Paediatric patients with Cushing disease and negative pituitary MRI have a higher risk of nonremission after transsphenoidal surgery

Abstract

Objective

Diagnostic workup of Cushing disease (CD) involves imaging evaluation of the pituitary gland, but in many patients no tumour is visualised. The aim of this study is to describe the association of magnetic resonance imaging (MRI) findings with the postoperative course of paediatric and adolescent patients with CD.

Patients

Patients with a diagnosis of CD at less than 21 years of age with MRI evaluation of the pituitary before first transsphenoidal surgery were included.

Measurements

Clinical, imaging and biochemical data were analysed.

Results

One hundred and eighty-six patients with paediatric or adolescent-onset CD were included in the study. Of all patients, 127 (68.3%) had MRI findings consistent with pituitary adenoma, while the remaining had negative or inconclusive MRI. Patients with negative MRI were younger in age and had lower morning cortisol and adrenocorticotropin levels. Of 181 patients with data on postoperative course, patients with negative MRI had higher odds of not achieving remission after the first surgery (odds ratio = 2.6, 95% confidence intervals [CIs] = 1.1–6.0) compared to those with positive MRI. In patients with remission after first transsphenoidal surgery, long-term recurrence risk was not associated with the detection of a pituitary adenoma in the preoperative MRI (hazard risk = 2.1, 95% CI = 0.7–5.8).

Conclusions

Up to one-third of paediatric and adolescent patients with CD do not have a pituitary tumour visualised in MRI. A negative MRI is associated with higher odds of nonremission after surgery; however, if remission is achieved, long-term risk for recurrence is not associated with the preoperative MRI findings.

Full text at https://onlinelibrary.wiley.com/doi/full/10.1111/cen.14560

COVID-19 May Be Severe in Cushing’s Patients

A young healthcare worker who contracted COVID-19 shortly after being diagnosed with Cushing’s disease was detailed in a case report from Japan.

While the woman was successfully treated for both conditions, Cushing’s may worsen a COVID-19 infection. Prompt treatment and multidisciplinary care is required for Cushing’s patients who get COVID-19, its researchers said.

The report, “Successful management of a patient with active Cushing’s disease complicated with coronavirus disease 2019 (COVID-19) pneumonia,” was published in Endocrine Journal.

Cushing’s disease is caused by a tumor on the pituitary gland, which results in abnormally high levels of the stress hormone cortisol (hypercortisolism). Since COVID-19 is still a fairly new disease, and Cushing’s is rare, there is scant data on how COVID-19 tends to affect Cushing’s patients.

In the report, researchers described the case of a 27-year-old Japanese female healthcare worker with active Cushing’s disease who contracted COVID-19.

The patient had a six-year-long history of amenorrhea (missed periods) and dyslipidemia (abnormal fat levels in the body). She had also experienced weight gain, a rounding face, and acne.

After transferring to a new workplace, the woman visited a new gynecologist, who checked her hormonal status. Abnormal findings prompted a visit to the endocrinology department.

Clinical examination revealed features indicative of Cushing’s syndrome, such as a round face with acne, central obesity, and buffalo hump. Laboratory testing confirmed hypercortisolism, and MRI revealed a tumor in the patient’s pituitary gland.

She was scheduled for surgery to remove the tumor, and treated with metyrapone, a medication that can decrease cortisol production in the body. Shortly thereafter, she had close contact with a patient she was helping to care for, who was infected with COVID-19 but not yet diagnosed.

A few days later, the woman experienced a fever, nausea, and headache. These persisted for a few days, and then she started having difficulty breathing. Imaging of her lungs revealed a fluid buildup (pneumonia), and a test for SARS-CoV-2 — the virus that causes COVID-19 — came back positive.

A week after symptoms developed, the patient required supplemental oxygen. Her condition worsened 10 days later, and laboratory tests were indicative of increased inflammation.

To control the patient’s Cushing’s disease, she was treated with increasing doses of metyrapone and similar medications to decrease cortisol production; she was also administered cortisol — this “block and replace” approach aims to maintain cortisol levels within the normal range.

The patient experienced metyrapone side effects that included stomach upset, nausea, dizziness, swelling, increased acne, and hypokalemia (low potassium levels).

She was given antiviral therapies (e.g., favipiravir) to help manage the COVID-19. Additional medications to prevent opportunistic fungal infections were also administered.

From the next day onward, her symptoms eased, and the woman was eventually discharged from the hospital. A month after being discharged, she tested negative for SARS-CoV-2.

Surgery for the pituitary tumor was then again possible. Appropriate safeguards were put in place to protect the medical team caring for her from infection, during and after the surgery.

The patient didn’t have any noteworthy complications from the surgery, and her cortisol levels soon dropped to within normal limits. She was considered to be in remission.

Although broad conclusions cannot be reliably drawn from a single case, the researchers suggested that the patient’s underlying Cushing’s disease may have made her more susceptible to severe pneumonia due to COVID-19.

“Since hypercortisolism due to active Cushing’s disease may enhance the severity of COVID-19 infection, it is necessary to provide appropriate, multidisciplinary and prompt treatment,” the researchers wrote.

From https://cushingsdiseasenews.com/2021/01/15/covid-19-may-be-severe-cushings-patients-case-report-suggests/?cn-reloaded=1

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/

%d bloggers like this: