Carcinoid heart failure in a duodenal neuroendocrine tumor: role of cardiac surgery in a challenging patient and brief review of the literature

Introduction

Carcinoid heart disease (CHD), a potentially serious cardiac manifestation, generally involves the right-sided heart valves [1]. In about 70% of patients, CHD occurs together with metastatic small bowel neuroendocrine tumors (NETs) and carcinoid syndrome. The pathophysiological mechanism of CHD remains uncertain. It is thought that chronic exposure to elevated circulating hormone levels, mainly serotonin, lead to plaque-like, fibrous thickening of the endocardial surfaces of heart valves [2]. The management of patients with CHD is complex [1]. Therapeutic options besides pharmacotherapy and control of systemic carcinoid disease include cardiac valve replacement surgery in selected patients, which has been correlated with an improvement in clinical outcomes [3]. Here, we present the case of a patient with well-differentiated, G1, metastatic NET of duodenal origin, concomitant with carcinoid symdrome and CHD, which rapidly progressed to cardiac failure and ultimately the patient’s death.

Case presentation

A 63-year-old Caucasian woman came to our attention in June 2015 because of chronic diarrhea, hematochezia, and abdominal pain of 1 year duration. Endoscopic colonoscopy with retrograde ileoscopy and gastroscopy were normal. A total-body computed tomography (CT) scan revealed bilateral pleural effusion, enlarged mediastinal lymph nodes, ascites, lytic lesion of the lumbar vertebra, multiple liver metastases, and a lesion of the duodenum/pancreas uncinate process. Percutaneous liver biopsy disclosed well-differentiated NET, G1, with 2% proliferation index (Ki67) and 2 mitoses/10 high power field. The immunohistochemical profile suggested a gastrointestinal origin, with CDX2 (caudal type homeobox transcription factor 2) and chromogranin A (CgA) positivity, while PAX-8 (paired box gene 8) was negative. ¹¹¹In-octreotide scintigraphy showed diffuse focal tracer uptake corresponding to the abnormalities found on CT. Serum CgA and urinary 5-hydroxyindoleacetic acid (5-HIAA) were elevated (1039 ng/mL, upper normal limit 100 ng/mL; 270 mg/day, upper normal limit 10 mg/day, respectively). The patient complained of diarrhea (10 bowel movements per day) and flushing (2–3 episodes per day). Therapy with long-acting repeatable (LAR) and short-acting octreotide was initiated. Intramuscular octreotide LAR was administered at a dose of 30 mg every 28 days and subcutaneous octreotide at a dose of 500 μg twice daily. After 2 months of biological treatment, the patient developed acute dyspnea. A chest CT scan revealed abundant bilateral pleural/pericardial effusion and a slightly enlarged heart. N-terminal pro-brain natriuretic peptide (NTpro-BNP) was elevated (2469 ng/L, upper normal limit 900 ng/L). Echocardiography showed a hypertrophic-hypokinetic left ventricle with low ejection fraction (40%), mild mitral and pulmonary valve insufficiency, moderate aortic valve and severe tricuspid valve insufficiency. Therapy with an angiotensin-converting enzyme inhibitor (perindopril) and ivabradine was started. Repeated echocardiography revealed severe aortic and tricuspid regurgitation, with septal leaflet shortening and a dilated right ventricle resulting in massive cardiac failure (carcinoid heart failure, CHF). The patient underwent surgical valve replacement. During the operation, both the aortic and tricuspid valves were replaced with mechanical prostheses (Carbomedics^®, Sorin SpA, Milan, Italy; 21 mm for the aortic and 31 mm for the tricuspid valve), while careful to avoid the atrioventricular (AV) node and His bundle. A hypothermic (30 °C) cardiopulmonary bypass was established, the aorta was cross-clamped, and access was made with standard transverse incision. Cristalloid cardioplegia was infused directly into the coronary ostia. The aortic and tricuspid leaflets showed compact fibrous tissue on both surfaces. The tricuspid commissures were fused; the septal leaflet was thickened and shortened. To avert the risk of atrioventricular block, a pacing lead (Myodexa^® St. Jude Medical, St. Paul, MN, USA) was placed in the right ventricular wall for prophylaxis. The bilateral pleural effusion was drained before opening the pleura and chest tubes were placed on completion of the operation. The pathological report noted large nodular areas of acellular fibrous thickening on the aortic and tricuspid valve flaps. The day before the operation, the patient received a continuous intravenous infusion of octreotide 500 μg/1 mL. Intraoperatively, infusion at a rate of 50 μg h⁻¹ was administered. The postoperative course was characterized by hypotension requiring octreotide administration in intermittent bolus injections of 20–100 μg. Acute renal failure occurred and the patient was dialyzed. Fifteen days after surgery, septic syndrome due to Klebsiella pneumoniae infection developed. The patient died in the intensive care unit 40 days after surgery from multiorgan failure.

Discussion

NETs are rare malignancies, heterogeneous in origin, clinical presentation and behavior. Their incidence has markedly increased over the last years to 6.98 per 100 000 persons [4]. Approximately, 60% of well- and moderately differentiated tumors (classified as G1 and G2, respectively) originate in the digestive system, followed by the bronchopulmonary system (27%). According to the most recent Surveillance, Epidemiology, and End Results (SEER) program of the U.S. National Cancer Institute data, the most common primary site is the terminal ileum, while less common sites include the stomach, the duodenum and the distal colorectal tract. The median overall survival (OS) is 5.8 years for metastatic small intestine NETs [4].

NETs can be classified as either functioning (20–30%) or nonfunctioning on the basis of their capacity to produce hormones (i.e., insulin, glucagon, gastrin, vasoactive intestinal peptide or somatostatin), peptides and neurotransmitters. Overproduction of these hormones or peptides is a distinctive feature of these tumors. Patients with locally advanced/inoperable or metastatic NETs may develop carcinoid syndrome, which is the most common of these hormonal syndromes. It is associated with tumor secretion of serotonin and characterized by diarrhea, flushing and bronchial constriction. While the exact pathology of carcinoid heart disease (CHD) remains obscure, substantial evidence implicates a major role for serotonin in stimulating fibroblast growth and fibrogenesis [5].

Although the onset of CHD in NET patients with carcinoid syndrome has been reported in approximately 50% of patients, according to recent studies its prevalence has fallen to approximately 20% [6]. CHD is characterized by cardiac endocardial fibrosis, abnormalities of the right side of the heart, which may eventually lead to serious heart failure [5]. In up to 15% of patients, CHD may also affect the left-sided valves. Since hormones are inactivated by the lung parenchyma, the presence of left-sided heart failure can only be explained by their production at a concentration exceeding the capacity of pulmonary metabolism or by the presence of intracardiac communication (shunts) between the left and the right heart.

The primary tumor site in our patient was the duodenum, which should be considered a potential positive prognostic factor for survival [4]. In such patients, however, the development of cardiac disease heralds a decline in clinical outcome, regardless of the primary tumor site [7]. Without treatment, prognosis is generally poor in NET patients with CHD: a 3-year survival rate of about 30% versus 68% in patients without CHD [8].

CHD can remain undiagnosed, as reported in a recent study involving 150 patients with carcinoid syndrome, 37% of which exhibited no physical signs of CHD [9]. Its early diagnosis poses a considerable challenge in daily clinical practice. Diagnosis relies on two-dimensional echocardiography and Doppler examination to assess the severity of valve stenosis and regurgitation and the severity of cardiac involvement [2,6,10]. Unfortunately, validated biomarkers of CHD are lacking to date. NT-pro BNP has been shown to have high sensitivity and specificity (87% and 80%, respectively) in predicting CHD and to correlate with patient survival [11]. In the study by Korse et al., patients with elevated NT-pro BNP and elevated CgA levels had worse overall survival than those with elevated CgA alone. Telotristat ethyl, a novel, oral inhibitor of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis, was demonstrated in a phase 3 study to reduce bowel movement frequency, with a response rate of 40–44% [12]. These encouraging data suggest a future role for this drug in the treatment of CHD.

A recently developed algorithm for the management of CHD patients [13] has suggested the importance of early multidisciplinary discussion to determine optimal treatment, potentially comprehending medical therapies (e.g., somatostatin analogs, interferon, inotrope positive agents) to control carcinoid syndrome and cardiac valve replacement in selected individuals.

Many relevant issues regarding surgical valve replacement in CHD remain unaddressed. The choice of the type of valve prosthesis (biological vs. mechanical) is controversial because the literature is limited to small, retrospective series or case reports [14]. Valve replacement has been associated with several drawbacks: allograft failure is the most severe side effect reported with biological prostheses, and anticoagulation is required when placing a mechanical prosthesis. Furthermore, optimal timing of valve replacement has not been established. Ultimately, the type of prosthesis and the timing of valve replacement surgery need to be decided individually, taking into account potential risks and life expectancy.

A literature search in the PUBMED database was performed to retrieve studies on the role of cardiac surgery in CHD. The relevant studies were selected according to the following criteria: studies including patients with NETs with confirmed histopathological or cytological diagnosis; studies reporting case reports of G1 or G2 NET and CHD/CHF treated with cardiac surgery. Overall, 34 studies, involving 80 patients, met the selection criteria. Table 1 presents the distribution of demographic, clinical, and surgical treatment data. The most frequent primary tumor site was the small bowel in 50 patients (62.5%), of unknown origin in 9 (11.2%), the pancreas in 3, and not reported in 14. The time from diagnosis of NET to cardiac surgery was 2–4 years in 48 patients (60%), longer than 5 years in 6 (7.5%), between 1 month and 1 year in 4 (5%), and not reported in 13.7%. In 11 patients (13.7%), the time of diagnosis coincided with the time of cardiac surgery. In the majority of patients (96.2%), surgery consisted of valve replacement: 2 valves and 1 valve in 47.5% and 46.2% of patients, respectively; 3 valves in 3; and all 4 valves in 2. Almost all patients (92.5%) underwent tricuspid valve replacement, 58.7% pulmonary valve replacement, and 5% and 3.7% aortic or mitral valve replacement, respectively.

Table 1. Studies on cardiac surgical approach in patients with carcinoid heart disease.

No of PTS	Age/Sex	Primary tumor site	Ki67	Surgery	Time between diagnosis and surgery	Valves	OS after surgery	Reference/Year
1	46/M	Small bowel	NA NET G1 or G2	Valve replacement	0 months	Pulmonary tricuspid	NA	[16]; 2017
1	51/F	Small bowel	NA NET G1 or G2	Biological valve replacement	5 months	Tricuspid	NA	[17]; 2017
1	65/F	Small bowel	NA NET G1 or G2	Replacement of valves with metallic prostheses	NA	Aortic, tricuspid, and pulmonary	NA	[18]; 2016
1	67/M	Small bowel	NA NET G1 or G2	Valve replacement	NA	Tricuspid	48 months	[19]; 2016
1	63/F	Small bowel	NA NET G1	Mechanical valve replacement	0 months	Aortic and mitral	Approximately 14 months	[20]; 2016
1	53/F	Ovarian	NA NET G1 or G2	Bioprosthetic Valve replacement	0 months	Tricuspid	36 months	[21]; 2015
1	65/F	NA	NA NET G1 or G2	Bioprosthetic valve replacement	NA	Pulmonary and tricuspid	NA	[22]; 2016
1	65/F	Small intestine	NA NET G1 or G2	Valves replacement	48 months	Tricuspid and pulmonary	12 months	[23]; 2015
2	NA	NA	NA	Valve replacement using biological xenografts	NA	Tricuspid valve and pulmonary	NA	[24]; 2015
1	NA/F	Small bowel	Ki67: 5% NET G2	Percutaneous valve implantation	84 months	Tricuspid valve and pulmonary	12 months	[25]; 2016
1	55/F	Unknown	NA NET G1 or G2	Transcatheter valve replacement	0 months	Pulmonary	12 months	[26]; 2015
3	31/M 58/F 55/F	Small bowel	NA NA NA	Valve replacement with stentless bioprostheses	0 months 9 months 36 months	Pulmonary	30 months 25 months 18 months	[27]; 2015
2	33/M 35/F	Pancreas NA	NA NET G1 or G2 NA NET G1 or G2	Valve replacement	0 months 0 months	Tricuspid and pulmonary	36 months NA	[28]; 2014
1	66/M	NA	NA NET G1 or G2	Valve replacement	0 months	Tricuspid	10 days	[29]; 2013
1	48/M	Small bowel	NA NET G1 or G2	Valve replacement	96 months	Tricuspid and pulmonary	24 months	[30]; 2013
1	67/M	NA	NA NET G1 or G2	Valve replacement	NA	Tricuspid and pulmonary	NA	[31]; 2013
1	58/F	Small bowel	NA NET G1 or G2	Balloon valvuloplasty	60 months	Pulmonary	6 months	[32]; 2013
21	Median age 60/ 11 F 10 M	Small bowel	NA NET G1 or G2	Valve replacement	48 months (median value)	3: tricuspid 15: tricuspid and pulmonary 2: tricuspid, pulmonary and mitral 2: quadruple valve replacement	4: <30 days 18: >30 days	[33]; 2013
12	Median age 63/ 8 M 4 F	8 Small bowel 4 Unknown	NA NET G1 or G2	Valve replacement	20 months	Tricuspid	2: <30 days 6: 24 months	[34]; 2011
1	NA/F	Ovarian	NA NET G1 or G2	Valve replacement	0 months	Pulmonary and tricuspid	6 months	[35]; 2009
1	46/F	Small bowel	NA NET G1 or G2	Valve replacement	6 months	Pulmonary and tricuspid	12 months	[36]; 2008
1	58/M	Small bowel	NA NET G1 or G2	Valve replacement	60 months	Pulmonary and tricuspid	24 months	[37]; 2005
1	55/M	Small bowel	NET G1 Ki67 < 1%	Valve replacement	36 months	Pulmonary and tricuspid	12 months	[38]; 2003
1	68/F	Ovarian	NA NET G1 or G2	Valve replacement	0 months	Tricuspid	36 months	[39]; 2001
8	Median age 64/ 4 F 4 M	4 Small bowel 1 Pancreatic 3 Unknown	NA NET G1 or G2	Valve replacement with bioprostheses	24 months	Tricuspid	5: <30 days 3: >30 days (146, 153 and 48 months)	[40]; 1995
1	64/F	NA	NA NET G1 or G2	Valve replacement	NA	Pulmonary and tricuspid	NA	[41]; 1994
4	NA/F	NA	NA NET G1 or G2	Valve replacement	NA	Pulmonary and tricuspid	NA	[42]; 1990
2	56/F 32/F	Small bowel Unknown	NA NET G1 or G2	Valve replacement	96 months 0 months	Pulmonary and tricuspid	49 months 61 months	[43]; 1985
1	62/M	NA	NA NET G1 or G2	Valve replacement	NA	Tricuspid	NA	[44]; 1984
1	62/M	Small bowel	NA NET G1 or G2	Valve replacement	300 months	Tricuspid	12 months	[45]; 1982
1	53/M	Pancreatic	NA NET G1 or 2	Valve replacement	NA	Tricuspid	8 months	[46]; 1981
1	60/F	Ovarian	NA NET G1 or G2	Valve replacement	8 months	Tricuspid	NA	[47]; 1980
1	30/F	NA	NA NET G1 or G2	Valve replacement	NA	Pulmonary and tricuspid	NA	[48]; 1979
1	24/F	NA	NA NET G1 or G2	Valve replacement	NA	Tricuspid	NA	[49]; 1978

G1: grade 1; G2: grade 2; NA: not available; NET: neuroendocrine tumor; OS: overall survival; PTS: patients.

Surgical studies published to date, evaluating the role of surgical approach in patients with neuroendocrine tumors and CHD.

In conclusion, CHD is a rare and severe complication of metastatic NETs and is associated with increased morbidity and mortality. On the basis of our analysis, including management of the patient treated at our Institution, we suggest surgical evaluation in asymptomatic CHD patients, including those with early and not severe cardiac damage. The literature reports higher postoperative mortality after valve replacement in patients with advanced cardiac disease, [15] whereas prompt adequate management of CHD could ensure continuity of treatment to maintain good hemodynamic function and improved outcomes.

Disclosure statement

ALS, MPB, FP, ET LM and FA have no conflict of interest to declare. MDM has received speaker fees from Boehringer Ingelheim, AstraZeneca, Eli-Lilly and attended advisory boards for AstraZeneca and Eli-Lilly. GVS has received speaker fees from Eli Lilly, Astra Zeneca, Pfizer, Roche, and Clovis Oncology.