A Case Report of Cortisol-Secreating Adrenal Adenoma Causing Cushing Syndrome

Cushing syndrome is a state of prolonged exposure to excess cortisol production. Causes can be varied ranging from exogenous intake or endogenous production from a pituitary source due to overproduction of adrenocorticotropic hormone (ACTH) or due to over secretion from unilateral or bilateral adrenal glands. Cushing syndrome in an adult can present with proximal muscle weakness, facial plethora, wasting of the extremities with increased fat in the abdomen and face, wide purplish striae, bruising with no obvious trauma, and supraclavicular fat pads. Here, we report a 38 year old male who presented with suspicion of having Cushing syndrome due to his clinical manifestations and high cortisol levels. He presented to the clinic with new onset diabetes, severe hypertension, chronic abdominal pain and distension which was being investigating by different specialties. The patient underwent CT scan of the abdomen which show right adrenal adenoma and on examination, he was found to have proximal weakness and purple striae. Laboratory data showed high morning cortisol, 24 urine free cortisol and ACTH levels which were strongly suggestive of ACTH independent Cushing syndrome.


Introduction
Cushing syndrome is a condition resulting from chronic overproduction of glucocorticoid (1) therefore the signs and symptoms depend on the duration and intensity of excess steroid production (2) which lead to multisystem manifestations due to overproduction of the hormone. The clinical manifestations can be categorized as reproductive, dermatologic, metabolic, cardiovascular, musculoskeletal, neuropsychiatric, and infectious (3)(4)(5). In addition to the considerable morbidity caused by hypercortisolism, there is also an increase in mortality rates. The source of increased glucocorticoids can be exogenous due to chronic administration of corticosteroids for any underlying inflammatory condition or endogenous source which can be ACTH dependent or ACTH independent (6). Pituitary ACTH-dependent Cushing's disease is five to six times more common than Cushing's syndrome caused by benign and malignant adrenal tumours combined (7). Thus, the incidence of Cushing's disease may be 5 to 25 per million per year. However, the reported incidences was much lower (1.2 to 2.4 per million per year) in one population-based study (8,9). In a United States study, the incidences were higher than previously reported in European studies as it was found to affect 6.2 to 7.6 per million person-years (10). Cushing syndrome due to adrenal adenoma is rare condition, but it is associated with high mortality rates if left untreated particularly from cardiovascular disease (3). However, median survival from cures was still excellent according to (cohort study) of patients who had been cured of hypercortisolism for at least 10 years at study (11).

Case Report
A 38-year-old male attended the endocrine clinic with history of chronic abdominal pain, recent onset Diabetes Mellitus and severe uncontrolled hypertension despite being on treatment (Table 4). Patient had previously visited several clinics and hospitals with the complaint of abdominal pain and distension which had been present for 3 years. His symptoms also included chronic fatigue, acne and the findings on the clinical examination demonstrated central obesity, proximal weakness, moon face, plethora, skin thinning, fat pads and purple striae ( Figure 5-12).  Whole body PET scan (vertex to mid-thigh) with contrast (oral and intravenous) enhanced CT was performed using a dedicated Discovery IQ PET 16 slice CT scanner 60 minutes after i.v. injection of 7 mCi of F-FDG. The blood glucose level was 115 mg/dl before the injection. The standardized uptake value (SUV) was calculated based in body weight and expressed in g/ml. There is an FDG negative well defined mildly enhancing soft tissue nodule measuring 27 x 23mm in the medial limb of right adrenal gland (arrow).

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Extensive workup was done to investigate the adenoma for assessment of a functional tumor evaluating for Primary hyperaldosteronism (Table 1), Pheochromocytoma (Table 2), Cushing disease or any other condition.   Based on the results of investigations done for the patient, the diagnosis of Cushing syndrome secondary to adrenal adenoma was confirmed clinically and biochemically supporting the CT and the MRI findings (Image 3, 4). So patient was referred for surgical removal of the functional adrenal adenoma for definitive treatment.

Histopathology
Histopathology showed encapsulated adrenal cortical adenoma composed of closely packed nests of polygonal cells with vaculated eosinophilic cytoplasm and central small nuclei (Figure 13 -14).  Immunohistochemical studies showed the lesion was positive for Inhibin ( Figure 14 A) and Melan A (Figure 14 B), while negative for chromogranin. Proliferation index as estimated by ki67 was less than 1%.
During his post-operative follow up, the patient's glucose profile improved and he was maintained on Metformin 2gm daily with an HbA1c of 4.4%. His blood pressure was maintained within target by monotherapy with Irbesartan (

Discussion
This is a typical case of cortisol secreting adenoma causing Cushing syndrome. The diagnosis is often delayed because Cushing syndrome is frequently masked by its overlapping symptoms with many common medical problems. Like the patient in this case attended many clinics including a gastroenterologist clinic for his abdominal pain and CT was done for him as part of the work up.
The question here is whether all the incidentaloma's should be investigated or not. The answer is yes especially with the incidence of increasing Cushing syndrome worldwide and because it is a serious disease with high morality if left untreated (12). Screening should be initiated in all patients with an incidentally discovered adrenal mass, particularly if the CT imaging density is low (<20 Hounsfield units) although in a recent review that argued the drawbacks of screening (cost, acceptability, and unnecessary procedures) may outweigh the benefits (13).
Recent studies have suggested a much higher prevalence among high-risk patient populations, such as patients with diabetes mellitus (particularly if poorly controlled), hypertension, and early-onset osteoporosis (particularly if with fractures) (14)(15)(16)(17). In a study done on two hundred patients with poorly controlled diabetes mellitus (HbA1C >8%) were screened for hypercortisolism and 5.5% were diagnosed with Cushing, mostly of adrenal origin (15).
Hypertension is frequently associated with Cushing syndrome with up to 67% prevalence demonstrated in a recent study (18). It resolved in 55% of the patients after treatment like in this patient, and if left untreated, it is a risk factor for cardiovascular events in association with diabetes and dyslipidemia (18). There may (19) or may not be (20) normalization of the risk factor after curative treatment of Cushing syndrome according as shown by different studies (19,20).
In conclusion, The Endocrine Society clinical practice guidelines recommend testing for Cushing syndrome in patients with multiple signs