Endoscopic Surgery Should Be Standard for Cushing’s Patients with Large Tumors

Cushing’s disease patients with macroadenomas — pituitary tumors larger than 10 mm — should undergo transsphenoidal pituitary surgery using the endoscopic technique, according to a new systematic review.

The study, “Endoscopic vs. microscopic transsphenoidal surgery for Cushing’s disease: a systematic review and meta-analysis,” was published in the journal Pituitary.

Cushing’s disease develops due to an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. The first-choice treatment for Cushing’s disease is transsphenoidal pituitary surgery, which is performed through the nose to remove pituitary tumors.

There are two main methods to conduct this kind of surgery: microscopic, which is done using a magnifying tool, and endoscopic surgery, which uses a thin, lighted tube with a tiny camera. The microscopic technique was the established method for transsphenoidal surgery, until physicians started doing endoscopic pituitary surgery in 1992.

Most surgical centers choose to perform either the microscopic or endoscopic technique but do not offer both. As a result, only a few small studies have compared the outcomes of microscopic and endoscopic surgical techniques in Cushing’s disease performed at the same center. These studies showed no clear differences in remission rates or surgical morbidity.

To date, no systematic review comparing the microscopic and the endoscopic surgical techniques in Cushing’s disease has been conducted and, therefore, convincing evidence to support either technique is lacking.

To address this, researchers set out to conduct a systematic review and meta-analysis that compares the endoscopic and microscopic transsphenoidal surgery techniques for Cushing’s disease with regards to surgical outcomes and complication rates.

Researchers searched through nine electronic databases to identify potentially relevant articles. In total, 97 cohort studies with 6,695 patients were included in the study. Among the total patient population, 5,711 received microscopical surgery and 984 were endoscopically operated.

Overall remission was achieved in 80 percent of patients, with no clear differences between the techniques. The recurrence rate was around 10 percent, and short-term mortality was less than 0.5 percent.

Cerebrospinal fluid leak (due to a hole or a tear) occurred more often in patients who underwent endoscopic surgery. On the other hand, transient diabetes insipidus — short-term diabetes — occurred more often in patients who received endoscopic surgery.

When classifying patients by tumor size, however, researchers found that patients with macroadenomas — tumors larger than 10 mm — had higher rates of remission and lower recurrence rates after endoscopic surgery. Patients with microadenomas (tumors smaller than 10 mm) had comparable outcomes with either technique.

“Endoscopic surgery for patients with Cushing’s disease reaches comparable results for microadenomas, and probably better results for macroadenomas than microscopic surgery,” the investigators wrote.

Taking these results into account, the researchers suggest that endoscopic surgery may be considered the current standard of care, though microscopic surgery can be used based on the neurosurgeon’s preference.

They also emphasize that centers that solely perform the microscopic technique should consider at least referring Cushing’s disease patients with macroadenomas to a center that performs the endoscopic technique.

From https://cushingsdiseasenews.com/2018/05/24/endoscopic-surgery-more-effective-macroadenomas-cushings-study/

Etomidate Found Effective in Severe Cushing’s Syndrome

Etomidate — a steroid synthesis blocker — is an effective treatment for patients with severe Cushing’s syndrome who do not respond to ketoconazole, according to a new case report from Mexico.

The report, “Etomidate in the control of severe Cushing’s syndrome by neuroendocrine carcinoma,” appeared in the journal Clinical Case Reports.

The investigators reported the case of a 51-year-old woman with ectopic Cushing’s syndrome caused by a pancreatic tumor. Ectopic Cushing’s refers to cases of excess secretion of adrenocorticotropin hormone (ACTH) outside the pituitary or adrenal glands.

The patient underwent distal pancreatectomy — the surgical removal of the bottom half of the pancreas — in 2015 due to an ACTH-secreting tumor. Although she had a good initial response, liver metastasis was evident by 2016.

Compared to measurements in 2016, morning blood cortisol, 24-hour urinary-free cortisol, and ACTH levels significantly increased in 2017. The patient also showed low levels of the luteinizing and follicle-stimulating hormones, which the scientists attributed to her severe hypercortisolism (excess cortisol levels).

The woman was being treated with ketoconazole to lower her cortisol values and later received chemoembolization — a method to reduce blood supply and deliver chemotherapy directly to a tumor — for her liver metastasis.

Although ketoconazole is generally the treatment of choice for the control of hormone production in the adrenal glands, its effectiveness is often limited and is associated with side effects, clinicians noted.

In April 2017, the patient arrived at the emergency room with sepsis — a potentially life-threatening complication of an infection — that originated in the gut.

Because ketoconazole had failed to lower cortisol levels, the patient started receiving infused etomidate, an inhibitor of the enzyme 11‐beta‐hydroxylase that prevents cortisol synthesis.

This treatment was stopped one day before the bilateral removal of the adrenal glands as a definitive treatment for the elevated production of cortisol.

While the patient experienced decreased levels of potassium, calcium, and magnesium with an initial dose of 0.04 mg per kg body weight an hour of etomidate, a gradual decrease of etomidate — depending on her cortisol levels — corrected these alterations.

After surgery, the patient showed a significant improvement in her general health, including control of her sepsis. She is currently taking hydrocortisone and fludrocortisone, with treatment for liver metastasis pending.

“Etomidate is a very effective drug in severe Cushing’s syndrome that is refractory to ketoconazole,” the researchers wrote.

“Control of the serum cortisol levels in ectopic Cushing’s syndrome can be obtained with infusion rates much lower than those used in anesthesia, without respiratory side effects,” they added.

The authors recommend an initial dose of etomidate of 0.04 mg/kg per hour, daily monitoring of 24-hour urinary cortisol and cortisol levels, and a gradual decrease of the etomidate dose according to daily measurements of metabolites.

From https://cushingsdiseasenews.com/2018/05/17/severe-cushings-syndrome-case-study-finds-etomidate-effective-therapy/

Study Describes 6 Common Surgical Failures in Cushing’s Disease Treatment

To help improve the effectiveness of surgical treatment of Cushing’s disease, researchers conducted a study to determine common failures. They classified these failures into six different categories.

Results were reported in the study, “Root cause analysis of diagnostic and surgical failures in the treatment of suspected Cushing’s disease,” published in the Journal of Clinical Neuroscience.

The surgical removal of lesions that secrete excess adrenocorticotropic hormone (ACTH) is the first line of treatment for patients with Cushing’s disease. But while this approach is effective in reducing cortisol levels, up to 31 percent of patients fail to achieve remission.

When initial surgery is ineffective, additional surgical procedures may help to improve patient outcomes. Medications also are used for those who do not see results from surgery.

Recognizing the factors that contribute to the failure of surgical treatment is crucial to avoiding a deterioration of patient health and to improving long-term outcomes.

Researchers at Harvard Medical School examined the clinical records of 51 patients suspected of having Cushing’s disease. These patients were followed and surgically treated at the Brigham and Women’s Hospital in Boston, from April 2008 to July 2017.

In more than 82 percent of the cases, tissue removed during surgery confirmed that the patients had excess ACTH caused by benign tumors in the adrenal gland. Among the remaining patients, two had additional ACTH-secreting tumors, four had no obvious tumor or abnormal tissue, one had a pituitary mass without ACTH secretion, and one had no evidence of tissue changes despite the detection of a tumor during exploratory surgery.

They were followed for an average of 18.3 months, during which 42 patients achieved remission as confirmed by blood tests. Of these, 34 patients did not require additional treatment; four patients needed additional surgeries to achieve control over cortisol levels; and four patients required additional radiosurgery.

Based on long-term patient outcomes, researchers were able to identify six categories of common diagnostic and surgical failures. They include:

  • persistently high cortisol levels despite the successful removal of lesions
  • the failure of tumor resection
  • recurrence of disease
  • a failure to identify the source of ACTH secretion
  • the absence of identifiable lesions during exploratory surgery
  • concurrent tumors.

While the first three are common among patients with a visible lesion on imaging scans, the latter three are characteristic of patients in whom physicians fail to detect a lesion.

Investigators believe that anticipating and recognizing these common failures may help to improve the effectiveness of surgery, symptom management, and overall treatment outcomes.

“The success of surgical intervention can be enhanced greatly by improving patient selection and surgical management by anticipating and subsequently deterring the six common failures described above,” the team concluded. They added that better imaging methods also might improve outcomes for Cushing’s disease patients.

From https://cushingsdiseasenews.com/2018/05/15/cushings-disease-surgery-6-common-failures-found-retrospective-study/

Rare Nasal Cancer May Have Caused Cushing’s Syndrome

A very rare case of Cushing’s syndrome developing as a result of a large and also rare cancer of the nasal sinuses gives insights into how to screen and treat such an anomaly, of which fewer than 25 cases have been reported in literature.

Paraneoplastic esthesioneuroblastoma (ENB), a very rare type of nasal tumor, may sometimes produce excess adrenocorticotrophic hormone (ACTH), leading to symptoms of Cushing’s syndrome, according to a recent case report that describes a case of ACTH-secreting ENB. The report aims to demonstrate the importance of recognizing its pathophysiology and treatment.

The case report, “A Case of Cushing’s Syndrome due to Ectopic Adrenocorticotropic Hormone Secretion from Esthesioneuroblastoma with Long Term Follow-Up after Resection,” was published in the journal Case Reports in Endocrinology.

It describes a 52-year-old Caucasian male who had a history of high blood pressure, severe weakness, abnormal production of urine, extreme thirstiness, and confusion.

He was scheduled to undergo surgery for a 7-centimeter skull base mass; the surgery was postponed due to severe high serum potassium concentrations and abnormally high pH levels. His plasma ACTH levels also were elevated and Cushing’s syndrome was suspected. Since imaging of the chest, abdomen, and pelvis did not show any ectopic (abnormal) sources of ACTH, the ENB was suspected to be the source.

Surgery was performed to remove the tumor, which was later found to be secreting ACTH. Consequently, following the procedure, his ACTH levels dropped to normal (below detection limit) and he did not need medication to normalize serum potassium levels. He then underwent subsequent chemoradiation and has shown no sign of recurrence 30 months after the operation, which is considered to be one of the longest follow-up periods for such a case.

Researchers declared it “a case of olfactory neuroblastoma with ectopic ACTH secretion that was treated with resection and adjuvant chemoradiation.”

“Given the paucity of this diagnosis, little is known about how best to treat these patients and how best to screen for complications such as adrenal insufficiency and follow-up,” they wrote. “Our case adds more data for better understanding of this disease.”

From https://cushingsdiseasenews.com/2018/04/03/rare-nasal-cancer-caused-cushings-syndrome-case-report-says/

ACTH/Cortisol Ratio May Be Simple, Reliable Test to Diagnose Cushing’s Disease

The ratio between adrenocorticotropic hormone levels and cortisol levels in the blood is higher among Cushing’s disease patients than in healthy people, a new study has found, suggesting that measurement could be used to help diagnose the disease.

Also, higher values at diagnosis could predict if the disease will recur and indicate larger and more invasive tumors.

The research, “The Utility of Preoperative ACTH/Cortisol Ratio for the Diagnosis and Prognosis of Cushing’s Disease,” was published in the Journal of Neurosciences in Rural Practice.

Cushing’s syndrome (CS) is characterized by excess levels of cortisol. In patients with suspected CS, clinicians recommend testing late-night salivary or plasma (blood) cortisol, 24-hour urine-free cortisol (UC), as well as morning cortisol levels after low-dose suppression with dexamethasone, a corticosteroid.

CS may be ACTH-dependent or ACTH-independent, meaning that the high cortisol levels are caused by excess ACTH production.

Patients with CD have elevated levels of ACTH. A tumor, usually an adenoma, causes the pituitary gland to produce excess levels of ACTH, which stimulate the release of cortisol from the adrenal glands. Cortisol usually inhibits ACTH production. However, in CD patients, this feedback mechanism is absent.

Despite extensive research and clinical data, the variable and usually nonspecific signs and symptoms of CD still represent relevant challenges for diagnosis. Clinical manifestations must be associated with biochemical tests, which often have led to conflicting results.

Studies showed that although ACTH levels correlate with the size of the pituitary adenoma, the levels of cortisol do not increase as much. In fact, lower cortisol/ACTH ratios have been reported in patients with macroadenoma – which is greater than 10 millimeters in size – than in those with microadenoma, which is smaller than 10 millimeters.

Conversely, the research team hypothesized that besides their utility for determining the cause of CS, the inverse ratio – ACTH/cortisol – also may be useful for diagnosis.

The team evaluated the pretreatment plasma ACTH/cortisol levels in CS patients with excess cortisol production due to abnormal pituitary or adrenal function. Data from patients were compared with that of individuals without CS.

The study included 145 CS patients diagnosed from 2007 to 2016, 119 patients with CD, 26 with ACTH-independent CS (AICS), and 114 controls with no CS.

Patients’ clinical, laboratory, imaging, postsurgical and follow-up data were analyzed.

Results showed that patients with CD had a significantly higher basal ACTH/cortisol ratio than controls or those with AICS.

“These results showed ACTH/cortisol ratio might be a simple and useful test for the diagnosis of ACTH-dependent CS,” the researchers wrote.

Importantly, the scientists observed that a ACTH/cortisol ratio above 2.5 indicated identified 82 percent of positive CS cases and 63 percent of controls.

Overall, “an ACTH/cortisol ratio [greater than] 2.5 would be beneficial to diagnose CD together with other diagnostic tests,” they concluded.

Patients with recurrent CD showed higher pretreatment ACTH levels and ACTH/cortisol ratio than those who achieved sustained remission. CD patients also exhibited more invasive, atypical and larger tumors, as well as lower postoperative remission and higher recurrence rates.

“Higher ACTH/cortisol ratio might predict poorer prognosis,” the investigators said.

From https://cushingsdiseasenews.com/2018/03/16/acth-cortisol-ratio-reliable-test-diagnose-cushings-disease/

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