Does Size Really Matter? Maybe Not for Cushing’s Pituitary Tumors

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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The size of pituitary tumors that cause Cushing’s disease do not affect the levels of cortisol or clinical features in patients, a study suggests.

The tumor’s ability to invade other brain tissues, however, likely impacts the chances of tumor removal and disease remission, researchers noted.

The study, “Clinical Study and Systematic Review of Pituitary Microadenomas vs. Macroadenomas in Cushing’s Disease: Does Size Matter?,” was published in the Journal of Clinical Medicine.

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Cushing’s disease is characterized by the excessive production of adrenocorticotropic hormone (ACTH), which increases cortisol production. The most common cause of ACTH overproduction is a tumor — called an adenoma — in the pituitary gland, a pea-sized gland at the base of the brain.

In most cases, patients have small ACTH-secreting pituitary tumors, called microadenomas, that measure on average less than six millimeters (mm) in diameter. Fewer cases — less than 10% — are caused by large tumors, called macroadenomas, which measure more than 10 mm in diameter.

Although larger pituitary adenomas may cause more symptoms, some studies have reported no differences in clinical presentation between patients, regardless of tumor size.

In this study, a group of researchers in Israel compared the symptoms and outcomes of Cushing’s disease patients with tumors of different sizes.

They reviewed clinical data from patients referred to the Endocrine Institute of Rabin Medical Center between 2000 and 2020 or the Maccabi Healthcare Services between 2005 and 2017. Tumor size was evaluated by radiological examination of the pituitary gland. Tumors with a diameter of at least 10 mm were considered macroadenomas.

The researchers also conducted a systematic review of studies published up to Nov. 31, 2021 in four databases — Medline Ovid, Medline (PubMed), Web of Science, and Google Scholar — studies involving adults with Cushing’s disease who had pituitary microadenomas versus macroadenomas.

In total, 105 Cushing’s disease patients (82 women, with a mean age of 41.5 years), who were followed for a mean of 5.7 years, were included in the study. MRI scans of the pituitary gland revealed 80 microadenomas measuring a mean of 5.2 mm, and 25 macroadenomas measuring a mean of 18.0 mm.

No differences were seen between patients with macro and microadenomas for age, gender, body mass index (a measure of body fat), prevalence of high blood pressure, bone-related disorders, or menstrual irregularities.

The most common sign of Cushing’s disease was weight gain, which was seen in 37 patients (46.3%) with microadenomas and 12 patients (48.0%) with macroadenomas.

Mean 24-hour urinary free cortisol levels were higher in patients with macroadenomas than in those with microadenomas (mean of 7.8- vs. 5.2-times the upper limit of normal).

The same trend was seen for levels of cortisol in the blood following a low-dose dexamethasone test (mean of 487.6 nanomoles per liter (nmol/L) vs. 372.0 nmol/L). However, these differences were not statistically significant. The test measures blood cortisol levels in the morning after patients take a tablet of dexamethasone, a corticosteroid that normally blocks cortisol production.

Among patients with available ACTH data, the levels of the hormone in the blood were significantly higher in patients with macroadenomas than in those with microadenomas (mean of 1.9- vs. 1.3-times the upper limit of normal).

Most patients underwent transsphenoidal surgery — the most common procedure to remove pituitary tumors by going through the nose — including 71 out of 74 (96.0%) with microadenomas and 23 out of 25 (92.0%) with macroadenomas.

After surgery, the rates of disease persistence or recurrence were similar in both groups: 30.4% among patients with macroadenomas and 35.2% among those with microadenomas.

Also, no differences were seen after surgery between both groups for adrenal insufficiency and the length of glucocorticoid replacement therapies. Adrenal insufficiency is a condition in which the adrenal glands become unable to produce sufficient amounts of steroid hormones, particularly cortisol.

From the literature review, out of an initial hit of 825 studies, the researchers analyzed nine clinical studies that met the inclusion criteria.

The systematic review confirmed some of their findings in the clinic. For example, ACTH levels in the blood were higher among patients with macroadenomas, as reported in seven of the nine included studies.

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The researchers also evaluated differences between patients with macroadenomas that had invaded surrounding brain tissues, namely to the cavernous sinus and the sphenoid sinus, which separates the pituitary gland from the nasal cavity.

Cavernous sinus invasion was evident in 10 patients (43.5%) and sphenoid sinus invasion in five patients (21.7%). Invading macroadenomas were associated with higher levels of ACTH, 24-hour urinary free cortisol, and blood cortisol levels following a low-dose dexamethasone test.

“Our study suggests classifying corticotroph tumors solely according to the tumor size may not be as clinically important as is tumor invasion; the latter is impacting the potential for complete tumor removal and biochemical remission,” the researchers wrote.

Overall, “ACTH-secreting microadenomas and macroadenomas present with similar clinical and biochemical characteristics,” they wrote, adding the only exception was high ACTH levels in the blood of patients with macroadenomas.

“This suggests there is a lack of association between tumor size per se with cortisol secretion values or clinical characteristics. Tumor location or extension may be more important than merely tumor size,” the researchers noted.