ELSEVIER
Malignant adrenal tumors
Frederick J. Rescorla, MD
From the Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
INDEX WORDS Malignant adrenal tumors; Adrenocortical carcinoma; Pheochromocytoma
Adrenal tumors, apart from neuroblastoma, are relatively rare in infancy and childhood. Most adrenal lesions are benign, and both benign and malignant tumors may be hormonally active thus, making accurate preoperative diagnosis difficult. The two main malignant tumors are adrenocor- tical carcinoma and pheochromocytoma. In both tumors, it may be difficult to determine benign from malignant and the biologic behavior and degree of invasion may portend a more malignant course. Surgical excision is the primary therapy for both tumors, including excision of metastatic and recurrent tumor. An open procedure should be considered for invasive adrenocortical carci- noma and in pheochromocytomas in which preoperative imaging demonstrates metastatic nodal disease. A laparoscopic approach is preferred for lesions in which preoperative imaging demon- strates a localized lesion. Chemotherapy, although without proven efficacy, is utilized in some children with metastatic or unresectable disease.
@ 2006 Elsevier Inc. All rights reserved.
Adrenal tumors, although relatively rare, can have a wide variety of presenting symptoms related to hormonal activity. The adrenal gland is divided into two anatomic and functional components. The outer, adrenal cortex has three zones: the outer zona glomerulosa which produces aldosterone, the middle zona fasciculata, and the inner zona reticularis, the latter two producing glucocorticoid and sex hormones. The inner component, the medulla, secretes norepinephrine and epinephrine. Tumors in the adrenal arise from one of these two layers and frequently secrete excessive products leading to clinical symptoms. Neuroblastoma, the most common adrenal tumor in childhood is covered elsewhere in this issue. The remain- ing malignant tumors of these regions are adrenocortical carcinoma (ACC) and the medullary tumor, pheochromo- cytoma.
Incidental adrenal masses
Many adrenal tumors in childhood are benign, and preop- erative evaluation may not allow differentiation of benign from malignant tumors (Figure 1). In adults, incidentally detected adrenal masses are primarily adenomas; however, in children, the most common adrenal mass is neuroblas- toma. Thus, the use of criteria commonly utilized in adults to guide nonoperative management may not be applicable in childhood. It is accepted in both adults and children that hormonally active tumors should be resected. In adults, hormonally inactive tumors that are less than 4 to 5 cm size have no disease in other locations and are benign in appear- ance on computed tomography (CT) are generally observed. A series of 26 such incidentally detected adrenal masses in children identified malignancy in 8 (31%).1 In a comparison of the benign and malignant lesions in this study, there was no clear difference in size, radiologic characteristic, or mode of presentation. In view of the difficulty in predicting benign disease in children and the significant malignant risk of nonfunctioning adrenal masses in children, it is the rec- ommendation that all pediatric incidental adrenal masses undergo resection.
Address reprint requests and correspondence: Frederick J. Res- corla, MD, 702 Barnhill Drive, Room 2500, Indianapolis, IN 46202- 5200.
E-mail: frescorl@iupui.edu.
Adrenocortical carcinoma
Epidemiology
Tumors of the cortex are much less common than medullary tumors. Adrenocortical carcinoma is a rare tumor compro- mising approximately 0.2% of all childhood cancers.2 The Children Oncology Group registered 38,000 children over a 4-year period between 2001 and 2005, and of these there were 39 with ACC (0.001%). This likely may have missed ACC patients as there was not an open protocol for ACC patients but simply a registry. The tumor occurs with greater frequency in southern Brazil, and Sabboga and coworkers3 identified 78 children over a 22-year period in 2 hospitals in the same city, one of the largest pediatric series. It occurs in 2 periods of life: one between age 1 and 10 years and the second in the fourth and fifth decades.4 Several series have noted a female predominance.4,5
Etiology
The association of ACC with Li Fraumeni syndrome, Beck- with-Wiedemann syndrome, and hemihypertrophy suggests the presence of a genetic basis.6-9 Li Fraumeni syndrome is an autosomal dominant familial cancer syndrome character- ized by susceptibility to sarcomas, breast cancer, brain tu- mors, and ACC.10 Most of these families carry germline inactivating mutations in the p53 tumor suppressor gene.11 Although studies have shown a 50% to 80% incidence of p53 mutations in children with ACC, there has not been as high of an incidence of familial cancer consistent with Li Fraumeni syndrome in such high frequency areas as Bra- zil.12-14 Studies from Brazil have shown a specific mutation, R337H, a p53 mutation with a specific susceptibility to
ACC.15 Studies in the United States and Europe, however, have identified p53 mutations with significant risk of Li Fraumeni familial tumors.16 In view of the high prevalence of p53 mutations in children with ACC, a genetic evaluation is indicated, and if positive, family screening of adult fe- male relatives completed due to the increased risk of early onset breast cancer.17
Children with Beckwith-Wiedemann and hemihypertro- phy are at increased risk for adrenal cortical tumors, which may be associated with onset of virilization.6 The lesions include cortical cytomegaly, cortical hyperplasia, cysts, and tumors. Other children at risk for adrenal tumors includes those with congenital adrenal hyperplasia and congenital renal anamolies. 18,19
Presenting symptoms
ACC is associated with excessive androgen production and virilization in 80% to 95% of cases.3,4 In the largest series in children, signs of virilization were pubic and/or body hair in 95%, clitoris or penile enlargement in 70%, and voice changes in 50%. Cushing’s syndrome was present in 74% and only 3.6% were asymptomatic.3 Cifti and coworkers4 in a series of 20 children noted virilization and/or Cushing’s syndrome in 83%. Symptoms of Cushing’s syndrome in- clude hypertension, central obesity, moon faces, and buffalo hump. Although some have noted virilization to be approx- imately twice as common as Cushing’s syndrome,20,21 oth- ers have noted a more equal rate between virilization and Cushing’s.4 The gradual onset of signs and symptoms are frequently unrecognized for several months, and some have noted a significant time period (as long as 8 months) be- tween onset of symptoms and diagnosis.4
Diagnostic tests
Laboratory testing includes evaluation of androgen and glu- cocorticoid levels and their breakdown products. These in- clude serum cortisol, testosterone and 17-ketosteroids, as well as urinary cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate, 17-ketosteroids, and 17-hydroxycorticoste- roids.22 As many benign lesions such as adrenal adenomas are hormonally active, it may be difficult preoperatively to determine the likelihood of malignancy. Ciftci and cowork- ers4 noted that 80% of carcinomas and 90% of adenomas were functional, thus allowing no differentiation on this basis. Some have noted a correlation between higher steroid levels and more advanced stage disease.
Children who present with symptoms of excessive an- drogen or glucocorticoid production should undergo imag- ing with CT or magnetic resonance imaging (MRI) scans. (Figure 2). In view of the potential for metastatic pulmonary disease, a chest CT should be performed if an adrenal tumor is identified, thus making abdominal CT more cost effec- tive. MRI may be somewhat more useful; however, is more costly and requires sedation or anesthesia in younger chil-
dren. Lung, liver, and lymph nodes are the major site of metastases, and these sites should be evaluated preopera- tively.4
Surgical treatment
Surgical excision is the most effective therapy for ACC, and the need for complete surgical excision has been shown in several studies.3,4,23 Perioperative steroid re- placement is required due to a suppressed hypothalamic- pituitary-adrenal axis. In general, an open procedure is recommended for adrenocortical carcinoma and a lapa- roscopic approach for benign lesions. Unfortunately, as noted previously, it is often difficult to determine a ma- lignant lesion preoperatively. If a child has a localized lesion, a laparoscopic approach is reasonable. The paraaortic and paracaval regions should be examined, and if lymph nodes are present, they should be excised. Total excision should be attempted even if it requires removal of adjacent strictures, such as an ipsilateral nephrectomy. The need for total resection is imperative. Some series have noted that all with incomplete resection or distant metastases died, whereas those with localized or regional disease that was totally resected survived.4 Retroperito- neal lymph node dissection is recommended by some,24 although there is no clear evidence to support this pro- cedure. Sampling of adjacent nodes appears a reasonable recommendation, and in cases with positive nodes iden- tified, lymph node dissection performed as surgical ex- cision is the only effective therapy. Ciftci and coworkers4 noted that 80% of the carcinomas had regional or meta- static disease, whereas all adenomas were localized.
Resection of metastatic disease is indicated if possible. Injection or ablation of metastatic disease may be the only option for some lesions. Hara and coworkers25 reported long-term survival (3 years) in a child with two liver me- tastases treated with percutaneous ethanol injection. Com- plete surgical resection, although a favorable factor, is not completely predictive of long-term survival. A study from St. Jude noted that 5 of 26 recurred despite complete resec- tion.26
Pathology
The definition of malignancy is difficult.27 Higher weight (>150g), vascular and capsular invasion, calcifications, mi- toses, and aneuploidy are more commonly seen with carci- noma; however, the clinical behavior may be more impor- tant in determining outcome.4 Predictors of favorable outcome have included low age, diagnosis within 6 months of onset of symptoms, and tumor weight less than 100 g.26,28
Chemotherapy and results
In cases where complete resection is possible, no further therapy is indicated. Close observation with imaging and endocrine studies is needed. The improved survival with complete resection has been shown by several stud- ies.3,4,26 Favorable factors reported in the literature in- clude younger age, complete resection at diagnosis, lack of recurrence, and smaller tumor mass.3,29-31 In the larg- est reported series, of the 55 with follow-up, the overall survival was 46%.3 The survival was 83% in those younger than 2 years compared with 36% in those over 2 years of age. Survival was 67% if a total excision was achieved. Although this series found no relationship to size, other smaller series have noted lower survival with larger tumors.31-33 Patients with unresectable or residual disease should be considered for systemic therapy. Che- motherapy with mitotane has been frequently utilized with varying response rates (34-61%).24,34,35 Other re- ports have noted success with use of cisplatin, carbopla- tin, and etoposide (VP-16), some in combination with mitotane.36,37 Unfortunately, in some cases, response rates are still relatively low (30%) and response duration short (7.9 months) with median survival of 11.8 months.37 There does not appear to be a role for adjuvant mitotane after complete resection.38 One study noted that diploid and near-diploid tumors had a good outcome regardless of tumor weight and noted that malignant tumors were aneuploid with reactivity to p53 protein and had a poor prognosis.39 Of interest in the aneuploid cases, small tumors (<100 g) had a good outcome, probably due to surgical treatment earlier in the disease process, whereas large tumors (>750 g) had a poor prognosis.
Pheochromocytoma
Epidemiology
Pheochromocytomas arise in the chromaffin tissue in the adrenal medulla, and due to their dramatic symptoms and the surgically correctable nature, have been a source of interest among surgeons for years. They account for approx- imately 1% of cases of childhood hypertension.40 Although the “rule of 10” has been taught for years: 10% extraadrenal, 10% malignant, 10% hereditary, 10% bilateral,41 pediatric cases are often slightly different. In childhood, approxi- mately 30% arise in extraadrenal locations, 42-45 where they are often referred to as paragangliomas, and more than 10% are familial.42 Most extraadrenal pheochromocytomas are located at sites of sympathetic tissue within the abdomen; however, they have also been noted in the posterior medi- astinum46 and can occur from the base of the skull to the bladder.47 The organ of Zuckerkandl located near the aortic bifurcation is one of the common extraadrenal sites. Pheo- chromocytomas are more common in the right gland and are bilateral in 20% to 70% of pediatric cases compared with 7% to 10% of adult cases.22,48,49
Etiology
Although most pheochromocytomas occur sporadically, they can also occur with both multiple endocrine neoplasia (MEN) syndromes 2A and 2B as well as von Hippel-Lindau disease,5º Sturge-Weber syndrome, and rarely neurofibro- matosis type 1.51 Although, in general, 90% have been viewed as sporadic and 10% familial, recent evidence sup- ports a genetic basis in many sporadic cases. The group of susceptibility genes for pheochromocytoma have included the RET proto-oncogene associated with MEN-2 and the tumor suppressor gene VHL associated with von Hippel- Lindau. In addition, mutations of succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB) were identified in and associated with familial paragangliomas of the neck (glomus tumors) and pheochro- mocytomas.52,53 A recent report by Neumann and cowork- ers54 of 271 sporadic pheochromocytomas identified 24% with germ line mutation of 1 of these 4 susceptibility genes. Of interest, in children less than 10 years of age, 70% had germ line mutations. In view of this, clinicians should have a strong suspicion for a familial syndrome in children with apparent sporadic pheochromocytomas, and some recom- mend analysis of all patients.54,55 In children with the MEN syndrome, medullary thyroid carcinoma is usually the first tumor to present clinically, and approximately 50% will develop pheochromocytomas. Once identified with MEN, patients should undergo yearly testing for pheochromocy- toma beginning in the second decade of life.56 In 1 longi- tudinal study of MEN children, the age of detection was from 12 to 22 years with a mean of 19 years.56
R
Presenting symptoms
Pheochromocytomas produce large quantities of cat- echolamines without the normal endocrine regulatory mech- anisms. The signs and symptoms include headache, palpi- tations, nervousness, weight loss, extreme hypertension, and tachycardia. Cifti and coworkers57 noted hypertension as the most common symptom followed by headache and sweating. Hypertension is more severe in children and can be associated with hypertensive retinopathy in 40%, cardio- myopathy in 40%, and electroencephalogram changes of hypertension in 20%.22,40
Diagnostic tests
The diagnosis rests on detection of elevated catecholamines and their metabolites. Adrenal pheochromocytomas secrete both epinephrine and norepinephrine, whereas extraadrenal tumors lack the enzyme to convert norepinephrine to epi- nephrine. Epinephrine has both alpha-agonist and beta-ag- onist effects, whereas norepinephrine has primarily alpha effects. Twenty-four-hour urine is collected for free cat- echolamines (epinephrine and norepinephrine) as well as their breakdown products normetanephrine, metanephrine, and vanillylmandelic acid. CT or MRI are useful in identi- fying the lesion, and extraadrenal areas should be carefully evaluated.
The use of iodine-131metaiodobenzylguanidine (MIBG) scanning should be considered as it can detect the presence of extraadrenal tumors and confirm uptake in adrenal le- sions. In a case from the author’s institution (Figure 3), a CT scan demonstrated a right adrenal lesion; however, the
MIBG provided evidence of a second lesion near the aortic bifurcation.
Surgical treatment
Preoperative preparation
Children with pheochromocytoma should be prepared with a 2- to 3-week course of an alpha blocking agent such as phenoxybenzamine or prazosin. This serves to treat the hypertension, allow correction of the chronic vasoconstric- tion, and block against the release of catecholamines during surgical manipulation. If the child remains tachycardie or hypertensive, a beta blocker is added before surgery. Some newer agents are available to block catecholamine synthe- sis, and some follow urinary levels of catecholamine me- tabolites to determine effect and suitability for the operative procedures. Intraoperative arterial catheter monitoring is essential, and the anesthesiologist must have access to agents to rapidly lower (nitroprusside) or raise (norepineph- rine, volume expanders) blood pressure.58
Laparoscopic adrenalectomy
In children with pheochromocytomas which are well local- ized on imaging and without evidence of distant disease by MIBG, a laparoscopic adrenalectomy is a reasonable and perhaps preferred approach. The technique of laparoscopic adrenalectomy was first described by Gagner and cowork- ers59 in 1992. Both transperitoneal and retroperitoneal ap- proaches have been described; however, the lateral trans- peritoneal technique is the most popular.
Utilizing a lateral transperitoneal approach with four 5-mm trocars, the spleen, colon, and pancreas are reflected anteriorly for left-sided tumors. On the right side, the right lobe of the liver is mobilized by incising the lateral and posterior attachments allowing visualization of the inferior vena cava, and the retroperitoneum is opened between the cava and upper pole of the kidney. The tumor is gently dissected from the surrounding tissue and the adrenal vein divided as early as possible. Two or preferably three clips are placed on the caval (right) or left renal vein side of the adrenal vein60 (Figures 4 and 5). The small arterial vessels can be divided with cautery or the ultrasonic dissector (Ultracision Harmonic Scalpel, Ethicon Endosurgery, Cin- cinnati, OH). One of the trocar sites is enlarged, the tumor is placed in an endoscopic bag, and, if necessary, the site is further enlarged to allow removal. Failure of the blood pressure to return to normal should lead to evaluation of other sites, such as the contralateral adrenal and the aortic bifurcation.
Data from adult series with several papers including at least 100 patients have documented lower complication rates, less pain and narcotic use, shorter hospital stays, and earlier return to work with the laparoscopic approach.61-66
Laparoscopic adrenalectomy has replaced the open proce- dure in adults due to the low incidence of malignant tumors, the morbidity associated with open adrenalectomy, shorter length of stay, and the relatively small size of most tumors (<6 cm).67 It has been somewhat slower to be implemented in children due to the smaller size of the child as well as the infrequent indication for small discrete lesions as neuroblas- toma, an infiltrative tumor is the most common adrenal tumor in childhood. Despite this potential drawback, the laparoscopic procedure has been utilized in both laparo- scopic and open procedures.
In 1997, Clements and coworkers68 reported a laparo- scopic left adrenalectomy for a pheochromocytoma in a child. Miller and coworkers69 in a 2-institution study re- ported 17 pediatric patients over a 4-year period, clearly lower than the number of cases in most adult series. The most common diagnosis was ganglioneuroma and adenoma, but also included 2 pheochromocytomas and 1 ACC. Of interest, the 1 child with ACC required conversion to open due to tumor thrombus in the renal vein. This descriptive study demonstrated the safety and efficacy of the technique with a mean length of stay of 35 hours. Of interest, the 2 children with pheochromocytomas required longer opera- tive time than the other patients. Patients with MEN asso- ciated pheochromocytomas may be considered for bilateral adrenalectomy, since more than 90% have bilateral tumors or medullary hyperplasia.22,70
Kadamba and coworkers71 reported 11 laparoscopic adrenalectomies in 10 children (1 bilateral). Two required conversion: 1 for blood pressure instability and 1 Stage IVS neuroblastoma with hepatomegaly. There has been 1 pedi- atric comparative outcome analysis; however, there were only 4 laparoscopic cases compared with 60 open cases.72 They noted that the length of stay was approximately one- half with the laparoscopic technique, and although operative charges were higher, total charges were similar.
Most adult studies have excluded patients with tumors greater than 6 cm or with ACC, although in many series, unsuspected carcinomas were removed laparoscopically. For bilateral pheochromocytomas, adreno-cortical preserv- ing partial laparoscopic adrenalectomy has been utilized.73 Adults with pheochromocytomas have been noted with both longer operative times as well as a higher complication rate.74 In one of the largest adult series, 56% of the patients had hypertension and 52% hypotension during operative removal.74 Some have utilized laparoscopic ultrasonogra- phy to evaluate infiltration of surrounding tissue, locate the vasculature of a large mass, and evaluate the contralateral adrenal by transcaval examination.74
Most adult surgeons have recommended an open tech- nique for tumors greater than 5 to 6 cm in size75-78 and for all cases of malignancy60; however, the safety of laparo- scopic excision of larger tumors has been demonstrated by some.79 The size limitation is related to the difficulty with laparoscopic manipulation of large tumors as well as the higher rate of malignancy with larger tumors. Several au-
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thors over the last few years have expanded the laparoscopic size limit to 11 to 15 cm.79,80 In addition, bilateral laparo- scopic adrenalectomies have been performed.74 Outpatient laparoscopic adrenalectomy has also been reported in healthy patients with small nonpheochromocytoma tu- mors.81 The author’s institution has performed seven lapa- roscopic adrenalectomies and has noted decreased length of stay (28 hours) compared with the open procedure (88 hours).
Pathology
The determination of malignancy is difficult in pheochro- mocytoma. Pathologic features have included capsular in- vasion, vascular invasion, necrosis, nuclear pheomorphism, and mitoses; however, none are reliable indicators of ma-
lignancy.82 The presence of metastatic disease and local invasion make resection difficult; however, they are the best predictors of malignant disease.82 Metastases mostly occur in the lung, liver, lymph nodes, and bone.83 Malignant pheochromocytomas are rare, and the incidence in child- hood is probably around 10%, comparable to the rate in adults. 42,83
Treatment and results
Treatment of pheochromocytomas is primarily surgical, even in malignant and metastatic cases. Completely re- sected tumors need no further therapy other than postoper- ative blood pressure measurements and urine cat- echolamines to monitor for recurrence.58 van Heerden and coworkers in a long term follow-up study noted recurrences in 6.5% of 98 patients with initial complete resection.84 Recurrence occurred from 5 to 13 years later, emphasizing the need for long term monitoring. This is similar to the rate of recurrence in pediatric patients from the same institution (7.1%).85 In van Heerden’s study, 4 developed distant met- astatic disease 5 to 10 years later, which proved fatal in all 4 patients. Of interest is that, of their patients with initial vascular invasion, none recurred in follow-up of 15.8 years.
Orchard and coworkers,86 in a study of recurrence in 110 patients, noted recurrence rates of 2.3%, 3.8%, and 11.2% at 1, 5, and 10 years, respectively. Relapse rates for paragan- glioma was 10% at 1 year. Of interest, in tumors with microscopic capsular invasion, the relapse rates at 1, 2, and 5 years were 20%, 20%, and 33%, respectively, compared with a relapse rate of 0 among patients with no tumor invasion. Others have noted higher recurrence rates in chil- dren. Cifti and coworkers57 had 4 recurrences among 16 children, all in the contralateral adrenal. Bloom and Fonkalsrud87 noted 4 recurrences in 7 patients, all also in the contralateral adrenal.
Pheochromocytomas are considered malignant when they occur at sites where paraganglion tissue is not normally identified,87 although others have considered them malig- nant when large tumors have local invasion.82 The rate of malignancy, as noted above, is around 10%.42,88 Extraadre- nal lesions are thought to have a higher rate of malig- nancy89,90 and as such must be followed every 6 months or annually with blood pressure and urine studies. 46,58 Ein and coworkers,82 in a series of two patients and review of six others with metastatic disease, felt that unresectable disease may be rendered resectable by chemotherapy. Therapy in their studies included cisplatin, doxorubicin, and high dose 131I-MIBG. Ein’s series of eight metastatic children re- ported seven survivors.82 Tekautz and coworkers91 reported the St. Jude experience, where they treated two with unre- sectable disease with neoadjuvant therapy in the form of vincristine, ifosfamide, and doxorubicin followed by exter- nal beam radiation. This resulted in a partial response in one which allowed gross total resection. Unfortunately, chemo- therapy and radiation have not been proven effective. 92-94 Another therapeutic option is higher doses of 131I-MIBG
and labeled octreotide, which has been utilized for some advanced cases in adults with encouraging results and might be of benefit in children with advanced disease.91,95-98
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