Adrenocortical Tumors, Primary Pigmented Adrenocortical Disease (PPNAD)/Carney Complex, and other Bilateral Hyperplasias: The NIH Studies
Author
Affiliation
C. A. Stratakis
Head, Program on Genetics and Endocrinology & Director, Pediatric Endocrinology, National Institute of Child Health & Human Development, Bethesda, Maryland
Key words
Adrenal cortex genetics
· tumor
· primary pigmented adreno- cortical disease (PPNAD) Carney complex · hyperplasias
Abstract
&
It has been estimated that up to 1 in 10 adults has at least one adrenocortical nodule up to 1 cm on autopsy; these benign tumors may contribute to metabolic syndrome, hypertension, obesity and abnormalities of the hypothalamic-pituitary- adrenal (HPA) axis that can be linked to other serious disorders such as osteoporosis, depres- sion and late-onset diabetes mellitus. In addition, up to 1 in 1500 of these adrenal “incidentalomas” may hide a carcinoma, which, if diagnosed late or left untreated, is associated with significant morbidity and mortality. Consistent with the theme of this symposium, in the present report, we review the efforts undertaken at the National Institutes of Health (NIH) in the last quarter cen- tury to unravel the complex clinical genetics
and molecular mechanisms involved in adrenal tumorigenesis. We first proposed that adreno- cortical tumors form in a molecular sequence of events similar to that in other organs: as the pathology of the tumor increases towards malig- nancy, genetic changes accumulate. For exam- ple, known genetic associations, like TP53 gene changes, occur during the latest stages of adren- ocortical tumorigenesis. At the NIH, significant progress has been made in the understanding of the genetics of primary pigmented adrenocorti- cal disease (PPNAD) and other forms of bilateral adrenocortical hyperplasias. This recently led to the identification of phosphodiesterase 11A (PDE11A) mutations as a low-penetrance pre- disposing factor to adrenocortical hyperplasias of both the pigmented and non-pigmented vari- ants.
received 12.4.2007 accepted 18.4.2007
Bibliography DOI 10.1055/s-2007-981477 Horm Metab Res 2007; 39: 467-473 @ Georg Thieme Verlag KG Stuttgart . New York ISSN 0018-5043
Correspondence
C. A. Stratakis, MD, D.Sc. Program on Genetics and Endocrinology · National Insti- tute of Child Health & Human Development National Institutes of Health Building 10-CRC Room 1(East)-3330 10 Center Dr. MSC1103 Bethesda Maryland 20892-1862 USA Tel .: +1/301/496 46 86/402 19 98
Fax: +1/301/402 05 74 stratakc@mail.nih.gov
Introduction & The basic premise of the work on the genetics of adrenal tumors that we have done at the National Institutes of Health (NIH) over the last 25 years is that the formation of adrenocortical tumors is associated with a molecular sequence of events similar to what has been described in other organs: as the pathology of the tumor increases towards malignancy, genetic changes accumulate ( Fig. 1). Although only a handful of cases of congenital adrenal hyperplasia with cancer are known, their existence provides support to this notion. We then hypothesized that identifying genes in the first phases of this process (e.g., hyperplasias) would provide information on the basic processes that start tumor formation in the adrenal cortex. The linkage of the cyclic AMP-sig- naling pathway through the ectopic receptor expression and mutations of the GNAS, PRKAR1A and PDE11A genes provide the framework from
which one can start approaching adrenocortical tumorigenesis.
The text that follows reviews our main findings on adrenocortical tumor clinical and molecular genetics and provides a classification for the some of the newest forms of bilateral hyperpla- sias, work that is largely in progress.
Molecular genetics of adrenocortical tumors &
Malignant neoplasias of the adrenal cortex account for only 0.05-0.2% of all cancers, with an approximate prevalence of two new cases per million of population per year [1-5]. Adrenal cancer occurs at all ages, from early infancy to the eighth decade of life [5-12]. In some areas of the world, higher incidence of adrenocortical tumors, especially in children, has been docu- mented [13]. The incidence of adrenal indidenta- lomas appears to also be higher in some familial
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HYPERPLASIA
ADENOMA
CANCER
Number of genetic changes by CGH
25
20
benign
malignant
15
10
5
0
4
6
10
20
Size of the tumor in cm
neoplasia syndromes like multiple endocrine neoplasia type-1 (MEN 1) [14] and familial adenomatous polyposis (FAP) [15]; it is unclear whether this finding is accompanied by a higher predis- position to adrenal cancer [15-18].
Some of the pioneering work in this field was contacted at the National Institutes of Health (NIH) by Dr. Chrousos or alumni of his laboratory [19,20]. A seminar paper indicated that adreno- cortical hyperplasia is a polyclonal process but carcinomas are monoclonal lesions [20], indicating that genetic changes at spe- cific loci in the genome are needed for adrenal tumorigenesis. Early investigations focused on obvious candidates, such as the corticotropin (ACTH) receptor (the MC2R gene) [21,22] and mol- ecules that participate in its signaling pathway, including the guanine-nucleotide binding protein (G-proteins) subunits Gsx [23] and Gio2 [24]. Loss-of-heterozygosity (LOH) of the MC2R gene locus on the short arm of chromosome 18 (18p11.2) was frequent in carcinomas but not in adenomas [22,25], suggesting that, perhaps, LOH of this gene participates in the dedifferentia- tion process leading to adrenocortical carcinogenesis. The Gsx gene (the Gsp proto-oncogene, GNAS gene) has not been found mutated in adrenal cancer [23], but patients with McCune- Albright syndrome who bear somatic mutations of this gene, do develop benign adrenal lesions [26]. Other candidate genes that were investigated in adrenocortical tumors included those cod- ing for aldosterone synthase (the CYP11B2 gene) and 21-hydrox- ylase (the CYP21B gene) [25,27], and for aldosterone-producing carcinomas, the angiotensin-II type-1 (AT-1) receptor gene [28]. The MEN 1 gene, menin, and the FAP gene, APC, have also been investigated as possible candidates [29-31] because patients with MEN1 and FAP do get adrenal tumors, which, however, are mostly benign and non-functional [14, 15]. Cytokines and growth factors and their receptors, which may be expressed eutopically or ectopically in adrenocortical tissue, have been recently impli- cated in carcinogenesis [19]. Expression of the major histocom- patibility class-II (MHC-II) antigens in adrenocortical tissue correlates with adrenocortical cell differentiation [32]. The expression of both transforming growth factor-o (TGFx) and epi- dermal growth factor receptor (EGFR) [33] is markedly elevated in carcinomas (unlike adenomas) and synaptophysin and other neuroendocrine markers are “inappropriately” expressed in
adrenocortical cancer [34]. The unexpected presence of proteins with neuroendocrine and other functions in adrenal cancer fol- lows a pattern similar to that observed in benign adrenocortical hyperplasias [35], although in cancer it seems to occur in a wider scale [19,34]. It is also worth noting that cortisol-producing adrenocortical carcinomas often respond to dexamethasone administration with a “paradoxical” rise of their glucocorticoid production [36], a feature that is almost universally present in primary pigmented adrenocortical disease (PPNAD), a benign, bilateral hyperplasia of the adrenal cortex [37,38]. The expres- sion of a variety of other factors has been investigated in adreno- cortical tumors, including inhibin A (INHA) [39-41].
Some of the most frequent genetic changes in adrenal tumori- genesis include the genomic loci on chromosomes 11 and 17 harboring the genes coding for p53 (TP53) (on 17p13.1), p57 (on 11p15.5) (KIP2), and the insulin-like growth factor type-II (IGF-II) (on 11p15.5), respectively [42-46]. LOH of the chromo- some 17 locus of the gene that codes for p53 in tumors from patients with Li-Fraumeni syndrome (LFS), led to the identifica- tion of germline TP53 mutations in this genetic condition. How- ever, LFS patients develop adrenal cancer rarely [47]: An analysis of 475 tumors in 91 families with LFS revealed that breast can- cer, bone and soft-tissue sarcoma, and brain tumors are most frequent, whereas adrenal cancer developed in only 1% of the patients [48]. In sporadic cancer, TP53 mutations may be present in approximately 30-50% of all lesions but p53 expression does not correlate with prognosis and it is rarely seen in monoclonal but highly differentiated tumors [49-51]. The latter finding sug- gests that TP53 mutations in sporadic cancer are a late event in the process of carcinogenesis, suggesting that other genetic events precede and may even predispose to TP53 mutations in adrenal cancer [44, 52]. These include mutations or other altera- tions in genes on chromosomes 2 and 17 (loci 2p16 and 17q22- 24, respectively) and the menin locus (11q13) [19,29,53].
Comparative genomic hybridization (CGH), a molecular cytoge- netic technique that allows for a genome-wide screening of tumor DNA to identify chromosomal gains and losses, was used on the study of adrenocortical tumors [54,55]. Copy number gain of a segment of chromosome 9 corresponding to cytoge- netic band 9q34 suggested that gene(s) in this locus may play a
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| Adrenocortical lesions | Age group | Histopathology | Genetics | Gene/locus |
|---|---|---|---|---|
| Macronodular hyperplasias (multiple nodules more than 1 cm each) | ||||
| Bilateral macro- adenomatous hyperplasia (BMAH) | middle age | distinct adenomas (usually 2 or 3) with internodular atrophy | MEN 1, FAP, MAS, HLRCS, other; isolated; other | menin, APC GNAS, FH, ectopic GPCRs |
| BMAH of childhood (c-BMAH) | infants, very young children | as above; occasional microadenomas | McCune-Albright syndrome (MAS) | GNAS |
| ACTH-independent macronodular | middle age | adenomatous hyperplasia (multiple) with internodular | Isolated, AD; | ectopic GPCRs; WISP-2 & Wnt- signaling; 17q22-24, other |
| adrenocortical hyperplasia | ||||
| (AIMAH), also known | hyperplasia of the zona fasciculata | |||
| as massive macronodular adrenocortical disease (MMAD) (AIMAH/MMAD) | ||||
| Micronodular hyperplasias (multiple nodules less than 1 cm each) | ||||
| Isolated primary pigmented nodular adrenocortical disease (i-PPNAD) | children; young adults | micro-adenomatous hyperplasia with (mostly) internodular atrophy and nodular pigment (lipofuscin) | Isolated; AD | PRKAR1A, PDE11A; 2p16; other |
| Carney complex (CNC)- associated primary pigmented nodular adrenocortical disease (c-PPNAD) | children; young and middle ages | micro-adenomatous hyperplasia with (mostly) internodular atrophy and (mainly nodular) pigment (lipofuscin) | CNC (AD) | PRKAR1A, 2p16; other |
| Isolated micro- nodular adrenocortical disease (i-MAD) | mostly children; young adults | micro-adenomatous hyperplasia with hyperplasia of the surrounding zona fasciculata and limited or absent pigment | isolated, AD; other | PDE11A, other; 2p12-p16, other |
“Abbreviations: MEN 1 = multiple endocrine neoplasia type 1; FAP = familial adenomatous polyposis (polyposis coli); MAS =McCune-Albright syndrome; HLRCS = hereditary leio- myomatosis and renal cancer syndrome; FH = fumarate hydratase; AD = autosomal dominant; CNC = Carney complex; GPCR = G-protein coupled receptors
role in the molecular process leading to adrenal cancer in at least some patients [55,56]. Another frequently lost chromo- some region was 2q22-q34, a locus that contains the INHA [40] and PDE11A [57] genes, which has been investigated in other but not adrencocortical tumors [55,57].
Primary pigmented adrenocortical disease (PPNAD)
&
In recent years, two primary adrenal disorders affecting the adrenal cortex have been implicated in the pathogenesis of cor- ticotrophin (ACTH)-independent Cushing syndrome (CS) [58]. Primary pigmented adrenocortical disease (PPNAD), also known as “micronodular adrenal disease”, is a congenital disorder, which, in the majority of the reported cases, is associated with Carney complex. The complex is a multiple endocrine neoplasia (MEN) syndrome that affects the adrenal cortex and other endo- crine glands, and is associated with abnormal pigmentation of the skin and mucosae, myxomas, and other neoplasms [59]. Massive macronodular adrenocortical disease is another form of bilateral adrenal hyperplasia, which leads to CS but is not associ- ated with any other clinical findings [60]. Macronodular disease should be contrasted with PPNAD: It is not congenital, almost always occurs in older patients, and its etiology is unclear. Other forms of bilateral adrenocortical hyperplasia distinct from
PPNAD and not always associated with hypercortisolism, include the lesions of the adrenal glands described in patients with the McCune-Albright and MEN type-1 syndromes [61,62], as well as other, newly-identified forms listed in Table 1.
PPNAD may occur independently or, more commonly, as part of the complex of “spotty skin pigmentation, myxomas and endo- crine overactivity” or Carney complex, which was described in 1985 [63-65]. This syndrome also encompasses several familial cases of cutaneous and cardiac myxomas associated with len- tigines and blue nevi of the skin and mucosae, which have been described under the acronyms NAME (for nevi, atrial myxoma, myxoid neurofibromata, and ephelides) and LAMB (for lentigi- nes, atrial myxoma, mucocutaneous myxoma, blue nevi) syn- dromes [66,67]. In PPNAD, the glands are most commonly normal-sized or small and peppered with black or brown nod- ules set in a cortex that is usually atrophic [65]. This atrophy is pathognomonic and reflects the autonomous function of these nodules and the suppressed levels of pituitary ACTH. Despite their small size (less than 6mm), the nodules are visible with computer tomography (CT-scan) or magnetic resonance imaging (MRI) of the adrenal glands, most likely because of the surround- ing atrophy [68]. The combination of atrophy and nodularity gives the glands an irregular contour, which is distinctly abnor- mal and diagnostic, especially in younger patients with CS. Occasionally, one or both of the glands may be larger and harbor adenomas with a calcified center, while macronodules larger
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than 10mm may be present in older patients [38]. Patients with PPNAD often present with a variant CS called “atypical” (ACS) [69], which is characterized by an asthenic, rather than obese, body habitus. This phenotype is caused by severe osteoporosis, short stature, and severe muscle and skin wasting. ACS was rec- ognized as early as 1956 and has since been described in several cases of patients with CS [69-72]; only recently, however, was this condition associated with PPNAD [38, 73]. Patients with ACS tend to have normal or near-normal 24-hour urinary free corti- sol (UFC) production, but this is characterized by the absence of the normal circadian rhythmicity of cortisol [38,73]. Occasion- ally, normal cortisol production is interrupted by days or weeks of hypercortisolism, which gives rise to a yet another variant called “periodic CS” (PCS). PCS is frequently found in children and adolescents with PPNAD [73]. In both ACS and PCS, as well as in classic CS, caused by PPNAD, paradoxical increase of UFC and/or 17-hydroxy-corticosteroids (17-OHS) is seen during the second phase (high dose dexamethasone administration) of the Liddle’s test [74]. This feature may be useful diagnostically for PPNAD [74]; it reflects, perhaps, a tendency that these nodules have for increased responsiveness to other steroids [75]. PPNAD is only rarely present and isolated. At the National Institutes of Health (NIH), where vigorous screening for Carney complex signs has been instituted under a research protocol, 19 patients have been treated for PPNAD since 1968. All these patients met the diagnostic criteria for Carney complex that were developed by Stratakis et al. [76], with the exception of a 32-year-old patient, who had PPNAD in her mid-twenties, underwent adrenalectomy and has had no other tumors or skin pigmenta- tion characteristic of the complex. Thus, we believe that fewer than 10% of the PPNAD cases represent isolated forms of the disease; most of these patients have Carney complex (CNC), a syndrome that has a well defined, but extremely variable phenotype.
CNC is associated with many other tumors, including cardiac myxomas [77], and other cutaneous tumors [78,79], breast myxomatosis [80,81], spotty skin pigmentation and other lesions [82,83], pituitary adenomas and acromegaly [76], large-cell cal- cifying Sertoli cell tumors (among the rarest of testicular neo- plasms), adrenocortical rests, and Leydig cell tumors [84], psammomatous melanotic schwannoma, epithelioid blue nevus, and ductal adenoma of the breast [76,85-87] and thyroid follicu- lar neoplasms, both benign and malignant [88]. Parent-of-origin effects in the inheritance of CNC have been observed [89]. The 2p16 (CNC2 locus) is likely to contain genes responsible for at least part of patients or the progression of the complex [76]. However, the gene that was found mutated in most patients with CNC and/or PPNAD was that of PRKAR1A on 17q22-24 [90].
Nomenclature and histology of bilateral hyperplasias: clinical hints
&
The various types of adrenocortical lesions, their histology and other information are given in Table 1. Table 1 lists no less than 6 types of bilateral adrenocortical hyperplasias (BAH). They are divided into two groups of disorders, macro- and micro-nodular hyperplasias on the basis of the size of the associated nodules ( Fig. 2). In macronodular disorders, the greatest diameter of each nodule exceeds 1 cm; in the micronodular group nodules are less than 1 cm. Although nodules less than 1 cm can occur in macronodular disease (especially the form associated with
McCune-Albright syndrome), and single large tumors may be encountered in PPNAD (especially in older patients), the size cri- terion has biologic relevance, as we rarely see a continuum in the same subject: most patients are either macro- or micro-nod- ular.
There are two additional basic characteristics that we use in this classification of BAHs: that of the presence of pigment and that of status (hyperplasia or atrophy) of the surrounding cortex. Pig- ment in adrenocortical lesions is rarely melanin; most of the pigmentation in both adenomas and BAH that produce cortisol is lipofuscin. The latter appears macroscopically as light brown to, some times, dark brown or even black discoloration of the tumorous or hyperplastic tissue; microscopically, lipofuscin can be seen but it is better detected by electron microscopy [91].
Clinical and molecular genetics of adrenocortical hyperplasias
&
As we already mentioned, aberrant cAMP signaling has been linked to genetic forms of cortisol excess. Macro-nodular adren- ocortical hyperplasia may be due to GNAS mutations associated with, either McCune-Albright syndrome or sporadic adrenal tumors [92]. Micro-nodular BAH, and its better-known variant, PPNAD, may be caused by germline inactivating mutations of the PRKAR1A gene [90,93,94].
Over the last several years, it has become apparent that there are several forms of micro-nodular BAH that are not caused by germline inactivating mutations of the PRKAR1A gene (Table 1). We described one such case associated with an atypical, epi- sodic, form of CS in a young child [91]. Her adrenal histology showed moderate diffuse cortical hyperplasia, multiple capsular deficits, and massive circumscribed and infiltrating extra-adre- nal cortical excrescences that in many cases formed micronod- ules that were non-pigmented. Synaptophysin, a marker for PPNAD, also stained the nodules, in addition to the surrounding cortex.
Recently, we reported that inactivating mutations of the PDE11A gene could be found in a subgroup of patients with PPNAD and other forms of BAH [57]. PDE11A is a dual-specificity phosphodi- esterase catalyzing the hydrolysis of both cAMP and cGMP; it is expressed in several endocrine tissues, including the adrenal cortex [95,96]. The PDE11A gene was mapped to the 2q31-35 chromosomal region and tumors from patients with PDE11A- inactivating mutations demonstrated 2q allelic losses [57]. The PDE11A locus, like that of other PDEs, has a complex genomic organization; of the four possible splice variants, only A4 appears to be expressed in the adrenal cortex, whereas A1 is ubiquitous, and A2 and A3 have a more limited expression pattern. More recent data show that PDE11A is widely expressed in adrenocor- tical tissue and its expression appears to be modified in a variety of tumors beyond PPNAD and other forms of BAH.
PDE11A sequence variants in the population and incidentalomas: a link?
&
All PDE11A sequence variants have been so far identified in an expanded set of over 2000 alleles [97]. These data support the notion that this gene is not necessarily causative of BAH but that is associated with a low penetrance predisposition to the devel- opment of BAH and possibly other ADTs leading to CS and, per-
LAHOM
A
B
haps, other conditions. In addition, two missense sequence changes (R804H and R867G) appear to be relatively frequent in the population [57,97]. The odds ratio for the R804H presence among patients with BAH or incidentally discovered adrenal tumors is 4.25 (95% confidence interval 0.95-19.13) and its pathogenicity is supported by in vitro data; the in vitro effects of R867G are less clear.
As mentioned, the previously identified PDE11A protein-truncat- ing mutations were also found in the population. At this point, we do not have access to the patients that were found as carriers of these genetic defects; however, their history was significant for various types of cancer suggesting that a carrier state for these defects may be a predisposing factor to a variety of tumors.
Conclusion
&
The last 25 years have been an exciting time in the study of adre- nal tumors: a number of new disorders have been described, most of the benign adrenocortical lesions have been linked in one way or another to cAMP-signaling dysregulation and we now know that cancer forms in the context of p53 mutations and/or IGF-II upregulation. A lot of this work was done at the NIH by people that were trained or associated with Dr. Chrousos. Do challenges remain? Of course: most of this new knowledge has yet to lead to new therapies: cancer of the adrenal cortex remains a lethal disease and surgery remains the mode of treat- ment for most adrenocortical lesions. It is our hope that phar- macological therapy of CS by molecular targeting in the future will replace adrenalectomy for benign lesions and lead to better
outcomes in cancer. It is also predicted that large genome-wide association and prospective studies will clarify the role of cer- tain genetic variants (such those of the PDE11A) in the formation of “incidentalomas” in the general population.
Acknowledgments
&
This work was supported by the National Institute of Child Health & Human Development (NICHD), NIH intramural project Z01-HD-000642-04 to Dr. C. A. Stratakis. We are also indebted to the NIH Office of Rare Disease (ORD) that funded in part this symposium and some of the research cited in this article.
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