Ectopic adrenocorticotropic hormone syndrome in a case of duodenal neuroendocrine tumor presenting with liver metastasis.

Ectopic adrenocorticotropic hormone (ACTH) syndrome is an uncommon disorder and comprises about 15% of all patients with Cushing's syndrome (CS). Duodenal carcinoids are rare, indolent tumors usually associated with a benign progression. We hereby report a rare case of CS resulting from ectopic ACTH secretion from a duodenal neuroendocrine tumor (NET) presenting with liver metastasis. A 37-year-old female presented with abdominal discomfort and dyspepsia of 1-month duration. Ultrasound abdomen suggested a well-defined hypoechoic lesion in the left lobe of the liver, suggestive of neoplasia. On clinical examination, she had Cushingoid features and persistent hypokalemia. Midnight ACTH and cortisol levels were grossly elevated at 1027 pg/ml (n < 46 pg/ml) and 87.56 μg/dl (n < 7.5 μg/ml), respectively. Both overnight and high-dose dexamethasone suppression test confirmed nonsuppressed cortisol levels - 86.04 and 84.42 μg/dl (n < 1.8 μg/ml), respectively. Magnetic resonance imaging brain showed a structurally normal pituitary gland. Computed tomography scan of the abdomen revealed hepatic lesion with bilateral adrenal enlargement. A diagnosis of ectopic ACTH-dependent CS was made. Intraoperatively, a duodenal lesion of 0.5 cm × 0.5 cm was identified alongside an 8 cm × 6 cm exophytic lesion in segment IV of the liver. Frozen section of the duodenal lesion was positive for NET. She underwent a Whipple's surgery, cholecystectomy, and left hepatic lobectomy. Postoperatively, she showed clinical and biochemical remission. Herewith, we report the third case of duodenal carcinoid tumor presenting as ectopic ACTH syndrome and the first with liver metastasis.

Introduction

Ectopic adrenocorticotropic hormone (ACTH) syndrome is an uncommon disorder and comprises about 15% of all patients with Cushing's syndrome (CS). Duodenal carcinoids are rare and are indolent tumors usually associated with a benign progression. ACTH-producing carcinoid tumors most commonly originate in the lung or thymus. We hereby report a rare case of CS resulting from ectopic ACTH secretion from a duodenal neuroendocrine tumor (NET) presenting with liver metastasis.

Case Report

A 37-year-old female presented to the Surgical Gastroenterology Department with abdominal discomfort and dyspepsia of 1-month duration. Ultrasound abdomen suggested a well-defined hypoechoic space occupying lesion in the left lobe of the liver, suggestive of neoplasia.

She had recent onset diabetes and hypertension on treatment but inadequate control. On clinical examination, she had Cushingoid features and persistent hypokalemia. Midnight ACTH and cortisol levels were grossly elevated at 1027 pg/ml (n < 46 pg/ml) and 87.56 μg/dl (n < 7.5 μg/dl), respectively. Both overnight and high-dose dexamethasone suppression test confirmed nonsuppressed cortisol levels - 86.04 and 84.42 μg/dl (n < 1.8 μg/dl), respectively. Magnetic resonance imaging brain showed a structurally normal pituitary gland. Computed tomography scan of the abdomen revealed hepatic lesion [Figure 1a] with bilateral adrenal enlargement [Figure 1b]. Based on above findings, a diagnosis of ectopic ACTH-dependent CS was made.

Figure 1

(a) Computed tomography scan with hepatic lesion. (b) Computed tomography scan abdomen with bilateral adrenal enlargement. (c) Gross specimen showing 0.5 cm × 0.5 cm lesion in the medial wall of the first part of the duodenum in proximity to the pancreas. (d) Scanner view of lesion suggesting of neuroendocrine tumor of intermediate-grade without perineural invasion, lymphovascular emboli, or muscular invasion and compressed normal tissue seen along left border

She was started on spironolactone 100 mg and ketoconazole 600 mg daily, following which hypokalemia, blood sugars, and blood pressure control improved. She was scheduled for surgical resection of the liver lesion.

Intraoperatively, a lesion of 0.5 cm × 0.5 cm size in the first part of the duodenum [Figure 1c] was identified alongside an 8 cm × 6 cm exophytic lesion in segment IV of the liver. Frozen section of the duodenal lesion was positive for NET. A Whipple's surgery with cholecystectomy and left hepatic lobectomy was performed. The patient received bolus of 100 mg hydrocortisone intravenous infusion perioperatively, and postoperatively, hydrocortisone was tapered over the course of 3 days. Repeat serum cortisol and serum ACTH levels on midnight of the 5th postoperative day dropped to 7 μg/dl and 25.30 pg/ml, respectively, suggesting normal functioning of hypothalamic–pituitary–adrenal axis. Hence, steroid replacement was not restarted. Other biochemical parameters also showed remarkable improvement as shown in Table 1.

Table 1

Biochemical characteristics

Investigation (n)	Before surgery	After surgery
Serum sodium (135-145 mmol/L)	145	141
Serum potassium (3.5-5.0 mmol/L)	1.8	4.2
pH (7.36-7.44)	7.56	7.38
Serum HCO3− (22-26 mmol/L)	36	24.9
Fasting blood sugar (<126 mg/dl)	219	78
Postlunch blood sugar (<200 mg/dl)	308	108
HbA1c (<5.7%)	7.7%	-
11:00 pm serum cortisol (<7.5 µg/dl)	87.56	7.0 (5 days postsurgery)
11:00 pm serum ACTH (<46 pg/ml)	1027	25.3 (5 days postsurgery)
Serum DHEAS (44-330 µg/dl)	1.0
1 mg ONDST (serum cortisol level, <1.8 µg/dl)	86.04	-
8 mg 2 days high-dose dexamethasone suppression test (serum cortisol level <1.8 µg/dl)	84.42	-
Serum TSH (0.45-4.5 µIU/ml)	1.08
Serum T4 (5.5-12.5 µg/dl)	7.24
Serum T3 (0.7-2 ng/ml)	0.56
8:00 am serum cortisol (6.5-22.6 µg/dl)	-	17 (3 weeks postsurgery)

TSH: Thyroidstimulating hormone, ONDST: Overnight dexamethasone suppression test, HbA1c: Hemoglobin A1c, DHEAS: Dehydroepiandrosterone sulfate, ACTH: Adrenocorticotropic hormone, T4: Thyroxine, T3: Triiodothyronine, HCO3−: Bicarbonates

Gross examination showed 0.5 cm × 0.5 cm gray-white nodule in the first part of the duodenum along with the specimen of liver lesion, pancreas, lymph nodes, bile duct, gallbladder, proximal resected margin (stomach), and distal resected margin (duodenum). Histopathology for both the hepatic and duodenal masses showed intermediate-grade NET without perineural invasion, lymphovascular emboli, or muscular invasion as depicted in scanner view of lesion [Figure 1d]. Immunohistochemistry was strongly positive for synaptophysin and chromogranin, and 6% of tumor cell nuclei showed strong positivity for MIB 1 [Figure 2]. Immunohistochemistry staining for ACTH was not done due to cost constraint which was the major limitation in the study. This would have helped to further establish the diagnosis of ectopic ACTH-secreting duodenal NET. Gross pathologic and histopathologic examination of the pancreas and other postoperative specimens received were normal and negative for NET. Histopathology identified tumor-free margins around the lesion.

Figure 2

(a) Duodenal lesion cells immunohistochemistry showing strong cytoplasmic positivity for synaptophysin. (b) Duodenal lesion cells immunohistochemistry showing strong cytoplasmic positivity for chromogranin. (c) View on H and E staining of duodenal lesion suggestive of neuroendocrine tumor, ×40. (d) MIB 1 in 6% of tumor cell nuclei showing strong positivity

On subsequent follow-up, she was weaned off antidiabetic and antihypertensive medications. Repeat electrolytes were normal. Three weeks postoperatively, she was clinically well. Morning (8:00 am) serum cortisol level was 17 μg/dl (n = 6.5–22.6 μg/dl). Clinically, the patient is currently in remission suggesting success of surgery.

Discussion

Ectopic ACTH production accounts for about 15% of all cases of CS and is usually due to small cell lung carcinomas (50%), nonsmall cell lung carcinomas (5%), lung carcinoids (10%), thymic tumors (5%), pancreatic tumors (10%), pheochromocytoma (3%), medullary thyroid cancers (5%), and other carcinoids (2%). Rare association with carcinoma of the prostate, breast, ovary, gallbladder, and colon (10%) has also been reported.[1]

Carcinoid tumors represent 1.2%–1.5% of all gastrointestinal tract neoplasms. Within the gastrointestinal tract, carcinoid tumors are most commonly found in the appendix, followed by the ileum, rectum, and stomach.[2] Duodenal carcinoids are extremely rare, and their characteristics and biological behavior have not been fully elucidated. Duodenal carcinoid tumors are most commonly found on the first part of the duodenum. These tumors are usually indolent, especially when they are small and limited to the submucosa, and the symptoms are generally nonspecific. The ideal treatment for duodenal carcinoids is an endoscopic or a radical surgical excision.[2]

Burke et al. identified three pathological characteristics of duodenal carcinoid tumors that are independent risk factors for metastases: invasion of the muscular layer, a size >2.0 cm, and the presence of more than two mitotic figures per high-power field.[3] In our case, size of the duodenal carcinoid was about 0.5 cm × 0.5 cm, without any invasion to muscular layer, and tumor was of intermediate grade with 2–20 mitotic figures per high-power field but had metastasized.

In cases of liver metastases, a surgical resection and/or cytoreductive techniques, such as radiofrequency ablation and chemoembolization, may improve carcinoid syndrome symptom that are mediated by hormones produced by the tumor, to improve the quality of life and increase survival. Somatostatin analogs may induce symptomatic and biochemical responses that stabilize the disease and reduce the growth of metastases through cytostatic effects. In our patient, there were no carcinoid syndrome symptoms.

The largest series of ectopic ACTH-producing tumors was reported by Aniszewski et al., but no case of duodenal carcinoid was described.[4] To date, only two cases of duodenal carcinoid with ectopic ACTH have been reported: one in Japanese[5] and one in English literature.[6] In our patient, preoperative imaging did not identify the duodenal carcinoid.

Conclusion

Herewith, we report the third case of duodenal carcinoid tumor presenting as ectopic ACTH syndrome and the first with liver metastasis, which was successfully treated with surgical resection.

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Conflicts of interest

There are no conflicts of interest.