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Cortisol-producing adenomas (CPAs) are preceded by the development of steroids-producing nodules (SPNs) with two distinct layers — one tumorigenic and one tumor suppressive — reported Japanese scientists in findings they hope could lead to better understanding and management of these noncancerous tumors.

The research was recently published by eBioMedicine.

Studying tissue samples from 74 patients who underwent adrenalectomy, of whom 12 had CPA, the researchers showed that the tissues adjacent to the tumors harbored nodules with two layers, which they called zona fasciculata (zF)-like and zona reticularis (zR)-like structures, and that produced two different hormones.

Further analyses showed that the zF-like layer enhanced cell proliferation, "but the zR-like structure had a tumor-suppressive effect," with upregulation of immune genes and the increased presence of macrophages, said lead author Tazuru Fukumoto, MD, Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, in Fukuoka, Japan, in an accompanying news release.

"We also found that this zF-like structure was the main cause for the development of CPAs."

Fukumoto and colleagues deduced that, when cells in the adrenal cortex acquire a gene mutation linked to CPAs, they develop into SPNs, "wherein their zF-like structure contributes to them becoming CPAs."

He added, "We hope our results will advance our understanding of the layered structure of the adrenal cortex and can lead to the prevention and treatment of adrenal cortex atrophy in the future."

Vindicating Results, Unanswered Questions

Constantine A. Stratakis, MD, PhD, Director of Human Genetics & Precision Medicine, Institute of Molecular Biology & Biotechnology Molecular Biology, Foundation for Research and Technology Hellas, Heraklion, Crete, Greece, told Medscape Medical News that he feels "vindicated" by the study.

He first proposed the concept of lesions in the adrenal gland that could lead either to illness or cancer against "the background of hyperplasia" in the mid-1990s, although he concedes that the actual process "is more complex than what I suggested at the time."

However, he cautioned that the current study is limited by the small number of samples for each patient group and by the physical restrictions of tissue sampling, which have resulted in these researchers making "sweeping generalizations" from their findings.

Stratakis nevertheless supports the contention of the study that the SPNs "somehow create a microenvironment that is conducive to the development of a cortisol-producing adenoma."

If these findings are replicated in a larger study, he said that the question then becomes, "What is in this microenvironment that allows for the development of the adenoma in the presence of steroid-producing nodules?"

The next question centers around the increased presence of macrophages in the non-tumorigenic layer. "What's the interplay between the local microenvironment and immune system?" Stratakis asked.

"It makes sense that the immune system plays a role in lesion development," he said, but what that role might be is currently unclear.

Answering such questions may eventually permit the development of drugs to target the microenvironment and prevent CPA development, said Stratakis, who noted that "humoral factors are much easier to target medically than gene mutations."

A New Pathologic Entity

Antonio Marcondes Lerario, MD, PhD, associate research scientist, Division of Metabolism, Endocrinology, and Diabetes in the Department of Internal Medicine at Michigan Medicine, University of Michigan in Ann Arbor, Michigan, welcomed the study.

"The authors did a fantastic job to characterize these nodules with an impressive level of detail," he told Medscape Medical News. "I'm not a pathologist, but this type of nodule will likely become a new pathologic entity. Perhaps this is the most important contribution of this study."

He continued that the clinical implications of the findings are less clear, however, as "these lesions are very small and most likely asymptomatic — you can think of an analogy with an ordinary skin mole."

"We can speculate that these micronodules might be prevalent in the normal population but go undiagnosed."

Lerario added that there are also some "interesting aspects about these nodules," such as their structured organization being similar to the normal adrenal cortex, "suggesting a lesser degree of self-sufficiency compared to larger tumors," in that these nodules "still 'obey' certain rules that govern the normal tissue."

"For the future, now that these micronodules have been 'discovered', the natural next steps in their research would be exploring their prevalence in the general population or investigating whether they accumulate with age."

Three Layers, Three Different Hormones

The study authors highlighted that the human adrenal cortex comprises three functionally and structurally distinct layers, each of which is associated with the production of the following adrenal steroid hormones:

• Zona glomerulosa: Aldosterone
• zF: Cortisol
• zR: Adrenal androgens

CPAs are a leading cause of adrenocortical tumors, they noted, the majority of which are linked to somatic mutations in genes such as GNAS, the protein of which is involved in the regulation of hormone activity and bone development, and PRKACA, which plays a role in lipid and glucose metabolism.

However, it remains unclear how CPAs develop from genetically mutated precursor lesions within adrenocortical tissues.

A Deeper Look at the Data

To attempt to answer this question, the team identified 74 patients who underwent adrenalectomy at Kyushu University Hospital between 2014 and 2020, including 12 with CPA, 56 with aldosterone-producing adenoma, two with nonfunctioning adrenocortical adenoma, two with adrenal ganglioneuroma, and two with adrenal myelolipoma.

They obtained paired resected samples of tumor and tumor-adjacent tissue for each tumor type and performed immunohistochemistry and immunofluorescence testing, as well as DNA and RNA isolation, on which a whole range of sequencing analyses were carried out.

Comparing tumor-adjacent CPA samples with those for other tumor types, the team found that, in six of the 12 tumor-adjacent CPA samples, there were adrenocortical nodular structures.

These structures were divided into two layers: An outer zF-like layer and an inner layer more like zR tissue. Moreover, the two layers had steroid-producing capabilities for cortisol and androgens, respectively. The team therefore dubbed the nodular structures "steroids-producing nodules."

All but one of the sampled SPNs harbored GNAS mutations, which were not observed in the atrophied adrenocortical tissue surrounding the tumor-adjacent samples. The team therefore suggested that the GNAS somatic mutations "confer the autonomous steroidogenic capacity to SPNs."

Comparing CPA tumor samples and those of adjacent tissue, the researchers showed that 107 genes were upregulated only in the SPNs, which included gene sets associated with immune response, whereas 456 genes were upregulated only in CPAs, including gene sets linked to cholesterol metabolism and angiogenesis.

Within the SPNs, the zF-like outer layer was found to have upregulation of genes associated with cell migration, while the genes upregulated in the zR-like inner layer were linked to immune responses.

"These observations suggest that the two-layered zF- and zR-like structures have distinct biological implications during adrenocortical tumorigenesis," the researchers wrote.

This was supported by the zR-like layer having, on average, a significantly higher proportion of macrophages than the zF-like layer, and the "proportion of macrophages was positively correlated with the enrichment scores of inflammation-related gene sets," the team noted.

Finally, they showed that patients with high median expression levels for the top 10 differentially upregulated immune-linked genes in the zR-like layer of the SPNs had a better prognosis than those with low expression.

The researchers acknowledged that the study was limited by the sectioning of the tumor samples, which may have been too thick to capture all the SPNs, and the small size of the SPNs, which constrained analytical possibilities and may have undermined the validity of the results.

The study was funded by KAKENHI, The Uehara Memorial Foundation, Daiwa Securities Health Foundation, Kaibara Morikazu Medical Science Promotion Foundation, Secom Science and Technology Foundation, ONO Medical Research Foundation, and Japan Foundation for Applied Enzymology. 

No relevant financial relationships were declared.