J A C C : C A S E R E P O R T S V O L . 2 , N O . 1 , 2 0 2 0

ª 2 0 2 0 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A N

C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

CASE REPORT

CLINICAL CASE

A Rare Case of CarcinoidConstrictive Pericarditis

Teresa S. Wang, MD,a Emily K. Bergsland, MD,b Ruth Zhang, MD,c Kai Ihnken, MD,d Kirsten Tolstrup, MDa

ABSTRACT

L

�

�

ISS

FrobD

of

Fra

Inf

Ma

We describe a case of atypical carcinoid heart disease. A 62-year-old woman with well-differentiated neuroendocrine

tumor metastatic to the liver and lymph nodes presented with recurrent unilateral pleural effusions and lower extremity

edema. Multimodality imaging and workup resulted in the diagnosis of carcinoid-related constrictive pericarditis, a rare

form of carcinoid heart disease. (Level of Difficulty: Intermediate.) (J Am Coll Cardiol Case Rep 2020;2:1–5)

© 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open

access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

HISTORY OF PRESENTATION

A 62-year-old woman presented with a 1-year historyof recurrent right-sided pleural effusions, chesttightness, and progressive lower extremity edema.She was hospitalized multiple times in the recent pastfor marked dyspnea on exertion requiring escalatingdoses of diuretics and repeated thoracenteses(Supplemental Figure 1). Physical examinationrevealed a chronically ill-appearing thin woman withblood pressure of 102/69 mm Hg and pulse rate of 58beats/min and regular. Pertinent physical findingsincluded moderate jugular venous distension withKussmaul sign, and dullness to percussion withdecreased breath sounds over the right posteriorlung base. Cardiac examination was otherwise

EARNING OBJECTIVES

Understand the typical and atypical symp-toms in presentations of carcinoid heartdisease.Describe the broad spectrum of cardiacmanifestations in carcinoid syndrome.

N 2666-0849

m the aDivision of Cardiology, Department of Medicine, University of

epartment of Medicine, University of California-San Francisco, San Francis

California-San Francisco, San Francisco, California; and the dDepartment o

ncisco, California. The authors have reported that they have no relationsh

ormed consent was obtained for this case.

nuscript received October 17, 2019; accepted November 5, 2019.

unremarkable, with no murmurs, rubs, or knocks.Extremities showed trace bilateral pitting edemawhile on moderate doses of diuretics.

PAST MEDICAL HISTORY

Past medical history included well-differentiatedneuroendocrine tumor (NET) arising in the ileumand metastatic to the liver and lymph nodes, forwhich she had undergone resection of the primarytumor and a synchronous liver metastasis. She hadresultant carcinoid syndrome so therapy with a so-matostatin analogue was started, but diarrhea per-sisted. Interestingly, the patient also carried agermline BRCA1 mutation and was status post bilat-eral salpingo-oophorectomy and prophylactic bilat-eral skin-sparing mastectomy. She had a history of 30pack-years of tobacco smoking and a family history ofcoronary artery disease in her father and maternalgrandfather.

DIFFERENTIAL DIAGNOSIS

Initial differential diagnosis was appropriately broad.Given her NET metastases, carcinoid heart disease

https://doi.org/10.1016/j.jaccas.2019.11.037

California-San Francisco, San Francisco, California;

co, California; cDepartment of Pathology, University

f Surgery, University of California-San Francisco, San

ips relevant to the contents of this paper to disclose.

FIGURE 1 Pulsed Wave Dopp

E/A ratio of 1.6 and shortened d

diastolic dysfunction. MV ¼ mit

ABBR EV I A T I ON S

AND ACRONYMS

NET = neuroendocrine tumor

Wang et al. J A C C : C A S E R E P O R T S , V O L . 2 , N O . 1 , 2 0 2 0

Rare Case of Carcinoid Constrictive Pericarditis J A N U A R Y 2 0 2 0 : 1 – 5

2

and obstruction of the vena cava due to largemetastases were strong considerations. Herright-sided heart failure symptoms andKussmaul sign were suggestive of constric-

tion or restrictive cardiomyopathy. A second primarytumor due to her BRCA1 mutation also was consid-ered. Other less likely considerations included coro-nary artery disease in the setting of her smokinghistory and family history, pulmonary hypertension,and dilated cardiomyopathy.

INVESTIGATIONS

To address the extent of her NET metastases, bloodtests and initial imaging were performed first. Labo-ratory test results demonstrated an elevated but sta-ble chromogranin A level of 23.0 ng/ml and urinary 5-hydroxyindoleacetic acid level of 20.7 mg per 24 hsuggestive of stable disease. Computed tomographyof the chest and abdomen showed extensive meta-static disease in the liver but no obstruction of thevena cava. Results from thoracocentesis performedat a local hospital interestingly demonstrated aborderline exudative process.

Cardiac tests were run concurrently. Electrocardiogramshowed sinus rhythm with reduced anterior forcesand nonspecific ST-T wave changes. Pharmacolog-ical stress testing showed no ischemia. Trans-thoracic echocardiography demonstrated preservedejection fraction of 66% (left ventricular internal

ler of the MV

eceleration time of 148 ms are suggestive of grade II

ral valve.

dimension at end-diastole 3.0 cm), normal pulmo-nary artery pressures, and no pericardial effusion.Importantly, there was an absence of valvularinvolvement (no classic “stubby” appearance of thetricuspid or pulmonic valves), making the hallmarktype of carcinoid heart disease less likely. However,transthoracic echocardiography demonstratedplethoric inferior vena cava with diastolic dysfunc-tion (mitral valve E/A ratio 1.6; deceleration time148 ms) (Figure 1) and mitral annulus reversus(Figure 2). In conjunction with a thickened appear-ance of the pericardium on computed tomography(Figure 3) and only mild biatrial enlargement (leftatrial volume index 35 ml/m2) on transthoracicechocardiography, constriction seemed more likelythan restrictive cardiomyopathy.

Subsequently, the patient underwent cardiaccatheterization. Simultaneous right and left hearttracings showed elevated right-sided (right atrialpressure 15 mm Hg) and left-sided (pulmonary capil-lary wedge pressure 15 mm Hg) filling pressures,equalization of right and left ventricular end-diastolicpressures within 5 mm Hg, and discordance duringthe respiratory cycle consistent with constriction.

MANAGEMENT

A phrenic-to-phrenic pericardiectomy was performedvia median sternotomy. Intraoperatively, extensiveadhesions were encountered near the right atriumand taken down to reveal a 5- to 10-mm thickenedpericardium. Gentle stripping of the pericardiumallowed freeing of the anterior wall of the right andleft ventricles, with resultant immediate improve-ment in systolic and diastolic function noted byechocardiography. Right-sided pleural empyema wasalso found and required decortication. Histology ofthe pericardium revealed dense thickened fibro-connective tissue with scattered lymphoplasmacyticchronic inflammatory infiltrate consistent withconstrictive pericarditis. One focus of neoplastic cellswas embedded within the adipose tissue (Figure 4A)and stained positive for synaptophysin (Figure 4B)and chromogranin A (Figure 4C), consistent withmetastatic NET.

DISCUSSION

Well-differentiated NETs arising outside of thepancreas (carcinoid tumors) are rare and thought tooriginate most commonly from chromaffin cells in theintestinal tract or lungs (1,2). Symptoms of carcinoidsyndrome are related to the release of peptides,which produce flushing, hypotension, bronchospasm,edema, and gastrointestinal hypermotility with

FIGURE 2 Tissue Doppler Imaging

Mitral annulus reversus (lateral Eʹ velocity 11.6 cm/s [left] < medial Eʹ velocity 13.1 cm/s) [right]) is suggestive of constriction.

J A C C : C A S E R E P O R T S , V O L . 2 , N O . 1 , 2 0 2 0 Wang et al.J A N U A R Y 2 0 2 0 : 1 – 5 Rare Case of Carcinoid Constrictive Pericarditis

3

secretory diarrhea. Serotonin, one of the most com-mon neuropeptides produced, is normally metabo-lized by monoamine oxidase in the liver and lung.However, high concentrations of serotonin can reachthe heart if the serotonin bypasses the liver or isproduced by the liver (i.e., hepatic metastases).

Carcinoid heart disease comprises a broad spec-trum of cardiac manifestations in patients withcarcinoid syndrome and may include valvulardysfunction, direct myocardial involvement, and

FIGURE 3 Computed Tomography Axial Slice

Thickened pericardium with calcifications in addition to right-

sided pleural effusion.

less frequently, pericardial involvement (3). In thelargest case series to date of 74 patients withcarcinoid heart disease, 97% had the hallmarktricuspid valve thickening and dysfunction, 14% hadpericardial effusion, and 4% had myocardial me-tastases (4). A smaller case series described 11 pa-tients with pathological confirmation of metastaticcarcinoid tumor involving the heart, but all of thesetumors were well-circumscribed intramyocardialmetastases (5).

Metastatic disease extending to the pericardium isuncommon. To our knowledge, only a handful of casereports in the literature have described direct peri-cardial invasion: a metastatic carcinoid tumor pro-ducing focal chronic pericarditis and fibrosis (6); acarcinoid tumor of the thymus leading to acute peri-carditis (7); and a metastatic carcinoid mass entirelywithin the pericardial space without myocardialinvolvement (8).

Only 1 case of carcinoid constrictive pericarditishas been previously reported (9). We describe thesecond case of a unique presentation of constrictivepericarditis due to metastatic carcinoid disease in theabsence of valvular involvement. Recurrent pleuraleffusions are an uncommon presentation of carcinoidheart disease, which classically presents with signsand symptoms of right heart failure. Interestingly, thepresentation of right pleural effusion was unique toboth case reports of constrictive pericarditis andpossibly were the result of severe diastolic dysfunc-tion leading to elevated pressures and subsequent

FIGURE 4 Histology of Pericardium

(A) Hematoxylin and eosin–stained section of pericardium showing a focus of neoplastic cells within adipose tissue. (B) Immunohistochemical stain showing neoplastic

cells positive for synaptophysin. (C) Immunohistochemical stain showing neoplastic cells positive for chromogranin A.

Wang et al. J A C C : C A S E R E P O R T S , V O L . 2 , N O . 1 , 2 0 2 0

Rare Case of Carcinoid Constrictive Pericarditis J A N U A R Y 2 0 2 0 : 1 – 5

4

unilateral pleural effusion. Alternatively, empyemain our patient may have resulted in chronic inflam-mation of the pericardium by extension that, com-bined with her carcinoid metastasis, contributed to a2-hit hypothesis and led to her symptoms. Never-theless, the use of multimodality imaging and inva-sive hemodynamic evaluation helped to clarify thisatypical presentation and diagnostic dilemma.

FOLLOW-UP

The patient’s post-operative course was unremark-able, and she had steady clinical improvement afterthe operation. By 2 months postoperatively, she wasable to drive and perform activities of daily livingwithout recurrent hospitalizations.

CONCLUSIONS

We report a rare case of constrictive pericarditiscaused by metastatic carcinoid disease in the absenceof valvular involvement and otherwise nonprogres-sive metastatic carcinoid tumor. This case providesuseful insights into the spectrum of carcinoid peri-cardial disease and highlights the importance ofpericardial stripping in the treatment of constrictivepericarditis.

ADDRESS FOR CORRESPONDENCE: Dr. Teresa S.Wang, Division of Cardiology, University ofCalifornia-San Francisco, 505 Parnassus Avenue,M1182, San Francisco, California 94143-0124. E-mail:teresa.wang@ucsf.edu.

J A C C : C A S E R E P O R T S , V O L . 2 , N O . 1 , 2 0 2 0 Wang et al.J A N U A R Y 2 0 2 0 : 1 – 5 Rare Case of Carcinoid Constrictive Pericarditis

5

RE F E RENCE S

1. Davar J, Connolly HM, Caplin ME, et al. Diag-nosing and managing carcinoid heart disease inpatients with neuroendocrine tumors: an expertstatement. J Am Coll Cardiol 2017;69:1288–304.

2. Bhattacharyya S, Davar J, Dreyfus G, Caplin ME.Carcinoid heart disease. Circulation 2007;116:2860–5.

3. Ram P, Penalver JL, Lo KBU, Rangaswami J,Pressman GS. Carcinoid heart disease: review ofcurrent knowledge. Tex Heart Inst J 2019;46:21–7.

4. Pellikka PA, Tajik AJ, Khandheria BK, et al.Carcinoid heart disease: clinical and echocardio-

graphic spectrum in 74 patients. Circulation 1993;87:1188–96.

5. Pandya UH, Pellikka PA, Enriquez-Sarano M,Edwards WD, Schaff HV, Connolly HM. Metastaticcarcinoid tumor to the heart: echocardiographic-pathology study of 11 patients. J Am Coll Cardiol2002;40:1328–32.

6. Rich LL, Lisa CP, Nasser WK. Carcinoid pericar-ditis. Am J Med 1973;54:522–7.

7. Gelfand ET, Basualdo CA, Callaghan JC. Carci-noid tumor of the thymus associated with recur-rent pericarditis. Chest 1981;79:350–1.

8. Collins N, Bellamy G, Hayes P. Intrapericardialcarcinoid metastasis. J Am Soc Echocardiogr2004;17:675–6.

9. Johnston SD, Johnston PW, O’Rourke D. Carci-noid constrictive pericarditis. Heart 1999;82:641–3.

KEY WORDS cancer, constriction, diastolicheart failure, pleural effusion

APPENDIX For a supplemental figure, pleasesee the online version of this paper.