We present a case of a 52-year-old male who developed Cushing’s Syndrome due to ectopic adrenocorticotrophic hormone (ACTH) secretion from a large esthesioneuroblastoma (ENB) of the nasal sinuses. The patient initially presented with polyuria, polydipsia, weakness, and confusion. Computed tomography scan of the head and magnetic resonance imaging showed a 7 cm skull base mass centered in the right cribriform plate without sella involvement. Work-up revealed ACTH-dependent hypercortisolemia, which did not suppress appropriately after high-dose dexamethasone. Subsequent imaging of the chest, abdomen, and pelvis did not reveal other possible ectopic sources of ACTH secretion besides the ENB. His hospital course was complicated by severe hypokalemia and hyperglycemia before successful surgical resection of the tumor, the biopsy of which showed ENB. Postoperatively, his ACTH level dropped below the limit of detection. In the ensuing 4 months, he underwent adjuvant chemoradiation with carboplatin and docetaxel with good response and resolution of hypokalemia and hyperglycemia, with no sign of recurrence as of 30 months postoperatively. His endogenous cortisol production is rising but has not completely recovered.
Esthesioneuroblastoma (ENB), or olfactory neuroblastoma, is a tumor of the nasal and paranasal sinuses, derived from the olfactory neuroepithelium [
A 52-year-old Caucasian male with a past medical history of hypertension presented to our hospital for planned resection of a large skull base mass of the right cribriform plate by the neurosurgery service. He had initially presented at an outside hospital with anosmia and right nasal airway obstruction. He was diagnosed with new onset diabetes mellitus. Computed tomography (CT) scan of the head and magnetic resonance imaging (MRI) of the face revealed a 7.5 × 4.1 × 3.4 cm mass of the right cribriform plate, extending intracranially into the right anterior cranial fossa and displacing the frontal lobe with no sellar involvement. Imaging at our center confirmed the findings (Figure
Magnetic resonance imaging scan of the head with contrast, T1, sagittal, coronal, and axial views. These demonstrate a 7.5 × 4.1 × 3.4 cm skull base mass in the right cribriform plate (white arrow)
Twenty-eight months later, magnetic resonance imaging scan of the head with contrast and T1 view showing posttreatment changes in anterior cranial fossa with no appreciable change in appearance of dural thickening along cribriform plate and anterior cranial fossa. There is some encephalomalacia and bilateral frontal lobes are unchanged from previous scans
As part of his hypokalemia work-up, he was found to have a significantly elevated random plasma cortisol of 1851 nmol/L and plasma ACTH of 152 pmol/L (1.5–11.2). 24-hour urine free cortisol was also grossly elevated at 32,027 nmol/day (<165). His renin and aldosterone levels were normal. His TSH was also normal. Thus, CS was suspected, and imaging was ordered to locate possible sources. CT scan of his chest, abdomen, and pelvis noted bilateral adrenal enlargement, but no distinct nodules and no apparent sources of ACTH secretion were found. This raised the possibility of ENB being the ectopic source. High-dose (8 mg) dexamethasone suppression testing was performed, with the next-day morning cortisol of 1895 nmol/L, which was not suppressed at all, and ACTH was still elevated at 75.7 pmol/L. He continued to be aggressively treated with KCl. Eplerenone, magnesium oxide, and ketoconazole were also added. On day 5, his potassium was stabilized in the low-normal range. He was discharged on day 6, with a plan for a definitive resection of the tumor in 3 weeks, after the Christmas and New Year holidays.
However, the patient was readmitted 3 days later, for confusion, hypotension, and continued hypokalemia refractory to his oral potassium medications. He was once again aggressively potassium repleted, and surgery was performed a week later. A bifrontal craniotomy was performed by the neurosurgery team and bilateral maxillary antrostomy, ethmoidectomy, and sphenoidotomy were performed by otolaryngology along with resection of the tumor under endoscopic guidance. The mass was revealed to be a mixed-consistency lesion eroding through the anterior right planum extending through the dura. Intraoperative biopsy showed that the tumor contained lobular growth of small round cells with uniform hyperchromatic chromatin, inconspicuous nucleoli, and scant fibrillary cytoplasm, with rare mitotic figures present (Figure
Histology staining of tumor.
The skull base tumor, measuring 3.5 × 3.0 × 2.0 cm in aggregate. On hematoxylin and eosin (H&E) staining, the tumor is composed of small, round, uniform cells with stippled chromatin and distinct but inconspicuous nucleoli, growing in a diffuse and lobular pattern within a neurofibrillary matrix
An immunohistochemical stain against synaptophysin, a neuroendocrine marker, shows diffuse, strong cytoplasmic positivity within tumor cells, confirming the neuroendocrine nature of this esthesioneuroblastoma
Immunochemistry shows patchy expression of ACTH in the tumor cells (original magnification 400x)
The postoperative course was uncomplicated, with decreasing daily potassium and insulin requirements and resolution of metabolic alkalosis (Table
Hospital course.
Laboratory | Day | 1 | 2 | 3 | 4 | 5 |
|
|
10–17 |
|
19– |
---|---|---|---|---|---|---|---|---|---|---|---|
K+ (mmol/L) | 2.0 | 1.9 | 2.2 | 2.8 | 3.4 | 3.6 | 2.3 | 2.5–3.7 |
|
3.1 | |
HCO3− (mmol/L) | 44 | 38 | 39 | 32 | 29 | 35 | 35 | 21–29 |
|
27 | |
pH | 7.64 |
|
7.55 | ||||||||
|
|||||||||||
|
|||||||||||
KCl (mEq) | 100 | 200 | 260 | 280 | 200 | 80 | 120 | (258) |
|
(135) | |
Insulin (Units) | 68 | 111 | 124 | 131 | 153 | 148 | 138 | (115) |
|
(54) | |
Eplerenone (mg) | 25 | 75 | 125 | 150 | 50 | ||||||
Ketoconazole (mg) | 200 | 200 | (350) | ||||||||
Dexamethasone (mg) |
|
(0.9) |
Hormonal changes.
Hormone | Day | 2 | 5 | 9 |
|
57 | 120 | 214 | 302 | 382 | 495 | 713 | 810 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Cort-S (60 min) | 30 | 215 | 243 | 210 | 276 | 235 | 232 | 364 | |||||
Cort-S (30 min) | 22 | 179 | 229 | 168 | 235 | 204 | 212 | 312 | |||||
Random cortisol | 1846 | 1895 | 1868 | 52 | 141 | 168 | 25 | 160 | 149 | 124 | 141 | ||
Plasma ACTH |
128 | 76 | <1 | <1 | 5 | 4 | 1 | 3 | 6 | 6 | 6 | ||
|
|||||||||||||
Treatments (per day) | |||||||||||||
Hydrocortisone |
|
Cortisol and ACTH changes before and after operation. The
This patient was diagnosed with ectopic ACTH syndrome (EAS) based on the preoperative findings of high plasma ACTH concentration, random serum cortisol, and 24-hour urinary cortisol. Other ectopic sources were ruled out by CT scan. At this point, it was strongly suggested that the ENB (Kadish stage B involving two paranasal sinuses) was the source of the ectopic ACTH [
Our report demonstrates an unusual presentation of CS due to ectopic ACTH secretion from ENB and adds key data to the literature concerning this rare condition. There are fewer than 25 cases in the literature. We describe an EAS-ENB with comprehensive follow-up up to 30 months after resection, which is one of the longest follow-up periods among studies to date [
Our patient required multiple medication dosage adjustments in order to manage his hypokalemia, including oral and intravenous KCl and magnesium, as well as antimineralocorticoid such as eplerenone and steroidogenesis inhibitors such as ketoconazole. These were titrated to give him low-normal potassium levels and to relieve symptoms of muscle weakness and numbness. Other case reports have described usage of metyrapone, etomidate, mitotane, and mifepristone as steroidogenesis inhibitors [
The patient was placed on different corticosteroid (dexamethasone and later hydrocortisone) for central adrenal insufficiency the months after tumor resection. Baseline ACTH and cortisol levels remained to be low-normal in our patient. He failed all his ACTH stimulation tests so far (cortisol level <500 nmol/L 60 min after 0.25 mg ACTH stimulation) but has had improvement of stimulated cortisol. The patient does not have clinical symptoms of adrenal insufficiency such as weight loss, cardiovascular collapse, and hypoglycemia. The chronic massive production of ectopic ACTH from EAS has suppressed his endogenous long term cortisol production (over 30 months). Central adrenal insufficiency usually only requires glucocorticoid replacement, not mineralocorticoid, with hydrocortisone preferred as the most physiological option [
In conclusion, we report a case of olfactory neuroblastoma with ectopic ACTH secretion that was treated with resection and adjuvant chemoradiation. Given the paucity of this diagnosis, little is known about how best to treat these patients and how best to screen for complications such as adrenal insufficiency and follow-up. Our case adds more data for better understanding of this disease.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
The authors would like to thank the entire hospital team for their care for this patient and those who continue to support his recovery from this tumor.