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We present a case of a 60-year-old woman who initially presented with pneumonia and abdominal pain and was diagnosed with ectopic adrenocorticotropic hormone (ACTH) syndrome secondary to small cell lung cancer. We review published literature and summarize the typical challenges in the diagnosis and treatment of ectopic ACTH syndrome. Recent research has shed new light on the mechanism of ectopic ACTH production and provided a potential new target for treatment.
A 60-year-old woman with a significant smoking history presented to the emergency department with complaints of lower-extremity edema and abdominal pain for 3 weeks. She had been seen at an outside hospital, where she was diagnosed with pneumonia, treated with antibiotics, and discharged the previous day. Her home medications included furosemide, atenolol, lisinopril, simvastatin, aspirin, cefpodoxime, and azithromycin. At the time of presentation, her physical examination was remarkable for facial swelling, striae on the trunk, and abdominal obesity. Her chest was clear to auscultation bilaterally. Her systolic blood pressure was elevated in the 170s mm Hg range. Admission laboratory data were significant for a potassium of 3.6 mEq/L, arterial blood pH of 7.54, CO2 partial pressure of 45 mm Hg, and bicarbonate of 38.3 mmol/L, consistent with metabolic alkalosis. Her fasting glucose level was elevated at 197 to 258 mg/dL, and her white blood cell count was elevated at 13,300/μl, with 81% neutrophils and no eosinophils. The chest x-ray on admission showed interval development of a patchy infiltrate at the right lung base and a prominent right hilum when compared with a chest x-ray from 1 month earlier.
The patient's cardiac enzymes were negative, a two-dimensional echocardiogram was normal, and there was no electrocardiographic change. At this point, the patient's differential diagnoses were still evolving around pneumonia with or without another gastrointestinal disease. Esophagogastroduodenoscopy revealed multiple esophageal ulcers, and a biopsy later confirmed both cytomegalovirus and herpes simplex virus esophagitis. To better evaluate the pulmonary infiltrate, especially the suspicious prominent right hilum, a computed tomography (CT) scan of the chest was obtained, which revealed a 4.1 × 3.8–cm mass invading the right middle lobe bronchus (Figure Figure11a). Extensive mediastinal lymphadenopathy was present (Figure (Figure11b), as well as bilateral adrenal masses. Bronchoscopy with bronchoalveolar lavage and subcarinal lymph node biopsy revealed small cell lung cancer (SCLC) (Figures (Figures2a2a and and22b).
Because the patient developed pancytopenia early in the hospitalization, a bone marrow aspirate and core biopsy were obtained, which showed a marrow extensively involved with metastatic small cell carcinoma (Figures (Figures2c2c and and22d). At this time, the presence of metabolic alkalosis and hyperglycemia raised the suspicion of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). Her cortisol level was elevated at 162.4 mcg/dL (normal <16 mcg/dL), her ACTH was elevated at 1237 pg/mL (normal <60 pg/mL), and her aldosterone level was normal at 1.6 ng/dL. These are consistent with the diagnosis of paraneoplastic EAS secondary to metastatic SCLC. Later, her blood cultures grew Klebsiella pneumoniae and cytomegalovirus. She was then started on broad-spectrum antibiotics. Chemotherapy was recommended for the underlying SCLC, and she was treated with one cycle of carboplatin and etoposide. She then developed septic shock with fever, tachycardia, hypotension, and hypoxia. Her respiratory status and hemodynamic stability continued to deteriorate despite antibiotics and intravenous fluid support. She eventually decided to receive comfort care only and expired on hospital day 27. No autopsy was performed.
The first case report regarding ectopic hormone production by tumors appeared in a 1928 Lancet article eloquently titled “A case of pluriglandular syndrome: diabetes of bearded women” (1). EAS is a classic paraneoplastic syndrome that can be associated with a variety of solid tumors, mostly of neuroendocrine origin, including aggressive, overt malignancies like SCLC (27%) and occult neoplasms like bronchial carcinoid tumors (21%) (2). EAS accounts for 12% to 17% of cases of Cushing's syndrome (3). One large retrospective study found that 14 of 840 (1.7%) SCLC patients had EAS, which was associated with a low response rate to chemotherapy and a worse overall survival (4, 5). Among EAS cases, those caused by SCLC have the worst prognosis.
The diagnostic challenges of paraneoplastic EAS are twofold. EAS can be the patient's predominant clinical presentation with an asymptomatic occult primary tumor. Alternatively, as in the case of our patient, EAS can be diagnosed after an aggressive primary malignancy is first identified. Challenges associated with the former scenario tend to be the localization of the indolent primary tumor that is secreting the ectopic ACTH. In the latter scenario, the aggressive feature of the primary malignancy and the toxicity from subsequent chemotherapy can cause broad metabolic and acid-base disturbances, which make the suspicion of EAS less likely, resulting in delayed diagnosis and increased comorbidities. The aggressive clinical course of SCLC often precludes the development of classic Cushingoid findings including striae, moon face, and truncal obesity. Instead, muscle wasting and weakness are the most common initial complaints in EAS associated with SCLC. In the case of our patient, the presence of significant metabolic alkalosis in the context of a newly diagnosed SCLC raised the red flag. Other common features of Cushing's syndrome include hypertension, hyperglycemia, and hypokalemia, all of which were also present in our patient. These latter symptoms, although classical for EAS, can also be common among critically ill patients due to etiologies other than EAS. A high prevalence (around 50%) of psychiatric disturbances is a distinctive feature of neuroendocrine tumors secreting ACTH, in contrast to skin pigmentation, which is more prominent in EAS of SCLC patients (3).
Once suspected, the diagnosis of EAS involves two steps: confirmation of elevated cortisol and ACTH levels and differentiation from pituitary sources of ACTH overproduction (Cushing's disease) (6). Patients with EAS tend to have higher ACTH levels than those with Cushing's disease, but there is no clear cutoff in the ACTH value. Bilateral inferior petrosal sinus sampling of ACTH level is considered the gold standard for differentiating between the two: it is elevated in Cushing's disease but is low or normal in EAS. Clinically, the most commonly utilized test is measuring the serum or urinary 17-hydroxycorticosteroid level before and after high-dose (8-mg) dexamethasone suppression. The high-dose dexamethasone suppression test can be combined with the corticotropin-releasing hormone stimulation test for the diagnosis of EAS with a sensitivity of 100% and specificity of 98% (6, 7). The lack of ACTH immunohistochemistry staining of the primary tumor does not exclude the diagnosis of EAS, as only a small subgroup of the tumor cells secrete the hormone.
In our patient, the presence of opportunistic infections like herpes simplex virus and cytomegalovirus also suggest EAS. Sieber et al reported three such cases of opportunistic infection in SCLC patients with EAS (8). Sarlis et al conducted a retrospective study of 54 patients with EAS and observed a direct correlation between cortisol level and the rate of opportunistic infection (9). This was confirmed in a separate study, where severe or life-threatening infections developed in about 15% of EAS patients and were related to the degree of cortisol increase (7). Although the exact mechanism of increased opportunistic infections is unclear, it has been proposed that the increased cortisol level and compromised immune system among EAS patients may be responsible.
When EAS is diagnosed with an asymptomatic primary tumor, localization of the occult tumor becomes paramount. Routine imaging studies like chest x-ray, high-resolution CT, and magnetic resonance imaging can usually locate the primary tumor without difficulty. When these routine studies fail, octreotide scan can be considered, which may increase the yield. The value of positron emission tomography scanning in evaluating EAS remains controversial (10). When all imaging studies fail, serial imaging to monitor change is warranted in the long-term follow-up of EAS patients. Despite repeated evaluation and long-term follow-up, the source of ectopic ACTH remains unidentified in a significant number of patients (12.5%) (7).
The ultimate and optimal treatment for EAS is the surgical resection of the primary ACTH-producing tumor or successful cytotoxic treatment targeting the underlying malignancy. In patients who cannot tolerate surgery and those whose primary tumor is unresectable, adrenal enzyme inhibitors like aminoglutethimide, ketoconazole, metyrapone, or etomidate and glucocorticoid antagonists like mifepristone should be considered (11), ideally before cytotoxic chemotherapy is initiated. When EAS becomes chronic because the primary tumor cannot be located or resected, long-term treatment options include surgical bilateral adrenalectomy (7). In patients who need, but are not candidates for, surgical bilateral adrenalectomy, treatment with mitotane should be considered. Mitotane is a derivative of the insecticide dichlorodiphenyltrichloroethane, which can cause direct necrosis and atrophy of the bilateral adrenal glands (11). It can also accelerate the metabolism of cortisol in the peripheral tissue. It essentially accomplishes a medical adrenalectomy.
The term “ectopic ACTH syndrome” is used in contrast to the “eutopic” secretion of ACTH by the pituitary gland during physiological conditions. ACTH is produced via the proteolytic conversion of its precursor proopiomelanocortin (POMC) (12). The POMC promoter is methylated and silenced in most tissues except the pituitary gland (13, 14). However, a nonfunctional and shorter POMC peptide can be detected in tissues outside the pituitary gland, transcribed via an alternative, weaker promoter (15). This shorter POMC peptide lacks the signal peptide required to enter the secretory pathway and cannot be secreted into the extracellular space. In the SCLC cancer cells, oncogene activation can trigger the demethylation and thus activation of the POMC promoter via a yet unclear mechanism (16). This leads to the ectopic transcription and translation of the POMC protein in tumor cells. Conceivably, methylation of the POMC promoter in tumor cells is a novel target for future treatment of EAS.
In summary, EAS secondary to SCLC is a diagnostic challenge because of the aggressive clinical course of SCLC. The coexistence of opportunistic infections, hypokalemia, metabolic alkalosis, and hyperglycemia should raise suspicion for EAS, and screening for the level and source of ACTH should be initiated. Adrenal enzyme inhibitors should be initiated immediately after the diagnosis of EAS. Patients suffering from EAS secondary to SCLC usually have a worse prognosis, likely due to the aggressive nature of the underlying disease (4, 5). Further research into the mechanism of ectopic POMC expression may provide a novel target for the treatment of patients with the EAS.