Transsphenoidal Surgery Recommended for Cushing Disease With Inconclusive or Normal MRI

In patients with a diagnosis of Cushing disease in whom magnetic resonance imaging (MRI) shows either no abnormalities or nonspecific abnormalities, surgery is preferable to medical treatment, according to study results published in The Journal of Clinical Endocrinology & Metabolism.

There is a consensus that the first line of treatment for Cushing disease is transsphenoidal surgery to remove the pituitary adenoma causing the disease, with an 80% remission rate following the intervention. However, in the absence of clear evidence of a pituitary adenoma on imaging, there is some controversy regarding the best treatment.

The goal of this retrospective single-center study was to assess the outcomes of surgery in patients with Cushing disease with clear evidence of a pituitary adenoma on MRI compared with outcomes in patients with inconclusive or normal MRI.

The cohort included 195 patients treated with transsphenoidal surgery between 1992 and 2018 (156 women; mean age at surgery, 41 years) classified into 4 MRI groups: 89 patients were found to have microadenoma, 18 had macroadenoma, 44 had nonspecific/inconclusive abnormalities on MRI results, and 44 had normal imaging results.

The researchers reported that MRI performance in their neuroradiology department improved with time; the proportion of inconclusive or normal MRI results decreased from 60% in 1992 to 1996 to 27% in 2012 to 2018 (P =.037).

In analyzing the influence of MRI findings on remission rates, the researchers found no significant difference among the 4 groups: remission rate was 85% for microadenomas, 94% for macroadenomas, 73% for inconclusive MRI, and 75% for negative MRI (P =.11). This finding indicates the overall percentage of patients in remission after transsphenoidal surgery is only slightly lower in those with normal or inconclusive MRI results compared with patients with clear evidence of microadenoma or macroadenoma.

There was no difference in remission rate after a microscopic vs endoscopic surgical approach (P =.16). The researchers found that endoscopic-assisted surgery allowed a higher visualization rate than microscopic-assisted surgery. Although the neurosurgeon had a better visualization rate than MRI (100% vs 72%, respectively), there were some false-positive findings; thus, positive predictive value was similar (84% vs 78%, respectively).

The study had several limitations including the retrospective design. In addition, in light of the long study duration, the researchers noted that changes in MRI technology and surgical procedures occurred over time.

The researchers proposed that after exclusion of nonneoplastic hypercortisolism, patients with Cushing disease, an inconclusive or normal MRI, and a pituitary adrenocorticotropic hormone gradient at bilateral inferior petrosal sampling be directed to an expert neurosurgeon for transsphenoidal surgery rather than treated medically.

 

Reference

Cristante J, Lefournier V, Sturm N, et al. Why we should still treat by neurosurgery patients with Cushing’s disease and a normal or inconclusive pituitary MRI [published online May 14, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2019-00333

From https://www.endocrinologyadvisor.com/home/topics/adrenal/transsphenoidal-surgery-recommended-for-cushing-disease-with-inconclusive-or-normal-mri/

Fluorescent Metabolite Might Help Surgeons Remove Pituitary Tumors

The resection of microadenomas — small, benign tumors in the pituitary gland underlying Cushing’s disease — could be aided by a fluorescent marker that is naturally produced by the tumor, a new study shows.

The findings were presented recently at the 2018 George Washington Research Days in a poster titled, “Enhanced 5-ALA Induced Fluorescence in Hormone Secreting Pituitary Adenomas.

Cushing’s disease is characterized by high cortisol levels that cause debilitating physical, mental, and hormonal symptoms. The excess cortisol is caused by tiny benign tumors in the pituitary gland, called microadenomas, with a size of less than 10 millimeters.

On account of their small size, these microadenomas pose imaging challenges to physicians. Up to 40 percent of microadenomas remain undetected in the gold-standard magnetic resonance imaging (MRI).

Pituitary adenomas, however, have a characteristic that distinguishes them from the surrounding healthy tissue. They process (metabolize) a natural haemoglobin metabolite, called 5-aminolevulinic acid (5-ALA), into protoporphyrin IX (PpIX) at much higher rates — up to 20 to 50 times higher — than normal tissues.

Importantly, PpIX emits red fluorescence when excited with blue light.

This means that exogenous 5-ALA is taken up by the adenoma cells and rapidly metabolized into the fluorescent metabolite, PpIX, which may establish its use for fluorescence-guided resection of pituitary adenomas.

To test this, researchers incubated human-derived corticotropinoma, as well as the adjacent normal gland cells with 5-ALA. They did the same with mouse model normal pituitary cells and a mouse model pituitary tumor cell line, called AtT20.

They then analyzed the cells’ fluorescence profile by microscopy and with a technique called flow cytometry.

The analysis showed that compared to normal pituitary tissue, human-derived adenomatous cells had a significant increase of tenfold in 5-ALA-induced PpIX fluorescence intensity.

Similarly, mouse pituitary tumor cells (AtT20 cell line) fluoresced seven times more intensely than normal murine pituitary tissue.

The microscopy analysis revealed that the 5-ALA localized in subcellular organelles called mitochondria.

On June 6, 2017, the U.S. Food and Drug Administration approved the use of 5-ALA (under the brand name Gleolan) as an optical imaging agent for patients with gliomas (brain tumors), as an add-on compound to assist surgeons in identifying the malignant tissue during surgery.

Now, these findings suggest that 5-ALA also may be used for fluorescence-guided surgery of microadenomas in Cushing’s disease.

“The supraphysiological levels of glucocorticoids, as seen in CD [Cushing’s disease], may enhance the 5-ALA fluorescence in corticotropinomas,” researchers wrote.

From https://cushingsdiseasenews.com/2018/04/13/fluorescent-metabolite-might-help-surgeons-removepituitary-tumors/

Detailed MRI Analysis Provides Correlations with Clinical Features and Response to Treatment in Cushing’s Disease

Detailed imaging analysis of patients with Cushing’s disease (CD) and other disorders caused by pituitary adenomas (tumors that arise from the pituitary, a small gland in the brain) provides correlation with clinical characteristics and treatment response, a new Turkish study reports.

The research, “Clinicopathological significance of baseline T2-weighted signal intensity in functional pituitary adenomas,” appeared in the journal Pituitary.

Diagnosis of pituitary adenomas is often done with magnetic resonance imaging (MRI), which provides data on the tumor’s localization, its invasiveness, as well as cell death and other changes. However, MRI does not enable precise evaluation of the tumor’s hormone production and behavior.

Studies on T2-weighted signal intensity (T2-WSI) — one of the basic parameters in MRI scans that highlights fat and water in the body — shows that it correlates with collagen content, degree of fibrosis (scarring), amyloid protein accumulation, and granulation pattern of somatotroph adenomas, which produce excessive levels of growth hormone, causing acromegaly (a hormonal disorder that results from too much growth hormone in the body).

Evaluation of granulation patterns is key in predicting response to somatostatin analogues (SSAs) treatment, the researchers observed. SSAs are intended to stop excess hormone production.

In contrast, analysis of T2-WSI in corticotroph adenomas — benign tumors typical in Cushing’s disease patients that release elevated levels of adrenocorticotropin (ACTH) – is still lacking.

The research team assessed the correlation of T2-WSI with clinical features, granulation patterns, and response to treatment in patients with functional pituitary adenomas (FPAs), which are collectively characterized by excessive production of one or more hormones.

Specifically, scientists focused on 29 patients with Cushing’s disease, 87 with acromegaly, and 78 with prolactinoma, a type of benign pituitary tumor that produces elevated amounts of prolactin.

Results showed that while most somatotroph adenomas (53%) were hypointense, which means a darker image on MRI, the majority of prolactinomas (55%) and corticotroph adenomas (45%) were at least generally hyperintense, meaning lighter on image.

Data also revealed that hyperintense somatotroph adenomas were larger, sparsely granulated, and exhibited reduced shrinkage after treatment with SSAs.

In contrast, hypointense tumors were associated with higher levels of baseline insulin-like growth factor (IGF)-1% ULN, a predictor of insulin sensitivity, and a better response to SSAs.

In women with prolactinomas, hyperintensity correlated with smaller tumor diameter. In turn, hypointense prolactinomas were linked with younger age at diagnosis, higher baseline prolactin levels, and resistance to treatment with a dopamine agonist.

Scientists also found that hyperintense corticotroph adenomas correlated with larger tumor size and a sparsely granulated pattern. No difference was found between hyper and hypointense adenomas on cortisol and ACTH levels.

Investigators also reported that T2-WSI was not correlated with better surgical outcomes or with recurrent Cushing’s disease. Analysis of tumor shrinkage in these patients was not possible, the researchers noted.

“Although in present there is no immediate clinical application, we believe that if medical shrinkage of corticotrophs ever became a part of clinical practice, similar analyses could be performed in the future,” the researchers wrote.

“Further studies with larger series are required in order to make stronger suggestions,” they added.

From https://cushingsdiseasenews.com/2018/03/23/detailed-mri-analysis-correlates-with-cushings-disease-clinical-features/

USC’s 7 Tesla MRI scanner first to identify Cushing’s disease in US patient

A noninvasive 7 Tesla MRI scanner at University of Southern California is the first 7T scanner to be used on a patient with Cushing’s disease in the U.S., according to a USC news release.

When a brain tumor was found to be “MRI-negative” in a 28-year-old female patient, physicians at the USC’s Pituitary Center were unsatisfied with the results. After deciding to use the Neuroimaging and Informatics Institute’s (INI) new ultrahigh field 7 Tesla MRI scanner to localize the tumor, the patient was officially diagnosed with Cushing’s disease and researchers were finally able to [be] see the tumor that would’ve otherwise appeared hidden in a standard MRI.

Cushing’s disease is caused by a pituitary microadenoma, or very small tumor, which results in chronically elevated cortisol. Symptoms include weight gain, skin bruising and hair loss and if left untreated, the condition can be fatal.  Because of this case, USC researchers believe the 7T scanner will be able to replace the standard, and invasive, method of clinical diagnosis, according to the news release.

“It’s clear that this is the beginning of a new frontier for ultrahigh field MR technologies,” said Arthur Toga, PhD, director of the INI, in a prepared statement. “The enhanced image quality opens many doors for neuroscientists in both research and clinical settings.”

From http://www.healthimaging.com/topics/neuroimaging/uscs-7-tesla-mri-scanner-first-identify-cushings-disease-us-patient

Desmopressin is Promising Alternative in Diagnosing Cushing’s Disease

Bilateral inferior petrosal sinus sampling (IPSS) — a procedure that uses desmopressin to determine levels of ACTH hormone from veins that drain from the pituitary gland, is a sensitive way to diagnose patients with Cushing’s disease and find tumors, a Chinese study shows.

The study, “Tumour Lateralization in Cushing’s disease by Inferior Petrosal Sinus Sampling with desmopressin,” appeared in the journal Clinical Endocrinology.

Cushing’s disease is characterized by excessive production of the adrenocorticotropin hormone (ACTH) caused by a tumor in the pituitary gland. ACTH is the hormone that causes the adrenal glands to produce cortisol.

Currently, pituitary imaging is insufficient to confirm a Cushing’s diagnosis. This is because 70 percent of pituitary adenomas in Cushing’s are microadenomas, which are physically very small. As a result, 40 percent of Cushing’s patients are reported as being healthy.

This means that a Cushing’s diagnosis requires a combination of techniques including clinical symptoms, imaging methods and endocrinological assays that include measures of serum cortisol and ACTH levels.

IPSS determines ACTH levels from veins that drain from the pituitary gland. ACTH levels are then compared to ACTH levels in blood. Higher levels in the pituitary gland indicate a pituitary tumor.

IPSS can also be used to determine tumor lateralization, which refers to which side of the pituitary gland the tumor is located on. The test is 69 percent accurate.

Doctors administer IPSS along with corticotropin-releasing hormone (CRH) stimulation. IPSS with CRH is considered the gold standard for preoperative diagnosis of Cushing’s, with a diagnostic sensitivity (or true positive rate) of 95 percent and specificity (or true negative rate) of 90 to 95 percent. Unfortunately, the high cost and limited availability of CRH make it impractical for many patients.

Desmopressin has been used to replace CRH to stimulate ACTH secretion for IPSS, and prior studies have shown that desmopressin’s sensitivity is comparable to that of CRH.

Researchers at Peking Union Medical College in Beijing conducted a retrospective analysis of their experience using desmopressin-stimulated IPSS to determine its diagnostic value for Cushing’s and its predictive value for tumor lateralization.

Researchers analyzed 91 Cushing’s patients who either had negative findings on the MRI imaging of the pituitary or negative high-dose dexamethasone suppression tests, which is another method of evaluation. All patients underwent IPSS with desmopressin, followed by pituitary surgery to extract the tumor.

Of the 91 patients tested, 90 patients had confirmed Cushing’s. And of these, 89 had positive IPSS findings, which led to a sensitivity of 98.9 percent for this test. One patient out of 91 who did not have Cushing’s also underwent this test, which led to a negative IPSS result and a specificity of 100 percent.

Researchers also determined tumor lateralization in patients who were ultimately diagnosed with Cushing’s and underwent surgery. Results of the IPSS showed a 72.5 percent concordance between the results from the IPSS and the surgery.

Therefore, IPSS with desmopressin is a comparable approach to IPSS with CRH for the diagnosis of Cushing’s. It also demonstrates moderate accuracy in determining the location of tumors.

“Like many medical centers in China, we currently have no supply of CRH, while desmopressin is readily available,” researchers concluded. “Moreover, desmopressin is cheaper than CRH. As our data and other studies indicate, IPSS with desmopressin yielded comparable outcomes to IPSS with CRH. Therefore, desmopressin-stimulated IPSS might serve as a possible alternative to CRH-stimulated IPSS.”

From https://cushingsdiseasenews.com/2017/11/14/ipss-desmopressin-alternative-method-diagnosis-cushings-disease/

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