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Adrenocortical Tumors¹

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. George P. Chrousos, Developmental Endocrinology Branch, National Institutes of Health, Building 10, Room 10N262, 9000 Rockville Pike, Bethesda, Maryland 20892-1862.

	Introduction

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Cushing’s syndrome due to adrenocortical tumors was reported at the turn of the century, almost a decade before the description of the endocrine syndrome by Harvey Cushing. At the time, the adrenal cortexes were known to secrete an active principle necessary for life, the absence of which led to Addison’s disease. The crucial role of the pituitary gland in the control of adrenal secretion was not suspected. Since then, we have learned a great deal about adrenocortical tumors, their incidence, clinical presentation, diagnosis, therapy, and prognosis. Some research on the cell and molecular biology of these tumors has also been performed, mostly in the last decade. The rapidly advancing knowledge in the biology of other more frequent nonendocrine or endocrine tumors promises that better understanding of adrenocortical tumorigenesis is also forthcoming.

We have been managing patients with adrenocortical neoplasms from both an endocrinological and an oncological perspective. There are persistent controversies in this field, and treating advanced stage adrenocortical malignancies has been an utter frustration. The desperate situation of the usually young patients with these vicious neoplasms makes the early detection of these tumors pivotal and the discovery of new effective therapeutic modalities imperative. The purpose of this brief review is to present the state of the art in this field and suggest new avenues of research.

	Classification

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Adrenocortical tumors are divided into benign and malignant groups. Either can be hormonally silent or hormone secreting. The vast majority of adrenocortical tumors are benign and hormonally silent (1, 2). The hormone-secreting tumors can produce glucocorticoids, androgens, mineralocorticoids, estrogens, and combinations thereof (3, 4, 5, 6, 7, 8). Adrenocortical tumors can be sporadic or hereditary, with the former representing the overwhelming majority.

Diffuse or nodular adrenocortical hyperplasia resulting from ACTH hyperstimulation in ACTH-dependent Cushing’s syndrome and congenital adrenal hyperplasia due to defects of cortisol biosynthetic enzymes, and nodular hyperplasia associated with isolated primary micronodular or massive macronodular adrenal disease or Carney’s complex are considered low grade premalignant states (4, 7).

	Incidence and epidemiology

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The frequency of small benign adrenocortical tumors gradually increases with age, ranging between 3–7% in adults over 50 yr (Table 1A) (1, 2). Usually they are discovered incidentally, in the context of abdominal computed tomographic (CT) or magnetic resonance imaging (MRI) scans performed for various unrelated purposes (Table 2A). Hormone-secreting benign adrenal adenomas are rare; equally rare are hormonally silent or hormone-secreting adrenocortical carcinomas.

	Clinical presentation

Top Introduction Classification Incidence and epidemiology Clinical presentation Laboratory studies Imaging procedures Pathology, staging, and... Molecular studies of... Association with chromosomal... Protooncogenes Tumor suppressor genes Factors specific to the... Therapy Conclusions and future... References

 
Patients with hormone-secreting adrenocortical neoplasms have associated endocrine syndromes that result from the secretion of cortisol or aldosterone and their precursors, adrenal androgens and their precursors, and/or estrogens (Table 2). The most common syndromes associated with adrenocortical tumors in adults are hyperaldosteronism and Cushing’s syndrome (3, 4, 8). Cushing’s syndrome is present in 30–40% of patients with adrenocortical carcinoma (3).

Virilization occurs in 20–30% of adults with functional adrenocortical carcinoma, whereas it is the most common hormonal syndrome in children with adrenocortical cancer (4). Virilization is secondary to hypersecretion of adrenal androgens, including dehydroepiandrosterone and its sulfate derivative, ⁵-androstenediol, and ⁴-androstenedione, all of which may be converted finally to testosterone and 5-dihydrotestosterone. The signs and symptoms in adult females include oligoamenorrhea, hirsutism, cystic acne, excessive muscle mass, deepening of the voice, temporal balding, increased libido, and clitoromegaly. In young girls, heterosexual precocious puberty occurs. The combination of Cushing’s syndrome and virilization is seen in 10–30% of the patients with adrenocortical carcinoma (3). This combined syndrome is usually associated with secretion of multiple steroid precursors.

Feminization and hyperaldosteronism, as pure hormonal syndromes, are quite rare manifestations of malignant adrenocortical neoplasms. Even more unusual presentations of adrenal cancers include hypoglycemia, nonglucocorticoid-related insulin resistance, and polycythemia (7).

Slightly over half of the adult patients with adrenocortical carcinoma have no recognizable endocrine syndrome. These patients present with either abdominal pain or fullness or with the incidental finding of an adrenal mass on imaging studies performed for unrelated reasons. A palpable abdominal mass is present in about half of the patients with nonfunctional adrenocortical carcinoma at the time of diagnosis (3, 7). Finally, in a significant proportion of the patients, metastatic disease may cause symptoms before a primary diagnosis is established (7). Local invasion commonly involves the kidneys and inferior vena cava, whereas metastatic disease may be found in the retroperitoneal lymph nodes, lungs, liver, or bone.

	Laboratory studies

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Several laboratory studies are useful in the establishment or confirmation of excessive steroid secretion and the monitoring of patients with adrenocortical neoplasms (Table 3). A single dose (1 mg), overnight dexamethasone suppression test may be helpful as a screening test (9). Hypercortisolism is best established by measuring the 24-h excretion of urinary free cortisol (UFC) (3, 5, 9, 10). Over 90% of patients with Cushing’s syndrome have UFC values greater than 200 µg/24 h, whereas 97% of normal individuals have UFC values less 100 µg/24 h (3, 9). Recently, UFC assays using high performance liquid chromatography have appeared in clinical practice. These assays measure authentic cortisol and have a lower upper limit of normal (UFC, <50 µg/24 h).

A low plasma ACTH level associated with elevated concurrent plasma cortisol concentrations is indicative of autonomous activity of the adrenal glands (9). There are several dynamic endocrine tests for the differential diagnosis of adrenal Cushing’s syndrome from the ACTH-dependent forms of the condition (9). These include the classic high dose dexamethasone suppression test and the ovine CRH stimulation test. Typically, both tests are associated with the lack of responsiveness of cortisol secretion to dexamethasone and CRH.

The clinical diagnosis of adrenally induced virilization may be confirmed by measurements of plasma adrenal androgens and testosterone and 24-h urinary excretion of 17-ketosteroids. Feminization or hyperaldosteronism can be confirmed by measurements of elevated plasma estradiol and/or estrone or of aldosterone, 11-deoxycorticosterone, and/or corticosterone, respectively.

All patients, particularly those with nonfunctional adrenal masses, should also be screened for pheochromocytoma even in the absence of sustained hypertension.

	Imaging procedures

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The diagnosis of adrenal neoplasms depends on the identification of an adrenal mass on CT and/or MRI. Both normal and abnormal adrenal glands are easily visible on CT because of the adipose tissue that surrounds these glands in the retroperitoneum (11). The presence of a large unilateral adrenal mass with irregular borders is virtually diagnostic of adrenal cancer (7). CT provides information about size, homogeneity, presence of calcifications, areas of necrosis, and extent of local invasion, thus also being helpful in making decisions about the resectability of the lesion. Tumors as small as 0.5 cm have been detected by CT, although the relative lack of retroperitoneal fat in children might decrease the sensitivity of the test in this age group (11).

Whether MRI will prove to be superior to CT scanning in diagnosing and differentiating adrenal masses remains to be seen. MRI provides information about the invasion of an adrenocortical carcinoma into blood vessels, particularly the inferior vena cava and the adrenal and renal veins, in which tumor thrombi may be identified occasionally. Studies have reported that MRI can distinguish with a fair degree of accuracy among primary malignant adrenocortical tumors, nonfunctioning adenomas, and pheochromocytomas by comparing the ratio of the signal intensity of each type of adrenal mass to that of liver (11). Thus, primary malignant adrenocortical lesions have an intermediate to high signal intensity on T2-weighted images. Nonfunctional adenomas have low signal intensity, whereas pheochromocytomas have an extremely high signal intensity.

Other imaging modalities, such as iodocholesterol scanning, venography, and arteriography, are rarely indicated (3, 7, 11). The [¹²⁵I]iodocholesterol scan is usually negative in malignant adrenocortical neoplasms and positive in steroid-secreting adenomas. [¹²⁵I]Iodocholesterol uptake may help define whether there is unilateral or bilateral autonomous steroidosynthetic tissue when adrenal masses are seen bilaterally on CT or MRI imaging. Also, it may help with the localization of adrenal rests or adrenal remnants after adrenalectomy. On occasion, selective arteriography may help distinguish between adrenal masses and upper pole renal tumors. Inferior vena cava venography may be indicated if CT or MRI findings suggest the presence of a tumor thrombus in this vessel. In general, these invasive techniques are reserved for the rare instance in which CT or MRI cannot supply the information needed.

	Pathology, staging, and prognosis

Top Introduction Classification Incidence and epidemiology Clinical presentation Laboratory studies Imaging procedures Pathology, staging, and... Molecular studies of... Association with chromosomal... Protooncogenes Tumor suppressor genes Factors specific to the... Therapy Conclusions and future... References

 
Histologically, adrenocortical tumors consist of lipid-depleted cells with granular cytoplasm and large multiple nuclei and nucleoli (7). Tumor cells have varying mitotic activity. The differentiation of benign from malignant adrenocortical neoplasms solely on the basis of histological findings is difficult, if not impossible (3, 5, 6, 12). Thus, several reports demonstrated that patients whose operatively excised tumors exhibited histologically benign features and subsequently developed local recurrences or distant metastases, whereas others, whose tumors had a microscopic appearance typical of malignancy, lived tumor-free for many years.

Several macroscopic and microscopic criteria are collectively used to define the malignancy of an adrenocortical tumor and to predict its behavior (12). Macroscopically, a wet weight of more than 500 g, a grossly lobulated cut surface, the presence of necrotic areas and/or calcifications, and intratumor hemorrhages predict malignancy. Microscopically, architectural disarray, frequent mitoses, marked cellular pleomorphism, nuclear atypia and hyperchromasia, as well as invasion of the capsule suggest malignancy.

Abnormal DNA contents have been detected in adrenocortical carcinomas by flow cytometric DNA analysis (13, 14). Aneuploidy occurs in neoplastic subpopulations through genetic instability and mitotic irregularities. Bowlby et al. reported that 83% of the carcinomas showed aneuploidy, suggesting that flow cytometric analysis may prove to be a complement to the conventional histopathological methods and a valuable tool in predicting the prognosis of patients with adrenocortical tumors (13).

The staging system for adrenocortical carcinomas depends upon tumor size, nodal involvement, invasion of adjacent organs, and presence of distant metastases (Table 4) (15). Staging is helpful in defining prognosis and therapy. Only patients with stage I and II disease are curable with surgery. Unfortunately, the great majority of the patients have either stage III or IV disease at the time of diagnosis. Despite complete resection, virtually 100% of patients with stage III disease have recurrent and metastatic disease within 5 yr of tumor resection. Moreover, the 5-yr survival for stage III adrenal carcinoma is generally less than 30%. The most frequent sites of metastases are lymph nodes (25–46%), lungs (47%–97%), liver (53%–68%), abdomen (33–43%), and bones (11–33%). Metastases have been reported in ovary, spleen, pleura, thyroid, pharynx, tonsils, mediastinum, myocardium, brain, spinal cord, skin, and sc tissue (4, 7). Despite aggressive surgical therapy, the mean 5-yr survival of patients with stage IV disease is 15–25%.

	Molecular studies of adrenocortical tumorigenesis

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Recently, the clonal composition of adrenocortical tumors was determined using X-chromosome inactivation analysis (16, 17). Like most tumors, adrenal adenomas and carcinomas were most often monoclonal, whereas ACTH-induced diffuse and macronodular hyperplasias were polyclonal (16). These findings support the fundamental contemporary assumption that tumors arise as monoclonal expansions of a single cell, which become tumorous in response to a series of multistep genetic aberrations involving overexpression of protooncogenes and/or inactivation of tumor suppressor genes as well as alterations of the proteins involved in the normal progression of senescence, induction of apoptosis, and differentiation. The rate of DNA defects developed and passed on with each replication, also called rate of genomic instability, is proportional to the rate of development of clones with survival advantages and, therefore, is proportional to the potential of a tumor to grow and prevail over the host. The ability of the cell to rapidly repair DNA aberrations is crucial for the prevention of clonal expansion and tumorigenesis. Defects in proteins responsible for DNA repair also participate in tumorigenesis.

	Association with chromosomal abnormalities and genetic syndromes

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The possibility that there is an inherited predisposition to develop adrenocortical tumors has been previously entertained (18, 19, 20, 21, 22, 23, 24). Adrenocortical carcinoma has been reported in siblings, and a high incidence of diverse malignancies has been noted in families and relatives of patients with adrenocortical carcinomas (20, 21, 22, 23). Also, high frequencies of congenital anomalies and secondary tumors have been demonstrated in patients with adrenal cancer (18, 20, 22, 23). There are several recognized genetic syndromes that have been associated with adrenocortical neoplasms, which are discussed below (Table 5).

The Wiedemann-Beckwith syndrome, a growth disorder associated with allelic loss of chromosome 11p15 and characterized by neonatal macrosomia, macroglossia, and omphalocele, has an increased incidence of Wilm’s tumors and adrenocortical carcinomas (18, 22). Koufos et al. (19) suggested that a recessive oncogene located on chromosome 11p confers predisposition to adrenal cortical tumors, hepatoblastoma, and rhabdomyosarcoma. In agreement with this, structural abnormalities at the 11p15 locus were described in 37% of sporadic adrenocortical tumors (22). Particularly, uniparental disomy at the 11p15.5 locus, which includes the H-ras-1, insulin-like growth factor II (IGF-II), insulin, H19 and P57^KIP2 genes, was observed in human adrenocortical carcinomas (20, 22). Cicquel et al. (20) also detected very high IGF-II messenger ribonucleic acid contents in 83% (five of the six carcinomas) of the adrenocortical carcinomas examined. Four of these five carcinomas showed abnormalities at locus 11p15.5, suggesting that there is a strong relation between IGF-II overexpression and rearrangements at the 11p15 locus in adrenocortical tumors (20, 22). These findings suggest that structural abnormalities and/or overexpression of the IGF-II gene may play a key role in the multistep process of adrenocortical tumorigenesis.

The Carney complex, an autosomal dominant disorder, is characterized by the association of primary pigmented nodular adrenocortical disease, myxomas, particularly of the heart, and psammomatous melanotic swannomas involving the peripheral nervous system, spotty pigmentation and blue nevi of the skin or mucosa, and diverse endocrine neoplasms (25, 26). Testicular Sertoli cell tumors, GH-producing adenomas, thyroid follicular carcinomas, ovarian cysts, and adrenocortical tumors were associated with this familiar syndrome, whose chromosomal locus was recently mapped on 2p16, but whose pathophysiological mechanism(s) remains unknown (25). From cytogenetic studies, the Carney complex appears to be due to gain of function mutations involving a protooncogene (26).

The familial and genetic nature of multiple endocrine neoplasia type 1 (MEN-1) syndrome was first pointed out by Wermer in 1954, who suggested that an autosomal dominant gene with high penetrance controls the trait. Recently, the gene for MEN-1 was mapped to chromosome 11q13, and several alterations in this region have been described in affected individuals (27). The most frequent endocrinopathies in MEN-1 are hyperparathyroidism and pancreatic-duodenal and pituitary tumors. However, other tumors are also seen more frequently than in the general population, including adrenocortical and thyroid tumors, carcinoids, lipomas, and pinealomas. In MEN-1, benign enlargement of adrenal cortex has been found in about one third of necropsy cases. Diffuse and nodular cortical hyperplasia, adenomas, and a single case of adrenocortical carcinoma were described in patients with MEN-1 (27). Loss of constitutional heterozygosity for alleles at 17p, 13q, 11p, and 11q was found in an MEN-1 adrenocortical carcinoma, whereas the benign adrenal lesions retained heterozygosity for the MEN-1 locus at 11q13 (27).

	Protooncogenes

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Table 6 summarizes the genetic alterations found in sporadic adrenocortical tumors. That hyperstimulation of the adrenals by ACTH could result in adrenocortical tumors was directly suggested by isolated case reports of carcinomas arising 3–36 yr after the diagnosis of classic congenital adrenal hyperplasia (7, 22). Recently, the ACTH receptor gene was cloned, and its chromosomal localization and sequence were determined (28, 29). The direct sequencing of the ACTH receptor gene did not reveal constitutively activating mutations in two series of sporadic adrenal cortical neoplasms and two cancer cell lines, indicating that this mechanism is not frequent in human adrenocortical tumorigenesis (30, 31).

Protein kinase C activity is a potential marker for human malignant diseases, such as breast and pituitary tumors, and malignant gliomas (36). Calcium-dependent protein kinase C activity was recently described, however, as not increased in benign or malignant adrenocortical tumors and in diffuse and macronodular adrenal hyperplasia compared to levels in normal adrenal tissue, suggesting that this molecular mechanism is infrequent in adrenocortical tumorigenesis (36).

Activation of K-, H-, and N-ras protooncogenes is important in the pathogenesis of various human tumors (37, 38). The prevalence of activating ras mutations in human adrenocortical tumors was 12.5% with an adenine to guanine transition at the second position of N-ras codon 61, resulting in a substitution of the amino acid glutamine by arginine (37). Equal prevalence was found in benign and malignant tumors of N-ras mutations in this series (37). However, Moul et al. failed to find any ras mutations in 11 adrenocortical tumors (38). Combined, these findings suggest that activating ras mutations are rare in adrenocortical tumors.

	Tumor suppressor genes

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Mutations of the p53 tumor suppressor gene were recently reported in sporadic adrenocortical carcinomas and adenomas (Table 6) (22, 23, 39, 40). Reincke et al. described p53 mutations in exons 5–8 in 27% of adrenocortical carcinomas and the 2 tumor adrenal cancer cell lines available at the time, but in none of the benign cortisol-secreting adrenal adenomas examined (23). This study demonstrated an excellent correlation between the p53 immunohistochemical findings and the DNA abnormalities. Furthermore, Lin et al. (39) demonstrated a high frequency of p53 gene mutations in 10 of 13 benign aldosteromas of Taiwanese patients. In 75% of the cases these mutations were clustered in exon 4. More recently, Reincke et al. (40) reported the absence of point mutations within exon 4 of the p53 tumor suppressor gene in 25 Caucasian patients from the U.S. and Europe with adrenal tumors, including 12 aldosteromas. Ethnic and environmental factors may be responsible for the mutational spectrum of the p53 tumor suppressor gene in different populations with adrenocortical neoplasms.

The retinoblastoma susceptibility gene (Rb), a tumor suppressor gene located at chromosome 13q, has been implicated in the pathogenesis of several tumors, including retinoblastoma and osteosarcoma (41). Overexpression of Rb was identified in the adrenocortical carcinoma of a patient from a family with the Li-Fraumeni syndrome, suggesting that Rb might constitute a secondary event in the adrenal tumorigenesis of this syndrome or might play a role in compensating for the inadequacy of p53, a primary defect in this condition (41).

	Factors specific to the adrenal cortex

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We have summarized the potential mechanisms of adrenocortical tumorigenesis in Table 7. These include general mechanisms that could be involved in tumorigenesis of any tissue. Other potential mechanisms could be of particular importance in adrenocortical tumorigenesis, however. These include abnormalities in the recently described steroidogenic acute regulatory protein (42). This protein enhances the mitochondrial conversion of cholesterol into pregnenolone by the cholesterol side-chain cleavage enzyme, suggesting that it is crucial for normal adrenal and gonadal steroidogenesis. More recently, steroidogenic acute regulatory protein messenger ribonucleic acid was expressed at high levels in normal human adrenals and adrenocortical tumors, and it was up-regulated in parallel with cholesterol side-chain cleavage cytochrome P450 by ACTH in adult adrenocortical cells (43).

Recently, the DAX-1 gene, a new member of the nuclear hormone receptor superfamily, was isolated and found to be deleted or mutated in several patients with X-linked adrenal hypoplasia (46). The DAX-1 product acts as a dominant negative regulator of transcription mediated by the retinoic acid receptor (46). Whether abnormalities in the DAX-1 gene or its product can be associated with human adrenocortical tumorigenesis remains unknown.

	Therapy

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Hormone-secreting adrenocortical tumors and hormonally silent adrenal masses with a diameter of 5 cm or more, or smaller masses with a suspicious imaging appearance should be excised (Table 8) (2, 3, 47). Surgical resection is also the only therapy for adrenocortical carcinoma that unquestionably cures or prolongs survival significantly, particularly if the disease is detected at stages I and II (7, 8, 15). Radical excision with en bloc resection of any local invasion offers the best chance for cure. A wide exposure is needed, using an extended subcostal incision or a thoracoabdominal approach (7). Patients apparently cured with surgery require continued surveillance. Mitotane after complete macroscopic resection in stage III and IV disease may be given to increase the length of time between recurrences; however, this has not been tested in a controlled study (6). An excellent review of the treatment of adrenal cancer appeared recently (47).

Several alternative chemotherapeutic regimens have been used for the treatment of metastatic adrenocortical carcinoma (Table 8). They include cisplatin, etoposide, 5-fluorouracil, doxorubicin, vincristine, gossipol, suramin, and melphalan (48, 49, 50). Gossipol, a spermatoxin derived from crude cottonseed oil, inhibits the growth of human adrenocortical tumors in nude mice. Oral gossipol (30–70 mg/day) was used with relative safely in out-patients with metastatic adrenal cancer; however, a partial tumor response rate was observed in only 17% (48). This is consistent with the generally poor response of adrenal cancer to most medical therapies.

Combining mitotane with cytotoxic chemotherapy has been associated with limited success (47, 48, 49, 50). Various regimens have been reported, including those using mitotane and 5-fluorouracil, cisplastin and etoposide, and cisplatin, doxorubicin and 5-fluorouracil. Theses studies have not shown a significant prolongation of survival, although some isolated reports of prolonged or complete remission were published (48, 49, 50).

	Conclusions and future directions

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Although the sequence of events leading to adrenal tumorigenesis is presently unclear, the process is multistep and variable from case to case. A multiplicity and variety of genetic abnormalities may account for the phenotypic heterogeneity of adrenocortical tumors.

Studies targeting cellular oncogenes and tumor suppressor genes as well as genes involved in normal senescence, apoptosis, and differentiation might provide not only knowledge of the mechanisms of adrenocortical tumorigenesis, but also a new generation of cancer markers that could help identify subjects at high risk for malignancies of the adrenal cortex. Such markers would help with the development of better management prevention strategies for these patients.

The advances in our understanding of molecular mechanisms of oncogenesis may also provide a better choice and administration schedule of therapeutic agents. New compounds are likely to be developed that take advantage of the differences between the control of the cell cycle in normal and cancer cells to maximize therapeutic effectiveness. Telomerase inhibitors, apoptosis inducers, genomic instability suppressants, and inducers of adrenocortical differentiation are among the potential classes of agents that could be administered or directed using gene therapy methods in adrenocortical cells to produce the long elusive cure for adrenocortical cancer. The use of monoclonal antibodies against adrenocortical antigens or promoters coupled to powerful toxins and expressed specifically in adrenocortical cells is probably a worthy alternative to pursue.

	Footnotes

² On sabbatical leave from the Division of Endocrinology, Hospital das Clínicas, University of Sao Paulo (Sao Paulo, Brazil).

Received January 8, 1997.

Accepted January 29, 1997.

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