A 54-year-old man comes to the office due to worsening fatigue, generalized weakness, and an unintentional 7-kg (15.4-lb) weight loss over the past several weeks. The patient has no prior medical conditions and takes no medications. He has a 40-pack-year history of smoking and does not use alcohol or illicit drugs. Blood pressure is 160/100 mm Hg and pulse is 80/min. Physical examination shows darkening of the skin in sun-exposed areas. There are scattered ecchymoses on the extremities. Mild proximal muscle weakness is present. Chest imaging reveals a 6-cm, irregular right lung mass with mediastinal lymphadenopathy. Which of the following is most likely responsible for the patient's current symptoms?

Question

A 54-year-old man comes to the office due to worsening fatigue, generalized weakness, and an unintentional 7-kg (15.4-lb) weight loss over the past several weeks.  The patient has no prior medical conditions and takes no medications.  He has a 40-pack-year history of smoking and does not use alcohol or illicit drugs.  Blood pressure is 160/100 mm Hg and pulse is 80/min.  Physical examination shows darkening of the skin in sun-exposed areas.  There are scattered ecchymoses on the extremities.  Mild proximal muscle weakness is present.  Chest imaging reveals a 6-cm, irregular right lung mass with mediastinal lymphadenopathy.  Which of the following is most likely responsible for the patient's current symptoms?

Quizplus · Accepted Answer

11ec160b_390f_06b9_9249_51fe640e9ddf_MD0001_00 This patient has fatigue, weakness, and weight loss associated with a suspicious lung mass. His hypertension, ecchymoses, and hyperpigmentation suggest paraneoplastic hypercortisolism (Cushing syndrome) due to ectopic ACTH secretion. As with primary adrenal insufficiency, excess ACTH secretion leads to hyperpigmentation, likely due to co-secretion of alpha-melanocyte-stimulating hormone (alpha-MSH) (both ACTH and alpha-MSH are derived from pro-opiomelanocortin) and direct stimulation of the MC2R receptor on melanocytes by ACTH. Although patients with paraneoplastic hypercortisolism may have many of the typical metabolic features of cortisol excess (eg, hypertension, hyperglycemia, edema), weight loss is more common than classic Cushingoid central obesity. Paraneoplastic hypercortisolism is most commonly associated with small cell lung cancer but can also be seen with other neuroendocrine tumors (eg, bronchial or pancreatic carcinoid). ACTH secreted by small cell lung cancer is not inhibited by high-dose exogenous corticosteroids (eg, dexamethasone), whereas pituitary ACTH secretion decreases via negative feedback. (Choice B) Cortisol is produced by the zona fasciculata of the adrenal cortex, and autonomous cortisol production (ie, ACTH-independent hypercortisolism) is almost always due to a primary adrenal disorder (eg, adrenal adenoma). Regardless of the source, excess cortisol in a patient with intact hypothalamus-pituitary function suppresses ACTH and patients do not develop hyperpigmentation. (Choice C) Given this patient's large lung mass and associated weight loss (instead of weight gain and central fat deposition), paraneoplastic ACTH secretion is more likely than an ACTH-producing pituitary adenoma (Cushing disease). (Choice D) Metastasis to the hypothalamus would likely cause endocrine insufficiency resulting from a lack of trophic hormones to the anterior pituitary. Decreased production of corticotropin-releasing hormone would lead to central adrenal insufficiency, not hypercortisolism. (Choice E) The adrenal glands are a common site of metastasis. If significant destruction of the adrenal cortical tissue occurs bilaterally, adrenal insufficiency may result. A subsequent increase of ACTH may cause hyperpigmentation; however, symptoms of adrenal insufficiency (eg, hypotension) would be expected, as opposed to the symptoms of cortisol excess seen in this patient. Educational objective: Paraneoplastic hypercortisolism, most commonly caused by small cell lung cancer, is due to ectopic ACTH secretion. Clinical features include hypertension, hyperglycemia, edema, and hyperpigmentation. Unlike nonparaneoplastic Cushing syndrome, central obesity is uncommon.

A 54-Year-Old Man Comes to the Office Due to Worsening