He Y, Wang J, Kong L, Jia B, Chi Y, Zhai X, Jin H, Wang Z. Clinical Characteristics of Cardiac and Pericardial Metastasis in Small Cell Lung Cancer with . J Cardiol and Cardiovasc Sciences. 2021;5(1):7-15

Original Research Article Open Access

Clinical Characteristics of Cardiac and Pericardial Metastasis in Small Cell Lung Cancer with Arrhythmia Yuling He1, Jingjing Wang1, Lingdong Kong1, Bo Jia1, Yujia Chi1, Xiaoyu Zhai1, Han Jin2, Ziping Wang1* 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, China 2Department of , Peking University First Hospital, China

Article Info Abstract

Article Notes Background: Cardiac and pericardial metastasis in small cell lung cancer Received: January 4, 2021 (SCLC) is more common than estimated, but there are a few related studies Accepted: February 16, 2021 in the literature. This study aims to raise the attention of such clinical *Correspondence: circumstances. Dr. Ziping Wang, Key Laboratory of Carcinogenesis and Methods: We analyzed the clinical data of 62 SCLC patients with arrhythmia Translational Research (Ministry of Education/Beijing), Department of Thoracic Medical Oncology, Peking University and confirmed eleven cases of SCLC with cardiac and/or pericardial metastasis Cancer Hospital and Institute, 52 Fucheng Road, Haidian by cytology or imaging diagnosis. Survival analysis was performed by the District, Beijing 100142, China; Telephone No: +86 10 8819 Kaplan-Meier method. 6660; Email: [email protected]. Results: Among 11 patients, 6 had pericardial involvement, 10 had © 2021 Wang Z. This article is distributed under the terms of the mediastinal lymph node metastasis, and 8 had hilar lymph node metastasis. Creative Commons Attribution 4.0 International License. The most common type of electrocardiogram (ECG) abnormality was supraventricular (10/11). Complete imaging data were obtained Keywords: in 7 patients through whole treatment after diagnosed with cardiac metastasis. Bronchial carcinoma Heart involvement Among them, 5 patients achieved partial response, and 2 of them achieved Clinical features improvements in ECG abnormality. In the two remaining patients, advances Electrocardiogram abnormality in imaging diagnosis were identified after treatment, and new abnormalities Atrial were found in their ECG. The median overall survival time of the 11 patients Treatment was 11 months. Conclusions: Cardiac and pericardial metastasis of SCLC can present different types of arrhythmia, and the ECG may change after treatment. Clinicians should take this condition into consideration, and aggressive treatment may achieve significant remission.

Introduction Small cell lung cancer (SCLC), accounting for 15% of lung cancer patients, develops rapidly and is highly sensitive to chemotherapy. A total of 70% of the patients had already advanced to systemic metastasis when they were initially diagnosed1, and a few of them 2 reported that 31% of lung cancer patients presented with cardiac metastasis; wereAbe S, confirmed et al.3, 44.4%; to have both heart were involvement. proven by Tamura autopsies. A, et Studies al. have indicated that 7.5-17.9% of such patients were SCLC2-4 standard is to detect the tumor cells in or carry . The gold cardiac magnetic resonance, as well as electrocardiogram (ECG) may alsoout cardiac provide biopsy. clues. AImages recent such prospective as computed study tomography found non-sustained (CT) and ventricular had a higher prevalence rate, as well as a worse prognosis, in unselected non-small cell lung cancer patients5. Previous studies found patients with heart metastasis, which were 2,6,7. However, clinicians often overlook the relevant diagnosis, as most confirmed by biopsies, have a higher incidence of abnormal ECG

Page 7 of 15 He Y, Wang J, Kong L, Jia B, Chi Y, Zhai X, Jin H, Wang Z. Clinical Characteristics of Cardiac and Pericardial Metastasis in Small Cell Lung Cancer with Arrhythmia. J Cardiol and Cardiovasc Journal of Cardiology and Cardiovascular Sciences. 2021;5(1):7-15 Sciences patients remain clinically silent, and they do not check for Table 1: Age and sex distribution. Male Female Range of age Median age the present study retrospectively analyzed the clinical Cardiac metastasis 11 3 45-77 60.93 heart metastasis during the diagnostic process. Therefore, Non-cardiac metastasis 39 9 35-79 60.44 cases of SCLC with cardiac and/or pericardial involvement Total 50 12 35-79 60.55 bydata imaging, of 62 SCLC and explored patients withtheir arrhythmia,clinical characteristics confirmed 11to raise the attention of diagnosing heart metastasis in SCLC Table 2: Clinical characteristic of 11 SCLC with cardiac metastasis. and then beginning effective treatment. We present the No. % Stage checklist. Limited stage 1 9.09 following article in accordance with the STROBE reporting Materials and Methods Extensive stage 10 90.91 Site of primary lesion We analyzed a database of 62 Chinese SCLC patients with Right upper lobe 3 27.27 arrhythmia—all had evidence of pathology and abnormal Right middle lobe 3 27.27 ECG recordings—from January 2007 to December 2020 Right lower lobe 1 9.09 Left upper lobe 2 18.18 determined to have heart involvement; one of them was Left lower lobe 1 9.09 in Beijing Cancer Hospital. Ultimately, eleven cases were Right hilar 1 9.09 Left hilar 0 0.00 spiralconfirmed scanner) by cytological enhancement examination imaging obtained of the other from the10 Involvement of surrounding structure casespericardial indicated effusion. that theChest tumor CT (GE invaded lightspeed the VCT 64-slice or Mediastinal lymph node 10 90.91 Hilar lymph node 8 72.73 due to lack of clear cytological or radiologic evidence. We Carina lymph node 3 27.27 assessedheart structure. those 11 The cases remaining regarding 51 patientsclinical characteristics,were excluded Peripheral vessel 7 63.64 imaging and ECG alterations (all data were obtained from Mediastinum 8 72.73 10 seconds 12-lead ECG and 24-hour ECG recordings in Involvement of heart structure our hospital), the healing processes, and outcomes. Clinical Left atrium 3 27.27 Right atrium 3 27.27 Right ventricle 1 9.09 efficacy was evaluated using Response Evaluation Criteria Pericardium 6 54.55 in Solid Tumors Version 1.1 through the CT images. Follow- Clinical symptom toup death was madecaused through by SCLC telephone or the last calls. follow-up Overall date. survival SPSS Shortness of breath 7 63.64 (OS) was defined as the period from initial chemotherapy Syncope 1 9.09 Kaplan-Meier survival analysis and the survival difference Asymptomatic 3 27.27 between(RRID:SCR_002865) the two groups version was 26.0 compared was used using to perform a log-rank the Treatment test. First-line 9 81.82 Second-line 2 18.18 Results

Clinical characteristics symptoms varied from no complaints to syncope or Among the 62 patients, 11 were diagnosed with cardiac boundary between the tumor and the heart. The clinical and/or pericardial metastasis based on clinical evidence. with echocardiography. Apart from one patient whose shortness of breath. Only five patients were administered patients with and without heart invasion as indicated There was no significant difference in sex and age among left ventricular ejection fraction could not be accurately primary lesion distribution, peripheral tissue involvement, measured due to (AF), another four symptomsin Table 1. and Table treatment 2 shows of thethe clinical11 cases. characteristics, All but one linepatients chemotherapy, had no significant and two impairment patients initiated of cardiac second-line, function. were at the extensive stage when diagnosed with SCLC. oneThe ofclinical them datachanged revealed to topotecan that nine due patients to heart received metastasis, first- Most patients had evidence of metastasis in mediastinal the other failed second-line chemotherapy and manifested as pericardial involvement. lymph nodes (10/11) and hilar lymph nodes (8/11). Over Electrocardiogram abnormalities half of these patients (8/11) presented with mediastinal involvement, and 7 of 8 had involvement of great vessels. patients. 7 patients already had cardiac and/or pericardial asThe pericardialpericardium effusion was the mostor thickening vulnerable site,or anfollowed unclear by metastasisTable 3 assummarizes well as arrhythmia the ECG abnormalities at initial diagnosis, of these while 11 the atrium and/or the ventricle. The imaging manifested

Page 8 of 15 He Y, Wang J, Kong L, Jia B, Chi Y, Zhai X, Jin H, Wang Z. Clinical Characteristics of Cardiac and Pericardial Metastasis in Small Cell Lung Cancer with Arrhythmia. J Cardiol and Cardiovasc Journal of Cardiology and Cardiovascular Sciences. 2021;5(1):7-15 Sciences the rest 4 patients, who developed heart invasion during All these patients received etoposide in combination with at the beginning. Supraventricular arrhythmia was the mostthe course,common only abnormality, had non-specific accounting ECG abnormalitiesfor 90.91%, patientplatinum was as lost the to first-line follow-up chemotherapy. after 115 months, Two ofand them the received radiotherapy during the treatment course. One among which AF has the highest incidence rate, followed pericardialremaining sixmetastasis patients hadat the an time OS range of initial of 3-14 treatment, months. lowby supraventricularvoltage of limb leads, tachycardia and left (SVT)or right (excluding axis deviation. AF). andThree all ofresponded them had satisfactorily cardiac metastasis to chemotherapy, and two which had Then came non-specific change, including ST-T changes, presented as markedly reduced sizes of primary lesions

Three patients had conduction block: one patient had a I° (AVB), and two patients had right chemotherapyand heart invasion. with Forsequential the remaining radiotherapy. two patients, However, one Treatmentbundle branch and block outcome (RBBB). pericardialpatient achieved metastasis partial soon response appeared, (PR) and after malignant first-line tumor EC Imaging data for seven patients were complete, and second-line of single agent topotecan was performed, but cells were identified in the pericardial effusion. Hence the could be used toTable assess 3: ECG the abnormalities clinical outcomes. (Table 4). ECGa changes No. % with an unsatisfied outcome. treatment, and pericardial involvement occurred after Arrhythmia 11 100.00 fourAnother cycles of case chemotherapy. was not sensitive Six out to of the seven first-line patients EP Supraventricular arrhythmia 10 90.91 experienced new ECG abnormalities when diagnosed Supraventricular premature 9 81.82 SVTb 6 54.55 c AF 8 72.73 with cardiac or pericardial metastasis, including AF, Ventricular premature 5 45.45 inSVT, 2 oflow 5 patientsvoltage andwho ST-T had change.good clinical Four patientsoutcomes had (which ECG 4 36.36 changes after treatment. These arrhythmias improved Sinus 2 18.18 Non-specific changes 6 54.55 were evaluated by imaging). Both patients had AF and ST- changes 3 27.27 SVT on initial admission. The 24-hour ECG revealed the Low voltage 2 18.18 disappearance of AF and a reduction of SVT frequency 1 9.09 (18312 beats per 24 hours, and the other recorded less 1 9.09 improvement in limb leads low voltage. Conversely, two than 1% per 24 hours after treatment). One patient had Conduction block 3 27.27 patients who progressed after treatment developed new RBBBd 2 18.18 AVBe 1 9.09 types of ECG abnormalities, including new-onset AF, SVT, a: electrocardiogram and emerging low voltage and ST-T wave changes (Fig 1, b: supraventricular tachycardia As of the end of the statistics, 2 of 11 patients with c: atrial fibrillation Fig 2). d: right e: atrioventricular block cardiac involvement were lost to follow-up, and the OS was Table 4: Electrocardiographic, clinical outcomes,calculated and survival according time afterto the treatment. last follow-up date. The other Patient No. Sex Age Treatment Evaluation ECG changes after treatment OSa 1 F 77 ECb PRc (-) 11 2 M 57 EC PR AF disappeared, SVT frequency reduced 10 3 M 45 EC PR (-) 3 4 M 55 EC PR (-) 11 AF disappeared, SVT frequency reduced, low Lost to 5 M 58 EC with concurrent radiotherapy PR voltage disappeared. follow up 6 M 59 EC with sequential radiotherapy→topotecan PDd New onset AF and SVT, ST-T wave changes 14 New onset AF and SVT, newly appeared low 7 M 60 EPe PD 4 voltage a: OS: Overall survival b: EC: Etoposide/carboplatin c: PR: Partial response d: PD: Progressive disease e: EP: Etoposide/cisplatin.

Page 9 of 15 He Y, Wang J, Kong L, Jia B, Chi Y, Zhai X, Jin H, Wang Z. Clinical Characteristics of Cardiac and Pericardial Metastasis in Small Cell Lung Cancer with Arrhythmia. J Cardiol and Cardiovasc Journal of Cardiology and Cardiovascular Sciences. 2021;5(1):7-15 Sciences

Figure 1a: Initial ECG in patient 6.

Figure 1b: Newly emerging ST-T wave changes in patient 6.

Page 10 of 15 He Y, Wang J, Kong L, Jia B, Chi Y, Zhai X, Jin H, Wang Z. Clinical Characteristics of Cardiac and Pericardial Metastasis in Small Cell Lung Cancer with Arrhythmia. J Cardiol and Cardiovasc Journal of Cardiology and Cardiovascular Sciences. 2021;5(1):7-15 Sciences

Figure 2a: Initial ECG in patient 7.

Figure 2b: Newly emerging limb leads low voltage in patient 7.

nine patients died of tumor. From the first chemotherapy 12.9 months) (Fig 3), while those of non-heart metastasis date, the median OS of the patients who developed heart was 12 months (95% CI: 9.7-14.3 months). There was no metastasis was estimated to be 11 months (95% CI: 9.1- significant difference between the two groups (P>0.05).

Page 11 of 15 He Y, Wang J, Kong L, Jia B, Chi Y, Zhai X, Jin H, Wang Z. Clinical Characteristics of Cardiac and Pericardial Metastasis in Small Cell Lung Cancer with Arrhythmia. J Cardiol and Cardiovasc Journal of Cardiology and Cardiovascular Sciences. 2021;5(1):7-15 Sciences

If a tumor compresses the coronary artery, the ECG may

infarction changes7,13 manifestrecorded ECG, as ST-T supraventricular wave abnormalities and ventricular or even myocardialpremature . Through analysis of the present which can be detected regardless of the presence of abeats basic are heart most disease. common However, non-specific when the manifestations, ventricular premature beat is polymorphic, or is associated with non-sustained , this may suggest a higher risk of mortality, new on-set , and so 14-16 Figure 3: Survival curve of 11 patients with cardiac metastasis. on a substantial part of arrhythmia in 11 patients. Although Discussion many . cardiovascular In addition to prematurediseases and beats, non-cardiac AF accounted factors, for such as electrolyte disorder, hypoxia, anemia, endocrine, Heart metastasis of SCLC can initially be detected by echocardiography, and cardiac magnetic resonance tumor compression or invasion of the heart or pulmonary is becoming the standard modality for further veindrugs and other factors, can cause AF, rare causes include tissue evaluation cancer,17,18 especially within 90 days after the initial diagnosis 8 underestimated, as most patients are asymptomatic or 19 . Patients with new-onset AF have a higher risk of . But this phenomenon tends to be experience atypical symptoms masked by the primary diagnosis, possibly due to the tumor-related systemic disease and did not go over relevant examinations. Among of AF . In turn, the incidence of AF increases after cancer20. apart from one who had syncope, which might correlate to inflammation, anti-tumor treatment, or comorbid states these analyzed patients, most had no specific symptoms, the arrhythmia caused by pericardial involvement. None of ExceptAmong forthe one eight patient patients who with was AF,undergoing seven manifested chemotherapy new- the patients who underwent echocardiographs presented onset AF after heart or pericardial involvement was found. remaining patients had no related risk factors that can and one who had hyperkalemia when AF occurred, all cardiacwith a decreasedfunction. We left should ventricular raise attention ejection and fraction. diagnose These it infindings a timely indicate manner that with early the heart help metastasis of clinical symptomsdoes not affect and cause AF. Half of the present analyzed cases also recorded examinations. repetitivean onset of tachycardia SVT. The common observed pathogeneses in adults may of be SVT correlated include Pericardium is the most susceptible site of cardiac toreentry, organic enhanced heart disease automaticity and is sometimes and trigger observed activity. in The its involvement, followed by the myocardium and terminal stage21 endocardium9,10 need to suspect cardiac or pericardial involvement in those pathway to invade the pericardium, including the . For cancer patients with arrhythmia, we retrograde and left. The atrium-subcarinal lymphatics is lymphatic the most routes common2,11. 2 also suggested a unique way that lung with a significant variation in the number of premature beats cancer can metastasize through the hilar lymph nodes; diagnosedor SVT after tumors the treatment. and new-onset On the premise arrhythmia of excluding should thebe Tamurathus, even A, patients et al. with lymph node metastasis in N1 stage considered,influence of especiallyother factors, for patients the correlation with imaging between indicating newly

In addition, direct invasion of the original lesion or the hematogenousshould consider pathway the possibility are also routes of pericardial for heart infiltration.metastasis. cardiac infiltration. amplitudesIn addition, of <5 half mm of inthese the limbpatients leads, had is nonspecificoften correlated ECG for the highest proportion (6/11), among which, 5 patients toabnormalities. the process Lowof electrical QRS voltage, signals defined from as their the sumgeneration of QRS hadAs is hilar shown lymph in Table1, node metastasis.pericardium Eight involvement patients accountedpresented with primary focus directly invading the mediastinum. In conclusion, we need to consider the possibility of tumor in the heart to conduction to the skin electrodes. The QRS disseminate to the heart through the lymphatic routes or disease,voltage mayand beobesity affected22 by myocardial infiltrative disease, directly invasion in patients with relevant lymph nodes and pericardial infiltration, chronic obstructive pulmonary mediastinal involvement. . The prevalence rate of RBBB and I° Previous studies have reported that there is a AVB increase with age, and patients without symptoms do correlation between cardiac metastasis and abnormal ECG not23,24 need treat. RBBB has no significant association with changes. Pericardial involvement can lead to pericardial cardiac disease, while I°AVB has a higher risk of developing tamponade. Myocardial metastasis can result in a AF . Non-specific ST-segment changes may be related conduction block and different types of arrhythmia10,12. to two causes: repolarization25 discordance due to bundle branch block, or improper measurement of ST-segment amplitude due to AF . Therefore, a change in QRS voltage Page 12 of 15 He Y, Wang J, Kong L, Jia B, Chi Y, Zhai X, Jin H, Wang Z. Clinical Characteristics of Cardiac and Pericardial Metastasis in Small Cell Lung Cancer with Arrhythmia. J Cardiol and Cardiovasc Journal of Cardiology and Cardiovascular Sciences. 2021;5(1):7-15 Sciences

structuralmay have heart certain disease, pathological dynamic significance, ECG changes while provide ST-T butimproved the outcome imaging of this or ECGpatient abnormalities. was not mentioned One patient in the hintschanges for mayheart secondary metastasis. to arrhythmia. For those without report.received In surgical another treatmentpatient who and experienced adjuvant chemotherapy, sudden death

of SCLC was found by autopsy. It was speculated that the SCLC is platinum-based doublet-treatment (cisplatin or with no definite past history, and pericardial infiltration carboplatinThe standard combined care with of etoposide). first-line chemotherapy In limited stages, for passed away before receiving treatment27-33. Previous cases standard chemotherapy combined with concurrent pericardial tamponade led to the sudden death. Two patients diagnosed with heart involvement in SCLC patients. SCLC 90% of patients. In extensive stages, 60-70% of patients suggested a potential benefit of receiving treatment after thoracic radiotherapy yields an objective response 26 in. radiotherapy may cause early cardiac events, such as pericardialis sensitive effusion, to chemotherapy valvular disease, and radiotherapy. and atrial arrhythmia, Thoracic cisplatinachieve anor carboplatin objective responsetreatment 1,26 with. Seven chemotherapy patients had 34. However, when Therecomplete is imaging no significant data through difference the whole in efficacy course between of their patients suffer from acute cardiovascular events, such as pericardialwhich were tamponade, associated withit is still worse a reasonable OS treatment approach to relieve the clinical symptoms31. Quraishi, M. A, treatment,disease. All they received all responded standard well, first-line suggesting chemotherapy. that even et al.4 reported that in patients with pericardial metastasis, patientsAlthough with five ofheart them invasion had heart can metastasisbe controlled at the through initial treatment. After chemotherapy, the ECG abnormalities of two patients improved along with the reduction of cardiac diagnosedthose receiving with treatment cardiac or had pericardial a longer OSmetastasis, than those active who lesions, while 2 patients progressed with the occurrence treatmentdid not. These can lead findings to a better serve prognosis. as a reminder that though electrophysiological activity, and further triggers different typesof pericardial of arrhythmia. metastasis. In The patients heart infiltrationwho only affects received the The present study had some limitations. First, the sample anti-tumor therapy, improved or newly appearing ECG whether or not they received treatment, or had different size was too small to compare the OS between patients changes may be hints for undetected cardiac metastasis. treatments. Second, none of these patients underwent cardiac magnetic resonance or biopsy leading to defects of therapeutic effect. clinical evidence in these patients. Additionally, diagnostic Timely prediction and active treatment may have a better suspicion bias on the ECG changes may exist once cases

more clinical data is needed to support these assumptions. chemotherapy,Table 5 summarizes and one the patient previously received reported cardiac SCLC present with cardiac or pericardial involvement. Therefore, radiotherapy.cases with heart All involvement.three of these Two patients patients achieved received Conclusion improvement, including relief of clinical symptoms, SCLC cardiac and/or metastasis is not uncommon.

Table 5: Clinical characteristics, treatment and prognosis of patients with heart metastasis from SCLC. Examination after Patient No. Sex Age Clinical symptoms Major objective examinations treatment Outcome treatment CTa: Tumor extends from pul- Operation, adjuvant 1 27 M 69 Hemoptysis (-) Not mentioned. monary vein to left atrium. chemotherapy Weakness of right CT: Right ventricular mass. ECG: Died within 1 2 28 M 62 (-) (-) limb. ST, PR elevation. month. Shortness of Autopsy: Pericardial tampon- 3 29 M 49 (-) (-) Sudden death. breath. ade, right heart involvement. PETb/CT: Intense focal activity in No residual 18FDGc Died within 20 4 30 M 69 Right chest pain. 6*EC right ventricle. uptake. months. Cardiac radiother- Reduction of cardiac Died within 1 5 31 M 64 Dyspnea, cough. CT: Pericardial effusion. apy mass month. Cognitive impair- CT: Tumor invades Left atrium 6 32 F 66 (-) (-) ment. and left ventricle. Died ECG: Low voltage, alternating Pericardial injection 7 33 M 62 Abdominal pain electric heart axis. Chest radio- Recovered ECG. with cisplatin, 4*EC Not mentioned. gram: Pericardial infiltration. a: CT: Computed tomography b: PET: Positron emission tomography c: 18FDG: 18F- fluorodeoxyglucose.

Page 13 of 15 He Y, Wang J, Kong L, Jia B, Chi Y, Zhai X, Jin H, Wang Z. Clinical Characteristics of Cardiac and Pericardial Metastasis in Small Cell Lung Cancer with Arrhythmia. J Cardiol and Cardiovasc Journal of Cardiology and Cardiovascular Sciences. 2021;5(1):7-15 Sciences

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