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Indications for surgery. Once the diagnosis of primary hyperparathyroidism is confirmed biochemically, patients should be selected for operation.

All symptomatic patients with biochemically proven hyperparathyroidism should be considered for surgery.

Operation is also advised for an asymptomatic patient younger than 50 years of age or any patient whose serum calcium levels exceed 11 mg/dL, especially if the patient has a decrease in bone density, hypercalciuria, or a decrease in renal function due to other diseases such as hypertension or diabetes mellitus.

Preoperative localization of the parathyroid glands

Localizing the abnormal parathyroids preoperatively is helpful for several reasons.

It permits a minimal access approach and reduces the operating time for many patients. P.340

It helps to define the anatomy of the neck in patients who have had prior surgery, in whom the normal anatomy may be distorted.

It aids in defining the pathology in patients who have had prior unsuccessful surgery for primary hyperparathyroidism and who still have either persistent or recurrent hypercalcemia.

Methods of preoperative localization

Scintigraphy using Tc sestamibi is helpful in localizing 75%–90% of parathyroid adenomas.

Tc sestamibi is taken up by the thyroid and parathyroid glands on initial images. Delayed images show persistent uptake by enlarged parathyroid glands but rapid washout from the thyroid. It is less accurate in imaging patients with multiglandular disease.

Sestamibi scanning is useful in imaging enlarged parathyroid glands in ectopic locations such as the mediastinum.

SPECT (single positron emission computerized tomography) may reveal anatomic relationships that traditional planar imaging does not.

Combination SPECT -CT may provide additional localizing information in subtle or difficult cases.

Ultrasonography will define an enlarged parathyroid in 70%–80% of the cases. The ultrasound criteria for an enlarged parathyroid gland include:

A hypoechoic area in close proximity to either pole of the thyroid gland

The presence of internal echoes that exclude a pure cyst or vascular structure

CT and MRI

CT is particularly successful in localizing enlarged parathyroids in the mediastinum. In addition, it allows visualization of parathyroids that may not be visible by ultrasound or dual-tracer imaging.

MRI seems to be as successful as CT in localizing parathyroids. It reveals enlarged parathyroids on the T 2 -weighted image.

Used alone or in combination, CT and MRI are the most accurate of the noninvasive localization studies but are also the most expensive.

Selective venous sampling and PTH assay. The Seldinger technique can be used in the venous system to obtain blood samples from different venous sites for PTH assay. Because the study is costly and time consuming, it is reserved only for patients in whom initial surgery was unsuccessful or who had a recurrence of hyperparathyroidism after initial successful treatment.

Retrograde injection of the thyroid veins is performed, and each of the draining thyroid veins is selectively cannulated.

A disproportionately high PTH level in one or more of the venous samples helps to localize the lesion to one side of the neck or the other.

Significant increase in samples obtained from veins on both sides of the neck suggests four-gland hyperplasia.

Thyrocervical angiography

If the thyrocervical trunk is selectively cannulated, and angiograms of the thyroid and parathyroid are obtained, enlarged glands in the neck can be seen.

If the internal mammary artery is selectively cannulated, enlarged parathyroids in the mediastinum can be found.

Stroke has been reported as a complication of thyrocervical angiography; therefore, this technique should not be used indiscriminately.

It is reserved primarily for patients who have previously had unsuccessful surgery, who develop recurrent hyperparathyroidism after operation, and who have had no success with other localization techniques.

Surgical treatment

Successful surgery requires a thorough knowledge of the anatomy of the normal parathyroids and their abnormal locations. When possible, all four parathyroid glands should be identified at surgery.

When a solitary adenoma is present, it should be completely excised.

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In the past, routine full neck exploration was performed. Visualization of the other three glands and biopsy of at least one of those glands was needed to to rule out the presence of multiple adenomas or four-gland hyperplasia.

Currently, improved localization techniques and the use of a rapid intraoperative assay of PTH levels allows for a minimal access approach to parathyroid adenomas in most patients.

A PTH level is drawn at the beginning of the operation, and then a limited dissection is performed through a small incision to identify and excise the previously localized adenoma.

Injection of sestamibi may be performed preoperatively and a hand-held gamma probe used intraoperatively to aid in the localization of the adenoma. However, this technique is limited by a low signal to background noise ratio and is generally not needed in most cases.

Following excision of the adenoma, additional PTH levels are drawn at specific intervals (various protocols can be followed, but levels drawn at 0, 5, and 10 minutes after excision are generally sufficient).

Due to the very short half -life of PTH in the circulation (about 2 minutes), a significant drop in the PTH level should be seen if all abnormal parathyroid tissue has been removed. A drop of the PTH level to less than 50% of the highest level (either preoperatively or at the time of excision) or a clear drop into the normal range is associated with a 95%–98% cure rate. If the levels do not drop sufficiently, then additional levels should be obtained and/or further exploration performed to ensure that all abnormal parathyroid tissue has been removed.

Management of four -gland hyperplasia. Two options are currently available.

Subtotal parathyroidectomy , leaving a well-vascularized remnant (100 mg of parathyroid tissue in the adult and 150 mg in the child) to provide for normal parathyroid function. Once again, intraoperative PTH levels are obtained to ensure that an adequate excision of parathyroid tissue has been performed. If the levels do not drop despite three and a half gland excision, supernumery parathyroid glands should be sought out and removed. There is a 5% recurrence rate after subtotal parathyroidectomy.

Total parathyroidectomy with autotransplantation of minced parathyroid tissue into a well-vascularized, accessible forearm muscle so that recurrence can be treated without reoperation on the neck. There is a real danger of permanent hypoparathyroidism after total parathyroidectomy and reimplantation if the autotransplant does not survive.

Postoperative management. Postoperative hypocalcemia usually develops after successful therapy.

Asymptomatic postoperative hypocalcemia requires no treatment.

Symptomatic hypocalcemia always requires treatment.

In severely symptomatic patients, treatment should begin with intravenous calcium gluconate.

Mildly symptomatic patients may be given oral calcium in the form of calcium lactate, calcium carbonate, or calcium gluconate. Doses ranging from 4–20 g/day may be required.

A Introduction

The thymus is important to the surgeon because it is the origin of a variety of tumors and is significantly involved in the development of cellular immunity. As such, it has been implicated in a variety of disease states.

Embryology

The thymus arises from the third branchial pouch and descends into the anterosuperior mediastinum.

It is a multilobulated structure with many fibrous septa. Each lobule has a cortex and a medulla.

The cortex consists primarily of lymphocytes, which appear to migrate to the medulla and then emigrate from the thymus.

The medulla also contains Hassall's corpuscles, which are composed of concentric layers of epithelial cells. Their function is unknown.

Anatomy

Development

Because of the bilateral origin of the thymus gland, it develops two lobes and a roughly H- shaped configuration.

Two limbs of the thymus extend into the neck and are often associated with the inferior parathyroid glands.

The inferior limbs extend along the surface of the pericardium and abut the pleura.

The thymus reaches maximal size shortly after birth and then begins to involute during adolescence and early adult life.

Functions

Cellular immunity. The thymus is essential for the development of cellular immunity, which controls such processes as delayed hypersensitivity reactions and transplant rejection.

The thymic-dependent portion of the immune system consists principally of the thymus and a circulating pool of small lymphocytes that produce cell -mediated immune reactions.

While removal of the neonatal thymus in certain strains of mice leads to significant impairment in immunologic capacity, it has no such effect in the human newborn.

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However, impaired thymic development may be associated with immunologic deficiency disorders.

The thymus is the first organ to manufacture lymphocytes during fetal life, but most of the cells produced in the thymus die there.

Immune system function and thymic lesions. Histologic abnormalities in the thymus, such as lymphoid hyperplasia or thymic tumors, are frequently found in association with certain

autoimmune diseases, suggesting a relationship between thymic function and immune system disorders. The autoimmune diseases are:

Myasthenia gravis (see IV C)

Systemic (disseminated) lupus erythematosus

Erythroid agenesis

Hypogammaglobulinemia

Rheumatoid arthritis

Dermatomyositis

Vasculature

Arterial supply to the thymus is derived from small branches of the internal mammary or pericardiophrenic arteries.

Venous drainage is primarily to a single thymic vein that drains into the left innominate vein.

B Thymic tumors

Incidence. Thymic tumors (thymomas) are among the most common tumors of the anterosuperior mediastinum in the adult.

While thymic tumors can occur at any age, they are most common in the fifth and sixth decades of life.

Males and females are equally affected.

Some 40%–50% of patients with thymomas have associated myasthenia gravis.

Pathology

While thymic tumors have been described according to their cell of origin as lymphoid, epithelial, spindle cell, or mixed, it is almost impossible to distinguish benign from malignant thymic tumors microscopically.

Two thirds of thymic tumors are considered benign, and of these, 10% are simple cysts (see Chapter 18, III A 1).

Spindle cell thymomas appear to have a better prognosis than epithelial thymomas, which have a poor prognosis.

The best index of the benign or malignant nature of the tumor is its tendency to invade contiguous structures.

Benign tumors are well encapsulated.

Malignant tumors are invasive, spreading by direct invasion of contiguous structures and onto adjacent pleural surfaces. Distant spread is extremely rare.

Diagnosis

Most patients who have thymomas are asymptomatic, and the tumor is discovered incidentally on a routine chest radiograph. Symptoms, when present, are related to invasion by malignant thymomas and consist of chest pain, dyspnea, or superior vena cava syndrome.

The existence of a thymoma is suggested by either:

An abnormality on chest radiograph, CT scan, or MRI (Fig. 16 -7)

The presence of myasthenia gravis

This condition should prompt a search of the mediastinum for a thymic tumor.

A lateral chest radiograph is most helpful because small tumors may be obscured by the great vessels in standard posteroanterior chest radiographs.

Recently, CT and MRI have been helpful in identifying the degree of invasion of thymic tumors.

Surgical treatment. Most thymic tumors are removed through a sternal -splitting median sternotomy.

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FIGURE 16-7 A: Posteroanterior and lateral chest radiograph, showing an anterior mediastinal mass in the right hemithorax in a patient with a thymoma. B: A CT scan from the same patient showing an anterior mediastinal mass without fixation to the underlying pericardium.

Thymic tumors that are not associated with myasthenia gravis or another clinical syndrome require mediastinal exploration and total removal of the tumor.

Benign tumors can be removed by local excision or thoracoscopically (video-assisted thoracic surgery) with sternotomy.

Malignant tumors

If possible, all areas of invasion should be removed.

When invasive thymic tumors are nonresectable or cannot be removed completely, postoperative radiation may be valuable. Chemotherapy using iphosphamide, etopiside, cisplatinum, and paclitaxel (Taxol) has been useful as has somatostatin analogue.

Thymic tumors that are associated with myasthenia gravis or other clinical syndromes should be removed, including the entire remaining thymus gland.

C Myasthenia gravis

Overview. Myasthenia gravis is an autoimmune disease of neuromuscular transmission that causes skeletal muscle weakness. It is characterized by spontaneous remissions and by exacerbations that are often precipitated by an upper respiratory infection. The most common symptoms are ptosis, double vision, dysarthria, dysphagia, nasal speech, and weakness of the arms and legs.

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Pathophysiology

Normal neuromuscular transmission

The neurotransmitter acetylcholine is produced at the nerve terminal of the myoneural junction.

The acetylcholine binds to receptor sites on the muscle end plates.

This action triggers muscle contraction.

Neuromuscular transmission in myasthenia gravis. It appears that antibodies to acetylcholine receptors develop, which decrease the available number of receptor sites on the muscle end plates, resulting in reduced muscle contraction.

Treatment

Medical treatment. Patients who have myasthenia gravis respond to drugs that stimulate the neuromuscular junction, such as neostigmine and pyridostigmine.

Surgical treatment

In patients who have thymic tumors, surgical removal of the tumor is advised, although the effect on the myasthenia is unpredictable. However, even in patients without thymic tumors, thymectomy appears to be the treatment of choice for all forms of myasthenia except purely ocular myasthenia. Thymectomy seems to:

Increase the percentage of permanent remissions

Decrease the morbidity and mortality of the disease

Improve the response to medication in patients who do not undergo complete remission

Preoperative and postoperative management have significantly reduced the morbidity and mortality rates of surgery.

Surgery in patients with myasthenia gravis creates several problems.

The sternal -splitting incision reduces the ability of patients with impaired muscle strength to ventilate properly and to mobilize secretions.

The use of parasympathomimetic drugs improves muscle strength but also increases pharyngeal and tracheobronchial secretions.

Preoperative plasmapheresis has been used with good results.

It eliminates the need for parasympathomimetic drugs and eliminates circulating acetylcholine receptor antibodies.

This produces significant improvement in perioperative muscle strength and virtually eliminates the need for prolonged ventilatory support.

Thymectomy can be performed by a transcervical route, thoracoscopically, or through a sternal - splitting incision—the former for normal thymus glands, the latter for large benign glands and most thymic tumors.

Results of medical and surgical treatment

Without surgery, spontaneous remissions occur in 18% of patients with myasthenia gravis, whereas thymectomy induces complete remission in approximately 38% of patients.

Sustained improvement is achieved with medication in only 33% of patients without surgery and in 85% of patients after thymectomy.

The best results from thymectomy are usually found in younger patients who have myasthenia of relatively short duration who have become increasingly refractory to medication.

Chapter 17

Multiple Endocrine Neoplasia and Tumors of the Endocrine

Pancreas

John S. Radomski

Herbert E. Cohn

Ronald J. Weigel

I Multiple Endocrine Neoplasia

A Overview

Multiple endocrine neoplasia (MEN) syndromes, formerly known as multiple endocrine adenomatosis, are characteristic patterns of endocrine hyperfunction inherited as autosomal dominant traits.

Many of the endocrine cell types involved originate from the neuroectoderm and have the ability to secrete peptide hormones, amines, or both, but no unifying molecular defect is currently known.

Certain features are present in all MEN syndromes.

All are autosomal dominant traits with significant phenotypic variability.

The involved endocrine glands develop hyperplasia, adenoma, or carcinoma.

The neoplasias in the involved glands can develop simultaneously or at different times.

Ectopic hormone production is common.

B Types

Three types of MEN have been identified (Table 17 -1).

Type 1 (Wermer's syndrome) involves the parathyroid glands, pancreatic islets, and pituitary gland and is caused by inheritance of a mutation of the menin gene on chromosome 11q13.

Hyperparathyroidism (see Chapter 16, III C) is present in 90% or more of the patients, with most having hyperplasia of multiple parathyroid glands.

Pancreatic tumors are present in 80% of patients.

These are usually nonbeta islet cell tumors, which can cause the Zollinger -Ellison syndrome (see II C).

However, other syndromes can occur (see II and Chapter 15, III ).

Pituitary tumors are present in 65% of cases. These are usually chromophobe adenomas, which produce acromegaly, galactorrhea, amenorrhea, or Cushing's syndrome.

Approximately 90% of patients present with hypercalcemia, hypoglycemia, peptic ulcer, or complaints secondary to a pituitary mass.

Type 2A (Sipple's syndrome) comprises medullary carcinoma of the thyroid, pheochromocytoma, and, in MEN 2A, parathyroid hyperplasia. MEN2 is caused by mutation of the Ret gene, which maps to 10q11.2.

Medullary thyroid carcinoma (see Chapter 16, I F 5 c) occurs in all patients.