Features and Molecular Mechanisms of ACTH-Secreting pNETs

In This Article

Abstract and Introduction

Abstract

Objective: Pancreatic neuroendocrine tumors (pNETs) causing ectopic adrenal corticotropic hormone (ACTH) syndrome (EAS) are rare and aggressive with little known information. We aimed to elucidate the clinical features and molecular mechanisms of pNETs with EAS by methylation analysis.

Methods: Seven patients with ectopic ACTH-secreting pNETs who were diagnosed at Shanghai Clinical Endocrine and Metabolic Diseases Center and Pancreatic Disease Center in Ruijin Hospital between 2001 and 2019 were enrolled. Twenty patients with ectopic ACTH-secreting thymic neuroendocrine tumors (TNETs) and 7 with nonfunctional pNETs (nf-pNETs) were also enrolled as controls. We collected clinical data and measured POMC promoter CpG methylation.

Results: All 7 patients had elevated ACTH and urinary free cortisol (UFC) levels with positive ACTH staining in the pancreas and were diagnosed with ectopic ACTH-secreting pNET. Of the 7 patients, 6 underwent surgery and 1 underwent transarterial embolization (TAE). Two patients were free of disease after surgery; 2 died within 90 days after surgery; and 3 had metastases and died within 1 year. Compared with ACTH-secreting TNETs, ACTH-secreting pNETs had similar clinical and biochemical features but a significantly poorer prognosis. POMC promoter CpG methylation was significantly lower in ACTH-secreting pNETs than in nf-pNETs and normal pancreas.

Conclusions: ACTH-secreting pNETs are aggressive and fatal. Surgery is definitively curative for patients with resectable primary tumors without metastasis. Pro-opiomelanocortin (POMC) promoter hypomethylation caused pNETs to produce ACTH. This study further supplements the genetic features of ACTH-secreting NETs.

Introduction

Ectopic adrenal corticotropic hormone (ACTH) syndrome (EAS), accounting for 10% of Cushing syndrome (CS),^[1] results in cardiovascular, metabolic, infectious, and skeletal complications, regardless of etiology.^[2–4] A total of 4% to 16% of EAS originates in the pancreas, mainly caused by pancreatic neuroendocrine tumor (pNET), which is rarely seen and has only been reported in a single case.^[5] The prognosis is poorly understood.

With the development of imaging techniques, especially 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT), the localization of pNETs has been clarified.^[6,7] There are 2 issues regarding ACTH-secreting pNETs: How to manage them and why they secrete ACTH. Treatments include excision of the primary tumor, bilateral adrenalectomy, transarterial embolization (TAE) of the hepatic metastasis,^[8] and medical control of the hypercortisolemia.^[9] However, radical surgery has been elusive, as most patients are diagnosed in locally advanced or metastatic stages. In patients with neuroendocrine tumors (NETs), the 5-year survival of EAS patients was significantly shorter than that of non-EAS patients.^[10] Therefore, it is meaningful to explore how ACTH is produced in this kind of NET. By comprehending the molecular mechanism, targeted treatment could be possible.^[11] The hypomethylation of the POMC promoter has been reported in small cell lung cancer (SCLC),^[12] thymic neuroendocrine tumors (TNETs),^[13] and pancreatic solitary fibrous tumors,^[14] but it has never been studied in pNETs.

In this single-institution study, we analyzed a continuous series of 7 patients with ACTH-secreting pNETs. The clinical characteristics, treatments and prognosis of these patients will be described, and one group of ACTHsecreting TNETs and 1 group of nonfunctional pNETs (nf-pNETs) simultaneously treated will be compared and discussed.

Table 1. Clinical features and treatments of 7 cases of ACTH-secreting pNET patients
Characteristic	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7
Age, years	50	24	39	53	31	59	56
Gender	F	M	F	F	F	M	F
Disease duration, m	8	5	24	6	10	9	2
Serum ACTH	306.7	1182.33	149.24	403.97	345.8	109.16	1112.13
Serum cortisol
8 AM	59.32	117.54^b	37.07	52.17	109.36^b	44.7	128.57^b
4 PM	35.99	133.66^b	32.65	52.17	60^a	47.27	184.24^b
0 AM	28.58	102.85^b	13.11	31.07	52.63	52.15	200.49^b
24-hour UFC	1208	15 352.47^b	787.2	1845.56^b	2817.22^b	491	27 834.52^b
LDDST	Unsuppressed	Unsuppressed	Unsuppressed	Unsuppressed	Unsuppressed	Unsuppressed	N/A
HDDST	Unsuppressed	N/A	Unsuppressed	Unsuppressed	Unsuppressed	Unsuppressed	N/A
CA199, U/mL	18.7	<0.8	36.3	127.7	17.8	70.6	65
NSE, ng/mL	9.88	19.29	11.09	12.888	16.48	44.32	>370^a
Tumor size, cm	1.1	3	2	5	7.9	2	3.5
Involvement	None	None	None	HA and PV involved	Liver	Superior vena cava	Liver, adrenal gland, retro LN
ENETS staging	I	IIa	IIa	IIIa	IV	IV	IV
NCCN staging	Ia	Ib	Ia	III	IV	IV	IV
1st treatment	Pituitary tumor resection	En	En	SSA + everolimus	TAE	PD	DP + left adrenalectomy + right partial adrenalectomy
2nd treatment	En	N/A	N/A	Right adrenalectomy	N/A	SSA + everolimus	Metyrapone
3nd treatment	N/A	N/A	N/A	PD	N/A	N/A	N/A
Outcome	Remission	Dead	Remission	Dead	Dead	Dead	Dead
Follow-up time, months	96	1	30	30	12	6	4

Plasma ACTH normal range, 7–65 pg/mL; serum cortisol normal range, 6.7–22.6 μg/dL; UFC: urinary free cortisol, normal range: 21–111 μg/24 hours.
Abbreviations: ACTH, adrenal corticotropic hormone; N/A, not available; SSA, somatostatin analogs; HA, hepatic artery; PV, portal vein; retro LN, retroperitoneal lymph node; En, enucleation; PD, pancreaticoduodenectomy; DP, distal pancreatectomy; UFC, urinary free cortisol.
^aExceeding the upper limit of available range.
^bDiluted until available range.

Table 2. Immunohistopathology ofACTH-secreting pNET patients
Characteristic	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6		Case 7
Site	Head	Uncinate	Uncinate	Head	Uncinate	Uncinate		Body
Grade	G1	G1	G1	G3	G3	G3		G2
Sample	Pancreas	Pancreas	Pancreas	Pancreas	Pancreas	Liver	Pancreas	Pancreas	Liver	Adrenal
Ki67	1%	1%	2%	30%	30%	2%	40%	20%	15%	10%
SSTR2	/	/	/	+	+	/	+	+	—	/
ACTH	+	+	+	+	+	—	+	+	+	+
CgA	+	+	+	+	+	—	+	+		+
NSE	+	+	+	+	/	/	/	+		+
SYN	+	+	—	+	+	—	+	+		+
Trypsin	/	/	/	/	—	/	/	+	—	/

+, positive; -, negative;/, not available.

Table 3. Clinical characteristics of ACTH-secreting pNET and TNET patients
Characteristic	Pancreas (N = 7)	Thymus (N = 20)	P value
Age, years	50 (31, 56)	38.5 (33.5, 50.75)	.542
Gender, male %	28.6%	60%	.209
Disease duration, months	8 (5, 10)	3 (2, 15)	.296
SBP, mmHg	146 (127, 153)	136 (129, 142)	.352
DBP, mmHg	90 (79, 104)	86 (77, 92)	.420
Serum Na, mmol/L	139.0 (136.0, 145.0)	140.8 (137.7, 143.7)	.899
Serum K, mmol/L	3.1 (2.4,3.3)	2.9 (2.5, 3.1)	.504
Serum ACTH	345.8 (149.2,1112.1)	342.4 (152.5, 533.4)	.782
Serum cortisol
8 AM	59.3 (37.1, 117.5)	42.6 (32.3, 61.3)	.086
4 PM	47.3 (32.7, 132.9)	38.6 (26.1, 62.9)	.340
0 AM	52.2 (25.0, 102.9)	37.2 (24.4, 58.0)	.583
24-hour UFC	2012.6 (698.0, 18 473.0)	1140.3 (633.0, 2749.1)	.429
CA199, U/mL	36.6 (17.8, 92.8)	33.0 (17.8, 97.3)	.886
NSE, ng/mL	16.5 (11.1, 44.3)	13.4 (11.7, 17.4)	.570
Ki-67, %	20.0 (1.0, 30.0)	1.5 (1.0, 4.3)	.133
Tumor size, cm	3.0 (2.0, 5.0)	4.3 (2.0, 5.3)	.662
Staging (NCCN), n
I-II	3	10	.745
III-IV	4	10

Plasma ACTH normal range, 7–65 pg/mL; serum cortisol normal range, 6.7–22.6 μg/dL; UFC, urinary free cortisol, normal range, 21–111 μg/24 hour.
Abbreviations: ACTH, adrenal corticotropic hormone; SBP, systolic blood pressure; DBP, diastolic blood pressure.