Ectopic ACTH secretion from a metastatic gastric carcinoma with neuroendocrine component

Abstract

An elderly gentleman was admitted to hospital with severe hypokalaemia of 1.75mmol/L. A background of a recently diagnosed metastatic gastric carcinoma with a neuroendocrine component pointed towards the diagnosis of ectopic ACTH secretion causing this dangerous electrolyte imbalance. He was treated with aggressive potassium supplementation and the adrenal steroid synthesis blocker metyrapone to acutely control his Cushing’s syndrome. Chemotherapy consisting of carboplatin/etoposide combination was initiated but unfortunately the patients’ health deteriorated, and he died three months after his initial diagnosis. This case highlights the accelerated presentation of hypercortisolism due to ectopic ACTH secretion. It discusses the classification of neuroendocrine tumours and their varied prognosis depending on the underlying tumour grade. It emphasises the importance of having a multidisciplinary team to be able to care for two underlying pathologies simultaneously: both the severe hypercortisolism and his metastatic gastric tumour.

Background

Ectopic ACTH secretion accounts for 9%–18% of ACTH dependent Cushing’s’ syndrome.¹ The most common causes are intrathoracic neuroendocrine tumours (NETs).¹ Gastric tumours as a cause of ectopic ACTH secretion are remarkably rare. This case highlights the complexity of managing severe hypercortisolaemia and the limited treatment options for patients with this aggressive malignancy.

Case presentation

A 75-year-old man presented with a few month’s history of vague epigastric discomfort, reduced appetite and significant weight loss in July 2019. He was known to suffer from diabetes, hypertension, ischaemic heart disease, hypothyroidism and asthma.

A CT scan of the thorax, abdomen and pelvis showed diffuse enhancement and thickening of the pylorus up to the pyloric antrum for a length of eight centimetres. Large hepatic and coeliac lymph node metastases were observed (figure 1). An oesophagogastroduodenoscopy was performed. This showed an ulcerating mitotic lesion on posterior antral wall, extending from the antrum through the pylorus and into the first part of the duodenum. Biopsies were taken (figure 2).

Figure 1.

CT scan image showing pyloric thickening (marked with arrow) and lymph node metastases.

Figure 2.

OGD images showing the pyloric tumour. OGD, oesophagogastroduodenoscopy.

He presented to casualty 2 weeks later with increasing fatigue and recurrent vomiting. He complained of new-onset worsening lower limb oedema and orthopnoea for which his general practitioner had recently started him on loop diuretics. Both his diabetes and hypertension had suddenly become difficult to control. On examination, he was generally weak, fluid overloaded with a raised jugular venous pressure, bilateral basal crepitations and lower limb oedema.

He was found to have severe new onset hypokalaemia of 1.75 mmol/L. Serum electrolytes taken just 2 weeks previously had shown a normal potassium of 4 mmol/L. His ECG showed global T wave inversions and U waves. He was admitted for aggressive potassium replacement via a central line. Arterial blood gases showed metabolic alkalosis (table 1).

Table 1.

Initial blood investigations

Test	Results	Range
Potassium	1.75	3.5–5.1 mmol/L
Sodium	141	135–145 mmol/L
Urea	7.9	1.7–8.3 mmol/L
Creatinine	80	59–104 umol/L
eGFR	87
Glucose	21.26	3.9–9 mmol/L
CRP	14	0–5 mg/L
Calcium	1.9	2.15–2.55 mmol/L
Phosphate	0.8	0.87–1.45 mmol/L
Magnesium	0.77	0.65–1.05 mmol/L
Bicarbonate	46	22–26 mmol/L
pH	7.675	7.35–7.45
Ionised calcium	0.92	1.12–1.32 mmol/L
ALP	80	40–129 U/L
GGT	262	8–61 U/L
ALT	168	5–41 U/L
Bilirubin	13.8	0–21 µmol/L
Haemoglobin	102	141–172 g/L
NT-pro-BNP	1940	5–125 pg/mL

ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; CRP, C reactive protein; eGFR, estimated glomerular filtration rate; GGT, Gamma glutamyl transferase; NT pro BNP, N-terminal pro B-type natriuretic peptide.

The combination of hypokalaemia, metabolic alkalosis and a recent diagnosis of a stomach lesion triggered a series of investigations to assess if severe hypercortisolaemia could be the underlying diagnosis. A 9am cortisol, overnight dexamethasone suppression test, 24 hours urinary cortisol and ACTH levels were performed (table 2).

Table 2.

Investigations for ectopic ACTH secretion

Test	Results	Range
9am cortisol	3325	145–619 nmol/L
ODST	2602	<50 nmol/L
24 hours urine cortisol	4316	57.7–806 nmol/24 hours
ACTH	358	10–48 pg/mL

ACTH, Adrenocorticotropic hormone; ODST, Overnight dexamethasone suppression test.

The histology for his gastric biopsies was discussed at a multidisciplinary team meeting. It showed a moderately to poorly differentiated intestinal-type adenocarcinoma with neuroendocrine differentiation. The poorly differentiated component expressed neuroendocrine markers CD56, synaptophysin and chromogranin, the latter being weakly expressed (figures 3–5). No Her-2 expression was seen in tumour cells. Ki 67 index was 70%.

Figure 3.

High power view of the neuroendocrine area.

Figure 4.

High power view of the adenocarcinoma area.

Figure 5.

Synaptophysin staining neuroendocrine areas.

It was concluded that the patient had a non-neuroendocrine neoplasm with a focal neuroendocrine component secreting ACTH. Blood Investigations to confirm a functional NETs resulted in a high serum chromogranin A (table 3).

Table 3.

Investigations for a functional neuroendocrine tumour

Test	Result	Reference
Chromogranin A	543	<102 ug/L
Gastrin	83.1	Up to 115 pg/mL
VIP	28	<71 pg/mL
Pancreatic Polypeptide	>180	Up to 100 pmol/L

VIP, vasoactive intestinal peptide.

Differential diagnosis

Our patient presented with symptomatic abrupt hypercortisolism which was confirmed biochemically to be ACTH dependent. This is due to pituitary tumours in 80% of cases vs ectopic causes in a minority of patients.²

A combination of a remarkably high ACTH, hypokalaemic metabolic alkalosis, a fivefold rise in serum chromogranin A and a metastatic gastric malignancy with a neuroendocrine component were highly suggestive of an ectopic source of ACTH secretion. Ectopic ACTH tumours tend to have higher ACTH levels than pituitary Cushing’s although there is no established cut-off.³ Hypokalaemia is more common in ectopic ACTH secretion but may be present in 10% of Cushing’s disease.² Chromogranin A is a neuroendocrine secretory protein located in secretory granules of immune cells, epithelial cells, neurons and neuroendocrine cells. High serum levels of chromogranin A are found in NETs.⁴

The main differential diagnosis was a mixed neuroendocrine non-neuroendocrine carcinoma (MiNEN) of the stomach secreting ACTH. However, this diagnosis can only be confidently made on whole tumour specimens rather than biopsy samples as each of the cellular components must make up >30% of the total.

One possible differential diagnosis is a combination of concurrent Cushing’s’ disease and gastric malignancy, though this possibility in our case was considered extremely remote. Another possible differential could be a separate NET secreting ACTH. However again, this was highly unlikely as no other tumours except for the gastric lesion with metastatic deposits were seen on the initial CT scan.

Treatment

His hypokalaemia was successfully treated with aggressive potassium replacement via a central line together with peripheral intravenous and oral replacement over the course of 2 days. Potassium chloride syrup was administered at 15 mmol four times a day. Peripheral intravenous replacement at 40 mmol of 20% potassium chloride per litre at a rate of 20 mmol/hour was initiated. A central line was inserted within hours of admission and peripheral potassium replacement was discontinued. 40 mmol of 20% potassium chloride in 100 mL normal saline was infused via the subclavian venous catheter over 1 hour. Potassium replacement was continuously titrated according to his serum potassium levels. Spironolactone, a potassium sparing diuretic, was also started.

Metyrapone was used to block adrenal cortisol synthesis with doses being cautiously titrated according to his 24-hour urinary cortisol results. He was started on a low dose at 250 mg four times daily and subsequently increased to 500 mg four times daily. Urinary free cortisol levels decreased to 1254 after 2 weeks but increased to 1822 nmol/24 hours after 2 months. Rapid increase in metyrapone doses must be avoided as symptoms of adrenal insufficiency may acutely develop.¹

Insulin was started to control his diabetes. He was unfit for any surgical intervention in view of the already disseminated disease. Following discussion with our oncologist, the plan was to administer six cycles of a combination of Carboplatin/etoposide chemotherapy once every 3 weeks.

Outcome and follow-up

Three cycles of carboplatin were given. Etoposide was never introduced due to the patient’s poor general health. Unfortunately, the patient’s health continued to worsen, and he developed severe weight loss, lack of appetite and poor mobility. A repeat CT scan showed an increase in the size of the liver metastases and worsening adrenal hypertrophy (figure 6). He was readmitted a few weeks later and treated palliatively with pain relief and fluid replacement. He passed away a few days later.

Figure 6.

(A) CT image showing adrenal gland enlargement (yellow arrows) and hepatic metastases (blue arrows) at diagnosis. (B) Repeat CT scan performed to assess response to chemotherapy shows persistent hepatic metastases (blue arrows) and significant adrenal enlargement (yellow arrows) after twelve weeks.

Discussion

Hypercortisolism due to ectopic ACTH secretion usually presents with particularly abrupt onset of signs and symptoms when compared with Cushing’s disease. This is due to the significantly higher amount of ACTH or ACTH precursors that are secreted by these tumours.⁵

The markedly high cortisol will overwhelm the 11 beta hydroxysteroid dehydrogenase type 2 enzyme that inactivates cortisol to cortisone. Excess cortisol acts as a mineralocorticoid on the renal tubular and collecting duct cells. In addition, this enzymes’ intrinsic activity is reduced in ectopic ACTH secretion resulting in more pronounced hypokalaemia.⁶ The recent introduction of loop diuretics in our case further exacerbated the hypokalaemia.

The patients’ worsening blood glucose control is a result of excess cortisol which increases gluconeogenesis and impairs insulin secretion. Immediate treatment with subcutaneous insulin was necessary as uncontrolled hyperglycaemia increases risks of infection. Moreover, he developed cortisolic myopathy which left him confined to bed further predisposing him to developing skin ulceration. The severity of hypercortisolism, hypokalaemia, diabetes and distant metastases are all predictors of mortality in NET associated Cushing’s syndrome.⁷

He became overtly hyperpigmented with time. Hyperpigmentation occurs because alpha, beta and gamma melanocyte stimulating hormones share the same prohormone as ACTH; promelanocortin (POMC) and are co secreted with ACTH. In addition, excess ACTH binds to melanocortin 1 receptor on the surface of dermal melanocytes stimulating them to produce melanin.⁸

Ectopic ACTH secretion from gastric tumours is rare. The following is a table (table 4) of reported cases in the literature identified through a PubMed search using the keywords ‘ectopic’, ‘ACTH’ and ‘gastric’:

Table 4.

A PubMed search using the keywords ‘ectopic’, ‘ACTH’ and ‘gastric’ resulted in the following cases listed below

Author, year	Age	Sex	Tumour histology	Sample	ACTH	Potassium
Davis,9 1962	n/a	n/a	Carcinoid	n/a	n/a	n/a
Card,10 1964	n/a	n/a	Adenocarcinoma	n/a	n/a	n/a
Imura et al, 1975	29	F	Carcinoid	resection	<0.03 on bioassay 115.9 ng/g on radioimmunoassay	n/a
Hirata et al, 1976	51	F	Carcinoid	resection	190 pg/mL (<120)	4.9 (no units)
Marcus et al, 1980	49	F	Metastatic gastric ACTH-producing apudoma	resection	High	2.7–3.4 mEq/L
Fujiwara et al, 1992	73	F	Papillo-tubular adenocarcinoma	biopsy	High	n/a
Tsuchiya et al, 2005	49	M	Carcinoid	biopsy	220 pg/mL	2.5 mEQ/L
Constantinos et al, 2007	52	M	Adenocarcinoma	biopsy	210 ng/L (0–46)	2.3 mmol/L
Doi et al, 2010	49	M	Carcinoid	resection-tumour debulking	220 pg/mL	2.5 mEq/L
Guha et al, 2012	45	M	Poorly differentiating mucin-secreting adenocarcinoma	biopsy	496 pg/mL	3.6 mmol/L
Lambrescu et al, 2018	57	M	Neuroendocrine carcinoma	biopsy	132.3 pg/mL	Low

ACTH, Adrenocorticotrophic hormone; F, female; M, male; n/a, not applicable.

The first case to report high plasma ACTH due to a gastric tumour is by Hirata et al in 1976. Previous cases by Davis et al⁹ and Card et al¹⁰ failed to confirm high plasma ACTH levels. Imura et al¹¹ found a discrepancy between the ACTH level detected on bioassay versus the higher level on radioimmunassay. Their serum contained big ACTH which is biologically less active and is not detected on bioassays.¹²

Tsuchiya et al also report a specific form of serum ACTH that is high—high molecular weight ACTH. This is the result of improperly processed POMC by the tumour. High molecular weight ACTH must be specifically tested for and is not detected by the usual ACTH assays. This could be a reason why some cases fail to detect high plasma ACTH.¹²

Adenocarcinomas are not usually ACTH secreting tumours. Possible reasons why some cases were reported as such may be limited pathological sampling of the tumour failing to detect the neuroendocrine component or lack of availability of immunohistochemical markers for neuroendocrine differentiation in the earlier case reports.⁷

The pathophysiology of ACTH secretion by NETs is not well understood. One hypothesis states that neuroendocrine cells are derived from neural crest cells and contain the POMC gene. The POMC gene may be derepressed to secrete ACTH. There is aberrant transcriptional regulation of the POMC gene and abnormal post translational processing of POMC that results in secretion of ACTH or its precursors pro-ACTH and N-POC.¹³ Prognosis in patients with ACTH secreting tumours depends on both the severity of hypercortisolism and the aggressiveness of the primary tumour.

The 2017 WHO classification for NETs grades well differentiated NETs into grade 1–3 depending on their mitotic count and ki 67 index. Grade 1: mitosis:<2/10 high pwer field (HPF) and Ki 67 index <3%, Grade 2: 2-20/10 HPF and ki67 index 3%–20%, grade 3:>20 mitosis/10 HPF and ki67 index >20%. It classifies poorly differentiated NETs as grade 3 neuroendocrine carcinomas (>20 mitosis/10 HPF and ki67 index >20%) which may be either small cell or large cell.

Gastrointestinal tumours harbouring both neuroendocrine and non-neuroendocrine components are labelled with multiple different terms such as composite carcinoid adenocarcinoma, mucin producing carcinoid and many others. It was only in 2017 that the WHO Classification of NETs coined the term MiNENs.

MiNENs are a group of tumours consisting of MiNEN. To classify as MiNEN each component must be >30%. A diagnosis of MiNEN may only be done on whole resected specimens not on biopsy specimens.¹⁴ The non-endocrine cells may be of any origin but are frequently ductal, adeno or acinar cell carcinomas. The 30% cut-off for each components was chosen arbitrarily in 1987 with no clinical evidence and only applies to whole resected specimens after examination of the entire specimen.¹⁵ Pathologists must be wary when examining small biopsy samples as the diagnosis of MiNEN may be missed if not enough cells are included in the specimen.¹⁴

The 30% threshold for the poorly differentiated neuroendocrine carcinoma (PDNEC) component in MiNEN has been queried. A case series of 88 patients found that the cut-off above which a PDNEC component influenced prognosis was 10%. A 5-year survival rates varied between 86% if <10% PDNEC to 53% if >10% PDNEC. (p<0.0001) if >10% PDNEC component, there is no difference in survival regardless of the extent.¹⁶

Synaptophysin and chromogranin A are the most specific immunohistochemical markers for neuroendocrine differentiation. NETs show a diffuse and intense immunostaining for both. Neuroendocrine carcinomas are diffusely positive for synaptophysin while chromogranin A can be absent or focally expressed with a typical paranuclear dot like pattern of immunoreactivity. In fact, weaker chromogranin A staining may indicate a poorer prognosis.⁴ Our patients’ histology showed only weak expression of chromogranin A indicating a PDNEC. CD56 is a membrane bound glycoprotein, is a sensitive but not a highly specific marker for NETs as it is expressed in multiple non NENs.¹⁷

Plasma chromogranin A is elevated in up to two-thirds of patients with advanced NECs. In well-differentiated tumours levels are lower. In our case it further confirms the patients’ tumour had neuroendocrine differentiation. However, it must be remembered that it may be secreted in multiple benign clinical conditions and in association with certain medications such as PPIs or steroids. Serum chromogranin A correlates with tumour burden.⁴ It is a good biomarker for follow-up of NETs as its concentration correlates with disease progression or treatment response but should not be used to make a diagnosis of NETs.⁴

Learning points.

• The physician must have a low threshold of suspicion of an ACTH secreting tumour in the setting of a recently diagnosed malignancy in a patient presenting with severe hypokalaemia and metabolic alkalosis.

• The importance of thorough clinical examination—picking up the subtle hyperpigmentation will point towards a pathology involving high ACTH.

• Severe hypokalaemia in this setting requires aggressive potassium replacement which necessitates a central venous access and nursing in an high dependancy unit (HDU) setting on cardiac monitor.

• The importance of a multidisciplinary care team involving the endocrinologists, oncologists, HDU team and physiotherapists (as the patient developed severe cortisolaemic myopathy) as well as social workers and spiritual advisors and the palliative team.