Incidentaloma and Aberrant Neuroendocrine Regulation

Adrenal incidentalomas are among the most common tumors in humans. The molecular mechanisms leading to the frequent formation of these adrenal lesions with an increasing incidence in the aging population remain unknown [1]. ACTH-receptor mutations associated with adrenal tumorigenesis have only been reported in a minor subset of patients and are not committed to play a significant role in adrenal tumor function. Since the ACTH receptor is thought to be associated with a higher differentiation state and a lower proliferation rate, its expression might only be a marker of differentiation without any causative role in tumor development [2].

The vast majority of adrenal incidentalomas are known to be clinically benign in apparent masses, and require neither medical nor surgical intervention. On the other hand, there is growing concern that a relevant percentage of these lesions do present subtle autonomous hormone overproduction.

Even small amounts of chronic hypersecretion of glucocorticoids may contribute to metabolic malfunctions including impaired glucose tolerance, insulin resistance, dyslipidemia and hypertension [3].

So far, nothing is known about the molecular or cellular mechanisms contributing to subclinical hypercortisolism in adrenal incidentalomas; a NIH state of science conference held in Bethesda in 2002 called for more intensive research in this area.

The recent papers by V. Contesse et al. [4] and C. Dall'Asta et al. [5] are of great interest in this context; their findings are not limited to overtly cortisol-producing adenomas but also to clinically unapparent incidentalomas with subtle hypercortisolism.

So far, the concept of aberrant receptor expression in adrenal masses has been considered to be a characteristic mostly of ACTH-independent macronodular adrenal hyperplasia (AIMAH) and as an extremely rare occurrence in sporadic adenomas.

Furthermore, these finding underline the involvement of multiple receptors including receptors that act through various signaling pathways. Thus, the expression of these illegitimate receptors may be relevant for identifying tumors with subtle autonomous glucocorticoid hypersecretion (SAGH) that may benefit from laparoscopic adrenalectomy even if the size criteria for surgical intervention are not fulfilled. Although there are no clear recommendations on how to proceed with patients that have subclinical hypercortisolism and adrenal masses less than 4 cm considering the potential long-term complications of chronic hypercortisolism, I would concur with the decision made by the group of V. Contesse [4] to remove the tumors by surgical intervention.

Not only a panel of pharmacologic tests may be available for the detection of tumors responsive to these neuroendocrine receptors in the future but also novel techniques of neuroimaging including PET should be conceivable. Further insight into the formation of adrenal tumors could also be gained by analyzing the development of the fetal adrenal. Thus, astonishing similarities exist between the normal human fetal adrenal cortex and adrenal cancers, such as high expression of growth factors including insulin-like growth factor II. Since there seems to be the same genes involved in adrenocortical development and adrenocortical tumorigenesis, new technologies such as microarray techniques could reveal several genes of known growth factors or key regulators of the cell cycle in addition to genes not previously associated with adrenal growth or function. Therefore, insight into the precise and coordinated growth and differentiation of the fetal adrenal cortex should be gained through identifying genes involved in the dysregulation of growth and function in adrenal tumors [6]. Several genetic alterations such as loss of imprinting or loss of heterozygosity of the 11p15 gene locus causing a strong IGF-II overexpression have been demonstrated in the majority of adrenocortical carcinomas. Although the molecular pathogenesis of adrenal tumorigenesis is poorly understood, accumulating data indicate that adrenocortical carcinogenesis is a multistep process with progression from normal adrenal cells to adenoma cells and finally to malignant adrenocortical cells [7].

Aside from the clinical implications, the most fascinating question is why mesodermally derived adrenocortical tissue has the capacity to express neuroendocrine receptor molecules and even components of the neural/neuroendocrine secretory machinery including synaptophysin and chromogranin during adrenal tumorigenesis. As we are learning from stem cell research that not only embryonic cells but also adult organs possess hitherto unexpected plasticity, it would be intriguing to test the hypothesis that are there ”stress-responsive progenitor cells” in endocrine glands. Shifting from slow ACTH-dependent regulation to more rapid pathways including neurotransmitters and neuropeptides may be an attractive mechanism to adapt to internal and external stimuli, even if this means uncontrolled proliferation of cells.

References

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• 2 Zwermann O, Beuschlein F, Klink A, Stahl M, Reincke M. .  Horm Metab Res. 2004;  36 406-410
• 3 Bornstein S R, Oelkers W. .  Horm Metab Res. 2004;  36 341-345
• 4 Contesse V, Reznik Y, Louiset E, Duparc C, Cartier D, Sicard F, Laquerriere A, Parmentier F, Kuhn J M, Vaudry H, Lefebvre H. .  J Clin Endocrinol Metab. 2005;  90 2843-2850
• 5 Dall'Asta C, Ballare E, Mantovani G, Ambrosi B, Spada A, Barbetta L, Colombo P, Travaglni P, Loli P, Beck-Peccoz P. .  Horm Metab Res. 2004;  36 578-583
• 6 Coulter C L. .  Endocrinol Metab. 2005;  16 235-242
• 7 Fottner C, Hoeflich A, Wolf E, Weber M M. .  Horm Metab Res. 2004;  36 397-405