or the somatostatin analog octreotide.[142] Other therapies that have shown promise in small clinical trials include an anti-CEA antibody (Labetuzumab) [143] [144] and tyrosine kinase inhibitors STI571 (Imanitib) and SD6474 (Zactima). STI571 has been used as therapy for gastrointestinal stromal tumors and has shown some efficacy against medullary thyroid cancer cells in vitro, however the doses needed to achieve inhibition indicate that it is less likely to be useful in clinical studies. [145] [146] SD6474 is an orally administered tyrosine kinase inhibitor that has shown activity against medullary thyroid cancer in a small phase II study. About 26% of patients had evidence of partial response by CT criteria. [20] [147]
ADRENOCORTICAL CANCER
Adrenocortical carcinoma is infrequent, representing less than 0.2% of all cancers,[148] and has an incidence of only 2 per 1 million population.[149] Adrenal cancer may develop at any age but most frequently appears in middle age. Hormonally functional tumors are slightly more common in women, and nonfunctioning tumors are more frequent in men. Although both functioning and nonfunctioning adrenal tumors occur, steroid-producing tumors [148] [150] are more common. Secreted hormones include cortisol, androgens, estrogens and aldosterone, with up to 35% of tumors secreting multiple hormones. Nonfunctioning tumors are usually diagnosed after the patient has complained of pain or presents with a large abdominal mass. The combination of retroperitoneal location and inefficient steroid biosynthesis makes it likely that adrenal cancers will attain a large size before symptoms due to the mass or to hormonal secretion are noted. Thus, early detection and cure are unlikely. [148] [150]
Clinical Features
Adrenocortical carcinomas may or may not produce steroid hormones. However, the steroid-synthesizing potential of adrenal tumors explains many of their laboratory and clinical features. For example, many women with functional adrenal cancers are virilized. This finding derives from the fact that the biosynthetic pathway to C19 steroids is almost always intact in functioning adrenal cancers, resulting in high urinary 17-ketosteroid (17-KS) excretion. Because adult men cannot be “hypervirilized,” excessive androgen synthesis will not be clinically apparent in them unless urinary 17-KS or plasma androgens are measured. However, women are easily virilized, and this detection bias may account to some extent for the apparent predominance of functional tumors in women. Table 75-5 lists the hormonal syndromes produced by adrenal cancer, with estimates of their frequency. Specific diagnostic features of these syndromes are described in the following paragraphs.
Table 75-5 -- Clinical Syndromes Produced by Adrenocortical Cancer and Their Frequency
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Syndrome |
Frequency (%) |
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Virilization and Cushing's syndrome |
50 |
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Virilization |
25 |
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Cushing's syndrome |
20 |
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Feminization |
<5 |
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Precocious puberty |
<5 |
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Hypokalemia alkalosis |
<5 |
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Hypoglycemia |
<5 |
Cushing's Syndrome
The characteristic endocrine abnormality of Cushing's syndrome is an increase of plasma 11-deoxycortisol and its urinary metabolite.[150] Cushing's syndrome may be a paraneoplastic syndrome associated with ectopic adrenocorticotropic hormone (ACTH) production by solid tumors. However, in such cases, virilization is rare. Virilization in association with Cushing's syndrome almost always indicates adrenal cancer,[151] because urinary 17-KS secretion ranges from 100 to 1000 mg/day—considerably higher than that produced by ectopic ACTH.
Virilization
Virilization is caused by testosterone, which is synthesized peripherally from adrenal androstenedione and dihydroepiandrosterone. It is the excess urinary 17-KS resulting from metabolism of these steroids that helps distinguish adrenal cancer from other virilizing syndromes. Occasionally, hirsutism is the only presenting feature with virilizing tumors.
Feminization
Plasma androstenedione may be converted peripherally to estrogen, a phenomenon that results in gynecomastia. Feminization with adrenal cancer is unusual. The relatively few cases in the world literature have been summarized.[152] Rates of aromatization are low; therefore, large quantities of androstenedione are required to produce significant plasma estrone concentrations. The major fraction of androstenedione is metabolized to urinary 17-KS. Thus, measurement of urinary 17-KS will distinguish the feminization caused by adrenal carcinoma from the gynecomastia seen with human chorionic gonadotropin (hCG)-producing tumors of the testis and with hCG-producing cancer. One should also be aware that prepubertal adrenal cancers have been reported to produce hCG in quantities large enough to cause a positive result in pregnancy testing.
Precocious Puberty
In children, precocious puberty or virilization may be an important and presenting clinical finding because androgens are the predominant products of adrenal cancer secretion. Isosexual precocious puberty in boys and virilization in girls are usual. A few cases of feminizing adrenal cancer causing isosexual precocious puberty have been reported in girls.[153]
Sodium Retention and Hypokalemic Alkalosis
Rarely patients with adrenal cancer will present with the picture of primary hyperaldosteronism. Most patients with Conn's syndrome have either idiopathic hyperaldosteronism (IHA) or an aldosterone-producing adenoma (APA). Carcinomas that secrete aldosterone are rare, although a syndrome of mineralocorticoid excess may be caused by secretion of deoxycorticosterone. [151] [154] [155] In this situation, urinary 17-KS is high, and the tumor is generally much larger than the APA.
Hypoglycemia
As with other large mesenchymal tumors in the abdomen, adrenal cancer may cause hypoglycemia. Measurement of plasma insulin levels will rule out insulin-secreting tumors as a cause of hypoglycemia.
Diagnosis
The diagnosis of adrenal cancer depends on clinical suspicion, urinary and plasma biochemical tests, and diagnostic imaging studies ( Fig. 75-9 ). The size of the adrenal mass is important because in masses larger than 6 cm, the incidence of cancer has been reported to be 35% to 98%.[156] Copeland demonstrated that 92% of 114 examined adrenocortical cancers were >6 cm.[157] The sensitivity, specificity and likelihood ratio of tumor size in predicting malignancy (based on SEER data) was recently reported as 96%, 51% and 2 tumors = 4 cm; and 90%, 78% and 4.1 tumors = 6 cm.[158] The most useful imaging tests are CT scan, ultrasonography, and MRI. The CT scan also defines local extent of cancer, thereby facilitating surgical planning. Evidence of calcification in an abdominal mass on CT scan or plain abdominal film suggests adrenal carcinoma. MRI scanning can define the presence or absence of regional extension and influence the decision in regard to resectability. The characteristics of the adrenal mass on T2-weighted MRI scanning can be useful in distinguishing adenomas and pheochromocytoma from carcinomas or metastatic cancer to the adrenal gland. [159] [160] Iodocholesterol imaging is not useful[161] because steroid synthesis rates are low. More recently, PET scans have been used to identify malignant and metastatic lesions but these results need further validation.
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Figure 75-9 Diagnosis and treatment of adrenal carcinoma. ACTH, adrenocorticotropic hormone. |
Pathology
Adrenal cancers are frequently large and can weigh more than 100 g. They can be locally invasive into kidney, liver, and large blood vessels,with the inferior vena cava involved in many cases of right adrenal tumors. Grossly, the tumor is yellow to tan, with areas of necrosis and hemorrhage. Cytologically, it may be difficult to distinguish carcinoma from adenoma. [162] [163] The tumor cells vary in configuration from spindle-shaped in less differentiated cancers to large polyhedral cells with abundant eosinophilic cytoplasm. Mitoses can be rare; some variation in nuclear morphology may be evident in both adenomas and carcinomas. Capsular invasion or blood vessel invasion is the most reliable sign of cancer. The combination of the following nine criteria was studied by Weiss and associates for usefulness in distinguishing malignant from benign adrenal tumors: nuclear grade III or IV; mitotic rate greater than 5/50 high-power fields; atypical mitoses; clear cells comprising 25% or less of the tumor; a diffuse architecture; microscopic necrosis; and invasion of venous, sinusoidal, and capsular structure. Tumors with four or more of these criteria were likely to metastasize and/or recur. [164] [165] The diagnosis of malignancy of a completely resected adrenal tumor, however, may be made only in retrospect by the finding of metastatic disease many years later. Patterns of steroid secretion cannot be predicted by histologic or histochemical characteristics of adrenal neoplasms.
Primary Treatment and Prognosis
The only curative therapy for adrenal cancer is aggressive en bloc resection of the primary tumor including the ipsilateral kidney.[166] This approach is attempted only in patients who have relatively limited cancers deemed to be potentially resectable.[167] Even with this approach, adrenocortical cancer is highly lethal, with a 5-year survival rate of 20% to 30%.[168] Fifty percent of patients have metastaticdisease at diagnosis. In patients with incurable adrenal carcinoma, suffering from symptoms secondary to tumor bulk or hormone excess, partial resection of tumor may offer significant palliation. In a minority of cases, the course may be indolent, with metastases developing over a period of 5 to 10 years. Metastases occur in lung, liver, and peritoneum, but uncommonly involve brain or bone.
Therapy for Metastatic Disease
Antihormonal Therapy
Some patients suffer more symptoms from hormonal excess than from tumor bulk. In them, antihormonal therapy can be useful. Metyrapone, an inhibitor of the 11b-hydroxylation step in cortisol biosynthesis, has been reported to be useful in the management of individual cases of Cushing's syndrome of adrenal carcinoma. However, it has proved largely ineffective in patients with metastatic disease.[169] Chemical confirmation of its effectiveness requires direct measurement of plasma cortisol. Urinary concentration of 17-OH steroids cannot be used to assess the efficacy of metyrapone, because the drug produces elevation in urinary 11-deoxycortisol, and therefore elevation in 17-hydroxycorticosteroids (17-OHCS), even though it decreases plasma cortisol.
Aminoglutethimide, an anticonvulsant that causes adrenal insufficiency, has been used in the treatment of adrenal carcinoma.[170] It is an effective palliative treatment in Cushing's syndrome secondary to adrenocortical carcinoma, adenoma, and ectopic ACTH production by extra-adrenal carcinoma, with the potential for rapid and sustained suppression of corticosteroid synthesis. [171] [172] Because the drug may alter extra-adrenal metabolism of cortisol, measurement of urinary 17-OHCS excretion alone may overestimate the effectiveness of therapy; plasma cortisol concentration is a more reliable index of drug efficacy.[173] The usual clinical dose is within the range of 1 to 2 g/day. Significant adverse effects include anorexia, dermatitis, somnolence, ataxia, and decreased thyroid function.
Ketoconazole is another 11-b-hydroxylase inhibitor and blocks the production of not only cortisol, but also mineralocorticoids and androgens.[174] There are some reports of its efficacy in treating metastatic ACC.
Antineoplastic Therapy
In animals, the drug o,p'-DDD (mitotane) induced adrenocortical necrosis. Studies also demonstrated that mitotane was capable of inhibiting steroidogenesis. [175] [176] [177] Mitotane was initially evaluated in the 1960s.[178] In 138 cases of adrenal cancer evaluated, 17-KS and 17-hydroxycorticosteroid excretion was decreased by 50% in 70% of cases. A minimum of 4 weeks of therapy was required to ensure an adequate trial of therapy. Although steroid secretion was frequently improved with mitotane, tumor regression was uncommon, occurring in only 34% of cases with measurable disease. The mean duration of antitumor response was 10 months. Although objective response correlated with increased survival, hormonal response did not. The prognosis in women was better than in men; 52% of women and 38% of men survived for 4 years following diagnosis, with median survival times of 56 and 19 months, respectively.[178] Complete regression of tumors was not achieved.
Other investigators have also reported experience with mitotane. Libitz and associates[179] reported 115 patients with adrenal carcinoma treated with mitotane between 1965 and 1969. The measurable disease response in this series was 61%, with a steroid excretion response of 89%. The improved response rate in this series is attributed to a shorter median time between diagnosis and treatment with mitotane. Nader and associates[180] reported only a 19% remission rate in 77 patients. These results are likely secondary to differences in patient selection. Most patients treated with mitotane have experienced some degree of toxicity when the dosage was increased to the therapeutic range of 8 to 10 g/day. In general, the toxic reactions are mild, consisting of anorexia, nausea, vomiting, or diarrhea. Neuromuscular toxicity develops in 40% to 60% of patients, usually in the form of lethargy and somnolence. Vertigo and dermatologic toxicity are observed in 15%. Leukopenia and liver function abnormalities are rare. [178] [179] Plasma mitotane levels may be useful in preventing toxicity.[181] With successful treatment of a functioning tumor, a substantial number of patients will develop signs of adrenal insufficiency. In summary, it is reasonable to expect objective rates of tumor regression following mitotane therapy in approximately 25% of cases. [150] [178] The median duration of remission is 1 year, although some remissions have lasted longer than 3 years. Dosage regimens vary. Most clinicians initially administer 10 g/day, reducing the dose gradually to 1 to 2 g/day as regression is obtained. Diminution in size of metastases is rarely apparent before 6 weeks, although laboratory evidence of decreased steroid production may be noted earlier. Prolonged regression has been reported, and an apparent cure was seen with combined use of mitotane and 5-fluorouracil (5-FU).[182] Mitotane treatment is generally not recommended in the adjuvant setting since trials addressing this question have not been able to show a survival benefit.[183]
Very few chemotherapeutic agents other than mitotane have been evaluated in adrenocortical carcinoma in other than anecdotal experiences. Partial responses have been reported with doxorubicin. [184] [185]Cisplatin has caused tumor regression in four patients, three of whom had previously received mitotane adjuvant therapy.[186] In two reports of only six patients, the combination of etoposide and cisplatin was reported to produce a response in five or six cases. [187] [188] One patient had a complete response lasting 1 year. In general, adrenocortical cancers respond poorly to chemotherapy, likely due to increased expression of the multidrug resistance (MDR-1) gene product which has been identified as p-glycoprotein. Mitotane has been demonstrated to inhibit p-glycoprotein, leading to increased efficacy of chemotherapeutic agents.[189] There has been recent interest in the use of suramin, a growth factor inhibitor, as therapy for adrenocortical carcinoma. In a Phase I study in 21 heavily pretreated patients, three cases developed partial response to suramin. [190] [191] [192] The role of suramin requires further definition, particularly because this drug may be associated with significant neurotoxicity. There was some interest in a new drug, gossypol, a naturally occurring (from the cotton plant Gossypium species) insecticide which appeared to inhibit the growth of adrenocortical cancer cell lines and tumors in vivo.[193] [194] However, poor response rates combined with high death rates in limited clinical studies have reduced enthusiasm for this agent.
Surgical Approach to the Adrenal Gland
The surgical approach to the adrenal gland is influenced by the type of adrenal tumor. Adrenalectomy may be performed laparoscopically or via the open approach. Both open and laparoscopic adrenalectomy can be performed via the transperitoneal or posterior approach. The choice of approach depends on several factors including size of the lesion, nature of the lesion, and surgeon expertise. Laparoscopic adrenalectomy has been reported by a number of institutions with excellent results and has rapidly become the procedure of choice for benign-appearing lesions smaller than 6 cm in size. Laparoscopic adrenalectomy in the setting of malignancy is a subject of debate.[158] Although the data on the risk of local recurrence and widespread intraperitoneal carcinomatosis following these procedures is conflicting, most authorities agree that open adrenalectomy is indicated for suspected or known adrenocortical cancers and malignant pheochromocytomas.
Adrenocortical Adenomas
Laparoscopic adrenalectomy via the transperitoneal approach can be performed with the patient supine or in the lateral decubitus position. The latter is preferred as it uses gravity to aid retraction of surrounding organs, however, the patient does need to be repositioned for a bilateral procedure. This approach is depicted in Figure 75-10 .
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Figure 75-10 Posterior approach to the adrenal gland: A, The patient is placed in a jack-knife, prone position, and a curvilinear incision is made in the flank. B, The 12th rib is removed subperiosteally, exposing the lumbodorsal fascia. C, The pleura is swept superiorly using a gauze-covered finger. D, The diaphragm is transected, exposing Gerota's fascia, which is then opened. E, The adrenal gland is exposed. F, Vessels of the gland are ligated with hemoclips and then transected. Abdominal approach to the adrenal gland: G, The adrenal glands commonly can be approached through a chevron incision. When only unilateral adrenal exploration is required, this incision can be limited to either a right or left subcostal incision. H, Basic anatomy of the adrenal glands as shown from an anterior approach. I, Positioning and trocar placement for laparoscopic adrenalectomy. The camera is inserted through port # 2, the fan retractor through port # 1; ports 3 and 4 are working ports. J, Dissection of the right adrenal. The liver is retracted upward with a fan retractor, and the adrenal is dissected circumferentially with L-hook or harmonic scalpel. K, Dissection of the left adrenal. The spleen is retracted upward, and the adrenal is dissected circumferentially. L, The right adrenal gland can be exposed by performing a Kocher maneuver and retracting the duodenum to the left. This allows good exposure of the right adrenal gland. M, Exposure of the left adrenal gland in the retroperitoneum is accomplished by mobilizing the spleen and retracting the spleen and stomach medially. |
The patient is placed in the lateral decubitus position with the table flexed at the waist to open the space between the lower rib cage and the iliac crest. After pneumoperitoneum is created, four 10-mm trocars are placed between the mid-clavicular line medially and the anterior axillary line laterally, 1 to 2 fingerbreadths below the costal margin. For a right adrenalectomy, a fan retractor is inserted through the most medial port to retract the liver. The right triangular ligament is divided and the liver is rotated medially. Rarely, the hepatic flexure of the colon may need mobilization during a right adrenalectomy. The right kidney is identified visually and by palpation with an atraumatic grasper. The adrenal gland is identified on the superomedial aspect of the kidney. Gerota's fascia is incised with cautery. Dissection of the adrenal is started superomedially and then proceeds inferiorly, dissecting around the adrenal in a clockwise manner. The periadrenal tissues are grasped or moved with a blunt grasper to facilitate circumferential dissection. The right adrenal vein is identified at its junction with the inferior vena cava, ligated with clips and divided using endoscopic scissors.
For a left adrenalectomy, the fan retractor is used to retract the spleen. The splenic flexure is mobilized early and the lateral attachments to the spleen and the tail of the pancreas are divided using electrocautery. Gravity allows the spleen and the pancreatic tail to fall medially. The remainder of the dissection proceeds similarly to that described for the right adrenal. In addition to the adrenal vein, the inferior phrenic vein, which joins the left adrenal vein medially, also needs to be divided.
Current techniques of adenoma localization permit a unilateral posterior approach to adrenocortical adenomas. This approach has several advantages over an abdominal approach, including a lower complication rate, avoidance of postoperative ileus, and shorter hospital stay. The adrenal gland is approached through a posterior incision, as shown in Figure 75-10A . The gland is approached through the bed of the 12th rib, and the kidney is retracted inferiorly to expose the adrenal gland. These incisions are well tolerated, and much of the postoperative care is dictated by the metabolic consequences of removing the hormonally active adenoma.
Adrenal tumors may also be resected via an open anterior transperitoneal approach and a chevron incision is often used, as shown in Figure 75-10 . On the right, a Kocher maneuver mobilizes the duodenum and exposes the adrenal gland. On the left, the spleen is mobilized; Gerota's fascia is then opened to expose the left adrenal gland.
Pheochromocytoma
Surgical treatment of resectable pheochromocytoma requires careful preoperative preparation. α-Adrenergic blocking agents are administered to inhibit the effects of excess norepinephrine secretion. Phenoxybenzamine is a selective α-adrenergic blocking agent, administered in an oral dose of 20 to 40 mg two to four times daily. Titration of the dose is performed by following physiologic parameters. Prazosin also has been used successfully in the preoperative setting. β-Adrenergic blockers (e.g., propranolol) are added to control tachycardia as a sequela of excess epinephrine secretion. After adequate pharmacologic control and correction of fluid and electrolyte imbalance have been achieved, surgical resection is performed. Intraoperative control of blood pressure can be maintained using short-acting intravenous medications such as nitroprusside. Careful physiologic monitoring during the operation is mandatory. Pheochromocytomas may also be resected via a laparoscopic approach.
MALIGNANT PHEOCHROMOCYTOMA
Ten percent of pheochromocytomas are malignant,[195] and malignancies are reported more commonly in tumors arising in extra-adrenal sites (25% to 40%).
Pheochromocytomas are also a component of MEN-2a and MEN-2b.[196] These syndromes are discussed in detail later in this chapter. Pheochromocytomas are also associated with other inherited disorders such as von Hippel-Lindau (VHL) caused by germline mutations of the VHL gene, neurofibromatosis type I caused by germline NF1 mutations and familial paraganglioma and pheochromocytoma syndromes caused by mutations in the succinyl dehydrogenase family of genes (SDHB, SDHC and SDHD). When pheochromocytomas develop in the MEN syndromes, they are frequently bilateral but rarely malignant. In contrast, patients with familial paraganglioma or pheochromocytoma syndrome caused by germline SDHB mutations appear to have a higher propensity for extra-adrenal and malignant tumors.[197] Some studies also suggest that older patient age and large tumors are associated with a higher risk of malignancy. However, malignancy cannot be determined on clinical features alone. Although risk of malignancy increases with size for all pheochromocytomas, size does not seem to reliably predict malignancy in pheochromocytomas with local disease only.[198] The pathologic diagnosis of malignancy can also be difficult, because pleomorphism, nuclear atypia, and abundant mitotic figures are seen in benign tumors.[199] Even capsular invasion can be seen in benign tumors, although invasion of adjacent tissues indicates malignancy. Recent data suggest that flow cytometry and molecular markers such as expression of Ki-67, tissue inhibitor of metalloproteinase (TIMP-4), and cyclooxygenase (COX)-2 can be useful in determining malignancy. [200] [201] [202] [203] Malignant pheochromocytomas can be nonfunctional.
Diagnosis
Functioning malignant pheochromocytomas exhibit the same secretory pattern as benign tumors. The diagnosis is made by finding elevated catecholamines or catecholamine metabolites in the urine or plasma, or both ( Fig. 75-11 ). Urinary metanephrines are useful in diagnosing functional pheochromocytomas,[203] but the results may be falsely negative. The single most useful screening test is analysis of a 24-hour urine for vanillylmandelic acid (VMA), metanephrine, and catecholamines. Alternatively, plasma free metanephrines and normetanephrines may be measured. These tests are highly sensitive (99%) but not specific (89%) for pheochromocytoma.[204] Plasma catecholamines can also be elevated.[205] Oral clonidine will not reduce elevated plasma catecholamines to normal levels in patients with pheochromocytoma.[206] The clonidine suppression test is therefore highly useful in distinguishing pheochromocytoma from other causes of hypertension associated with elevated plasma catecholamine levels. Angiography has been largely superseded by CT and MRI scanning for tumor localization. Van Heerden and associates[207] reported that both techniques are highly accurate in localizing tumor at all sites, obviating other more invasive diagnostic procedures such as angiography and selective venous sampling for catecholamine levels.
|
Figure 75-11 Diagnosis and treatment of pheochromocytoma. MEN, multiple endocrine neoplasia; MIBG, metaiodobenzylguanidine;VMA, vanillylmandelic acid. |
Another useful technique for localization is radionuclide scanning with 131I-MIBG, which concentrates in adrenergic tissues. The MIBG scan has proved to have a sensitivity of 87%[208] and a specificity of 96%.[209] An MIBG scan in a patient with metastatic pheochromocytoma is shown in Figure 75-12 . Other more recently described techniques for localizing pheochromocytomas include PET with 6-[18F] fluorodopamine ([18F]-DA) and 2-[fluorine 18]fluoro-2-deoxy-D-glucose ([18F]-FDG-PET). Preliminary studies show that PET scanning may be superior to MIBG scanning for localizing pheochromocytomas. [210] [211]
|
Figure 75-12 MIBG scan in patient with metastatic pheochromocytoma. A, 131I-MIBG scan in a patient with metastatic pheochromocytoma demonstrates hepatic and bony metastasis. B, Magnified view of chest and abdomen. |
Course and Treatment
Complete surgical resection[212] after careful preoperative preparation with α- and β-blocking agents is curative in localized pheochromocytoma. If a malignant pheochromocytoma is suspected preoperatively, open rather than laparoscopic adrenalectomy is indicated. Malignant pheochromocytoma metastasizes to lung, brain, and bone. Metastatic disease generally progresses slowly. However, life-threatening complications due to secretory products can develop over a period of many years. Survival for up to 20 years has been noted.[212]
Modern therapy for inoperable metastatic disease uses the same strategies employed in preparing a patient with primary pheochromocytoma for surgery. Blockade of α-adrenergic receptors is accomplished with phenoxybenzamine; a gradual increase in dose can be required as disease advances. β-Adrenergic blockade may be of additional benefit but should always follow establishment of α-adrenergic blockade. Otherwise, the absence of the vasodilating effects of the β-adrenergic receptors can precipitate severe hypertension. Surgery and radiation have palliative roles in treating metastatic disease; surgical reduction of metastatic tumors can decrease catecholamine secretion and result in symptomatic improvement. The results of chemotherapy are mainly anecdotal. However, a series of 14 patients treated with a combination of cyclophosphamide, vincristine, and dacarbazine (DTIC) has been reported.[213] The rates of biochemical response and measurable cancer reduction were 79% and 57%, respectively. Median duration of response was greater than 20 months. Other chemotherapy agents including streptozotocin, doxorubicin, and carmustine (BCNU) have not been effective.[214] Thalidomide, alone or in combination with temozolomide, has shown some promise in treating pheochromoctyomas, but their use may be limited due to severe toxicity.[215] Some studies have suggested a therapeutic value of 131I-MIBG, however complete remissions are rare and disease has been reported to progress after therapy. [216] [217] [218]
PARATHYROID CARCINOMA
Parathyroid carcinoma is one of the rarest cancers. Schantz and Castleman[219] reported the largest study of such cases. These investigators described 487 cases of hyperparathyroidism, of which only 70 (14%) were documented to be parathyroid carcinoma. In most series, parathyroid carcinoma accounts for about 1% of cases of hypercalcemia and hyperparathyroidism. The prevalence in Japan is higher.
Data concerning the possible origin of parathyroid carcinoma from pre-existing abnormalities are rare. For example, transition to carcinoma from hyperplasia in patients with MEN-1 and MEN-2 syndromes does not appear to occur. However, parathyroid carcinoma has been reported to have developed in patients with familial hyperparathyroidism,[220] suggesting that transition from hyperplasia to cancer can take place. More recent data show an increased incidence of parathyroid carcinoma in families with the hyperparathyroidism and jaw tumor (HPT-JT) syndrome, which is caused by germline HRPT2mutations.[221] Interestingly, somatic and germline HRPT2 mutations have been detected in cases of apparently sporadic parathyroid carcinoma.[222]
Diagnosis
Almost all cases of parathyroid carcinoma are associated with hypercalcemia, and about 70% have values greater than 14 mg/dL, which is rare in benign hyperparathyroidism. The disease usually is diagnosed at surgery for hyperparathyroidism. No unequivocal diagnostic tests distinguish benign parathyroid neoplasms from carcinomas, although plasma calcium concentration and PTH levels tend to be higher (>10 times normal) in carcinoma than in adenoma or hyperplasia.[223] Evidence of a neck mass,[223] cervical lymphadenopathy, hoarseness, or intraoperative finding of invasion of adjacent structures such as the strap muscles, thyroid, esophagus, or recurrent laryngeal nerve also suggests the presence of cancer.
The histologic pattern of parathyroid cancer shows frequent mitosis, and blood vessel and capsular invasion also may be seen. In one study, these features and a trabecular pattern with thick fibrous bands were considered characteristic of malignancy and helped to distinguish cancer from benign hyperplasia or adenoma.[223] However, as with many endocrine tumors, it is difficult to differentiate benign from malignant tumors by histologic features alone.
Natural History
The 5-year survival rate of patients with parathyroid carcinoma varies between 29% and 44%, [223] [224] and the 10-year survival rate averages 20%. A smaller, more recent study has been reported, however, with an 89% (eight of nine cases) survival rate at a median follow-up period of 6 years.[225] Although parathyroid cancer metastasizes to lung, bone, and liver in about 20% of patients, metastatic disease is less commonly a cause of morbidity and death than is the severe hypercalcemia associated with this disease.
Management
When parathyroid carcinoma is recognized at surgery, careful en bloc excision of the cancer and involved structures is indicated.[225] In most cases, this is accomplished by an ipsilateral thyroid lobectomy with segmental resection of involved strap muscles and adjacent fibrolymphatic tissue. This tumor usually does not metastasize via the lymphatics; therefore, radical neck dissection is not warranted. Careful dissection without tumor spill is important, because local recurrence has been demonstrated. Local recurrence occurs in about two thirds of patients, in some due to intraoperative seeding. If hypercalcemia persists or recurs after surgery, an attempt should be made to locate the metastasis using selective venous catheterization and measurement of hormone levels in the event other diagnostic modalities fail. Prolonged remission of hypercalcemia has been reported after resection of metastases.[226] In case of unresectable disease, debulking should be attempted for palliation of hypercalcemia.
Nonsurgical treatment of recurrent or metastatic parathyroid cancer is disappointing. Radiation therapy has not been of significant value in treating primary or recurrent neck disease, although it may have some palliative benefit in controlling pain in bone metastases. Cytotoxic chemotherapy has been tested only infrequently, but it appears that dacarbazine has some activity in this disease. [227] [228]Essentially, all patients with incurable parathyroid cancer require control of hypercalcemia. Diphosphonates, mithramycin, and calcitonin have been only marginally effective. It appears that the more recently developed pharmacologic therapies for hypercalcemia—etidronate[229] and gallium nitrate[230]—may be more effective in the palliative management of the severe hypercalcemia associated with parathyroid cancer. A new class of drugs known as calcimimetics can reduce PTH by binding directly to the calcium-sensing receptor cells on the parathyroid gland. Cinacalcet hydrochloride, a calcimimetic, has been shown to be useful in controlling hypercalcemia in patients with refractory parathyroid carcinoma.[231]
MULTIPLE ENDOCRINE NEOPLASIA
MEN syndromes are characterized by the familial occurrence of endocrine neoplasms in various sites. MEN syndromes are inherited as autosomal dominant with high penetrance, variable expressivity, and pleiotropic expression. The neoplasms of the MEN syndromes may be either benign or malignant. [133] [232] Manifestations of MEN-1, MEN-2a, and MEN-2b are summarized in Table 75-6 . Steiner and associates[233] were the first to characterize MEN-1 and MEN-2.
Table 75-6 -- Syndromes of Multiple Endocrine Neoplasia
|
MEN-1 |
MEN-2 |
|
Pituitary tumors |
MEN-2a and -2b |
|
Eosinophilic adenoma (acromegaly) |
Medullary carcinoma of the thyroid |
|
Prolactinoma |
Pheochromocytoma |
|
Nonfunctional tumors |
MEN-2a |
|
ACTH-secreting tumors |
Hyperparathyroidism |
|
Hyperparathyroidism |
MEN-2b |
|
Pancreatic tumors |
Mucosal neuromas |
|
Most common |
Marfanoid habitus |
|
Gastrinoma |
Typical facies |
|
Insulinoma |
Bowel abnormalities |
|
Pancreatic polypeptide-secreting tumor |
|
|
Glucagonoma |
|
|
VIPoma |
|
|
GRFoma |
|
ACTH, adrenocorticotropic hormone; MEN-2a, -2b, multiple endocrine neoplasia types 2a, 2b. |
Multiple Endocrine Neoplasia Type 1
MEN-1 syndrome is a disorder of three glands: parathyroid, pancreatic islet cells, and pituitary. Recently, the disease gene for MEN-1, menin, has been localized to the long arm of chromosome 11.[234]Menin has been reported to encode for a nuclear protein[235] of still undefined function, although recent studies suggest roles in physiologic regulation of cell growth, control of the cell cycle, and genome stability.[236]
Clinical Features
Parathyroid hyperplasia is the most frequently noted abnormality.[237] Adenomas of the pituitary gland are noted in 50% to 80%of patients with MEN-1. [237] [238] When pituitary adenomas are functioning, prolactin is the most common hormone produced.[239] Acromegaly caused by growth hormone-secreting adenomas occurs in approximately 25% of adenomas.[238] Cushing's syndrome secondary to pituitary adenoma is uncommon. Approximately 80% of patients with MEN-1 will have functional pancreatic islet cell tumors.[239] Islet cell tumors represent the most common cause of death in patients with MEN-1, with 60% of deaths resulting from ulcer disease or problems caused by islet cell tumors.[238]
A wide spectrum of pancreatic islet cell tumors can occur in MEN-1. In a comprehensive review,[238] pancreatic tumors were present in 100 of 122 patients (82%) with MEN-1 with the following frequency: gastrinoma (64%); insulinoma (24%); glucagonoma (3%); and nonfunctioning tumor (9%). Rare cases of secretion of vasoactive intestinal peptide (VIP) and other peptides were observed. Forty-two percent of the gastrinomas were malignant, and 25% of the insulinomas were malignant. This finding is in contradistinction to sporadic insulinomas, in which only 10% are malignant. Pancreatic polypeptide (commonly), α- and β-hCG (less commonly), and other peptides such as ACTH may be elevated in patients with MEN-1 and may serve as tumor markers. The adrenal cortex may be abnormal in about one third of cases, usually with hyperplasia associated with pituitary adenomas producing ACTH. Rarely, a pancreatic tumor may produce ACTH ectopically.[240] Clinical Cushing's syndrome is uncommon. Bronchial carcinoids may occur in approximately 5% of cases.
Surgery
Management of MEN-1 first requires an awareness of the existence of the syndrome. Because almost all of these patients eventually will manifest hyperparathyroidism, continued surveillance of serum calcium is necessary. Parathyroidectomy usually is curative. In cases in which all four glands are enlarged, complete resection with forearm implantation is the preferred treatment. However, parathyroid hyperplasia can be limited to one or a few glands. In this case, it is preferred to resect the abnormal glands and to obtain a biopsy of the normal-appearing parathyroids. The location of these normal glands should be marked with nonabsorbable suture. If possible, all parathyroid tissue on one side of the neck should be removed to avoid the need for repeat bilateral neck exploration. Detectable pituitary tumors may be treated with bromocriptine or are occasionally removed by transsphenoidal resection. The management of pancreatic islet cell tumors is described elsewhere in this chapter.
Multiple Endocrine Neoplasia Type 2
MEN-2 syndrome first was reported by Sipple[241] in 1961. MEN-2 tumors include MTC, pheochromocytoma, and adenoma or hyperplasia of the parathyroid glands. When mucosal neuromas—with or without marfanoid habitus—are present as part of a distinctive syndrome, the designation is MEN-2b. Parathyroid disease is rare in MEN-2b. Specific MEN-2a [242] [243] and MEN-2b[244] gene defects map to different regions of the RET proto-oncogene in the centromeric region of chromosome 10. More than 70% of pheochromocytomas occurring with MEN-2 are bilateral. These tumors may be derived from a hyperplastic adrenal medulla, yet still be benign, although carcinomas may occur in the same family. This progression from hyperplasia to tumor is similar to the progression noted in MTC.
RET encodes a receptor tyrosine kinase with an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity. Genotype–phenotype correlations have been observed in MEN-2a and MEN-2b, with the type of RET gene mutation indicating the aggressiveness of the disease.[245]
Clinical Features
The clinical presentation of patients with MEN-2 can be dictated by any of the three neoplasms seen in the syndrome. However, all patients with MEN-2 have medullary carcinoma of the thyroid. In reviews of MEN-2a, pheochromocytoma was seen in 21% to 41% of patients, and parathyroid hyperplasia or adenoma was present in 17% to 60%.[246] All patients had medullary carcinoma of the thyroid. [123] [247] In a series of patients with MEN-2b, all had medullary carcinoma, and 60% developed pheochromocytomas.[248] In general, MEN-2b tends to be a more rapidly progressive clinical entity because the medullary carcinoma of the thyroid that develops in this syndrome has a more aggressive course than that seen in MEN-2a. Patients suspected of having MEN-2 syndrome should be screened for medullary carcinoma of the thyroid, pheochromocytoma, and hyperparathyroidism. The most effective way to screen for medullary carcinoma of the thyroid is to measure plasma calcitonin levels initially. All patients with medullary carcinoma of the thyroid will have either elevated basal plasma calcitonin levels or elevation after pentagastrin and calcium infusion stimulation tests.[126] In patients at risk for inherited medullary thyroid cancer, genetic screening for RET mutations has replaced yearly calcitonin measurements, because detection by this method allows treatment prior to the development of cancer.[245] The appropriate screening tests for pheochromocytoma include measuring urinary levels of epinephrine, norepinephrine, VMA, and metanephrines as described previously, or serum metanephrines. When these tests are abnormal, tumor localization studies, including MRI and abdominal CT scanning, should be undertaken. When there is biochemical evidence of pheochromocytoma with a negative CT scan, MIBG scan may be useful. MIBG concentrates in pheochromocytoma cells, permitting tumor detection by scintigraphy.[249] Hyperparathyroidism can be assessed by measurement of calcium and PTH levels.
Surgery
Management of patients with MEN-2 syndromes is primarily surgical. The surgical treatment of medullary carcinoma is total thyroidectomy, because the tumor always is bilateral. Central lymph node dissection also should be performed. In patients with MEN-2a and hyperparathyroidism, only abnormal parathyroid glands should be removed at the time of surgery. Patients with pheochromocytoma should undergo preoperative α-adrenergic blockade with phenoxybenzamine. [248] [249] After adequate α-blockade has been obtained, β-blockers may be added if the patient has significant tachycardia, although in many instances β-blockade is not needed.
Postoperatively, patients with resected MTC may be followed with serum calcitonin levels, which are a sensitive marker for recurrence of disease. Likewise, appropriate urinary catecholamine studies will demonstrate recurrence of pheochromocytoma. Because MEN-2 syndromes exhibit autosomal dominance, it is important to evaluate family members of patients with documented MEN-2 for presence of the syndrome. Genetic analysis for inheritance of the allele containing the mutant RET gene will identify family members likely to develop MEN. Family members who have not inherited the disease allele require no further evaluation. Genetically affected members can be offered early thyroidectomy, usually by age 5 or 6 years in MEN-2a and prior to 6 months of age in MEN-2b.[245]
CARCINOID TUMORS
Carcinoid is an English translation of a term first used by German pathologists in the early 20th century—“karzinoid”—to describe a carcinoma-like tumor that behaves less aggressively than carcinomas.[250] Although their malignant potential was noted, other unique characteristics of the tumors also were described. These tumors arise from enterochromaffin cells in the gastrointestinal tract and lung.[251]Enterochromaffin cells take up and reduce silver. Silver staining documented the argyrophilic nature of carcinoid tumors, ultimately leading to their being described as neoplasms of the diffuse endocrine or APUD system.[252] Other tumors of the APUD system include medullary carcinoma of the thyroid, pheochromocytoma, and pancreatic endocrine tumors. Newer immunohistochemical techniques including neuron-specific enolase (NSE) [253] [254] [255] and chromogranin A[256] hormone assays have allowed further characterization of the synthesis and secretion of neuroendocrine peptides by carcinoid tumor cells. It is important to know that these neoplasms have common characteristics as defined by the APUD concept to be able to understand that the production of polypeptides arises from pancreatic islet cell tumors.
Carcinoid tumors typically have been classified as originating in the foregut (lung and upper gastrointestinal tract and, less often, pancreas), the jejunum and midgut (which includes the ileum and appendix), and the hindgut (colon and rectum). The origin of carcinoid tumors may, in part, explain the ectopic hormone secretion and syndromes related to primary tumor site.[257]
About 85% of carcinoid tumors develop in the gastrointestinal tract, usually the appendix. In one report, 44% of carcinoids were appendiceal, accounting for more than three fourths of all tumors in that organ.[258] In the same series, the intestine (19%), rectum (15%), and lung (10%) also were common sites. A recent National Cancer Database (NCDB) study using Godwin's initial experience[258] was recently published,[259] and a revised classification of neuroendocrine tumors of the lung, pancreas, and gut has more recently been released.[260]
Carcinoids account for one third of tumors in the small intestine. Carcinoids of the appendix commonly are discovered incidentally. Most are smaller than 1.0 cm and are cured by surgical resection.[259] In the Mayo Clinic series, no tumor of 1.0 cm or less recurred after resection.[215] Therefore, appendectomy alone is adequate treatment. With the uncommon large appendiceal carcinoid, a true cancer operation (e.g., right hemicolectomy) can be required. Carcinoids of the rectum are similar to appendiceal carcinoids and typically are small and are best treated with conservative local measures. Carcinoids of the small intestine are the most clinically important tumors because of their frequency of presentation, their more advanced stage at diagnosis, and their association with the carcinoid syndrome. The largest and most carefully followed series of patients with small bowel carcinoid has been reported from the Mayo Clinic, where 183 consecutive cases have been followed for a median period of 15 years.[261] Approximately 40% of the tumors occurred within 2 feet of the ileocecal valve, with very few in the proximal small intestine. Thirty-five percent of patients had more than one lesion, and most primary tumors were 2.0 to 4.0 cm in diameter. More than 80% of patients with resectable primary tumors were free of disease at 20 years’ follow-up. The overall survival rate in these patients was similar to that of an age- and sex-matched control group. Of the 72 patients who had resected regional node metastases, one half experienced recurrence by 16 years, with continued evidence of relapse after that time. Patients who had unresectable abdominal metastases and hepatic metastases fared least well, with median survival rates of 5 and 3 years, respectively. These data confirm that, even with advanced disease, carcinoid tumors tend to have a relatively indolent course. Goblet cell or adenoid carcinoid tumors may be more aggressive than typical gastrointestinal carcinoids.
Clinical Pathology
Carcinoid tumors usually are readily identified microscopically. Immunohistochemical staining is performed to identify and classify these tumors. In addition to immunohistochemical staining to reveal specific tumor-produced peptides, other semispecific markers including NSE[255] and chromogranin A[256] aid in diagnosis.
Carcinoid Syndrome
Many patients with metastatic carcinoid tumor manifest the signs and symptoms of abnormal hormone production—the malignant carcinoid syndrome.[262] Serotonin (5-hydroxytryptamine, 5-HT), synthesized by the tumor from tryptophan and metabolized to 5-HIAA, which appears in the urine, is particularly important because urinary 5-HIAA levels are used to monitor the course of carcinoid syndrome. However, the relation of serotonin levels to symptoms of the clinical carcinoid syndrome is uncertain.
Carcinoid tumors also release the enzyme kallikrein, which acts on α2-globulin to produce bradykinin and its precursor, lysyl-bradykinin, both of which can induce flushing. [263] [264] Serotonin may be responsible for intestinal hypermotility and hypersecretion, but it probably does not cause the characteristic flushing that occurs with the carcinoid syndrome.[265] Vasodilation, which causes flushing, can be due to one or more substances released by the tumor cells, including bradykinin, substance P (midgut carcinoids), tachykinins, and prostaglandins. The symptoms of the carcinoid syndrome vary in frequency. Flushing is most frequent, followed by diarrhea, heart disease, and bronchoconstriction.
Flushing
Two types of flushing generally are accepted as accompanying the usual metastatic ileal carcinoid. It is thought that any of the activities that drive plasma catecholamines, which instigate the flushing, maybe mediated, in part, by peptides such as the tachykinin substance P or the amine serotonin. Stressors associated with hypercatecholemia include exercise, excitement, emotion, ethanol, and decongestants such as ephedrin. One type of flushing is red and diffuse, involving the face and upper body; it is of short duration and can be provoked by alcohol, excitement, emotional stress, and catecholamine release.[266] The other is more prolonged, produces venous dilation and a purplish hue about the face, and can give rise to permanent dilation of facial veins and even telangiectasia. This flush is more commonly precipitated by alcohol ingestion. Because infusion of serotonin does not cause either flush, it has been suggested that the kinins cause this symptom.[267] Brief flushes may be due to catecholamine-induced release of vasoactive substances such as kallikreins; these flushes can be blocked effectively by α-adrenergic blocking agents.[268] Carcinoid of the foregut produces a more intense and erythematous flush (such as seen in a serotonin burst), sometimes associated with itching, conjunctival suffusion, and facial edema suggestive of histamine release. Occasionally, gastric carcinoids cause an urticarial reaction, which may be inhibited by the histamine H1- and H2-receptor antagonists diphenhydramine and cimetidine. [269] [270]
Diarrhea
The diarrhea of carcinoid syndrome does not necessarily correlate with flushing. Diarrhea appears to be related to increased gut motility, rather than to secretion of fluids. Methysergide, a serotonin antagonist, sometimes is effective in treating or preventing diarrhea, hence the presumption that serotonin is directly responsible for this symptom. Infusion of serotonin produces intestinal dysmotility similar to that seen in the carcinoid syndrome.[270] Diarrhea of the carcinoid syndrome rarely is of high volume and, therefore, typically requires only mild palliative antidiarrheal therapy. Although abdominal cramping can be associated with this diarrhea, other possibilities for abdominal pain must be considered, including intermittent partial small bowel obstruction secondary to mesenteric fibrosis or bowel obstruction secondary to tumor bulk.
Heart Disease
The cardiac disease associated with the carcinoid syndrome is an endomyocardial fibrosis typically involving the right side of the heart, although left-sided lesions have been described. Fibrotic deformation of the tricuspid and pulmonary valves usually leads to pulmonary stenosis and tricuspid insufficiency. [271] [272] When left-side lesions are involved (primarily mitral valve), there is usually a patent foramen ovale. In the Mayo Clinic series, carcinoid heart disease was a late complication, with only 5 of 91 deaths identified as having a primary cardiac cause. In that series, most patients with heart disease had high levels of 5-HIAA as well as a lengthy history of carcinoid cardiac disease averaging more than 5 years.
Other, relatively rarer, signs and symptoms may be associated with carcinoid syndrome. Bronchoconstriction may occur in both pulmonary and extrapulmonary carcinoid and usually is associated with flushing. The classic triad of dermatitis, dementia, and diarrhea seen with pellagra occasionally has been identified. This syndrome is secondary to niacin deficiency as a result of shunting of dietary tryptophan from niacin synthesis to indole synthesis. It is very rare, because of better overall nutrition in the population. It is treated simply with nicotinamide from over-the-counter vitamin supplements.
Diagnosis
The diagnosis of carcinoid tumor is made by finding tumor or symptoms related to tumor bulk, biologically active peptides, or urinary tumor markers ( Fig. 75-13 ). While measurement of 5-HIAA is the most common and reproducible test for the presence of carcinoid syndrome, significantly raised levels of 5-HIAA usually occur only after there is a 20% to 25% liver tumor burden. In most laboratories, the upper limit of normal for 24-hour urinary 5-HIAA excretion is 6 to 10 mg. In one study, 5-HIAA measurements were 100% specific and 73% sensitive for the presence of carcinoid syndrome.[273] Not all patients with carcinoid tumor have the associated syndrome, and the sensitivity of assays for detecting the presence of tumor alone is inadequate. Although markedly elevated 5-HIAA in the urine is remarkably specific for carcinoid tumor, a low-level false-positive increase of 5-HIAA may be seen in patients with noncarcinoid tumor and after intake of certain foods (e.g., bananas, walnuts, and pecans) and serotonin reuptake inhibitors (e.g., Zoloft, Prozac) and medications (e.g., acetaminophen, salicylate, guaifenesin). [273] [274] [275] [276] [277] 5-HIAA also may be elevated to low abnormal levels (<30 mg) in patients with diarrhea or malabsorption from any cause. In addition to excellent specificity and high sensitivity, 5-HIAA measurement has a high level of consistency, both in individual patients and among groups. In the Mayo Clinic series, the level of 5-HIAA excretion remained constant in a group of 85 patients in whom paired determinations were done during a 10-day period.[261] Moreover, in any given patient, the level of 5-HIAA secretion is a relatively accurate indicator of tumor bulk. Platelet serotonin levels have been reported to be more sensitive than urinary 5-HIAA levels and may be useful in patients with tumors that produce low levels of serotonin.[278] Recently, serum NSE and chromogranin A levels have been shown to correlate with the presence and natural history of gastrointestinal neuroendocrine tumors. [255] [256] For midgut carcinoids, which produce high levels of serotonin, the sensitivity of chromogranin A levels is only slightly better than urinary 5-HIAA levels. However, for foregut and hindgut derived tumors, chromogranin A levels are highly sensitive compared with urinary 5-HIAA levels.[279]
|
Figure 75-13 Diagnosis and treatment of carcinoid tumors. |
The most commonly used modality for imaging carcinoid tumors is CT scanning, although the technique is more sensitive for detecting metastases, rather than primary tumors.[280] Recently, localization of carcinoid and islet cell tumors has been investigated by nuclear medicine techniques, including octreotide scan ( Fig. 75-14 ).[281] The sensitivity of somatostatin receptor or octreotide scanning is reported to be up to 87%, with a positive predictive value of 100%, making it the most useful imaging study for carcinoid tumors.[282] 131I-MIBG scans also have shown usefulness in evaluating carcinoid tumors.[283] PET scans using 11-C-labeled 5-hydroxytryptophan also have shown promising results when compared to CT scan in small series.[284]
|
Figure 75-14 111In octreotide scan. Patient with metastatic carcinoid with octreotide scan showing bony and visceral metastases with anterior and posterior views. |
Treatment
Patient management depends not only on traditional methods of dealing with bulky disease and its manifestations, but also on management of associated medical problems typically caused by overproduction of hormonally active peptides. In this regard, treatment of carcinoid is similar to that of other neuroendocrine tumors, such as islet cell tumors. For patients on long-term somatostatin therapy, a long-acting somatostatin analog is effective and may be given monthly.[285]
Surgery
Surgery has an important role throughout the course of carcinoid tumor management. Resection of the primary tumor and of associated resectable nodal metastases is primary therapy.[286] Also, complications secondary to recurrent or residual carcinoid may benefit from surgical intervention. Nearly one half of all carcinoids arise in the appendix, and most are small and cured by appendectomy, although right hemicolectomy is recommended for lesions larger than 2 cm. [261] [287] The same is true for small lesions of the rectum, but tumors larger than 2 cm in diameter require standard cancer operations such as a low anterior resection or abdominoperineal resection.[286] In small bowel tumors, small bowel resection with removal of mesenteric nodes is recommended. It follows that the surgical approach to bronchial, gastric, or gonadal carcinoid will depend on the location and stage at presentation.
These tumors often elicit a mesenteric fibrosing reaction, in which the bowel becomes shortened and kinked, frequently causing partial small bowel obstruction. Pain or physiologic abnormalities secondary to partial bowel obstruction may be greatly relieved by palliative surgical resection or bypass, or both. The indolent course of carcinoid tumors mandates a high index of suspicion for such complications and an aggressive approach in considering surgical palliation.
Management of hepatic metastases is important given the frequency of such metastases. In many patients, bulky hepatic metastases constitute most of the tumor burden, so that tumor reduction may, at the least, diminish production of peptides that promote the carcinoid syndrome, as well as extend survival.[288] Principles of surgical management of hepatic metastases are similar to those for islet cell tumors. The indications to proceed with hepatic metastases resection are more liberal in carcinoid tumors than in metastases from other solid tumors. For example, partial resection of hepatic metastases is contraindicated in metastatic colon cancer, as neither effective palliation nor prolongation of survival is achieved. However, the much longer survival in carcinoid tumor makes palliative resection of hepatic metastases appropriate to decrease tumor burden and improve patient well-being. A variety of cancer therapies for hepatic metastases may be attempted, including hepatic irradiation, hepatic embolization, and liver-directed chemotherapeutic agents. These therapies are discussed in the following individual treatment sections.
Radiation Therapy
Radiation therapy seldom is used to treat carcinoid tumor or carcinoid syndrome. Patients with carcinoid syndrome often have extensive hepatic metastases, and the dose-limiting toxicity of hepatic radiation limits its usefulness. Palliative treatment of bone metastases is an indication for radiation therapy. A trial of whole-abdomen radiation therapy (20–25 Gy)[289] yielded mixed results, with reduction of abdominal pain but less consistent control of the cancer. Radiation therapy should be considered in patients who require local control and palliation.[290]
Antihormonal Therapy
When the symptoms attributed to serotonin are mild, they can be managed successfully over lengthy periods with simple measures, such as administration of opiates and diphenoxylate hydrochloride with atropine. With more severe symptoms, the peripheral serotonin antagonists methysergide and cyproheptadine are effective in controlling diarrhea and, in some cases, malabsorption.[291] Another approach has been the use of agents known to inhibit serotonin synthesis. α-Methyldopa, which partially inhibits the decarboxylation of 5-hydroxytryptophan (5-HTP) to serotonin, has been disappointing, except in patients with the rare 5-HTP-secreting metastatic carcinoid of gastric origin.[292] Parachlorophenylalanine (PCPA) inhibits the enzyme tryptophan 5-hydroxylase, which converts tryptophan to 5-HTP, the immediate precursor of serotonin.[293] Although good to excellent control of diarrhea has been observed, the toxic effects of PCPA, including hypersensitivity reactions and mental aberrations, have limited its clinical value.
Somatostatin inhibits carcinoid flush,[294] but is not practical for therapy because it has a half-life of less than 2 minutes.[295] Synthetic octapeptide analogs of somatostatin, octreotide acetate, lanreotide, and vapreotide have a longer half-lives, and can be given subcutaneously every 4 to 8 hours to maintain the action of somatostatin. As well, the long-acting repetitive, Sandostatin LAR (Novartis), has been shown to be highly effective in control of both carcinoid flushing and diarrhea.[285] Somatostatin influences the inhibition of numerous gastrointestinal hormones, gastric secretion, gastric and small intestinal motility, splanchnic blood flow, pancreatic enzyme secretion, intestinal nutrient absorption, and gallbladder contractility.[296]
Somatostatin analogs have two established uses in carcinoid tumors: chronic treatment of symptoms such as diarrhea and flushing,[297] and treatment of carcinoid crisis.[296] Kvols and associates,[297] in 1986, described the use of the somatostatin analog octreotide in therapy for carcinoid syndrome. Fifty-seven patients with carcinoid tumor and carcinoid syndrome were treated with daily doses of octreotide acetate, ranging from 100 to 1127 mg (mean, 414 mg). Flushing was abolished in most patients, and diarrhea was controlled adequately in approximately 75%. Control of symptoms usually was associated with a decrease in the urinary 5-HIAA level, but reduction in tumor bulk was not seen consistently. The median duration of response to somatostatin analog was 4 months, with some patients escaping control quite early but others continuing for more than 2 years. Increased doses of somatostatin may partially overcome resistance.[298] More recent studies have confirmed that somatostatin improves symptoms but has little effect on tumor regression.[299]
Somatostatin analog usually is well tolerated. [296] [297] Minimal irritation at the injection site and alterations in bowel patterns have been observed. Fecal fat excretion may increase, and aberrations in glucose tolerance resulting in hyperglycemia have been observed. Very early studies in the 1980s demonstrated that neostimulated pancreatic enzyme inhibition due to octreotide acetate diminishes after a continued use of octreotide. Clinically significant fat malabsorption is not a widespread problem. We routinely use and recommend pancreatic enzyme supplementation when beginning either subcutaneous octreotide acetate or the long-acting repeatable octreotide.
Long-term therapy may predispose to the formation of gallstones; the drug promotes cholelithiasis by inhibition of cholecystokinin release and a resultant inhibition of gallbladder emptying. Approximately 50% of patients receiving chronic therapy will develop cholelithiasis and should, therefore, undergo elective cholecystectomy at the time of tumor debulking.[300]
Chemotherapy
Because the disease is indolent, little information is available on the role of chemotherapy.[301] Antineoplastic therapy may be called for in patients whose cancers are aggressive, with progressive liver metastases, signs of partial or impending complete intestinal obstruction, or severe symptoms of carcinoid syndrome uncontrollable by other methods. Controlled clinical trials have been difficult to carry out because of the rarity of the tumor, but cooperative study group trials have been useful in assessing tumor responsiveness. In our experience, the less positive the octreoscan and more active the PET scan, the more effective chemotherapy may be.
During the 1970s, systemic therapy with single agents was reported, with 5-FU and streptozotocin shown to be active drugs.[302] The Mayo Clinic experience with more than 200 patients suggests that with single agents the response rates of greater than 10% were seen with only three adequately tested drugs: doxorubicin, 7 of 33 (21%); 5-FU, 5 of 19 (26%); and dacarbazine (DTIC), 2 of 15 (13%).[303] Based on initial observations of patient response to 5-FU and streptozotocin, investigators at the Mayo Clinic studied that regimen and noted an overall response rate of 33% in 43 patients. A larger series of patients was reported in a phase III study by the Eastern Cooperative Oncology Group (ECOG)[304] comparing 5-FU plus streptozotocin to cyclophosphamide plus streptozotocin. Response rates for the two treatment arms were not significantly different (33% vs. 26%, respectively), nor were there significant differences in overall survival. Assuming the 5-FU plus streptozotocin regimen to be standard, the ECOG subsequently reported their trial of this combination, with streptozotocin given less frequently to decrease toxicity, compared with doxorubicin alone.[305] Twenty-three percent of patients in each arm responded, further documenting doxorubicin activity. Most recently, ECOG reported the results of their largest trial of combination chemotherapy.[306] This trial randomly allocated patients with measurable carcinoid tumors to the standard regimen of 5-FU plus streptozotocin (FS) and a new regimen of 5-FU and doxorubicin (FA). Patients who had either renal or heart disease making them ineligible for streptozotocin or doxorubicin-containing therapies were treated with DTIC. Of 208 patients who were eligible and analyzed for response and survival, FA and FS therapies were associated with response rates of 13% and 16%, respectively, in the randomized group. With DTIC, the response rate was approximately 10%, with no significant differences between previously treated and untreated patients. Although the response rates for FA and FS did not differ, there was a trend toward improved survival in the FS group. The median survival time of the group was 24 months, compared with 16 months for patients receiving FA (P = 0.11). This suggestive disparity between response rate and survival time may reflect the fact that reduction in tumor bulk has little correlation with survival in patients with an indolent disease such as carcinoid tumor. Alternatively, it may be true that survival is a better measure of tumor response, with inadequate determination of response by traditional techniques.
Because no highly effective chemotherapy regimen is available, it is clear that patients should be carefully selected for use of cytotoxic chemotherapy in metastatic carcinoid tumor and carcinoid syndrome. Less toxic and more effective palliative therapies for carcinoid syndrome should always be used initially, reserving chemotherapy for those patients who are significantly disabled by unresponsive hormonally related symptoms or those with refractory symptoms due to tumor bulk. Clinical trials of more recently available drugs (taxanes, gemcitabine, camptothecins) need to be carried out. More recent clinical trials suggest potential benefit and possible indications for such anti-agonist compounds such as RAD001 and mTOR inhibitors.[307]
Interferon
Early clinical trials from Sweden suggested a role for low-dose human leukocyte interferon in the treatment of carcinoid tumors.[308] Subsequently, this group reported the results of three consecutive studies using interferon.[301] In the first study, involving 36 patients, an overall response rate of 47% was observed. In the second randomized trial, human leukocyte interferon was compared with FS. No response was observed in the 10 patients treated with chemotherapy, but 5 patients in the interferon-treated group did respond. In the third study, 20 patients were treated with recombinant interferon; an objective response rate of 55% was observed, with the bulk of responses being symptomatic or chemical responses manifested by a decrease in 5-HIAA, rather than by reduction in tumor bulk. The Mayo Clinic subsequently reported the results of their phase II trial of recombinant interferon-α (IFN-α) in 24 patients with malignant carcinoid syndrome.[309] Five patients (20%) with measurable tumor experienced objective tumor regression, and nine patients (37.5%) had a significant reduction in urinary 5-HIAA excretion. Flushing and diarrhea were transiently relieved, with objective responses lasting less than 2 months. The results suggest a limited role for this agent in treating carcinoid tumor. Clinical trials currently are being developed in which chemotherapy and interferons are being combined, although early results do not suggest additional benefit compared to single modalities.[310] Similarly, combinations of octreotide and IFN-α are being investigated to determine whether lower doses of interferon would be effective and whether the tachyphylaxis associated with octreotide could be overcome by the addition of interferon.[311] Patients with carcinoid tumors treated with interferon may develop a wide variety of autoimmune diseases, such as thyroid disease (thyrotoxicosis, hypothyroidism), pernicious anemia, and vasculitis.[312]
Hepatic-Directed Therapy
The results of surgical resection for hepatic metastases and anecdotal reports of hepatic and abdominal radiation in carcinoid tumors have already been described. The Mayo Clinic has investigated the role of hepatic arterial occlusion in metastatic carcinoid and islet cell tumors.[261] Significant improvement in symptoms and reduction in hepatic metastases were noted in 14 patients with carcinoid tumors, but the median length of response was less than 7 months. Mayo Clinic investigators also have examined the role of sequential hepatic arterial occlusion (HAO), followed by systemic chemotherapy with DTIC and doxorubicin alternating with the combination of 5-FU and streptozotocin in carcinoid tumors. [261] [313] With 65 carcinoid cases treated, more than two thirds of all patients demonstrated objective regression with either HAO or HAO plus chemotherapy. The median duration of regression was longer in the groups receiving chemotherapy, but this trial was not randomized, and better-risk cases may have been selected for the chemotherapy plus HAO treatment. Other groups are investigating the role of selective hepatic arteriography with sequential hepatic arterial embolization or chemoembolization.[314] [315] [316] Significant reduction in the signs and symptoms associated with both carcinoid tumors and islet cell tumors have been reported in the majority of patients so treated. In a study of 15 patients with advanced metastatic carcinoid tumors, hepatic artery chemoembolization improves symptoms and short-term quality of life.[317] Unfortunately, there is a paucity of data on the benefit of either intermittent or prolonged continuous hepatic arterial infusion of chemotherapeutic agents in patients with metastatic carcinoid tumors.
PANCREATIC ISLET CELL TUMORS
The advent of radioimmunoassay (RIA), immunofluorescence, and other techniques for identifying peptide hormones has expanded our knowledge of the prevalence and endocrine effects of islet cell tumors.
The pancreatic islet contains a cells (glucagon), β cells (insulin), and δ cells (somatostatin), as well as enterochromaffin cells (serotonin). These cells are all part of the APUD system, and tumors so derived secrete a wide variety of polypeptides. Some of these peptides share the characteristics and functions of classic hormones: (1) their release follows a physiologic stimulus; (2) they have the ability to effect response in a distant organ; and (3) these effects are mimicked by exogenous infusion of the hormone. By contrast, some abnormal peptides produced by islet cell tumors have no known clinical hormonal effects.[318]
Equally important, these peptide-secreting tumors are, for the most part, nonautonomous. This is thought to be due to tumor cell regulation by somatostatin and its predominant tumor cell receptor somatostatin receptor subtype 2. [319] [320] Clinically, in evaluating patients with islet cell tumors, it is important to understand that there appear to be two different types of patients with APUDomas. The first group consists of those patients who experienced their tumors singularly, in the absence of significant personal or family history of endocrine disorders. The second group includes those with clear evidence of an inherited predisposition to multiple neoplasia of the endocrine system in an autosomal dominant pattern. These MEN syndromes have been described earlier.
As with carcinoid tumors, the approach to the patient with an islet cell tumor must be individualized, balancing management of the effects of hormone production with symptoms of tumor bulk. In any individual patient, one or the other management issue may predominate. Treatment should be directed not only by the presence of symptoms, but also by a consideration of the relatively lengthy natural history of islet cell tumors ( Fig. 75-15 ).
|
Figure 75-15 Diagnosis of pancreatic islet cell tumors. Ppoma, pancreatic polypeptide-secreting tumor; VIP, vasoactive intestinal peptide; VIPoma, vasoactive intestinal peptide secreted by a pancreatic islet tumor. |
Diagnosis
Specific syndromes and diagnostic tests for each of the more common islet cell tumors are discussed separately. However, a few generally applicable principles should be understood. RIA[321] of peptides obtained by selective venous catheterization is most helpful in localizing tumors and may demonstrate the presence of metastatic spread, particularly in patients with gastrinomas (Zollinger-Ellison syndrome). CT scan and arteriography are particularly helpful in tumors greater than 1.0 cm in diameter. However, because many islet cell tumors and their metastases may be small, neither procedure may be adequately sensitive. As with most endocrine neoplasms, islet cell tumors have a rich vascularity, so that “tumor blush” can be seen on angiography. This sign may be a useful finding in differentiating between endocrine and nonendocrine gastrointestinal tumors. Ultrasonography is of some use in imaging both pancreatic primary tumors and hepatic metastases. Newer imaging techniques are required, therefore, for better diagnosis and staging. For example, MRI has been shown in some studies to be superior to contrast-enhanced CT scans for the identification of all islet cell tumors.[318] The mainstay of diagnosis remains the RIA to detect NSE and chromogranin, which are secreted by these tumors. [255] [256]
Insulinoma
The average age of presentation of insulinoma is in the mid-40s, and the sine qua non in diagnosing this syndrome is fasting or inappropriate hypoglycemia accompanied by a relatively high plasma insulin level. [322] [323] Other tests have been proposed, including a hypernormal response to tolbutamide, the response of plasma insulin to an infusion of calcium gluconate, and the ratio of proinsulin [323] [324] to insulin in the plasma. The key to the diagnosis is a high index of suspicion.
Sporadic insulinomas usually are single and benign; about 10% are malignant.[325] Differentiation of benign from malignant is difficult based on the pathologic features alone, but the presence of metastases defines malignancy. In patients with carcinoma, proinsulin may be increased in plasma[326] or circulating hCG.[327] In both malignant and benign insulinomas, jaundice may occur secondary to biliary tract obstruction from tumors in the head of the pancreas. The typical patient with symptoms of insulinoma has a single small, benign pancreatic nodule. In atypical cases, with multiple primary endocrine tumors, including an insulinoma, MEN-1 syndrome should be suspected.[239]
These tumors usually are imaged with high-resolution, fine-cut CT, MRI, or abdominal ultrasound as the initial study. Although not very sensitive for small, primary tumors, these studies are useful to identify metastatic tumors, if present. If these studies are negative, some authors recommend proceeding with exploration with manual palpation of the pancreas and intraoperative ultrasound, citing success rates greater than 90% at initial exploration.[328] Because insulinomas almost always are confined to the pancreas, selective arteriography and portal venous sampling usually identify the lesion.[325]However, these techniques are technically demanding and not always accurate. Endoscopic ultrasound is being used increasingly to image these tumors. In a prospective series of 37 patients, endoscopic ultrasonography was highly sensitive and specific for pancreatic endocrine tumors, as ultimately confirmed by surgical excision.[329] Endoscopic ultrasound has been reported to be accurate for identifying tumors larger than 5 mm in the pancreatic head.[330] Invasive localization procedures usually are reserved for patients who present with recurrent or persistent disease.
Surgical resection usually is curative because of the small size and benign nature of insulinomas. As in carcinoid tumor, partial resection may afford palliation in patients whose symptoms are disabling or cannot be controlled with nonsurgical modalities. A patient with unresectable malignant insulinoma and recurrent episodes of hypoglycemia often benefits, during the early stages, from appropriate diet and administration of an insulin antagonist. Frequent feedings between meals and at bedtime are administered with sufficient glucose to control symptoms. Adjustments in the carbohydrate content of the diet may be required, depending on the reactivity of the individual tumor, because the stimulus of a large glucose load may lead to an exaggerated release of insulin.[331] Parenteral glucose supplementation becomes an important adjunct in frequent or sustained hypoglycemic attacks; in emergencies, rapid injection of 50% glucose can be required.
Corticosteroids, human growth hormone (hGH), and glucagon have been useful palliative agents in individual patients. [332] [333] However, because of their limited effectiveness, they are best used in combination with other antihormonal measures. Furthermore, glucagon stimulates pancreatic insulin secretion and may cause paradoxic exacerbation of a hypoglycemic episode.
A major advance in the palliation of malignant insulinoma came with the development of diazoxide. Its potent hyperglycemic properties, originally recognized during its use as an antihypertensive agent, have now been extended to the palliation of insulinoma and leucine-sensitive hypoglycemia of infancy. [334] [335] Its principal action is to inhibit insulin release directly from the β cell. It also may have an extrapancreatic hyperglycemic effect.[336] Diazoxide is administered orally in divided doses, ranging from 100 to 1000 mg/day. Although the plasma insulin level often can be reduced to a level that causes no symptoms, the tumor will continue to grow and metastasize if malignant, because diazoxide lacks anticancer activity. Diazoxide can cause edema, which can be corrected or prevented with a thiazide diuretic, which also may serve to reinforce the hyperglycemic effects.[323] Octreotide is valuable in the general management of all hormone-producing islet cell tumors and has been found to reduce plasma insulin levels in at least 65% of patients with insulinoma.[337] Octreotide is especially useful when there are insulinoma metastases, because there appears to be upregulation of somatostatin receptor subtype 2 (SST 2) of the metastatic lesions. A caveat remains when using octreotide. Up to 60% of the primary insulin-secreting tumors may not have SST 2 receptors, and hypoglycemia may worsen. Initiation of octreotide acetate requires close monitoring when used in insulinoma therapy.[320]
Chemotherapeutic agents such as streptozocin, 5-fluorouracil, and doxorubicin have been used to treat metastatic insulinomas, but have limited efficacy.[338]
Glucagonoma
Glucagon from pancreatic a cells plays an important role in modulating serum glucose concentrations. Unregulated secretion of glucagon by α-cell tumors[339] produces a distinctive clinical syndrome.[340]A cutaneous rash, described as a necrotizing migratory erythema, is the most characteristic feature.[341] Mild insulin-resistant diabetes and weight loss attributable to the catabolic effects of glucagon also are seen. Glossitis, cheilosis, and venous thromboses can develop. Glucagon inhibits intestinal motility, and the glucagonoma syndrome often includes ileus and constipation. Because symptoms commonly are mild and nonspecific, the tumor often is recognized late, when metastases are present.[340] Most tumors have grown to greater than 4 cm[342] in size at diagnosis, and 50% to 80% are metastatic. [342] [343]
The diagnostic test for glucagonoma is the finding of a high plasma glucagon concentration (normal, <60 pg/mL). In patients with glucagonoma, the plasma hormone level typically is markedly elevated and often is greater than 1000 pg/mL.[343] The diagnosis is further suggested by failure of glucose to suppress glucagon, by an abnormal rise in plasma glucagon following infusion of arginine, by the presence of hypoaminoacidemia, and, if tumor is available, immunoperoxidase staining for glucagon. Reviews suggest that the tumor is more common in women and typically presents in the fifth and sixth decades. [344] [345] Symptoms persist for many years before the diagnosis is made; survival, even with metastatic disease, may be lengthy. The primary tumor is in the tail or body of the pancreas in 50% of patients and in the head of the pancreas in 8% of patients; the remaining 42% of patients have diffuse involvement. CT scans and MRI are useful in identification of the primary tumor, as is octreoscanning.[346] The tumor is resectable for cure in less than one third of cases,[344] and recurrence after resection, mainly in the liver, is common.
In addition to surgical resection, octreotide produces an improvement of skin rash in up to 90% of patients and complete disappearance of rash in 30%. [347] [348] Chemotherapeutic agents may have some activity.
Somatostatinoma
Somatostatin first was identified in pituitary cells, and a role in the regulation of growth hormone secretion was ascribed to it. Subsequently, it was recognized as a hormone of the islet δ cells. Somatostatin may serve as a paracrine regulator of other pancreatic islet cell hormones.[348] Inhibition of secretion of those hormones may account for some of the signs of somatostatinoma. In a review of 20 patients, 11 were noted to present with diabetes, 13 with gallbladder disease, and 7 with diarrhea.[349]
Somatostatinoma occurs most frequently in the head of the pancreas,[350] and as many as 80% of patients have evidence of metastases at diagnosis.[349] Somatostatinomas produce such common symptoms as diabetes (type 2–like diabetes mellitus) and gallbladder disease; therefore, the clinician usually does not consider the diagnosis of somatostatinoma until late in the disease, by which time metastases are likely. Surgical resection usually is not curative. [349] [351] Because of the relatively mild hormonally induced symptoms produced by somatostatin, octreotide does not have the same palliative benefit it has in other islet cell tumors. Cytoreductive surgery and chemotherapy may be the most appropriate palliative strategies.
Gastrinoma
Gastrin, the polypeptide hormone normally secreted by the G cell of the gastric antrum, stimulates gastric acid secretion. Tumors of the pancreatic or duodenal wall G cells are responsible for the signs and symptoms of Zollinger-Ellison syndrome, a disorder characterized by hypersecretion of gastrin. First described in 1955,[352] this syndrome is characterized by hypersecretion of gastric acid, severe peptic ulcer disease, and an islet cell tumor of the pancreas. It is estimated that less than 0.1% of patients with peptic ulcer disease have Zollinger-Ellison syndrome.[353]
The hallmark of the gastrinoma syndrome is recurrent peptic ulcer disease in spite of adequate medical or surgical treatment. Intermittent diarrhea, often with steatorrhea, may be present as a result of digestive enzyme inactivation in the small intestine by unbuffered gastric acid. All manifestations of the Zollinger-Ellison syndrome are secondary to hypersecretion of gastric acid.[354] A history of the MEN-1 syndrome has great significance, and gastrinoma may be present in up to 50% of these patients.[355] The combination of high gastric acid secretion and hypergastrinemia is strongly suggestive of gastrinoma, but this combination also can occur in patients with retained gastric antrum following surgery for peptic ulcer (antrectomy and Billroth II gastric resection) and following gastric outlet obstruction. Gastric rugal hypertrophy, multiple ulcers, or ulceration of the small bowel on radiographic studies suggests gastrinoma.[356]
In a review of 60 patients treated surgically for gastrinoma at Ohio State University, Ellison and associates[357] reported that the duration of ulcer symptoms prior to diagnosis averaged slightly more than 4 years. The incidence of MEN was 27%, and a primary tumor was detected in nearly 90% of cases. Gastrinoma can occur not only in the pancreas but also in extrapancreatic locations, including the duodenum, the stomach, and the retroperitoneal lymph nodes. More than one third of patients in the Ohio State series had multiple tumors; metastatic disease in the liver was identified in 20% of patients.[357]
The clinical diagnosis of Zollinger-Ellison syndrome has changed. Although the original case reports stressed the appearance of extensive and multiple gastric ulcers, a heightened index of suspicion and early detection have altered this pattern of disease presentation. The complete diagnosis of Zollinger-Ellison syndrome is based on four steps.[355] The first step is to identify fasting hypergastrinemia in association with a basal acid output greater than 15 mEq/hour. Generally, a gastrin level greater than 1000 pg/mL is pathognomonic. Less convincing elevations in fasting serum gastrin can be further evaluated by the secretin test, in which a peak level of serum gastrin higher than 200 pg/mL over the baseline following administration of secretin is considered diagnostic.[358] The remaining three steps include documentation of peptic ulcer disease, localization of the primary tumor, and assessment of malignancy.[359]
Localization of gastrinomas has been discussed extensively. [360] [361] Techniques such as abdominal ultrasonography, CT scan, MRI, selective venous sampling for gastrin, and abdominal arteriography all have a role in the diagnosis and management of this disease. Octreotide scanning is very useful for identifying primary and metastatic lesions,[362] and is valuable as an initial imaging modality. Endoscopic ultrasound also is being used increasingly to identify gastrinomas. Because gastrinomas are so frequently malignant, [363] [364] it is necessary to use every diagnostic modality to rule out metastatic disease before planning surgery.
The role of surgery in Zollinger-Ellison syndrome has changed over the past 20 years as a result of the introduction of RIA to diagnose hypergastrinemia and use of histamine H2-receptor antagonists. The latter therapy has very significantly reduced the need to remove the end organ (the stomach); therefore, few patients will require surgical management to control the signs and symptoms of hypergastrinemia. In addition, gastrinomas are significantly less likely than insulinomas to be isolated, benign, or completely resectable. In a collected series of 457 surgical patients, only 69 patients (15%) were considered to have received surgery with curative intent.[357]
Ellison and associates[357] also analyzed 60 cases from their own institution to determine whether the introduction of the RIA for gastrinoma made earlier diagnosis more likely, with a higher possibility of curative resection. Before the introduction of the assay for serum gastrin levels, 15 of 25 (60%) patients underwent complete excision of all gross tumor. Of the 30 patients who underwent surgical treatment following availability of the assay, 18 (60%) had complete tumor resection. These results indicate no differences in rates of curative resection. However, resectability was associated with prolonged survival, with a 5-year survival rate of 69% in patients with resected tumor, compared with 38% in patients with unresectable disease. The 10-year survival rates were 38% and 9%, respectively. Nearly one half of the deaths were due to the effects of tumor and metastases. These data suggest, but do not prove, that earlier surgical intervention may prevent progression to the complications of bulky malignant tumor in some cases.
Medical management in gastrinoma is directed toward the hypersecretion of gastric acid. Before the introduction of histamine receptor antagonists, the only practical way to treat recurrent duodenal and jejunal ulcers was total gastrectomy. Cimetidine was reported to enhance recovery and make surgery less complicated, and to obviate surgery in some patients.[364] Histamine H2-receptor antagonists alone or in combination with anticholinergic agents such as propanthe-line have been successful in producing long-term remissions of peptic ulcer disease complicating gastrinoma.[355] Second- and third-generation histamine H2-receptor antagonists, such as ranitidine, famotidine, and the ion pump inhibitor omeprazole, have been reported to have progressively superior antisecretory activity, with few failures observed in patients who receive adequate doses.[365] Treatment for symptoms arising from tumor bulk from metastatic gastrinoma are discussed at the conclusion of this section.
Tumors Secreting Vasoactive Intestinal Peptide
In 1958, Verner and Morrison[366] described a syndrome of watery diarrhea, hypokalemia and hypochlorhydria, and metabolic acidosis (the WDHA syndrome), which is due to high circulating levels of vasoactive intestinal peptide secreted by a pancreatic islet tumor (VIPoma). Most studies of VIP infusions in healthy volunteers have supported the concept that the diarrhea in VIPoma patients may be caused directly by elevated circulating levels of vasoactive intestinal polypeptide.[367] Because most patients with this syndrome have metastatic disease at presentation, usually to the liver, management is mainly medical, with chemotherapy or somatostatin analog. Surgical resection is rarely curative. As with carcinoid tumors and other islet cell tumors, however, in patients with locally unresectable disease or those with hepatic metastases, surgical cytoreduction may improve symptom control.
Ghrelin Secreting Tumor
Ghrelin is a 28-amino acid peptide that is secreted in the stomach and stimulates growth hormone release. A recent publication described a patient with hypertension and perspiration and a malignant gastric ghrelinoma with hyperghrelinemia.[368] Although this tumor is exceedingly rare, the expression of ghrelin peptide has now been identified in almost all gastric and intestinal carcinoids, as well as pancreatic neuroendocrine tumors. Its possible role as a tumor marker along with chromogranin A (CGA) in all gastroenteropancreatic neuroendocrine tumors remains to be clarified.
Surgical Management
Pancreatic islet cell tumors present a challenge for the endocrine surgeon. Most are sporadic, but they also can occur as part of the MEN-1 syndrome. Patients with MEN-1 usually develop multicentric tumors that often preclude the ability to perform a curative resection. The commonly occurring islet cell tumors secrete gastrin, insulin, glucagon, pancreatic polypeptide, or somatostatin. These tumors can have profound physiologic effects; even in cases in which complete resection is not possible, tumor debulking may be indicated to alleviate the physiologic effects of hormone secretion.
Gastrinoma
Gastrinomas occur within the pancreas or are found submucosally within the duodenum. Most gastrinomas are located in the “gastrinoma triangle,” which is surrounded by the cystic duct superiorly, the second and third portions of the duodenum inferiorly, and the junction of the body and neck of the pancreas medially. Approximately 75% are malignant, with liver metastases a common finding. CT scanning is the best method for evaluating patients for resection. Patients with solitary tumors in the tail of the pancreas can be treated with enucleation or distal pancreatectomy; however, a Whipple procedure may be needed for large or obviously malignant tumors in the head of the pancreas. Duodenal tumors can be resected locally from the wall of the duodenum. It may be necessary to use intraoperative ultrasound, endoscopy with duodenal transillumination, and a longitudinal duodenotomy to identify these tumors. Usually, all enlarged peripancreatic and periduodenal lymph nodes are removed. Occasionally, localized metastases can be resected to control excess gastric secretion. Patients with unresectable gastrinoma whose acid secretion cannot be controlled medically require a total gastrectomy with esophagojejunostomy.
Insulinoma
Approximately 75% of insulinomas are solitary benign tumors. Preoperative evaluation begins with a double-contrast, fine-cut CT scan. Small tumors that cannot be found by CT scan may be localized preoperatively with transgastric endoscopic ultrasound, which has been reported to have a sensitivity of 83% to 93%.[369] Selective arteriograms with calcium stimulation are used rarely. At laparo-tomy, the entire pancreas should be exposed by a generous Kocher maneuver. A combination of inspection, palpation, and intraoperative ultrasound will identify most tumors and their relation to the pancreatic duct. Small, benign tumors in any part of the pancreas can be enucleated provided they are not in close proximity to the duct. After enucleation, the pancreatic surface is closed, and the area should be drained because of the possibility of pancreatic fistula.
Larger tumors (≤5 cm) in the head of the pancreas also can be enucleated; however larger tumors in the tail are best treated with a spleen-preserving distal pancreatectomy. Large, potentially malignant, tumors in the head of the pancreas may need a Whipple procedure. Resection of peripancreatic and duodenal nodes also is advised. Some centers now are approaching these tumors laparoscopically. Although feasible, long-term follow up data are needed. [370] [371]
Medical Management
Somatostatin Analog
The somatostatin analog octreotide is as useful in the treatment of syndromes associated with ectopic hormone production in islet cell tumors as it is in treatment of carcinoid tumors. In 1985, Santangelo and associates[372] described a single patient with life-threatening pancreatic cholera, successfully controlled by the synthetic somatostatin analog. A later series of patients from the Mayo Clinic significantly supplemented these data; in this series, 24 patients with islet cell tumor were treated.[373] The response to somatostatin analog was prompt and palliated symptoms. However, the median duration of response was only 2.5 months, with only 2 of 24 patients (8%) continuing to benefit beyond 1 year. In another review of 66 cases treated with octreotide, only 8 patients (12%) showed any indication of objective tumor response.[337] The short duration of response and low incidence of objective tumor regression suggest that somatostatin analog in the treatment of metastatic islet cell tumors has a more limited role than in carcinoid tumors. Two recent publications suggest that high-dose octreotide therapy may have additional stabilizing and antiproliferative effects in some patients who suffer malignant, advanced, midgut carcinoid tumors. [374] [375] Patients on long-term octreotide therapy should have a cholecystectomy at the time of initial exploration due to the high incidence and morbidity of biliary complications.[300]
Interferon
As somatostatin analogs were being shown to be useful in patients with pancreatic cholera, the first reports of the use of interferon in such patients appeared.[376] In the initial report, two patients with the therapy-resistant pancreatic cholera syndrome were treated successfully with human leukocyte interferon, with reduction in tumor mass in one of the patients. Extending these observations, Swedish investigators reported on 22 patients treated with human leukocyte interferon, with an objective response rate of 77% and a median duration of response of 8.5 months.[301] Most of these responses were documented by decreased hormone production. Only 6 of 22 cases (27%) had objective reduction in tumor bulk. Further evaluation of interferon, with and without chemotherapy, is warranted. The mechanism of action of interferon in islet cell and carcinoid tumors is unknown.
Chemotherapy
As with carcinoid tumors, the use of cytotoxic chemotherapy in a patient with an islet cell tumor is not a first choice for therapy.[377] Chemotherapy usually is attempted in patients with symptoms due to tumor bulk that may not be palliated by cytoreductive surgery or in patients with uncontrolled syndromes of hormone excess. In contrast to carcinoid tumors, islet cell carcinomas generally are more responsive to chemotherapy. The first chemotherapeutic drug to elicit significant attention in the treatment of islet cell tumors was the antitumor antibiotic streptozotocin. This drug has a diabetogenic action in some animals that is correlated with selective uptake of the drug by pancreatic β cells. [377] [378] In 1975, Kahn and associates[379] described two patients with pancreatic cholera and islet cell carcinoma successfully treated with intra-arterial streptozotocin. Subsequently, a number of chemotherapeutic drugs were identified as having activity in islet cell tumors. With the identification of 5-FU as a potentially useful drug in these tumors, combination chemotherapy also began to be investigated. In a phase II trial of the combination of 5-FU and streptozotocin, six objective responses were noted in eight patients. In 1980, a larger study from the ECOG was reported, in which streptozotocin alone was compared with streptozotocin plus 5-FU in advanced islet cell carcinomas.[302] The combination was superior to streptozotocin alone in overall rate of response (63% vs. 13%). These responses generally were of long duration and yielded meaningful improvements in performance status and symptoms. The median survival time of patients receiving the combination was 26 months, compared with 16.5 months in the group receiving streptozotocin alone. The combination was associated with a higher degree of nausea and vomiting, myelosuppression, and nephrotoxicity. With the identification of doxorubicin as a potentially useful drug in islet cell tumors,[380] the ECOG also piloted a randomized trial in which doxorubicin plus streptozotocin was compared with the earlier standard of 5-FU plus streptozotocin. Results from this study demonstrate that the doxorubicin plus streptozotocin combination produced objective response in 69% of cases, with a median duration of response in excess of 20 months and a median survival time of 2.2 years.[381] This regimen is superior to the 5-FU plus streptozotocin combination in both tumor response and survival. A study of 12 patients with islet cell carcinomas treated with the combination streptozotocin, doxorubicin, and 5-FU reported a 54% response.[300]However, these were partial responses; no complete responses were found.
A number of other chemotherapy drugs have demonstrated activity in islet cell tumors. Chlorozotocin, an analog of streptozotocin, has been shown to be less nephrotoxic but more myelosuppressive than the parent drug. In phase II trials of chlorozotocin, responses were significant when it was used alone or with 5-FU. [382] [383] Unfortunately, chlorozotocin is no longer being produced. DTIC also has activity in islet cell tumors, and this agent is undergoing a prospective clinical trial by the ECOG. Other agents of interest include etoposide and cisplatin, which are active in various neuroectodermally derived tumors. The combination of etoposide and cisplatin has been shown to have activity in small cell lung cancer, and a recent trial demonstrates that more than 60% of anaplastic carcinoid and islet cell tumors respond to this combination, whereas well-differentiated tumors do not respond.[384] A phase II trial with DTIC, 5-FU, and leucovorin reported an overall response rate of 27%; however, 50% of the patients had carcinoid tumors, which, as a subset, demonstrated particularly poor response.[385]
Liver-Directed Therapy
As with carcinoid tumor, islet cell tumors often result in predominantly hepatic metastases, and reduction in tumor bulk in the liver may significantly influence hormone production and quality of life. For that reason, resection of hepatic metastases is warranted in selected patients. The use of hepatic radiation has been reported only anecdotally. Of two patients treated at the National Cancer Institute, one patient with a VIPoma had significant resolution of watery diarrhea for 25 months; the other, with gastrinoma, had significant diminution in abdominal pain and of gastrin levels.[386] Endocrine and tumor response to hepatic arterial occlusion, with or without chemotherapy, can be impressive. The Mayo Clinic experience documents, in 46 patients with islet cell tumor regression rates of 43% with hepatic artery occlusion alone, versus 78.1% when chemotherapy was included. [261] [313] Chemotherapy in addition to hepatic arterial occlusion improved the duration of response, but this was not a randomized comparison. However, both objective tumor responses and hormonal regressions were common, and the increased activity of chemotherapy in these tumors supports the use of systemic therapy with or without HAO techniques. The use of cryosurgery for treatment of hepatic metastases that are resistant to chemotherapy also has been reported.[387] This approach has been reported to be effective in treating symptoms, but effect on survival has not yet been demonstrated.
Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com
Abeloff: Abeloff's Clinical Oncology, 4th ed.
Copyright © 2008 Churchill Livingstone, An Imprint of Elsevier
REFERENCES