Endocrine Surgery in Children
David L. Schwartz, M.D.,* Donald S. Gann, M.D., ** and J. Alex Haller, Jr., M.D .***
Surgically correctable endocrine abnormalities, benign or malignant, are commonly the result of discrete tumors causing excess hormone production. The pheochromocytoma, parathyroid adenoma, and adreno- cortical carcinoma are examples of this hyperfunctional state. Hormonal imbalances can also reflect glandular hyperplasia, in which case therapy is directed toward the whole organ or toward stimulating factors. Func- tional hyperplasia, including Cushing’s syndrome, hyperthyroidism, organic pancreatic hypoglycemia, and congenital aldosteronism, en- compass a broad spectrum of disease. Endocrine responses may reflect advanced pathology in other organs; the hyperparathyroidism associated with renal failure is a case in point. Bizarre paraneoplastic syndromes, manufacturing a variety of hormones and vasoactive substances, are equally confusing in adults and children. Rare forms of “ectopic” hor- mone production, limited to the pediatric age group, will be mentioned.
The scope of endocrine related surgery widens when one considers that intracranial lesions, the Zollinger-Ellison syndrome, insulinoma, carcinoid, and gonadal tumors have all been described in children. Many of the detailed classic descriptions of endocrine disease serve both the adult and child. There are, however, not only many significant and unique features in pediatric endocrinology, but also pathologic conditions that exist only in infants and children. We shall emphasize those distin- guishing aspects which are relevant to the clinical evaluation of the pa- tient, the approach to surgical therapy, the postoperative care, family counseling, and ultimately, the outcome of the young patient’s endocrin- opathy.
PHEOCHROMOCYTOMA
The diagnosis, the operative treatment, and the longterm care of pa- tients with chromaffin tumors is now intimately dependent upon a
From the Departments of Surgery and Biomedical Engineering, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland
*Formerly, Fellow in Surgery and Chief Resident in Pediatric Surgery
** Professor of Biomedical Engineering; Associate Professor of Surgery
*** Robert Garrett Professor of Pediatric Surgery, Children’s Surgeon-in-Charge
knowledge of the biochemistry of the catecholamines. The catechola- mines play a role both in neural transmission and in metabolism. These latter functions include the oxidation of free fatty acids, glycogenolysis, inhibition of insulin-secretion, and the blockade of the peripheral effects of insulin on glucose transport. The measurement of catecholamines and their metabolites in the urine and plasma yields an accurate chemical diagnosis in over 90 per cent of patients with functioning chromaffin tumors. With the availability of precise analysis, the pharmacologic stress tests are no longer of major importance. However, provocative tests with histamine or tyramine can be used to elicit a hypertensive response in those patients who are suspected of having residual tumor following primary excision.
The first report of a pheochromocytoma in a child was made by Marchetti27 in 1904, and since that time many cases have been described. Generally, the childhood tumor is benign and therefore represents a cur- able form of hypertension. Hypertension is uncommon in children and when present is usually due to renal disease or coarctation of the aorta. The differential diagnoses of hypertension in infants and children are many, but those of endocrine etiology include Cushing’s syndrome, adrenogenital syndrome, aldosteronism, hyperthyroidism, diabetes mel- litus, adrenal steroid therapy, and pheochromocytoma.
Signs and Symptoms
Pheochromocytomas are well differentiated, functionally mature neoplasms and may originate from the adrenal medulla, anywhere along the sympathetic chain, the paraganglia, and the organs of Zuckerkandl, which are paraganglia along the aorta, extending from the third portion of the duodenum to the origin of the inferior mesenteric artery. The signs and symptoms of this tumor are legion and well known, many being com- mon to both adults and children. However, the younger patients more often present with nausea, weight loss, abdominal pain, visual changes, convulsions, and sustained hypertension (92 per cent). Their blood pres- sure elevation is often severe, and if untreated, results in advanced retinopathy, renal damage, encephalopathy, cardiac failure, and death.
The evaluation of a youngster suspected of having a pheochromocy- toma must take into account the unusual features of this tumor in children.23 Fifty per cent are either bilateral, multiple, or extraadrenal (Fig. 1). The extraadrenal sites include the perinephric region, organs of Zuckerkandl, mediastinum, urinary bladder, and neck. Twenty-five per cent are bilateral, while this is true in only 5 per cent of adults. The tumor of multicentric origin is difficult to localize and treat, and at one time the associated surgical mortality was greater than 70 per cent. Today, a surgical mortality of less than 10 per cent is expected. There is a 10 per cent familial incidence in children, and the disease is inherited as a simple mendelian dominant with varying penetrance. Therefore, the family of an affected child should be investigated. Ten kindreds with 25 cases of familial pheochromocytoma have been reported.6 The recogni- tion that one is dealing with a familial case assumes importance because other members can be treated; younger members of the family will be af- fected more often; the tumors are more apt to be bilateral, multiple, ex-
,
traadrenal, or extraabdominal and have a higher malignancy rate. The familial tumors have a predilection for the organs of Zuckerkandl and are associated with neurocutaneous syndromes, other neural tumors, thyroid carcinoma, and polyglandular syndromes.
An elevated urinary VMA, without other confirmatory data, may not always signify the existence of a pheochromocytoma in children. VMA elevations have been recorded in ganglioneuroma, ganglioneuroblas- toma, retinoblastoma, carotid body tumor, malignant carcinoma, and adrenal medullary hyperplasia.
Management
Tumors of the adrenal cause increases in urine output of epineph- rine, whereas the converse is not necessarily valid. Tumors producing only norepinephrine are extraadrenal in less than one-third of the cases. It is helpful to localize the tumor prior to surgery because the probability of multicentric origin is high in children, and because leaving tumor behind places the patient at high risk. A transabdominal approach is gen- erally accepted for intraabdominal tumors, so that a thorough exploration can be performed. The work-up should include a chest x-ray, which will virtually always demonstrate an intrathoracic pheochromocytoma. Oc- casionally an abdominal x-ray will show calcification in the tumor. An in- travenous pyelogram may reveal renal displacement, hydronephrosis sec- ondary to ureteral obstruction, or a small kidney resulting from renal artery involvement by the tumor. Pheochromocytomas of the urinary bladder are apt to occur in children and are characterized by hematuria and paroxysmal hypertension on micturition. The diagnosis will require cystoscopy for confirmation and partial cystectomy as treatment.
Retroperitoneal carbon dioxide insufflation has been generally aban- doned because of its inconsistency. Aortography, with selective retro- grade techniques, is useful in the diagnosis of the primary adrenal
pheochromocytomas, as well as for the localization of extraadrenal tumors. Aortography in the small child has not only the risk of inducing a paroxysmal attack, but is also associated with a potential postcatheteriza- tion arterial thrombosis. Of greater value is the catheterization of the vena cavae, with multilevel venous catecholamine determinations. This latter technique is difficult and not readily available, but is most useful in the detection of multiple tumors, recurrences, and metastases. Since secretion by the pheochromocytoma may be episodic, it is essential to ob- tain simultaneous controls from an arm or leg with each central venous sample. At times, the exact extent of disease is determined only at surgery.
The major causes of death in patients undergoing surgical excision of pheochromocytomas are due to unsuspected multicentric tumors, sus- tained hypertension during induction, and surgical manipulation of the tumor. Severe hypotension, potentiated by a chronically contracted in- travascular volume, can be a serious problem following tumor excision. It is our feeling that preoperative treatment with an alpha-adrenergic blocking agent has significantly improved the prognosis, both in adults and children. We use Dibenzyline, given in doses of 40 to 100 mg every 12 hours for 10 days to 2 weeks. This drug allows the intravascular volume to readjust toward more normal levels. Preoperative blood volume stud- ies are obtained, and blood is given in amounts calculated to expand the intravascular volume to 10 per cent above normal. In our series of nine cases, no pressure support was necessary either during or following surgery.
The selection of anesthetic agent is also crucial. Halothane is used in our hospital because it elicits little or no sympathoadrenal activity. It can, however, potentiate catecholamine-induced arrhythmias. Atrial and ven- tricular arrhythmias can be easily controlled by small doses of beta- blockers, such as propranolol (20 to 40 mg).
Multiple small tumors may be present in a single gland, and for this reason bilateral adrenal pheochromocytomas are treated by total adrena- lectomy. In children, the blood pressure may return to normal within 1 to 2 months following surgery. Irreversible renovascular changes, resulting in a persistent hypertension, are less common in children than in the adult. If the blood pressure remains elevated in the immediate postopera- tive period for longer than 12 to 18 hours, a radioactive renogram should be performed to rule out any accidental impairment of the renal vascula- ture. If this study is normal, urine should be collected on the 5th post- operative day to determine catecholamine excretion levels. Persistent hypertension following surgery should be aggressively investigated be- cause of possible missed lesions, or functional metastases. At this junc- ture in the patient’s course, vena caval sampling for catecholamines would be most helpful. If residual tumor is suspected, secondary explora- tions are often curative.
At times, the histology of the pheochromocytoma is difficult to clas- sify as to its benign or malignant nature. It bears repeating, that child- hood familial cases, who demonstrate persistent hypertension following curative surgery, should be suspected of harboring a malignant pheochromoblastoma. A diagnosis of malignancy may depend upon the
eventual demonstration of metastatic tumor in nonchromaffin tissue. The metastases are frequently functional and tend to be more primitive than the primary tumor, producing metabolic products of dopamine (3 methoxy-tyramine and HVA). Malignant pheochromoblastoma does not respond to radiotherapy or chemotherapy. Treatment is symptomatic, most recently employing blockage of biosynthesis. Metastases may ap- pear in lungs, bone, brain, liver, and lymph nodes.
NEUROBLASTOMA AND GANGLIONEUROBLASTOMA
Aside from brain tumors, neuroblastoma is the most common soft tis- sue neoplasm in infancy and early childhood. It arises from neural crest ectoderm, most commonly from the adrenal medulla, but may reside within the thorax, pelvis, retroperitoneal sympathetics, and neck, in de- scending order. The natural history of these neoplasms is poorly under- stood and unpredictable. Many of these patients have elevated urinary levels of dopa, dopamine, and the metabolities of norepinephrine.37 Gjessing19 was the first to describe the association of neural tumors and cystathioninuria. Geiser and Efron18 examined patients with neuro- blastoma and ganglioneuroblastoma and found that 50 per cent excreted cystathionine in the urine. Cystathionine is otherwise not excreted, ex- cept in rare cases of congenital cystathioninuria. It is of diagnostic im- portance to note that cystathioninuria is independent of VMA excretion. Primary hepatic tumors in children are also capable of secreting cysta- thionine, and for this reason must be considered in the differential diag- nosis. A response to treatment is heralded by a return to normal excretion patterns of both the catecholamine metabolites and cystathionine.
The majority of cases present before 5 years of age, peaking at 11/2 years. Familial neuroblastoma has been reported in a pattern suggestive of autosomal dominance. The appearance of an abdominal mass is com- monly the first sign of neuroblastoma. Abdominal pain, bone pain, diar- rhea, hypertension, and signs of increased intracranial pressure can be present in varying combinations. On occasion, the earliest clinical mani- festation may be paralysis secondary to spinal cord compression, or prop- tosis caused by retroorbital tumor. Following the report by Solomon and Chutorian,34 it has become apparent that children with occult neuroblas- toma can present with opsoclonus and cerebellar ataxia. Selenick et al.34 reviewed a collected series of 23 patients with neuroblastoma and myo- clonic encephalopathy. The tumors were found in the posterior medias- tinum (61 per cent), abdominal retroperitoneum (13 per cent), adrenal (13 per cent), superior cervical ganglion (4.3 per cent), and sacrococ- cygeal area (4.3 per cent). Several important observations were noted: (1) approximately 50 per cent of the cases had neurologic symptoms months or years before the tumor was identified and treated; (2) residual neuro- logic deficit was present in 82 per cent, consisting of cerebellar deficit in 14 patients and mental retardation in 9; and (3) the VMA excretion was elevated in only 8 of 17 cases studied. Steroids and ACTH have been used to treat the persistent neurologic findings with unpredictable effective- ness. We have treated four similar cases with progressive disappear-
ance of the neurologic findings following excision of a well circum- scribed thoracic neuroblastoma.
Neuroblastomas are extremely aggressive tumors and metastases are present in 60 to 90 per cent at the time they are first diagnosed. Those under 2 years of age are particularly vulnerable to hepatic involvement (66 per cent). Over 2 years of age, osseous metastases can occur in as many as 80 per cent, and can be confirmed by both x-ray and bone mar- row aspiration. It is of some diagnostic interest that skeletal metastases are often bilaterally symmetrical. Sonography has been used to localize the tumor, and differentiate it from Wilms’ tumor.
Treatment of Neuroblastoma
There is no standardized protocol for the treatment of neuroblas- toma. The age of the patient, tumor size, location, invasiveness, the presence of visceral and osseous metastases, and the tumor histology, all have a direct bearing on the selection of optimum therapy. For these reasons, the treatment plan must be individualized and modified as the details of each case change. There are, however, several therapeutic axioms which have withstood the test of time. Although the overall mor- tality of neuroblastoma is high (60 to 70 per cent), the prognosis is better in cases of mediastinal location and diagnosis before the first year, with the greater maturity of the tumor, and in the absence of metastatic disease.
Postoperative Therapy
The primary approach is surgical with postoperative irradiation to the tumor bed. As much of the tumor should be removed as is technically feasible, at times necessitating the sacrifice of normal, but invaded, contiguous organs. The neuroblastoma can be so extensive, especially those in the retroperitoneum, that only biopsy is safe. In these instances, excision is often possible following a course of 3000 r, given over a 3 week period. A cure rate of 88 per cent can be achieved in cases free of metastases, in whom the treatment consists of total excision, followed by local x-ray therapy. In patients with known metastases, 5 year survivals of 35 per cent and 20 per cent may be anticipated, depending upon whether complete or incomplete excisions of the primaries were per- formed. Undifferentiated tumors, which do not mature beyond rosette formation, have a poor prognosis. Bone metastasis, at any age, is associ- ated with an eventual mortality of 100 per cent, even with the most aggressive therapy.
As early as 1927, Cushing and Wolbach10, 12 described regression of a malignant neuroblastoma to the more benign ganglioneuroma. At least 30 similar cases have been described. Another unusual feature of neuro- blastoma occurs in infants under 1 year of age with metastases confined to the liver. These patients have been cured following resection of the primary.
In 1951 Farber and associates introduced nitrogen mustard and folic acid antagonists as adjuncts to surgical resection in disseminated neuro- blastoma. Subsequently, the alkylating agent cyclophosphamide (Cy-
toxan) and the alkaloid vincristine sulfate have been utilized. These chemotherapeutic agents have provided patients with subjective remis- sions, objective regressions, and at times have reduced tumors to resect- able size. For purposes of counseling, it may be stated that patients free of tumor for 2 years will probably remain free of any further risk of recur- rent neuroblastoma.
Ganglioneuroblastomas
The ganglioneuroma and ganglioneuroblastoma are also tumors of neural crest origin that are capable of endocrine secretion. The benign tumor is cured by local excision, but untreated cases can undergo malig- nant degeneration. In 1959 Green et al.21, 35 described a syndrome of neurogenic tumors, high levels of urinary catecholamines, and severe, chronic, medically resistant, watery diarrhea. There is a high probability of developing a lethal malabsorption state in unrecognized cases, and because of this threat, it has been suggested that exploration be per- formed, even in the absence of a demonstrable tumor. Most tumors are found in the posterior mediastinum, adrenal, or at the level of the aortic bifurcation, and complete extirpation is usually possible with cessation of diarrhea. In 1964, Oates et al.31 suggested that the diarrhea associated with neural tumors was related to catecholamine controlled release of kinin peptides.
ADRENAL HYPERCORTICISM
Adrenal cortical overactivity is the etiology of a vast array of clinical problems, each dependent upon the relative balance of glucocorticoids, mineralocorticoids, androgens, and estrogens. In childhood, virilizing adrenal hyperplasia due to a variety of congenital enzymatic defects in cortisol production is the most common adrenal cortical disease, whereas Cushing’s syndrome is second in frequency. Harvey Cushing’s classic description of patients with truncal obesity, hirsutism, striae, hyperten- sion, osteoporosis, glycosuria, and bilateral adrenocortical hyperplasia was presented in 1932. His cases, believed to be pituitary basophilic adenomas, are a rare cause of adrenal cortical hyperplasia. The initial complaint in children is most often back pain, muscular weakness, im- paired growth, and hirsutism. Adolescent girls often present with second- ary amenorrhea. Many of the signs and symptoms of Cushing’s syndrome are directly related to decreased protein anabolism, now thought to be a direct effect of cortisol within the muscle cell.
The primary endogenous causes of Cushing’s syndrome in children include adrenocortical carcinoma (50 per cent), bilateral adrenocortical hyperplasia (30 per cent), and benign adrenocortical adenoma (15 per cent). The carcinomas and adenomas occur most frequently in young female children with evidence of virilization5 and rare feminization. These tumors are occasionally large enough to be palpable. Bilateral adre- nal hyperplasia affect older males and females equally, are practically never palpable, and feminization has not been reported. Paraneoplastic syndromes, associated with ectopic ACTH production and consequent
Cushing’s syndrome, are well documented in adults, and have also been described in children with thymic carcinoma and ganglioneuroblastoma. The pathogenesis of Cushing’s syndrome is obscure, but those related to bilateral adrenocortical hyperplasia may depend upon an abnormal re- lease of hypothalamic CRF (corticotrophin-releasing factor).
The diagnosis of adrenal hypercorticism is now relegated to the en- docrinologist. Biochemicalanalyses have become standardized. The meas- urement of plasma and urinary cortisol, the absence of diurnal variation, the response to the administration of ACTH, of metapyrone, and of dex- amethasone, permit functional localization of the lesion within the pitui- tary-adrenal axis. However, these determinations are not infallible, and if a tumor is strongly suspected on clinical grounds, further studies should be considered. X-rays of the skull may show sella turcica expansion, while abdominal radiographs may reveal calcifications in the region of the adrenal gland. Diagnostic confirmation may be obtained by intra- venous pyelography, presacral pneumography, tomography, aortography, and adrenal venography. The latter technique is particularly valuable in tumor localization when combined with cortisol assays of venous blood obtained from both adrenals by selective catheterization.
Before the advent of exogenous steroid therapy, the risk of unilateral adrenal surgery was high, and of course, fatal in totally adrenalectomized patients. Coupled with the observation that Cushing’s syndrome some- times underwent periods of spontaneous remission, external irradiation of the pituitary was the initial approach. Less than 30 per cent of these patients showed signs of lasting remission. Today, with pharmacologic support and a multispecialty approach, excellent postoperative results are anticipated. Because children with Cushing’s syndrome have a high incidence of adrenal tumor, surgical intervention assumes even greater importance. The abdominal approach is advised, so that both adrenals may be inspected, and metastatic disease noted. Ten per cent of the tumors are bilateral, and 25 per cent have extracapsular extension. Capsular, vascular, or nodal involvement by tumor are ominous signs, in- dicative of a very poor prognosis. Metastatic disease can rapidly induce virilization or feminization. The functioning metastases of malignant adrenocortical tumors have been treated with biosynthetic blocking agents, resulting in transient amelioration of symptoms. Patients who have had potentially curative resections, should have follow-up hormone determinations, as elevations may signal early recurrence.
Historically, the treatment of bilateral adrenocortical hyperplasia has taken several forms including pituitary irradiation (most recently the proton beam), hypophysectomy, unilateral adrenalectomy with pituitary irradiation, subtotal adrenalectomy, “medical adrenalectomy” with o,p’- DDD, and total adrenalectomy. Bilateral adrenalectomy is safe and offers the patient the best hope of cure. Subtotal adrenalectomy has been aban- doned because it is associated with a 50 per cent recurrence of symptoms as a result of regenerative hypertrophy of the residual adrenal. Following total adrenalectomy, there is immediate improvement and a disappear- ance of all physical signs and symptoms of Cushing’s syndrome within a year. In 1972, Kaplan and Shires25 reported a 15 year old male who un- derwent bilateral adrenalectomy for Cushing’s disease. Following auto-
transplantation of one-half of an adrenal into the sartorius muscle of the thigh, their patient has not required exogenous steroid replacement. Au- totransplantation of a portion of the adrenal in an attempt to maintain en- dogenous hormone production has been successful in a limited number of cases. This approach is worthwhile, as failure of the transplanted tis- sue to function does not deleteriously affect the prognosis of the patient.
It is important to note that functional chromophobe adenomas have developed in 10 to 15 per cent of patients following bilateral total adrena- lectomy, presenting with sellar enlargement, visual impairment, and increased circulating levels of ACTH and MSH (melanocyte-stimulating hormone). These tumors can usually be satisfactorily controlled by de- livering 4000 r. to the pituitary. Isolated cases have not only been unaf- fected by the x-ray, but have gone on to malignant transformation, requir- ing some form of hypophysectomy. Whether or not these pituitary tumors existed prior to adrenalectomy is a moot point, but their rapid growth and associated hyperpigmentation (Nelson’s syndrome), following adrenalec- tomy, cannot be questioned.
HYPERALDOSTERONISM
Conn’s syndrome in children is rare, and almost invariably results from bilateral adrenocortical hyperplasia.8 Isolated cases of functioning aldosteronomas are known to exist, the youngest being 31/2 years old. Adrenocortical hyperplasia and the adrenal adenoma cannot be differen- tiated on clinical grounds. In adults, three times as many females have the syndrome, while in children males predominate. These patients char- acteristically demonstrate a challenging array of signs and symptoms, including headache, polyuria, weakness, paresthesias, “periodic paraly- sis,” tetany, hypertension, mild mental retardation, poor physical growth, an inability to concentrate urine, and a hypokalemic alkalosis. In primary aldosteronism, peripheral edema is absent. Childhood aldosteronism can often be traced to early infancy. The lack of documented tetany is not un- usual, as this symptom is more prevalent in adults. Excess aldosterone produces a medically refractory systolic and diastolic hypertension, which is more severe in most young patients. In Conn’s syndrome there are elevated levels of urinary aldosterone or its glucuronide metabolite, tetrahydroaldosterone. Secondary aldosteronism in childhood is most commonly related to chronic glomerulonephritis and congenital or ac- quired renovascular disease. Plasma renin assays aid in distinguishing primary aldosteronism (low renin) from secondary forms (high renin). As in the adult, the treatment of hyperaldosteronism is surgical excision of a primary tumor, or adrenalectomy in cases of hyperplasia. Following elec- tive surgery, a return to normotensive levels is expected. Sporadically, the hypertension approaches malignant levels and dictates urgent inter- vention. The majority of these patients require bilateral total adrenalec- tomy. Postoperative hypertension persists in one half of these children, and the irreversible nature of the blood pressure elevation is thought to be directly related to chronic renovascular arteriolarsclerosis. For this reason, a renal biopsy is recommended at the time of adrenalectomy.
In 1962 Bartter et al.2 described a syndrome of hyperplasia and hyper- trophy of the renal juxtaglomerular apparatus and primary aldosteronism with hypokalemic alkalosis. Many of the clinical features of Bartter’s syndrome are similar to those of congenital adrenocortical hyperplasia, but differ in that these patients are normotensive. It is postulated that these patients have an inherited vascular “hyporesponsiveness” to angio- tensin II. Consequently, the adrenal cortex undergoes hyperplastic changes in response to persistent stimulation by the renin-angiotensin cycle. Subtotal adrenalectomy has been performed when clinical deterio- ration has occurred after prolonged medical management of the aldos- teronism.36 Recurrence of symptoms following surgery has been routine. For this reason, and because most patients can be easily managed medi- cally, Bartter’s syndrome should not be considered an indication for surgery.
POSTNATAL SEXUAL DIFFERENTIATION AND PRECOCITY
During intrauterine development, abnormal endocrine influences can produce significant structural abnormalities of the external genitalia, which will require anatomic correction. Unusual patterns of sexual dif- ferentiation may herald the existence of a benign or malignant tumor of the central nervous system, adrenal, ovary, testes, or liver. It is the aim of this section to briefly highlight these circumstances, in which a surgical discipline offers an important role in the coordinated care of these complex children.
Sexual precocity is largely idiopathic (75 to 90 per cent), with females being affected twice as often as males. Precocious sexual development is often an integral component of many central nervous system lesions, sev- eral of which can be successfully treated by the neurosurgeon. In gener- al, a female with premature onset of feminization should have a thorough neurologic evaluation including skull x-rays and visual field perimetry. Gliomas and astrocytomas of the posterior hypothalamus and cranio- pharyngiomas produce a complex of symptoms, part of which may be sexual precocity. Functioning chromophobe adenomas of the pituitary, on occasion, can be the primary cause of virilizing adrenal hyperplasia. Gliomas of the optic chiasm7 frequently develop in childhood, and de- pending upon whether they invade the anterior or posterior hypothal- amus, produce sexual infantalism or precocity. Teratomas, gliomas, or cysts of the midbrain, in the region of the corpora quadrigemina or the pineal body, are apt to cause sexual precocity by secondarily compressing the hypothalamus.38 The necessity for surgery in all patients with ex- panding intracranial lesions is often dictated not so much by the existing endocrine abnormalities, but for the relief of the hydrocephalus asso- ciated with obstruction of the ventricular system of the brain.
Ovarian Tumors
It may be stated generally, that ovarian tumors in children have the same overall prognosis as those in adults. The subject of ovarian tumors
is discussed in detail in another section of this symposium, but several concepts in the care of children with these neoplasms require emphasis. When a child presents with abnormal sexuality, and the central nervous system and adrenal origins have been ruled out, the ovary should be in- vestigated. Not all functioning ovarian tumors in children are palpable. If an abdominal mass is present, and excess estrogen is confirmed by en- docrine assay, laparotomy is warranted. Depending upon the strength of the endocrine data, an occasional patient, without a palpable abdominal mass, may require exploration. If the ovarian tumor mass is localized, be- nign or malignant, a unilateral salpingo-oophorectomy is performed. Because of the high risk of radiation-induced sterilization in the young female, external irradiation should only be given for histologically proven ovarian malignancy.11
There are no hard and fast rules governing the treatment of child- hood ovarian malignancies. Initial surgery followed by x-ray is generally the adopted plan. There are those who feel that, in the face of poor 3 year survival rates, a “second look” operation is indicated 6 months following the first exploration, and would include the asymptomatic patients as well. This would allow the surgeon to stage the disease, excise any un- suspected recurrent tumor, and direct the radiotherapist to specific areas of residual tumor. Patients with recurrent disease, who are free of distant metastases, should undergo contralateral salpingo-oophorectomy, hys- terectomy, and omentectomy. The use of chemotherapy in the treatment of adult ovarian malignancy has been encouraging, but it does not seem to significantly alter the course of these desperately ill children.
There are several histologic variants of mass ovarian lesions in children that are capable of producing aberrations in sexual develop- ment.13, 14 These tumors account for 1 per cent of all childhood malignan- cies. Benign ovarian cysts may induce sexual precocity, but a direct cause and effect relationship is debatable, because resectional therapy is not always followed by permanent regression of abnormal sexual develop- ment. Whether the excess estrogen is related to autogenous ovarian hyperfunction or central gonadotropic stimulation is not known. They are generally palpable, are most often unilateral, and are classified as follicu- lar or thecalutein. A unilateral ovarian cyst probably warrants removal, whereas bilateral cysts are best treated expectantly. Ovarian cysts are not uncommon in the neonate, but feminization is rare.
Childhood ovarian granulosa-cell tumors are capable of producing dramatic estrogen affects, with the onset of menses recorded as early as infancy. These tumors usually present as a palpable, unilateral abdom- inal mass, and as many as 50 per cent are malignant. The presence of ascites is not synonymous with tumor implantation of the peritoneum. Although radiosensitive, there is a 3 year mortality of 40 per cent. Ovarian teratomas are frequently malignant and on occasion may resem- ble the granulosa-cell tumor, both clinically and hormonally. Extracapsu- lar extension requires radical surgery, as failure to do so will invariably lead to recurrence within 6 months. The teratocarcinomas (adenocar- cinoma, embryonal carcinoma, and chorioepitheliomas), despite the com- bination of surgery, irradiation, and chemotherapy, have a combined 3 year mortality of 45 per cent, while that for choriocarcinoma is 90 per cent.
There are several miscellaneous ovarian tumors that produce sexual changes.30 A dysgerminoma has been reported in a case of hermaphrodi- tism. It is a malignant tumor, but like the seminoma, is radiosensitive. The rare, benign thecoma is capable of producing precocious puberty, while the equally rare arrhenoblastoma results in virilization.
Testicular Tumors
Testicular tumors arise from either the germinal cells or the stromal supporting elements of the testicle. Germinal tumors comprise about 60 per cent of testicular tumors in children, whereas in adults they account for over 95 per cent. Nongerminal or interstitial tumors are more com- mon in children.3 In comparing testicular tumors in children and adults, there are several conspicuous differences. These tumors are rare in Negro children, a much greater percentage are benign, and an overall survival of 75 per cent is much better than adult survival statistics. Nongerminal testicular tumors in children are generally benign, and their treatment consists of orchiectomy and high ligation of the cord structures. Although childhood germinal tumors (embryonal carcinoma, teratoma, and teratocarcinoma) have a higher incidence of malignancy, they have a better prognosis than one may expect: in infants under 2 years of age, 40 per cent have a 2 year survival, and 35 per cent have a 5 year survival.
Seminomas, choriocarcinomas, and teratocarcinomas are very un- usual in children. These tumors may be associated with high levels of circulating chorionic gonadotropin, which does not characteristically alter sexual development. The existence of elevated levels of gonado- tropin suggests a primary testicular malignancy, or recurrent tumor fol- lowing initial surgical therapy. The germinal neoplasia are hard, solid, and encapsulated, with the latter characteristic bearing no consistent relationship to the presence or absence of metastatic disease. Since no single institution has any large series of patients, the treatment of children with malignant testicular tumors varies considerably. The most aggressive approach consists of orchiectomy, retroperitoneal node dissec- tions, postoperative irradiation, and chemotherapy.
The interstitial Leydig cell tumor is usually benign and in the infant it is capable of producing virilization9 and macrogenitosomia. The rare Sertoli cell tumor is thought to be homologous to the granulosa-cell tumor of the ovary, and similarly, is capable of feminization. There have been reports of complex tumors that have mixed Leydig cell and Sertoli cell elements, the clinical presentation depending upon which cell type predominates.
The gonadoblastoma is a very rare tumor, and these affected testicles are not capable of normal function. These tumors are small, slow grow- ing, contain immature germ cells, and arise from dysgenetic gonads. Al- though the dysgenetic gonad may remain static for many years, their malignant potential justifies their removal. There are a small number of male patients that have persistent abnormal virilization following ex- cision of a testicular mass, histologically consistent with a Leydig cell
tumor. Under these circumstances, a diagnosis of virilizing adrenal hyperplasia, with testicular ectopic hyperplastic adrenal tissue, should be considered. This is a particularly strong possibility in males with preco- cious puberty and bilateral testicular masses. This suspicion can be proved by observing atrophy of the testicular masses following adminis- tration of cortisone. Correction of the abnormal sexual development depends upon the treatment of the adrenocortical hyperplasia.
Hepatoma
Sexual precocity associated with a primary hepatoma is an intriguing syndrome, in which a malignant tumor produces “ectopic” hormones. Lipsett26 described a series of male patients, ranging in age from 1 to 8 years, that presented with rapidly advancing sexual development. Each child was found to have a hepatoblastoma capable of elaborating an ac- tive gonadotropin-like hormone. There were no teratoid or trophoblastic tissues present in the specimens. This aggressive neoplasm grows rapid- ly, but if the tumor is localized to a single hepatic lobe, resection for po- tential cure is feasible. For this reason, early recognition of the etiology of virilization in these patients assumes paramount importance. Periodic postoperative gonadotropin assays are used to monitor recurrence of tumor.
PRENATAL SEXUAL DIFFERENTIATION
Adrenal tumors, central nervous system lesions, gonadal neoplasia of both sexes, and “ectopic” hormone production have been described as po- tential sources of postnatal aberrations in sexual development. The fol- lowing discussion focuses on the prenatal forms of abnormal sexual dif- ferentiation, and the role of the surgeon in both diagnosis and correction of the resultant anomalies of the external genitalia.24 Of all the causes of virilization in childhood, congenital adrenal hyperplasia (adrenogenital syndrome), is the most common. There are six types of prenatal adren- ogenital hyperplasia, all of which have been extensively detailed as to their biochemical abnormality and corresponding clinical features, in- cluding virilism, sodium loss, and hypertension. The normal feedback control of pituitary ACTH is lacking, based upon a defect in the biosynthe- sis of cortisol, thereby stimulating the adrenal cortex to continue synthe- sizing hormones with androgenic activity. The C-21-hydroxylase defect, the most common form of adrenogenital syndrome, results in simple virilism, by impairing the conversion of progesterone to the corticoid steroid nucleus. The enzymatic block is due to a nonsex-linked recessive mutant gene, which expresses itself in the homozygous state: the fe- males show pseudohermaphroditism and the males, macrogenitosomia praecox. The treatment of adrenogenital syndromes properly falls within the province of the pediatrician and endocrinologist, and consists of corti- costeroid replacement. As the normal pituitary-adrenal axis is re-estab- lished, the signs of virilization disappear.
Females with adrenogenital syndrome differ from other female pseu- dohermaphrodites (maternal ingestion of androgens, maternal arrheno- blastoma, and idiopathic causes) in that their urinary 17-ketosteroids are elevated and their virilization is progressive, unless treated with steroid replacement. There are a number of patients with adrenogenital syn- drome, however, in whom the end-organ effects of androgen stimulation persist, despite adequate replacement therapy. These consist of a cres- cent fold of skin across the posterior vaginal fourchette and irreversible clitoral hypertrophy. The skin fold is simply excised, and the clitoral hypertrophy may be adequately reduced in size by recession techniques. Clitorectomy is no longer a generally accepted procedure. The need for major surgery in patients with adrenogenital syndrome is sporadic, and is related to androgenic influences before the 12th fetal week. The degree of labioscrotal fusion can be extensive, producing a number of urogenital sinus variants, and rarely, a cloaca. The vagina may end at varying dis- tances above the perineum, or may not communicate with the urogenital sinus at all. The abnormal location and anatomic defects of the vagina depend upon whether the müllerian tubercle undergoes maldescent or fails to canalize. Vaginoplastic procedures are available for the correction of these genital anomalies. The complex nature of urogenital defects may be compounded by incomplete lower intestinal maturation, re- sulting in an imperforate anus and associated colourethral fistula.
In most instances of adrenogenital syndrome, there is no difficulty in assigning a gender role to the patient. In the female, the uterus, tubes, and ovaries are usually normal, attested to by the fact that they are able to bear normal offspring. However, there is an occasional patient with adrenogenital syndrome who is a genotypic female, but presents with ambiguous genitalia. In most circumstances, genetic and endocrine evaluations are capable of determining the sex of these patients. At times only surgical exploration and biopsy of the gonads will yield the data needed to assign a definitive gender.
There are patients with abnormal sex differentiation, resulting from chromosomal aberrations, in whom a primary resectable lesion does not exist. In these individuals, surgical consultation is obtained in an effort to characterize the gonads, assess the anatomy of the reproductive system, and plan correction of any associated genitourinary abnormalities. There are a small group of phenotypic females that have gonads palpable within the labia, or demonstrated by gynecogram to reside in the pelvis. Histo- logically, these gonads resemble testes, although they are capable of feminization. Laparotomy commonly fails to reveal a uterus, tubes, or ovaries.
When a sex abnormality is present in a patient with a chromatin- negative nuclear pattern, the diagnosis includes male pseudoherma- phroditism, a true hermaphrodite, or a form of gonadal aplasia or dys- genesis. Male pseudohermaphrodites, with female external genitalia, are reared as females. Normal femininity is achieved, as their testes secrete estrogen. Gonadectomy, followed by permanent estrogen therapy, should be performed after adolescence, because these gonads have a malignant potential. The sex of the male pseudohermaphrodite with male genitalia will be determined by the size of the phallus and the
anatomy of the external genitalia. If uterus and tubes are present, they should be removed and testosterone administered if masculinization is inadequate. True hermaphrodites with miniature male genitalia, are more appropriately reared as females, following excision of testicular gonads. At times, male genitalia as well as a vagina coexist, and the selection of sex in this circumstance should await gonadal biopsy.
Operative procedures involving patients with questionable gender produce irreversible changes in the developmental and behavioral pat- terns of sexuality. The proper timing and the decisions taken in the operating room are of immense importance to both parents and patient. For these reasons, it is imperative that the surgeon, as part of a team effort, have a working knowledge of the differential diagnosis of ab- normal sexuality, and possess a full understanding of the physical and psychosexual adjustments that will be required for the lifetime of his patient.
THYROID
Approximately 2.5 per cent of Graves’ disease is found in children, all ages being affected, but peaking around adolescence. The two major forms of hyperthyroidism are toxic nodular goiter and exophthalmic hyperthyroidism, the former being unknown in children. The approaches to treatment include the thioureas, radioactive iodine, subtotal thyroidec- tomy, and most recently, total thyroidectomy. Although there are many reported series, each espousing one form of therapy or another, there are several conclusions which seem pertinent. There is sufficient circum- stantial data in the literature suggesting a strong correlation between head and neck irradiation and the subsequent appearance of thyroid car- cinoma. Because of this association, isotope therapy in children with Graves’ disease is generally not warranted.1 Besides the potential car- cinogenic, leukemogenic, and genetic sequelae of 131I, there is the high risk of eventually developing permanent hypothyroidism. Glennon et al.20 have reported a 48 per cent incidence of hypothyroidism in a 17 year follow-up, even with low dose 131I (3 mCi or less).
Most pediatric endocrine clinics are utilizing the thioureas initially, while subtotal thyroidectomy is reserved for those patients with the fol- lowing: relapse on adequate medical therapy, toxic drug reactions (1.5 to 10 per cent), difficulty in adhering to the drug regimen, the development of idiopathic neutropenia, failure of the drug to control symptoms, the need for excessive dosages, and progressive enlargement of the thyroid. Antithyroid drugs may achieve a 60 to 75 per cent permanent remission after an average of 3 years of treatment. It has been argued that surgery should be the first line of therapy, because it promptly resolves the thyro- toxicosis, avoids a prolonged, expensive drug program, and may eventu- ally be required in spite of adequate medical supervision. However, it should be emphasized that a significant number of partially thyroidec- tomized patients become hypothyroid in the immediate postoperative period, some as long as 30 years after subtotal thyroidectomy, the in- cidence varying from zero to 70 per cent. If insufficient quantities of the
gland are excised, recurrent hyperthyroidism will appear, and may do so at any time following surgery. In a small number of patients, surgery is also complicated by permanent hypoparathyroidism. Subtotal thyroidec- tomy, performed by experienced personnel, has a very low morbidity and a zero mortality.
It has recently been suggested by Altman1 that medically refractory hyperthyroid patients be considered for total thyroidectomy as the initial surgical procedure. There can be as much as a 15 per cent recurrence of symptoms following subtotal thyroidectomy in children, with over half presenting a hyperthyroid state 10 years after surgery. The surgical complications of total thyroidectomy versus subtotal excision are re- ported to be comparable. However, patients who require a second opera- tive procedure are subject to a greater likelihood of recurrent laryngeal nerve injury, permanent hypoparathyroidism, and the need for postopera- tive tracheostomy. Total thyroidectomy eliminates the need for further surgery and its accompanying risks. Altman has reported 8 such patients, all of whom have had excellent results.
Juvenile thyroid carcinoma comprises approximately 4 per cent of childhood tumors. Winship et al.40 reported a collected series of 468 thyroid carcinomas in children, in which 73 per cent had radiation ex- posure for benign conditions of the head and neck (cervical adenitis, ton- sillitis, acne, nevi, and enlarged thymus). More than 90 per cent are well differentiated, with the papillary variety being four times more common than the follicular form. A majority of patients have regional cervical nodes involved at the time of diagnosis. In spite of the locally aggressive nature of this tumor, 10 year survival rates of 90 per cent are not unusual. Pulmonary metastases, present in 12 per cent, are not synonymous with a poor prognosis, with many 20 year survivors having been recorded. Dis- tant metastases most frequently affect the lungs, skull, vertebrae, ster- num, ribs, and pelvis. Because of the high risk of carcinoma, a single, hard, irregular juvenile thyroid nodule in a child warrants urgent surgi- cal exploration. The operative procedure for a histologically proven thyroid carcinoma should be no less than a subtotal thyroidectomy and an ipsilateral modified neck dissection. A simultaneous node dissection is advised because 50 per cent of clinically negative nodes contain tumor when examined histologically. There are advocates of asynchronous dis- section, to be performed only when the nodes become clinically suspi- cious. Metastatic tumor will trap and respond to radioactive sodium iodide. For this reason, as much of the thyroid should be removed as is technically feasible in an attempt to reduce the amount of thyroid tissue competing for the 131I. Undifferentiated thyroid carcinoma is rare in children and like its adult counterpart has an extremely guarded prog- nosis. Following thyroid surgery for cancer, sufficient thyroid extract should be administered to suppress pituitary TSH.
Brief mention should be made of the subhyoid median ectopic thyroid gland. The differential diagnosis includes thyroglossal duct cyst, cervical dermoid, and lymph node. Thyroid scanning should be consid- ered preoperatively in any patient in whom the normal thyroid cannot be confidently palpated, separate from the mass in question. In this way, ac- cidental removal of an ectopic thyroid gland and the associated hypothy-
roidism is obviated. A lingual thyroid is rare, and its excision, like the midline ectopic thyroid, produces a hypothyroid patient. An enlarging lingual thyroid will undergo significant reduction in size following ex- ogenous thyroid supplements. In the event that the lingual thyroid remains a discomfort to the patient, or respiratory embarrassment de- velops, the thyroid tissue should be excised, and thyroid extract given throughout the patient’s lifetime.
PARATHYROID
Pediatric parathyroid adenomas are extremely rare, and carcinoma of the parathyroid is essentially unknown. Adult adenomas are found pre- dominantly in females, whereas in children there is an equal sex distribu- tion. The clinical presentation of hyperparathyroidism is quite variable, making the diagnosis especially difficult in children. In youngsters, the associated skeletal changes may be confused with congenital bone cysts, polyostotic fibrous dysplasia, giant cell tumors, and osteogenesis imper- fecta. The constitutional manifestations are similar to adult complaints of abdominal discomfort, weakness, lassitude, constipation, and behav- ioral disturbances. It may also be noted that a functioning parathyroid adenoma in a child can be a rare cause of failure to thrive. The incidence of renal lithiasis is only 25 per cent, as compared to 75 per cent in adults. Peptic ulceration is a well known complication in adults, but has been reported sporadically in children. The diagnosis of hyperparathyroidism depends upon a high index of suspicion and laboratory confirmation. The documentation of hypercalcemia, hypophosphatemia, and an elevated PTH immunoassay is sufficient to warrant exploration. In an effort to diagnose and localize an adenoma, arteriography, radioactive scanning, and PTH assay following neck massage in conjunction with venography have been used. The combination of immunoassay and venous sampling appears to us to offer the greatest promise for the future.
Unlike the adult type, juvenile parathyroid adenomas have not been found in the mediastinum. Occasionally, the lower parathyroids may reside within the substance of the thyroid or thymus. Excision of the of- fending adenoma(s) is curative, and in children has not resulted in a mor- tality. Violation of the tumor’s capsule subjects the patient to a definite risk of local recurrence, which may be impossible to eradicate. Para- thyroid hyperplasia is treated by subtotal parathyroidectomy, leaving 0.5 cm2 of tissue.
Because the upper glands are commonly larger than the lower in hyperplasia, this condition may be viewed by the occasional surgeon as multiple adenomas. This misdiagnosis leads in turn to the need for addi- tional exploration with its attendant risks. Therefore, we feel that biopsy proven identification of all glands at the initial operation is mandatory.
Children with chronic renal failure develop osteodystrophy more commonly than adults (50 versus 25 per cent). Secondary hyperparathy- roidism complicates the uremic state as a result of a vitamin D resistant osteomalacia and phosphate retention. A significant number of children develop severe bone pain, progressive deformity, and fractures, despite
adequate therapy with vitamin D, calcium, and aluminum salts. Parathy- roidectomy should be considered in these selected cases. Renal osteo- dystrophy assumed little clinical importance prior to the advent of chronic hemodialysis and renal transplantation, as all patients with renal failure eventually succumbed. Renal transplantation not only cures the renal disease, but is also the definitive treatment of the associated renal rickets. In children, in whom there is to be a prolonged delay in their planned kidney transplantation, subtotal parathyroidectomy should be considered for coexisting, progressive, disabling bone disease. Posttrans- plant hypophosphatemia, secondary to improved renal phosphate clear- ance and steroid immunosuppression, commonly produces a persistent hypercalcemia, which generally disappears after oral phosphate supple- ments. Therefore, the need for posttransplant parathyroidectomy is lim- ited to the rare case of phosphate resistant hypercalcemia.
HYPOGLYCEMIA
There are more than 30 causes of spontaneous hypoglycemia in in- fants and children, 70 per cent of which are functional. The remainder are due to insulinoma, islet cell dysfunction (with or without beta cell hyperplasia), anterior pituitary insufficiency, Addison’s disease, diffuse central nervous system disease, excessive glycosuria, hepatic failure, cre- tinism, adrenogenital syndrome, neuroblastoma, and large mesodermal tumors capable of producing insulin-like substances.
Chronic, intermittent hypoglycemia in an infant or young child will eventually lead to irreversible, tragic brain damage. For this reason, it is imperative that these patients be thoroughly evaluated and promptly treated. Exploration may be required to determine whether the patient has idiopathic spontaneous hypoglycemia (ISH) or a surgically correctable pancreatic dysfunction. ISH of the newborn rarely persists beyond 2 weeks, and they usually have a low birth weight, whereas infants with islet cell tumors have a normal birth weight and persistent hypoglycemia. Although insulinomas have been reported during infancy, most cases present after 4 years of age.4 There are numerous tests available to help in the differential diagnosis of ISH and insulinoma, all of which can be sub- ject to misinterpretation, investigative bias, variations in methodology, and changing conditions under which the analyses are obtained. Suffice it to say, there is as yet no simple algorithmic approach to these difficult patients. Many testing combinations have been reported and include: Whipple’s triad, leucine, glucagon, and tolbutamide tolerances, oral glu- cose tolerance, blood glucose determinations following 24 to, 36 hours of starvation, epinephrine and insulin sensitivity, growth hormone and plasma insulin radioimmunoassay, selective celiac arteriography, and pancreatic scanning. The majority of patients with ISH will respond to medical therapy utilizing ACTH, prednisone and diazoxide, with glu- cagon, growth hormone, or long-acting epinephrine being held in reserve for nonresponders. The natural history of ISH is the slow amelioration of symptoms and eventual cure, without further medication, whereas the insulinoma patients may have, at best, only transitory response to dietary
and medical control. Failure of the patient with suspected ISH to improve should signal the need for surgical consultation. Even if an exhaustive work-up is unsuccessful in demonstrating a pancreatic tumor, explora- tion is mandatory. In those cases in whom an insulinoma is unequivocal, excisional therapy stands unquestioned.
A single islet cell tumor may be located anywhere in the pancreas (25 per cent head, 75 per cent body and tail), and 15 per cent may be mul- tiple. Two per cent of insulinomas are ectopic,29 and have been found in the liver, duodenal wall, hilus of the spleen, lesser sac, wall of the stom- ach, and Meckel’s diverticulum. There are no records of carcinomatous change within a juvenile pancreatic adenoma, but 10 to 12 per cent of adult cases are malignant. When a single tumor is found in the head of the pancreas, simple enucleation will suffice. A subtotal resection of the gland is advised for a palpable adenoma in the tail, because multiple adenomas are most often located in this region. When a definite lesion is not appreciated, the operative decision is more difficult. Biopsy proof of pancreatic islet cell hyperplasia warrants subtotal resection, the extent of which remains unsettled. Harken et al.22 reported a series of 10 patients who underwent a standard two-thirds pancreatic resection for islet cell hyperplasia, with a 50 per cent recurrence of medically resistant hypogly- cemic symptoms. The unsuccessfully treated patients ultimately required total pancreatectomy followed by good longterm results. It is their recommendation that an 80 to 90 per cent resection be performed initially in cases of islet cell hyperplasia. Fonkalsrud et al.16 have suggested that pancreaticoduodenectomy with preservation of the tail be considered in cases strongly suspected of adenoma but which cannot be confirmed by gross examination. It is their feeling, should secondary dis- tal pancreatectomy be required, that it would be safer after “blind” pancreaticoduodenal resection than the reverse sequence. This proce- dure has generally been limited to patients who are at least 10 years old.
The hypoglycemic patient may occasionally require excessive steroid dosage to remain asymptomatic. The potential complications, however, of steroid therapy may far exceed the risk of curative surgery. Surgical correction of pancreatic hyperinsulinism can be achieved with low mor- bidity and mortality. Excellent clinical response is anticipated, irrespec- tive of whether the final pathology reveals normal islets, insular hyper- plasia, or insulinoma.
CARCINOID
The carcinoid tumor and the malignant carcinoid syndrome have been extensively described in the adult literature. Most carcinoid tumors in children present as acute appendicitis and pathologically appear as small nodules at the distal end of the appendix. The diagnosis is usually unsuspected and is most often a coincidental finding on microscopic ex- amination of the resected appendix. Although isolated case reports of primary metastasizing appendiceal carcinoids have appeared, the vast majority of carcinoids of the juvenile appendix are benign, with simple appendectomy being curative.
The carcinoid syndrome, consisting of flushing of the skin, changing cyanosis, watery stools, abdominal cramps, and rightsided valvular heart disease, usually connotes the presence of hepatic metastases. Carcin- oids have been found throughout the adult gastrointestinal tract. The rec- tal carcinoid is usually benign whereas the colonic variety are very malig- nant, and have not occurred in the pediatric age group. Unrelated, synchronous tumors of the bowel, extrahepatic biliary tree, ovary, and pancreas have been noted in adult cases, but not in juvenile carcinoids. Ileal carcinoids are preeminent in their ability to produce functional hepatic metastases in all age groups. Field et al.15 and McCartney et al.28 have described two such patients, aged 15 years and 4 years. Functional bronchial carcinoids with hilar nodal metastasis in children have also been reported. The humoral aspect of these neoplasms is closely linked to serotonin, a vasoconstrictor, found in highest concentrations within the Kultschitzky (argentaffin) cells of the small intestine. The malignant car- cinoid syndrome can no longer be explained by a simple cause-and-effect relationship of serotonin production by malignant tissue. It is now appar- ent that other substances may be involved, including hydroxytryptophan, kallikrein (a bradykinin-releasing enzyme), histamine, and ACTH.
A malignant carcinoid should be widely excised en bloc with its node bearing area. Unlike the more common juvenile small intestinal lympho- sarcomas, longterm survivors with ileal carcinoid and hepatic metastases are well known. These neoplasia are slow growing and a mean 5 year sur- vival of 45 per cent has been observed in a large series of patients with metastatic disease. Functional metastases should be removed because they are capable of producing chronic, disabling, and, at times, life-threat- ening symptoms, including emaciation and sprue-like syndrome second- ary to massive diarrhea, progressive valvular heart disease with failure, intestinal obstruction, and a pellagra-like picture. Irradiation, chemother- apy, and antiserotonin agents (methysergide, cyproheptadine, chlorpro- mazine and p-chlorophenylalanine) have little effect upon the unre- sected, functional metastases.
ZOLLINGER-ELLISON SYNDROME
The Z-E tumor is a nonbeta cell pancreatic islet cell tumor, character- ized by gastric hypersecretion, elevated serum gastrin, and medically resistant peptic ulceration. Over 1000 cases have been recorded, with an estimated 2 per cent occurring in the pediatric age group.33 Abdominal pain, diarrhea, melena, vomiting, and anemia are symptoms found in all ages. Cases plagued by severe diarrhea develop nutritional sequelae. On occasion, the initial event is a catastrophic intestinal perforation or life- threatening gastrointestinal hemorrhage. Our most recent experience in diagnosing a case of Z-E tumor in a 9 year old male reemphasized the his- torical importance of prolonged ulcer symptoms, unrelieved by adequate medical management. In both children and adults, a saga of multiple, un- successful, standard operative procedures for peptic ulcer diathesis should likewise signal the need for urgent diagnostic evaluation.
The usual approach to the preoperative diagnosis includes: gastric
analysis, augmented histamine stimulation, upper gastrointestinal series, serum gastrin immunoassay, and, most recently, the calcium challenge test described by Passaro.32 Hepatic and pancreatic scanning and selective superior mesenteric and celiac axis arteriography have been used for diagnosis and localization. These investigative methods have met with varying success, depending upon the expertise available. The demonstration of hypergastrinemia in properly screened patients is sufficient to warrant exploration.
About 20 per cent of patients with Z-E tumors have single adenomas of the parathyroid, adrenal, thyroid, or pituitary, in descending order of frequency. Three per cent have the syndrome of multiple endocrine adenomatosis. Potential pluriglandular involvement necessitates routine assessment of serum calcium and phosphorus, urinary steroid collec- tions, thyroid function studies, and skull x-rays. Family screening should also be undertaken, because asymptomatic endocrine adenopathies may be transmitted as an autosomal dominant trait with incomplete pene- trance. Associated nonpancreatic tumors can be responsible for symp- toms more severe than the Z-E tumor. In these instances, the offending gland may require removal, either prior to or simultaneous with the procedure selected for the Z-E tumor. Hyperparathyroidism is the condi- tion most representative of this surgical dilemma. This issue is made more complex by the fact that Z-E tumor appears to be capable of secret- ing a calcitonin-like substance, suggesting that the hyperparathyroidism may indeed be a secondary phenomenon.
After establishing a firm diagnosis of Z-E syndrome, the initial surgical procedure should be a total gastrectomy, combined with tumor excision if possible. This approach applies to children as well as adults and is based upon careful, longterm analysis of many patients. The target organ of hypergastrinemia is the stomach and any procedure short of total gastrectomy is doomed to early, relentless, exacerbation of symp- toms. A series of 250 adult surgical cases revealed that only 27 per cent were living without gastrectomy. Survival increased to 75 per cent fol- lowing total gastrectomy. Wilson et al.39 reported 15 children with Z-E syndrome, of which eight had less than total gastrectomy, resulting in a 75 per cent mortality. All seven children with total gastrectomy are living as long as 11 years following surgery. Children tolerate gastrectomy remarkably well and continue to grow and develop normally.
What about excision of a single pancreatic adenoma without gastric resection? Identification of an isolated pancreatic lesion is the exception rather than the rule. This finding has been particularly evident in child- hood cases. There are several poignant considerations which militate against any procedure less than a total gastrectomy. These include the following: (1) 30 per cent of the Z-E tumors are multiple, and occasion- ally the tumor may be ectopic, i.e., stomach, duodenal wall, splenic hilus, and adjacent nodes; (2) 60 per cent are malignant, with metastases in 44 per cent; (3) the metastases are often functional and occult; (4) 10 per cent of cases reflect a generalized pancreatic islet cell hyperplasia; (5) re- sidual pancreatic tumor, as small as several millimeters, is capable of producing severe peptic complications; and (6) the ulcer diathesis may be so fulminant, that total gastrectomy is the only sure method of control.
There is a possible exception to total gastrectomy. A number of adult pa- tients have had Z-E tumors localized within the duodenal wall, in whom tumor excision alone sufficed to eliminate the disease. An isolated ul- cerogenic tumor within the wall of the duodenum has not been reported in children.
The Z-E tumor is slow growing, and these patients usually succumb to the ravages of the ulcer diathesis and not to the tumor or its metastases per se. Prolonged survival, despite metastatic tumor, has been an espe- cially gratifying observation in children. All postoperative cases should have regularly scheduled gastrinassays, with elevations signaling reac- tivation of disease.
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Department of Surgery Johns Hopkins Hospital Baltimore, Maryland 21205