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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 3 1122-1128
Copyright © 1999 by The Endocrine Society

Original Studies

Synaptophysin Immunoreactivity in Primary Pigmented Nodular Adrenocortical Disease: Neuroendocrine Properties of Tumors Associated with Carney Complex

Constantine A. Stratakis, J. Aidan Carney, Lawrence S. Kirschner, Holger S. Willenberg, Silke Brauer, Monika Ehrhart-Bornstein and Stefan R. Bornstein

The Unit on Genetics and Endocrinology, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (C.A.S., L.S.K.), Bethesda, Maryland 20892-1862; Emeritus Staff, Mayo Clinic (J.A.C.), Rochester, Minnesota 55905; and the Diabetes Research Institute (H.W.), Dusseldorf; and University of Leipzig (S.B., M.E.-B., S.R.B.), 04103 Leipzig, Germany

Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., D.Sc., Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Carney complex (CNC) is characterized by lentiginosis and myxomatosis together with a variety of endocrine, neural crest-derived, and other tumors, including primary pigmented nodular adrenocortical disease (PPNAD). PPNAD is characterized by lipofuscin-containing, autonomously functioning, cortisol-producing nodules surrounded by mostly atrophic adrenocortical and normal adrenomedullary tissue. The nature and origin of the tumors, including the myxomas and PPNAD, are unclear. In this study, seven paraffin-embedded PPNAD tumors, one skin myxoma, and two cell lines (one myxoma and one PPNAD) established from patients with CNC were stained with antisera for synaptophysin (SYN), neuron-specific enolase, chromogranin A, tyrosine hydroxylase, and the neural cell adhesion molecule (NCAM). In addition, one PPNAD specimen and one myxoma were analyzed by electron microscopy. The results showed that chromogranin A and tyrosine hydroxylase stained adrenomedullary tissue, but not the PPNAD nodules or the extranodular adrenal cortex. SYN, neuron-specific enolase, and NCAM also stained the medulla. PPNAD nodules and the PPNAD cell line, but not the extranodular adrenal cortex, stained intensely for SYN. The myxoma cell line, but not normal fibroblasts, stained for SYN and NCAM. Ultrastructural analysis of a PPNAD tumor and a skin myxoma revealed a well developed rough endoplasmic reticulum, prominent mitochondria, and vesicle-like structures dispersed throughout the cytoplasm. We conclude that immunostaining for SYN, a marker protein for neuroendocrine cells, clearly distinguishes PPNAD nodules from surrounding adrenocortical tissue and can be helpful in the detection of small nodules in apparently unaffected cortex. The cells of a cutaneous myxoma were also stained positive by two of the three neuroendocrine markers. Finally, both PPNAD and myxoma cells demonstrated ultrastructural features suggestive of neuroendocrine properties. These results support the previously suggested hypothesis that the genetic mechanism leading to CNC involves genes with a neuroendocrine role.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE INVESTIGATION of adrenocortical cells in physiological and pathological states has provided evidence suggestive of neuroendocrine differentiation (1, 2, 3, 4). Although the adrenal cortex is not considered part of the diffuse neuroendocrine system, there is clearly an occasional overlap of the results of immunohistochemically detected neuroendocrine markers among adrenocortical neoplasms and adrenomedullary tumors such as pheochromocytoma (3). Neuroendocrine markers, including synaptophysin (SYN) and the neural cell adhesion molecule (NCAM), have been identified in adrenocortical adenomas, adrenocortical carcinomas, and a human adrenocortical carcinoma cell line (3, 4). NCAM is also expressed by normal human adrenal zona glomerulosa cells (4). Neuropeptides, such as adrenomedullin and vasoactive-intestinal peptide, are present in this zone in rodents (5, 6). In multiple endocrine neoplasia type 1 (MEN-1), there is adrenocortical involvement; the syndrome is caused by a gene that causes a variety of neuroendocrine tumors (7). A recent report suggested that neuroendocrine features of adrenocortical cells may be a wider phenomenon than previously suspected (8).

As with the MEN and lentiginosis syndromes, the complex of myxomas, spotty skin pigmentation, and endocrine overactivity, or Carney complex (CNC), affects both neural crest- and nonneural crest-derived tissues (9). Two genetic loci have been identified for this autosomal dominant disorder on chromosomes 2p (10) and 17q (11), respectively, but the responsible genes remain unidentified. It has been suggested that the CNC genes play an important role in the early differentiation of the neural crest and other endocrine tissues (9, 10). This hypothesis is supported by the role that recently cloned genes for disorders similar to CNC appear to play. The genes for MEN-1, Cowden disease, and Peutz-Jeghers syndrome, menin, PTEN, and STK11/LKB1, respectively, are widely expressed and appear to be involved in as yet unidentified pathways that control growth and, possibly, differentiation in various tissues, including neuroendocrine cells (12, 13, 14, 15).

Among the endocrine manifestations of CNC, primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent (9, 10). This condition is a unique abnormality of the adrenal cortex with unusual features, characterized by multiple, small, pigmented nodules set in an otherwise atrophic cortex (16, 17). The origin of these nodules is unknown (18); the issue is complicated by the lack of specific molecular markers for PPNAD cells. Similarly, there are no molecular markers specific for the myxomas that are also a component of CNC. The histology of the latter tumors is identical to that of sporadically occurring myxomas, and their origin and cellular nature are debated (19, 20). PPNAD and myxomas, sporadic and those associated with CNC, have been shown to be polyclonal lesions with a great degree of cytogenetic and genomic instability (21, 22), possibly reflecting the uncontrolled activation of a molecular signaling pathway leading to unchecked growth (22). A similar mechanism has been postulated for Peutz-Jeghers syndrome, in which, for the first time, inactivating mutations of a protein kinase, the STK11/LKB1 gene, have been linked to a cancer susceptibility syndrome (14, 15). In the present study, we investigated the expression of a variety of neuroendocrine proteins in PPNAD and cutaneous myxoma tumors and cell lines, using specific immunohistochemical markers. Among these, antiserum for SYN uniformly stained the PPNAD nodules and not the surrounding adrenal cortex. Further, immunoreactivity for SYN and two other neuroendocrine markers, NCAM and neuron-specific enolase (NSE), was present in a myxoma and primary cell lines from patients with CNC. Ultrastructural features of a PPNAD tumor and the myxoma provided evidence consistent with neuroendocrine differentiation of these lesions.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

The institutional review boards of the NICHHD, NIH, and the Mayo Clinic have approved NICHD protocol 95-CH-059 on PPNAD, CNC, and associated conditions. Hospital records, biopsy reports, and other clinical information were reviewed. Tissue slides of lesions excised from patients were reviewed by one of the authors (J.A.C.). The clinical profile of the investigated patients is given in Table 1Go.


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  		Table 1. Description of patients with sporadic PPNAD or Carney complex and performed studies

 
Cell lines

Primary cell cultures were established from one PPNAD tumor and one skin myxoma (Table 1Go). Briefly, tissue obtained at surgery was immersed in normal saline and processed immediately for tissue culture. In one case, a single PPNAD nodule with the characteristic pigment was dissected from the surrounding tissue, minced and placed in culture medium DMEM with 10% heat-inactivated FBS and 1% glutamine and antibiotics (Life Technologies, Gaithersburg, MD). The center of the skin myxoma was excised, minced and placed in the same culture medium. The cells were grown at 37 C in a 5% CO2 humidified atmosphere and subjected to immunohistochemistry after the first two passages.

Light and electron microscopy

For light microscopy, formalin-fixed tissue was embedded in paraffin, sectioned, and stained by the hematoxylin and eosin method; multiple whole mount cross-sections of the glands were examined, as previously described (16). Fragments of fresh tissue were fixed in 2% phosphate-buffered glutaraldehyde and processed for electron microscopy (EM), as previously described (23).

Immunohistochemistry

Deparaffinized sections of the adrenoglandular tissue and myxomatous tumor were immunostained using the unlabeled peroxidase-antiperoxidase method (23). Antibodies against NCAM (mouse anti-human NCAM, clone NCAM-OB11, Sigma-Aldrich Co., Deisenhofen, Germany), synaptophysin (mouse anti-human, Dako Corp., Hamburg, Germany), chromogranin A (CgA; rabbit antihuman antiserum, IgG, Dakopatts, Hamburg, Germany), neuron-specific enolase (NSE), and tyrosine hydroxylase (TH) were used, as previously described (1, 4, 23, 24). For specific staining of adrenocortical cells in normal adrenal gland tissue, specific antiserum against 17{alpha}-hydroxylase (courtesy of M. Waterman, Nashville, TN) was used, as previously described (23, 24).

A total of seven paraffin-embedded PPNAD tumors, one skin myxoma, and two cell lines (one myxoma and one PPNAD) established from patients with PPNAD or CNC (Table 1Go) were stained with antisera for NCAM, SYN, CgA, NSE, and TH.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Light microscopy and immunohistochemistry

Representative images are shown in Figs. 1Go and 2Go. Immunostaining of the PPNAD specimens with neuroendocrine markers and 17{alpha}-hydroxylase showed intermingling of medullary and cortical cells (Fig. 1Go, panels 1 and 2), as in normal adrenal glands (data not shown). Despite the apparent lack of absolute separation between cortex and medulla, antisera for markers known to be specific for chromaffin cells, such as SYN, CgA, and TH stained only the cells of the medulla in normal glands. In glands from patients with PPNAD, however, the cortical nodules, but not the extranodular adrenal cortex, demonstrated intense SYN immunoreactivity (Fig. 1Go, panels 3–6). All PPNAD specimens showed SYN immunoreactivity; in addition, SYN staining revealed small nodules of PPNAD-affected tissue in apparently nonnodular cortex (by hematoxylin-eosin staining) and, rarely, in the medulla (Fig. 1Go, panels 5 and 6). Thus, SYN staining occasionally identified PPNAD nodules that were not as easily identifiable by hematoxylin-eosin staining, because these were either small or within the medulla.



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  		Figure 1. Neuroendocrine markers: staining of normal adrenal cortex (C) and medulla (M), and adrenocortical nodules caused by PPNAD (p). Panel 1, Normal adrenal gland stained with antisera for synaptophysin and 17{alpha}-hydroxylase; synaptophysin did not stain normal cortex. There was intermingling of medullary and cortical cells (arrow; magnification, x10). Panel 2, This intermingling, shown at higher magnification in another adrenal gland stained by CgA and 17{alpha}-hydroxylase, can be widely spread through the normal cortex and medulla (magnification, x40). Panel 3, PPNAD nodules stained intensely with antiserum for synaptophysin, whereas the surrounding adrenal cortex did not (magnification, x10). Panel 4, PPNAD nodules from another specimen were stained with synaptophysin antiserum; the medulla was also stained, but not the surrounding adrenal cortex (magnification, x10). Panel 5, In this specimen, which was stained with synaptophysin antiserum, a PPNAD nodule appeared to have developed within an island of medullary cells and was surrounded by synaptophysin-negative cortex (magnification, x10). Panel 6, Higher magnification of a PPNAD nodule bordering with adrenal medulla; both the nodule and the medulla were stained with the synaptophysin antiserum, whereas the intervening adrenocortical cells were unstained (magnification, x20). Panels 7 and 8, Antisera for CgA (panel 7) and TH (panel 8) stained the medulla in adrenal glands with PPNAD, but did not stain the nodules or the surrounding extranodular adrenal cortex.

 


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  		Figure 2. Antiserum for synaptophysin stained cells of a skin myxoma excised from a patient with CNC [panels a (magnification, x10) and b (magnification, x20)] and cultured cells from a myxoma of another patient (c), but did not stain normal human fibroblasts (d).

 
In all specimens, CgA and TH antisera stained adrenomedullary tissue but did not stain PPNAD nodules or any other adrenocortical tissue (Fig. 1Go, panels 7 and 8). All medullas were stained by antisera for NSE and NCAM, which also stained PPNAD nodules lightly (data not shown). The myxoma cell line, but not normal fibroblasts, was stained lightly for both SYN (Fig. 2Go) and NCAM (data not shown).

EM

Ultrastructurally, vesicular mitochondria and smooth endoplasmic reticulum were prominent in PPNAD cells (Fig. 3Go). Liposomes, lysosomes, and filopodia were also present in PPNAD cells. Some dense core vesicle-like structures could be detected along the cell membranes, and the rough endoplasmic reticulum was prominent. In myxoma cells, the rough endoplasmic reticulum was also prominent, in part filling the entire cytoplasm (Fig. 4AGo), and dense core vesicle-like structures (Fig. 4BGo) were present along the cell membranes, as in PPNAD cells.



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  		Figure 3. Ultrastructure of cells of a PPNAD nodule revealed liposomes (LIP), smooth endoplasmic reticulum (SER), typical round and vesicular mitochondria (MIT), and the nucleus (NUC) with several vesicle-like structures (arrows; magnification, x11,500).

 


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  		Figure 4. Ultrastructure of cells of a skin myxoma showed abundant rough endoplasmic reticulum (RER; left panel; magnification, x15,500), round mitochondria with sparse cristae (MIT), and vesicle-like structures (arrows) adjacent to the cell membrane (right panel; magnification, x11,500).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We and others have shown that normal human adrenocortical cells and cells of adrenocortical tumors and certain tumor cell lines may demonstrate neuroendocrine properties (2, 3, 4, 8). The adrenal cortex is not part of the diffuse neuroendocrine system (25), and thus, the presence of neuroendocrine markers is unexpected. It is clear, however, that staining of the adrenal cortex for neuroendocrine markers is not due to adrenomedullary cells dispersed in the cortex, because double staining with enzymatic markers identifies the particular cortical cells as the sites that express these markers (23). One possible explanation for the phenomenon is that remnants of the fetal cortex are responsible for the staining (2). According to this hypothesis, normal cortical cells would be nonstaining, whereas tumors descended from clonal expansion of fetal tissue-derived cells would stain positively with neuroendocrine markers. Another suggested hypothesis is the following. Oncogenesis may be associated with dedifferentiation of adrenocortical cells (2), which, in turn, may express genes that under physiological conditions would be silenced. This theory does not explain the inconsistent, but unequivocal, staining of normal adrenocortical cells with such markers as NSE and NCAM. This phenomenon, on the other hand, could be due to cell-cell interactions, a paracrine communication between cortical and neighboring cells that takes place in the normal adrenal gland (23).

In our study, sections of seven PPNAD tumors were stained with antisera for NCAM, SYN, CgA NSE, and TH. These markers stained the adrenal medulla of the examined glands, appropriately. Neither TH nor CgA stained the PPNAD nodules, whereas NSE and NCAM lightly stained the nodules as well as foci in the extranodular cortical tissue. These findings are consistent with those of other studies in normal glands, adrenal adenomas, and carcinomas (2, 3, 4, 8). SYN, on the other hand, specifically and intensely stained PPNAD nodules, but not the extranodular tissue, in all tumors studied. Interestingly, SYN also stained a skin myxoma and a myxoma cell line from each of two patients with CNC, but did not stain a normal fibroblast cell line.

SYN is a glycoprotein that is a major part of the membrane of neuronal presynaptic vesicles (26). It is considered a re- liable neuroendocrine marker that has been found in almost all neuroendocrine neoplasms studied to date, as well as in neurons and diffuse neuroendocrine system cells (27, 28). Its presence in endocrine tumors correlates with the EM presence of cytoplasmic dense core granules (29). Although these structures are difficult to distinguish from Golgi-associated vesicles on purely morphological grounds, they tend to be grouped in little clusters close to the plasma or nuclear membranes in neuroendocrine cells (8, 25, 29). Importantly, we observed vesicle-like structures arranged in groups along cell membranes in both PPNAD and myxoma cells.

These findings support the hypothesis that the genes causing PPNAD and CNC play a neuroendocrine role, similar to that of PTEN and, perhaps, menin and STK11/LKB1 (12, 13, 14, 15). Such a role would explain the emergence of neural crest-associated tumors in CNC (pituitary adenoma and psammomatous melanotic schwannoma, for example) and their association with PPNAD despite the absence of carcinoid and other neuroendocrine tumors in the complex. Accordingly, carcinoid and other neuroendocrine tumors do not appear in either Cowden disease or Peutz-Jeghers syndrome despite the unequivocal expression of their causative genes in neuroendocrine tissues (13, 14, 15). It is possible that oncogenicity is tissue specific and depends on many factors; in this case, the absence of classic neuroendocrine tumors from a syndrome caused by mutations in a gene with important actions in neuroendocrine tissues would not be surprising.

The detection of SYN in PPNAD cells follows the recent identification of neuroendocrine features in other benign lesions affecting the adrenal cortex (30). These also include massive macronodular adrenocortical disease, which has been associated with the aberrant expression of such molecules as the gastric inhibitory polypeptide (31, 32), arginine vasopressin (33), and the ß2-adrenergic (34) receptors. In this regard, we recently demonstrated the aberrant expression of a cytokine receptor in an adrenocortical adenoma associated with Cushing’s syndrome (35).

The origin of PPNAD and myxoma cells, which appear to be stained by a neuroendocrine marker such as SYN but also have other unusual properties (16, 18, 19, 20), is unclear. It is unlikely that these tumors have a common embryonic origin with the neuroendocrine tumors that occur in CNC (pituitary GH-producing adenoma and psammomatous melanotic schwannoma). Rather, the data from this study suggest that adrenocortical PPNAD and myxomatous cells, which are of mesodermal origin, have assumed some neuroendocrine properties because of altered genetic regulation. Several studies support this latter theory in massive macronodular adrenocortical disease (31, 32, 33, 34), sporadic adrenal adenoma (35), and adrenocortical cancer (2, 3, 4, 8).

We conclude that immunostaining for SYN, a marker protein for neuroendocrine cells, clearly distinguishes PPNAD nodules from surrounding adrenocortical tissue. Neuroendocrine markers are also expressed by myxoma cells, a tumor frequently associated with PPNAD in patients with CNC. By EM, both PPNAD and myxoma cells demonstrate some neuroendocrine properties. These findings support the hypothesis that PPNAD and myxomas in CNC share defects in molecular pathways with a neuroendocrine role.

Received October 14, 1998.

Revised December 4, 1998.

Accepted December 10, 1998.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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A. Lacroix, N. N'Diaye, J. Tremblay, and P. Hamet
Ectopic and Abnormal Hormone Receptors in Adrenal Cushing's Syndrome
Endocr. Rev., February 1, 2001; 22(1): 75 - 110.
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C. A. Stratakis, N. Sarlis, L. S. Kirschner, J. A. Carney, J. L. Doppman, L. K. Nieman, G. P. Chrousos, and D. A. Papanicolaou
Paradoxical Response to Dexamethasone in the Diagnosis of Primary Pigmented Nodular Adrenocortical Disease
Ann Intern Med, October 19, 1999; 131(8): 585 - 591.
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