Perrin C. White
Adrenocortical tumors are rare in childhood, with an incidence of 0.3-0.5 cases per 1 million child-years. They occur in all age groups but most commonly in children younger than 6 yr of age and are slightly more frequent (1.6-fold) in females. In 2–10% of cases, the tumors are bilateral. Almost half of childhood adrenocortical tumors are carcinomas. Mutations in many genes can influence the risk of developing adrenal tumors (Table 595.1 ).
Table 595.1
Genes Involved in Adrenal Neoplasia
| SYNDROME | ADRENAL NEOPLASIA TYPE | GENE MUTATION | OTHER PHENOTYPE |
|---|---|---|---|
| Li-Fraumeni syndrome | Adrenocortical carcinoma | TP53 | Sarcoma, choroid plexus tumor, brain cancer, early breast cancer, leukemia, lymphoma |
| Multiple endocrine neoplasia type 1 | Diffuse hyperplasia, nodular hyperplasia, adrenal adenoma, adrenocortical carcinoma | MENIN | Foregut neuroendocrine tumors, pituitary tumors, parathyroid hyperplasia or tumors, collagenoma, angiofibroma |
| Lynch syndrome | Adrenocortical carcinoma | MSH2, MSH6, MLH1, PMS2 | Colorectal cancer, endometrial cancer, sebaceous neoplasms, ovarian cancer, pancreatic cancer, brain cancer |
| Beckwith-Wiedemann syndrome | Adrenal adenoma, adrenocortical carcinoma | IGF2, CDKN1C , H19 methylation changes on 11p15 | Macrosomia, hemihypertrophy, macroglossia, omphalocele, ear pits; Wilms tumor, hepatoblastoma |
| Familial adenomatous polyposis coli | Bilateral macronodular adrenal hyperplasia, aldosterone-producing adenoma, adrenocortical carcinoma | APC | Intestinal polyps, colon cancer, duodenal carcinoma, thyroid cancer, desmoid tumor, supernumerary teeth, congenital hypertrophy of the retina, osteoma, epidermoid cysts |
| Neurofibromatosis type 1 | Adrenocortical carcinoma, pheochromocytoma | NF1 | Malignant peripheral nerve sheet tumor, café-au-lait spots, neurofibroma, optic glioma, Lisch nodule, skeletal abnormalities |
| Carney complex | Primary pigmented nodular adrenal disease, adrenocortical carcinoma | PRKAR1A | large-cell calcifying Sertoli cell tumors, thyroid adenoma, myxoma, somatotroph pituitary adenoma, lentigines |
| Primary pigmented nodular adrenal disease | PDE8B or PDE11A | ||
| Overexpression of steroidogenic factor-1 | Adrenal adenoma, adrenocortical carcinoma | Somatic amplification of NR5A1 | |
| McCune-Albright syndrome | Nodular hyperplasia, cortisol-secreting adenoma | Activating somatic mosaic mutation of GNAS | Hyperfunction of bone (producing fibrous dysplasia), gonads, thyroid, and pituitary. |
| Cortisol-secreting adenomas | Activating somatic mutations in PRKACA | ||
| Genetic causes of excess cortisol and aldosterone secretion | Hypertrophy of zona glomerulosa, aldosterone-producing adenoma | Germline or somatic activating mutation in KCNJ5 | |
| Aldosterone-producing adenoma | Germline and somatic activating mutations in CACNA1D | ||
| Aldosterone-producing adenoma | Somatic mutations in ATP1A1 or ATP2B3 | ||
| von Hippel-Landau syndrome | Pheochromocytoma | VHL | Retinal and central nervous system hemangioblastomas, renal clear cell carcinomas |
| Multiple endocrine neoplasia syndromes MEN2A and MEN2B | Pheochromocytoma | RET | Medullary thyroid carcinoma and parathyroid tumors; type 2B also may include multiple mucosal neuromas and intestinal ganglioneuromas, a marfanoid habitus, and other skeletal abnormalities |
| Pheochromocytoma, often malignant | SDHB, SDHD, SDHC | Paragangliomas, sometimes associated with gastrointestinal stromal tumors and/or pulmonary chondromas (Carney-Stratakis dyad or triad) |
Tumors may be associated with hemihypertrophy, usually occurring during the 1st few years of life. They are also associated with other congenital defects, particularly genitourinary tract and central nervous system abnormalities and hamartomatous defects.
Perrin C. White
The incidence of adrenocortical carcinoma is increased in several familial cancer syndromes resulting from abnormalities in genes that encode transcription factors implicated in cell proliferation, differentiation, senescence, apoptosis, and genomic instability. These include tumor protein 53 (TP53) , menin (the MEN1 gene involved in multiple endocrine neoplasia type 1), the APC gene involved in familial adenomatous polyposis (FAP) coli, and the PRKAR1A gene encoding a cyclic adenosine monophosphate–dependent protein kinase regulatory subunit (also see Chapter 597 ).
Germline mutations in TP53 (on chromosome 17p13.1) occur in 50–80% of children with adrenocortical carcinoma. They have been found in patients with isolated adrenal carcinoma as well as in patients with familial clustering of unusual malignancies (choroid plexus tumors, sarcomas, early-onset breast cancers, brain cancers, and leukemias); this latter condition is termed Li-Fraumeni syndrome. A 15-fold increased incidence of childhood adrenocortical tumors is found in southern Brazil, associated with a R337H mutation in TP53 .
Overexpression of insulin-like growth factor 2 (encoded by IGF2 , on chromosome 11p15.5) occurs in 80% of sporadic childhood adrenocortical tumors, as well as in those associated with Beckwith-Wiedemann syndrome, in which there is loss of the normal imprinting of genes in this chromosomal region. However, <1% of patients with Beckwith-Wiedemann syndrome develop an adrenocortical carcinoma. Further implicating insulin-like growth factors (IGFs) in pathogenesis, many pediatric adrenocortical tumors overexpress the IGF receptor, IGF1R.
Mutations in the MENIN gene on chromosome 11q13 cause multiple endocrine neoplasia type 1 . Approximately 10% of MEN1 patients have adrenocortical tumors, of which ~14% are malignant.
Adrenocortical carcinomas also occur in patients with Lynch syndrome , a hereditary cancer syndrome (mainly colorectal and endometrial cancer) caused by mutations in genes involved in DNA mismatch repair. Finally, occasional adrenocortical carcinomas occur in patients with FAP, neurofibromatosis type 1, Werner syndrome, and Carney complex.
Overexpression of steroidogenic factor-1 (SF1, encoded by the NR5A1 gene), a transcription factor required for adrenal development (see Chapter 592 ) is associated with decreased overall survival and recurrence-free survival when it occurs in adults with adrenocortical carcinomas, but it is seen in most pediatric adrenocortical tumors, where it does not seem to have prognostic significance. Conversely, the messenger RNA encoding the nephroblastoma overexpressed (NOV) protein (also termed cysteine-rich protein 61, or connective tissue growth factor, or NOV gene-3) is significantly downregulated in childhood adrenocortical tumors. NOV is a selective proapoptotic factor for human adrenocortical cells, suggesting that abnormal apoptosis may play a role in childhood adrenocortical tumorigenesis.
Symptoms of endocrine hyperfunction are present in 80–90% of children with adrenal tumors. Tumors that secrete cortisol and aldosterone are discussed in Chapters 597 and 599 ; sex steroid secretion is discussed in the next section. Other tumors are detected as a consequence of symptoms related to local tumor growth, such as abdominal pain, or as incidental findings on abdominal imaging.
Tumors can usually be detected by ultrasonography, CT, or MRI. Preoperatively, the presence of metastatic disease should be determined by MRI or CT of the chest, abdomen, and pelvis. Because these tumors are metabolically active, 18 F-fluorodeoxyglucose PET/CT has very good sensitivity and specificity in distinguishing benign from malignant lesions, but it cannot distinguish adrenocortical carcinomas from other metabolically active tumors such as metastases, lymphoma, or pheochromocytoma. Radiochemical imaging of these tumors by positron emission tomography with 11 C-metomidate or single photon emission CT with 123 I-iodometomidate have been proposed but are not routinely available.
Differentiation between benign and malignant tumors by histologic criteria (architecture, cytologic atypia, mitotic activity, atypical mitotic figures) is usually not possible; almost all pediatric adrenocortical tumors would be classified as malignant by the criteria used to classify adult tumors. Size is a useful prognostic factor, with tumors weighing less than 200 g, 200-400 g, and >400 g being classified as low, intermediate, and high risk (>10 cm diameter has also been suggested as a high-risk category). Incomplete resection and gross local invasion or metastasis are also associated with a poor prognosis. However, most tumors occurring in children younger than 4 yr of age fall into favorable prognostic categories.
For functioning tumors, the differential diagnoses are those of the main presenting signs and symptoms. The differential diagnosis for Cushing syndrome is discussed in Chapter 597 . For virilizing signs, the differential includes virilizing forms of adrenal hyperplasia (see Chapter 596 ) and factitious exposure to androgens, such as topical testosterone preparations. The differential diagnosis for hormonally inactive adrenocortical adenomas includes pheochromocytomas, adrenocortical carcinoma, and metastasis from an extraadrenal primary carcinoma (very rare in children). Careful history, physical examination, and endocrine evaluation must be performed to seek evidence of autonomous cortisol, androgen, mineralocorticoid, or catecholamine secretion. Not infrequently, a low level of autonomous cortisol secretion is detected that does not cause clinically apparent symptoms; this condition is sometimes referred to as subclinical Cushing syndrome.
Functioning adrenocortical tumors should be removed surgically. There are no data on which to base a recommendation regarding nonfunctioning childhood incidentalomas; in adults, such tumors may be closely observed with imaging and repeat biochemical studies if smaller than 4 cm in diameter, but it is not certain that this is prudent in small children. Adrenalectomy may be performed either transperitoneally or laparoscopically. Some adrenocortical neoplasms are highly malignant and metastasize widely, but cure with regression of masculinizing or Cushingoid features may follow removal of less malignant, encapsulated tumors. Postoperatively, patients should be closely monitored biochemically, with frequent determinations of adrenal androgen levels and imaging studies. Recurrent symptoms or biochemical abnormalities should prompt a careful search for metastatic disease. Metastases primarily involve liver, lung, and regional lymph nodes. The majority of metastatic recurrences appear within 1 yr of tumor resection. Repeat surgical resection of metastatic lesions should be performed if possible and adjuvant therapy instituted. Radiation therapy has not been generally helpful. Antineoplastic agents such as cisplatin and etoposide, ifosfamide and carboplatin, and 5-fluorouracil and leucovorin have had limited use in children, and their success is not established. Therapy with o,p′-DDD (mitotane), an adrenolytic agent, may relieve the symptoms of hypercortisolism or virilization in recurrent disease. Treatment with higher doses of mitotane for more than 6 mo is associated with improved survival. Other agents that interfere with adrenal steroid synthesis, such as ketoconazole, aminoglutethimide, and metyrapone, may also relieve symptoms of steroid excess but do not improve survival.
A neoplasm of 1 adrenal gland may produce atrophy of the other because excessive production of cortisol by the tumor suppresses adrenocorticotropic hormone stimulation of the normal gland. Consequently, adrenal insufficiency may follow surgical removal of the tumor. This situation can be avoided by giving 10-25 mg of hydrocortisone every 6 hr, starting on the day of operation gradually decreased postoperatively. Adequate quantities of water, sodium chloride, and glucose also must be provided.
Perrin C. White
Adrenal masses are discovered with increasing frequency in patients undergoing abdominal imaging for reasons unrelated to the adrenal gland. There are no published data on the frequency of the occurrence of such tumors in childhood. They are likely to be infrequent, being found in approximately 7% of autopsies of persons older than age 70 yr but in <1% of those younger than age 30 yr. They are detected in 1–4% of abdominal CT examinations in adults.
The unexpected discovery of such a mass presents the clinician with a dilemma in terms of diagnostic steps to undertake and treatment interventions to recommend. The differential diagnosis of adrenal incidentaloma includes benign lesions such as cysts, hemorrhagic cysts, hematomas, and myelolipomas. These lesions can usually be identified on CT or MRI. If the nature of the lesion is not readily apparent, additional evaluation is required. Included in the differential diagnosis of lesions requiring additional evaluation are benign adenomas, pheochromocytomas, adrenocortical carcinoma, and metastasis from an extraadrenal primary carcinoma. Benign, hormonally inactive adrenocortical adenomas make up the majority of incidentalomas. Careful history, physical examination, and endocrine evaluation must be performed to seek evidence of autonomous cortisol, androgen, mineralocorticoid, or catecholamine secretion. Functional tumors require removal. If the adrenal mass is nonfunctional and larger than 4-6 cm, recommendations are to proceed with surgical resection of the mass. Lesions of 3 cm or less should be followed clinically with periodic reimaging. Treatment must be individualized; nonsecreting adrenal incidentalomas may enlarge and become hyperfunctioning. Nuclear scan, and occasionally fine-needle aspiration, may be helpful in defining the mass.
Perrin C. White
Calcification within the adrenal glands may occur in a wide variety of situations, some serious and others of no obvious consequence. Adrenal calcifications are often detected as incidental findings in radiographic studies of the abdomen in infants and children. The physician may elicit a history of anoxia or trauma at birth. Hemorrhage into the adrenal gland at or immediately after birth is probably the most common factor that leads to subsequent calcification (see Fig. 593.1 in Chapter 593 ). Although it is advisable to assess the adrenocortical reserve of such patients, there is rarely any functional disorder.
Neuroblastomas, ganglioneuromas, adrenocortical carcinomas, pheochromocytomas, and cysts of the adrenal gland may be responsible for calcifications, particularly if hemorrhage has occurred within the tumor. Calcification in such lesions is almost always unilateral.
In the past, tuberculosis was a common cause both of calcification within the adrenals and of Addison disease. Calcifications may also develop in the adrenal glands of children who recover from the Waterhouse-Friderichsen syndrome; such patients are usually asymptomatic. Infants with Wolman disease, a rare lipid disorder caused by a deficiency of lysosomal acid lipase, have extensive bilateral calcifications of the adrenal glands (see Chapter 104.4 ).
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