Case Report Shows Rare Adrenal Tumors Associated with Cushing’s Disease

Pituitary tumors that produce too much adrenocorticotropic hormone (ACTH) have been associated with the development of rare tumors on the adrenal glands, called adrenal myelolipomas, for the first time in a case report.

The study, “Case report of a bilateral adrenal myelolipoma associated with Cushing disease,” was published in the journal Medicine.

Myelolipomas, composed of mature fat cells and blood-forming cells, are usually asymptomatic and do not produce hormones. In many cases, these tumors are detected by accident when patients undergo imaging scans for other conditions.

The cause of these tumors is unknown, but due to their benign nature, they do not spread to other parts of the body. However, they can grow up to 34 centimeters (about 13 inches), leading to tissue death and hemorrhage.

Researchers at Soon Chun Hyang University College of Medicine in Seoul, Korea, described the case of a 52-year-old man with myelolipoma possibly caused by an ACTH-secreting pituitary tumor.

During a routine checkup, researchers detected a mass in the patient’s spleen. Further abdominal evaluations identified tissue lesions in both adrenal glands consistent with myelolipoma. Besides the masses, the patient did not show any other Cushing-associated physical characteristics.

However, the patient’s ACTH levels were two times higher than the normal upper limit. Cortisol levels were also increased and unresponsive to low-dose dexamethasone treatment.

No additional lesions were found that could help explain the high ACTH and cortisol levels. But analysis of blood samples collected from the veins draining the pituitary glands revealed the right gland was producing too much ACTH, strongly suggesting Cushing’s disease.

Both the left adrenal gland and pituitary tumor were surgically removed. The samples collected during surgery confirmed the benign nature of the adrenal tumors, and the diagnosis of abnormal, ACTH-positive pituitary gland tissue.

Three days after the surgeries, hormone levels were back to normal. But a follow-up evaluation five months later again showed increased ACTH levels. Cortisol levels, however, were normal.

For the next seven years, the patient was evaluated every six months. During a five-year period, the size of the right adrenal gland was found to have grown. Imaging analysis confirmed the existence of small, new lesions in both pituitary glands.

“This case confers valuable information about the clinical course of adrenal myelolipoma associated with Cushing disease,” the researchers said. It also “supports the notion that ACTH can be associated with the development of bilateral adrenal myelolipomas.”


Adrenal Gland Lump Led to 5-year-old Developing Cushing’s, Starting Puberty

Non-cancerous adrenal gland tumors can lead to rare cases of Cushing’s syndrome in young children and puberty starting years before it should, a case study of a 5-year-old boy shows.

Removing his right adrenal gland eliminated the problems, the Saudi Arabian researchers said.

Their report dealt with tumors in epithelial cells, which line the surface of many of the body’s structures and cavities.

The research, “Testosterone- and Cortisol-secreting Oncocytic Adrenocortical Adenoma in the Pediatric Age-group,” appeared in the journal Pediatric and Developmental Pathology.

Most tumors in adrenal gland epithelial cells are benign and generate normal levels of hormones. But there are cases when the tumors over-produce steroids and other kinds of hormones, including sex hormones. Sometimes the over-production can lead to Cushing’s syndrome.

The 5-year-old boy’s over-production of adrenal gland hormones led to both symptoms of Cushing’s syndrome and signs that he was starting puberty, the researchers said.

One reason the case was rare is that the average age when Cushing’s develops is 40, doctors say. Another is that epithelial adrenal gland tumors account for only 0.2 percent of all tumors in children, the researchers said.

Signs that the boy was starting puberty began appearing eight months before his parents took him for treatment. Doctors discovered he had the weight gain and rounded face associated with Cushing’s, but a battery of tests detected no other problems. No family members were experiencing the symptoms he was, doctors added.

Biochemical tests showed that the boy had a high level of cortisol in his blood, which doctors were unable to lower with the corticosteroid suppression medication dexamethasone.

Physicians also discovered that the boy had elevated levels of the male hormone testosterone, the cortisol precursor 17-hydroxyprogestrone, the cortisol-releasing hormone adrenocorticotropin, and another male hormone that the adrenal gland produces — dehydroepiandrosterone sulfate

In contrast, doctors discovered a below-normal level of luteinising, a sex hormone that the pituitary gland generates.

Another unusual manifestation of the boy’s condition was that his bone growth was that of a child a year older than he.

Doctors discovered a non-cancerous tumor in his right adrenal gland that they decided to remove. When they did, they discovered no evidence of bleeding, tissue scarring or cell death.

They put the boy on a hydrocortisone supplement, which they reduced over time and finally ended.

Twenty-eight months after the surgery, the boy showed no signs of Cushing’s disease or early puberty. And his weight, cortisol and adrenocorticotropin hormone levels were normal.

“To the best of our knowledge, our patient represents the first male patient” with a benign epithelial-cell adrenal gland tumor “in the pediatric population, with clinical presentation of precocious [early] puberty and Cushing’s syndrome,” the researchers wrote.

“As these tumors are exceptionally rare, reporting of additional cases and investigation of clinicopathological [disease] data are needed for better characterization of these tumors,” they wrote.


Patient’s Atypical Cushing’s Symptoms Lead to Discovery of Novel Genetic Mutations

New genetic mutations were found in a patient who exhibited atypical symptoms of Cushing’s syndrome, notably an abnormal protrusion of the eye, a case report shows.

The research, “Extensive ARMC5 genetic variance in primary bilateral macronodular adrenal hyperplasia that started with exophthalmos: a case report,” was published in the Journal of Medical Case Reports.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a disorder characterized by multiple lumps in the adrenal glands and excessive cortisol production. It is a rare cause of Cushing’s syndrome.

According to recent research, PBMAH is caused by mutations in the ARMC5 gene, which data suggest may act as a tumor suppressor.

Researchers presented the case of a 52-year-old Chinese woman who exhibited a protrusion of both eyes (exophtalmos), which was first thought to be Graves’ ophthalmopathy. An injection of triamcinolone acetonide, a corticosteroid, into the area behind the eye globe did not improve symptoms.

The patient later was diagnosed with diabetes, which was treated with insulin, and hypertension, treated with insulin and amlodipine. She also developed muscle weakness and bruised easily. She had no other relevant chronic illness or infectious disease, and did not smoke tobacco or drink alcohol.

Physical examination showed skin atrophy, moon face, buffalo hump (between the shoulders), and purplish abdominal striae (stretch marks), which researchers defined as a typical Cushingoid appearance. The patient also experienced elevated pressure inside the eye, and had edema, conjunctival congestion, and lid retraction. No liver, spleen, respiration, cardiac, abdominal, blood counts, urinary, sensory, or motor abnormalities were noted.

Biochemical evaluation showed elevated cortisol and reduced adrenocorticotropin (ACTH) levels. Administering  dexamethasone did not lower the level of cortisol. Abnormal responses of the hormone vasopressin also were detected.

A computed tomography (CT) scan of the adrenal glands showed bilateral multiple lobular masses, and an MRI of the eye orbits indicated bilateral exophthalmos with hypertrophy of the retro-orbital fat, which lines the orbit.

After PBMAH was diagnosed, the patient’s adrenal glands were removed. Pathological findings showed multiple, homogenous, golden-yellow-colored nodules on the glands.

The surgery successfully lowered the level of cortisol and increased that of ACTH. The patient began taking hydrocortisone and metformin for diabetes. After six months, her exophtlamos, blood glucose levels, and blood pressure had improved.

Genetic analysis revealed six specific ARMC5 mutations in five of the seven adrenal nodules analyzed. “All the mutations are novel and not found in available online databases,” the researchers wrote. The mutations may lead to resistance to cell death in the tumor cells, and cause an increase in the production of cortisol, they observed.

As a result of the ARMC5 mutations, gene expression (conversion of genetic information) of the messenger RNA (mRNA, which is converted from DNA in the first step of protein synthesis) was lower in the adrenal tumor samples, in comparison with normal adrenal cortex.

Overall, the study “highlights the importance of early recognition of atypical symptoms of Cushing’s syndrome such as exophthalmos, which would save the patient from harmful effects of excessive cortisol exposure,” the researchers said. Screening for ARMC5 mutations also would help improve diagnosis and genetic counseling, they said.


Temozolomide May Partially Improve Aggressive Pituitary Tumors Causing Cushing’s Disease

The chemotherapy temozolomide partially improved a case of an aggressive pituitary tumor that caused symptoms of Cushing’s disease (CD), according to a new study in Poland. However, after tumor mass and cortisol levels were stabilized for a few months, the patient experienced rapid progression, suggesting that new methods for extending the effects of temozolomide are needed.

The study, “Temozolomide therapy for aggressive pituitary Crooke’s cells corticotropinoma causing Cushing’s Disease: A case report with literature review,” appeared in the journal Endokrynologia Polska.

Aggressive pituitary tumors are usually invasive macroadenomas, or benign tumors larger than 10 mm.

A very rare subset of pituitary adenoma — particularly corticotropinoma, or tumors with excessive secretion of corticotropin (ACTH) — exhibit Crooke’s cells. These tumors are highly invasive, have a high recurrence rate, and are often resistant to treatment.

Information is not widely available about the effectiveness of treating aggressive pituitary tumors, particularly those that cause Cushing’s disease. The management of these tumors usually requires neurosurgery, followed by radiotherapy, and pharmacotherapy. However, the chemotherapy medication temozolomide has been increasingly used as a first-line treatment after initial evidence of its effectiveness in treating glioblastoma, the most common form of brain cancer.

In this study, researchers at the Jagiellonian University, in Poland, discussed the case of a 61-year-old man with ACTH-dependent Cushing’s syndrome caused by Crooke’s cell corticotropinoma.

The patient first presented with symptoms of severe hypercorticoidism — the excessive secretion of steroid hormones from the adrenal cortex — in December 2011. He also showed advanced heart failure, severe headaches, and impaired vision, which had started two or three years before diagnosis. Examinations revealed osteoporosis and a fracture in the Th5 vertebra.

His morning ACTH levels were high. The same was observed for mean cortisol levels even after dexamethasone treatment, which was suggestive of a pituitary tumor secreting ACTH. MRIs showed the existence of a tumor mass, later identified as a macroadenoma with high cell polymorphism, the presence of Crooke’s cells, and ACTH secretion.

The patient was referred for transsphenoidal nonradical neurosurgery, performed through the nose and the sphenoid sinus, and bilateral adrenalectomy, or the surgical removal of the adrenal glands, in 2012-2013. However, he developed fast, postoperative recurrence of hypercorticoidism and tumor regrowth. This led to three additional transsphenoidal neurosurgeries and radiotherapy.

The patient’s clinical status worsened as he developed severe cardiac insufficiency. Doctors began temozolomide treatment in April 2015, which did not result in adverse effects throughout treatment.

The initial standard dose (150–200 mg/m2) was given once daily in the morning for five consecutive days, in a 28-day cycle. The patient also received 600 mg of ketoconazole, an antifungal medication. Ondansetron was administered to prevent nausea and vomiting.

Subsequent examinations revealed clinical and biochemical improvements, including a reduction in ACTH and cortisol levels. In addition, the patient also showed reduced cardiac insufficiency, less frequent and less severe headaches, visual field improvements, and better physical fitness and mood.

However, clinical symptoms worsened after the eighth temozolomide cycle. The tumor size also suddenly increased after the ninth cycle, reaching the inner ear. Temozolomide was then discontinued and ACTH levels increased by 28 percent one month later. The patient also demonstrated deteriorated vision, hearing loss, and strong headaches.

Clinicians then decided to start treatment with the Cushing’s disease therapy Signifor (pasireotide), but a worsening of diabetes was observed, and the patient died in February 2016.

“The most probable reason for death was compression of the brainstem, which had been observed in the last MRI of the pituitary,” the researchers wrote, adding that “due to the very short duration of treatment, any conclusions on the treatment with Signifor cannot be drawn.”

Overall, “the results of the presented case suggest that [temozolomide] treatment monotherapy could have only partial response in aggressive corticotroph adenoma causing Cushing’s disease, followed by sudden progression,” the investigators wrote. This contrasts with mostly responsive cases reported in research literature, they noted.

“Therefore, further research on the factors of responsiveness and on novel methods to extend the duration of the effect of [temozolomide] should be carried out,” they wrote.


ACTH-producing Lung Tumors Hard to Detect, But May Be Cured with Surgery

Ectopic Cushing’s syndrome can be challenging to diagnose, especially when it comes identifying the problem source. But appropriate hormone management protocols, used in combination with advanced imaging methods, may help physicians identify ectopic ACTH-producing tumors.

The findings in a case report of a young man with ectopic Cushing’s syndrome were published in the International Journal of Surgery Case Reports, under the title “Case report: Ectopic Cushing’s syndrome in a young male with hidden lung carcinoid tumor.”

Cushing’s syndrome is caused by high amounts of glucocoticosteroids in the blood. The most common cause is a malfunction of the glands that produce these hormones. In some cases, however, the disease may be caused by tumors elsewhere in the body that have the ability to produce adrenocorticotropic hormone (ACTH).

In half of all Cushing’s patients, ectopic ACTH is produced by small lung cell carcinomas or lung carcinoids (a type of slow-growing lung cancer). But some tumors in the thymus and pancreas also have been found to produce ACTH.

Researchers at Damascus University Hospital in Syria presented the case of a 26-year-old man who had ectopic Cushing’s syndrome due to lung carcinoids.

The patient presented with increased appetite and rapid weight gain for more than a year. These were associated with headache, fatigue, proximal muscle weakness, and easy bruising. He had no family history of hormonal disorder.

Based on the initial physical and symptom evaluation, the clinical team suspected Cushing’s syndrome. Blood analysis revealed high levels of cortisol and ACTH hormones, which supported the diagnosis.

Administration of dexamethasone, a treatment used to inhibit the production of glucocoticosteroids by the pituitary gland, reduced cortisol levels within normal range, but not ACTH levels. This led to the diagnosis of ectopic Cushing’s syndrome.

The next step was to identify the tumor causing the syndrome. The team conducted imaging studies of the brain, chest, and abdomen, but found no tumor.

Because ectopic ACTH is commonly produced by lung cancers, the team then analyzed the patient’s lungs. Again, they failed to detect a tumor.

The patient was discharged with prescription of 200 mg of Nizoral (ketoconazole) once-daily, calcium, and vitamin D. After three months of treatment, he remained stable, with no evidence of symptom improvement.

At this point, the team decided to surgically remove both adrenal glands in an attempt to reduce the hormone levels. Treatment with prednisolone 5 mg and fludrocortisone 0.1 mg once daily was initiated, along with calcium and vitamin D.

Eighteen months later, the patient’s condition worsened and he required hospitalization.

Imaging tests targeting the neck, chest, and abdomen were conducted again. This time, physicians detected a 2 cm mass in the middle lobe of the right lung, which was removed surgically. Detailed analysis of the small tumor confirmed that it was the source of the excessive ACTH.

“ACTH secreting tumors can be very hard to detect,” the researchers stated. “Initial failed localization is common in ectopic ACTH syndrome and it is usually due to carcinoid.”

Cases where the ectopic ACTH production is caused by a carcinoid tumor can be challenging to diagnose because tumors are small and relatively slow-growing. Imaging data is often hard to analyze and the tumors can be confused with pulmonary vessels, the researchers explained.

“In such cases we should first aim to lower blood cortisol medically or through bilateral adrenalectomy to avoid Cushing’s complications,” which should then “be followed up through imaging studies (CT, MRI, scintigraphy or PET) to detect the tumor and resect it, which is the definitive treatment of these patients,” the researchers concluded.


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