Ectopic Cushing’s Syndrome Could Be Divided Into Two Subtypes, Researchers Propose

Patients with a form of Cushing’s syndrome caused by a tumor outside the pituitary gland that produces excess adrenocorticotropic hormone (ACTH) could be classified into two subgroups, researchers suggest in a recent study.

These subgroups are divided by clinical and biochemical characteristics — mostly by type and stage of the ACTH-secreting tumor. This classification system could lead to more tailored treatment approaches, the researchers say.

The study, “Two types of ectopic Cushing syndrome or a continuum? Review,” was published in the journal Pituitary.

Most cases of Cushing’s syndrome develop due to a pituitary tumor that secretes high levels of ACTH. But in 20 percent of patients whose disease is caused by excess ACTH, the tumor is located elsewhere in the body. This is called ectopic Cushing’s syndrome (ECS).

Tumors causing ECS can be quite diverse, ranging from undetectable and benign to those that have spread throughout the body.

While studies suggest that different tumors cause different ECS manifestations, there is a lack of studies thoroughly reviewing this association.

To address this, researchers carried out a systematic review of available literature on ECS, with the goal of better defining ECS subtypes and highlighting differing aspects between the groups.

Investigators found that in half of cases, patients had an aggressive form of ECS, which was caused by a malignant tumor, known as small cell lung carcinoma (SCLC).

In these patients, the clinical presentation of Cushing’s syndrome is often atypical, leading physicians to rely on clinical tests to make a diagnosis.

Patients with ECS due to SCLC tend to have extremely high cortisol and ACTH levels. The appearance of symptoms is generally quite sudden — often in less than three to six months. The tumor is normally quite advanced upon diagnosis, which makes it very hard to treat.

The remaining patients had an indolent form of ECS, which was attributed to carcinoid tumors. Patients with carcinoid tumors tend to have signs and symptoms very similar to that of patients with Cushing’s disease.

Their cortisol and ACTH levels are slightly elevated, and symptoms are generally more progressive — occurring over the course of more than six months. Consequently, their prognosis is usually good, and the treatment typically cures about 75% of cases.

“Although there is no absolute differentiation between the two extremes of ECS, a classification could be established in two groups, guided by its clinical and biochemical characteristics, and mainly by the type and stage of the ACTH-secreting tumor,” the researchers concluded.

There are, however, a small percentage of tumors that do not fit into either of these two groups, and can present with characteristics of both or neither, the researchers warn.

For treatment, physicians should conduct a surgical removal or complete elimination of the tumor. However, this is sometimes not possible in patients with ECS. In these cases, physicians should direct therapies to the adrenal glands.