Complete heart block and cardiac tamponade secondary to Merkel cell carcinoma cardiac metastases.

Abstract: This is a unique case of Merkel cell carcinoma, a rare neuroendocrine tumor, metastasizing to the heart and inducing a progression of cardiac complications such as new-onset atrial fibrillation, malignant pericardial effusion with tamponade physiology, first-degree heart block, and complete heart block. Metastases to the heart are relatively rare but should be suspected if a patient with a known neoplasm presents with new cardiac manifestations. This is the first case report of cardiac metastases from Merkel cell carcinoma causing cardiac tamponade or complete heart block. This case highlights the clinical decision-making involved in managing cardiac tamponade and complete heart block in the setting of metastatic disease to the heart.

Key Words: Merkel cell carcinoma, heart block, cardiac metastases, cardiac tamponade

Introduction

This case report describes the progressive infiltration of the heart by an aggressive Merkel cell carcinoma, a rare skin cancer of probable neuroendocrine origin. As the tumor invaded the heart, a number of cardiac complications occurred, including new-onset atrial fibrillation, malignant pericardial effusion with tamponade physiology, first-degree heart block, and complete heart block.

Case Report

In January 2004, a 66-year-old white male was admitted to our inpatient medicine ward with increasing dyspnea and fatigue for I week. He was afebrile, with a blood pressure of 146/75 and an irregular pulse of 135. On examination, jugular venous pressure was measured at 7 cm, heart sounds were muffled, and lungs were clear to auscultation bilaterally. Notably, no pulsus paradoxus was detected. He had new-onset atrial fibrillation in a rapid ventricular response and new cardiomegaly on chest radiography.

The patient's medical history was significant for Merkel cell carcinoma, a rare neuroendocrine tumor involving the right thigh first diagnosed 5 years before admission. He had undergone wide local excision with subsequent chemotherapy and radiotherapy for a total dose of 50 Gy. Six months before admission, he had a recurrence in his right groin and was given additional radiotherapy with a total dose of 37.5 Gy, with a good tumor response to treatment. However, 4 months before admission, the patient was noted to have a new anterior mediastinal mass consistent with metastatic disease, for which he received an additional 35 Gy of radiation.

At the time of admission to our ward, a transthoracic echocardiogram showed a large circumferential pericardial effusion, 2.4 cm anteriorly and 3.5 cm laterally. The inferior vena cava was dilated with minimal respiratory variation, and there was a 25 to 30% variation in mitral E-wave velocity, suggesting tamponade physiology. Assessment of chamber collapse was difficult because of the 4 X 5 cmextracardiac mass at the right ventricular/right atrial junction. The patient was in atrial fibrillation with rapid ventricular rate at the time, which also made it a technically limited study. Transesophageal echocardiography then revealed a tumor adjacent to the right atrial wall along with extensive tumor burden in the pericardial space adherent to the right heart chambers (Fig. 1).

The patient was diagnosed with a malignant pericardial effusion and tamponade physiology. Pericardiocentesis was urgently performed in the cardiac catheterization laboratory, producing 1,150 mL of serosanguineous drainage. Just before the procedure, right heart catheterization was done, revealing tamponade physiology. The right atrial pressure was 23 mm Hg, right ventricular pressure was 45/22 mm Hg, pulmonary artery pressure was 42/23 mm Hg, pulmonary capillary wedge pressure was 23 mm Hg, aortic pressure was 135/86 mm Hg, and pericardial pressure was 25 mm Hg. The patient remained in atrial fibrillation, with a rate of 120 to 140 beats per minute for several hours after the procedure. A discussion was held with the team and the patient. A pericardial window was offered to the patient, given the large amount of effusion present and the need for a definitive diagnosis of the atrial mass that could be accomplished by biopsy, considering that the patient also had a remote history of melanoma with some minimal lymphatic invasion, which had been excised previously. The following day, a subxiphoid pericardial window was performed, draining an additional 250 mL of fluid from the pericardium. At this time, as suggested by echocardiography, a 4 X 4 cm exophytic mass was seen growing out of the right atrium with pericardial tumor studding on the posterior diaphragm. Biopsy of the right atrial mass was consistent with metastatic Merkel cell carcinoma. Immunohistological staining pattern revealed tumor cells with a characteristic paranuclear dot-like staining for epithelial marker cytokeratin 20. Neuroendocrine features were seen by positive staining for chromogranin A and synaptophysin (Fig. 2). Pericardial biopsy revealed mesothelium-lined fibroadipose tissue and acute inflammatory cells without diagnostic tumor infiltration.

After surgery, the patient remained in rate-controlled atrial fibrillation. Digoxin was initiated for rate control, but the patient spontaneously converted back to normal sinus rhythm. The anterior chest wall tube was removed without any evidence of recurrent effusion, and he was discharged home. Shortly after discharge, the patient underwent syngeneic hematopoietic cell transplantation and two courses of high-dose chemotherapy with melphalan for Merkel cell carcinoma with the goal of temporary remission.

Eight months later, the patient presented again to the hospital, now in a fluid-overloaded state, with acute onset of dyspnea the night before and a new productive cough for 3 days. Of note, he had received 4 U of platelets with aggressive prehydration and posthydration the day previously. The patient was afebrile, with a blood pressure of 124/65 and a pulse of 65, and had an oxygen saturation of 95% on 5 L of oxygen by nasal cannula. Examination revealed a jugular venous pressure of 11 cm, diffuse crackles in bilateral lung fields, and 3+ pitting edema in the bilateral lower extremities. Electrocardiography displayed a new complete heart block with a narrow-complex junctional escape rhythm of 60 beats per minute. The most likely cause of the complete heart block was thought to be extracardiac compression by the metastatic tumor with possible infiltration of the cardiac conduction system. Serial serum troponin T values were elevated, also supporting the likelihood of intracardiac tumor infiltration. No new signs of ischemia were seen on electrocardiography. Transthoracic echocardiography revealed a preserved ejection fraction without any significant pericardial effusion. Computed tomography of the chest revealed an 8-cm pericardial mass surrounding the right atrium, right ventricle, and aortic root. It displaced the right coronary artery anteriorly. Increasing right-sided loculated pericardial effusion and left-sided pleural effusion were also noted (Fig. 3).

On review of electrocardiograms from months prior, evidence of metastatic infiltration of the conduction system was found. Eleven months prior, the patient had been in normal sinus rhythm. Seven months later, a routine electrocardiogram showed first-degree atrioventricular (AV) block. At the time of this admission, the conduction disease had progressed to complete heart block.

The patient was admitted to the inpatient ward for worsening heart failure and presumed chronic obstructive pulmonary disease exacerbation. Therapy was initiated with antibiotics, intravenous Lasix, and a prednisone taper over 12 days. All AV nodal blocking agents were discontinued without any improvement in conduction. After discussion with the team and the patient, it was decided that a pacemaker would be warranted if a slow escape rhythm developed. He was observed on telemetry while his chronic obstructive pulmonary disease exacerbation was treated. On the sixth day, he was noted to have an escape rate of 29 beats per minute while awake. A permanent pacemaker was clearly indicated at this time. As a sequelae of the malignant process, the patient had severe thrombocytopenia (platelet count, 11,000) precluding immediate implant. Pacer implantation was delayed for 2 days, and the patient was given transfused platelets. Possibly as a sequelae of steroid therapy, tumor lysis syndrome developed 2 days later, and the patient died as a result of multiorgan failure before a pacemaker could be implanted.

[FIGURE 1 OMITTED]

Discussion

This case highlights a unique case of Merkel cell carcinoma, a rare neuroendocrine tumor, metastasizing to the heart and inducing a progression of cardiac complications including new-onset atrial fibrillation, malignant pericardial effusion with tamponade physiology, first-degree heart block, and complete heart block.

Merkel cell carcinoma is a rare, aggressive skin cancer of possible neuroendocrine origin with high recurrence rates after excision. Distant metastases will be seen in 40% of these cases, most often to the lungs, liver, bones, meninges, and brain. (1) Merkel cell carcinoma is seen as a small, blue cell tumor on histology and is distinguished from small-cell lung cancer and the small-cell variant of melanoma by immunohistochemistry. Treatment includes wide surgical incision for nonmetastatic disease and adjuvant radiotherapy at 45 to 60 Gy to the primary site and involved lymph nodes. (2) There are a few case reports of cardiac metastases from Merkel cell carcinoma in the literature, although it is unusual. (1,3-5)

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Metastatic spread to the heart occurs in approximately 21% of cancer patients. (6) Cardiac metastases are often asymptomatic and only discovered at autopsy. Tumors most likely to metastasize to the heart include lung, esophageal, lymphoma, breast, malignant melanoma, and leukemia. In general, metastatic cardiac tumors are exponentially more common than primary cardiac tumors, and it is uncommon for the heart to be the only site of metastases from an extracardiac tumor. The pericardium is the most common site of involvement (59% of cases), and the myocardium and epicardium are affected in 29% and 12% of cases, respectively. In addition, intracardiac metastases are more commonly seen within the right side of the heart. (6)

Presenting symptoms can mimic any type of heart disease and can vary, depending on the site of involvement. Pericardial effusion and tamponade are often presenting features of cardiac metastatic involvement. External compression of the coronary arteries may manifest as ischemia. Infiltration and subsequent fibrosis of the cardiac conduction system may lead to conduction disturbances and complete AV block. Neoplastic infiltration of the autonomic fibers supplying the atria can result in atrial arrhythmias. Congestive heart failure may result from neoplastic invasion of the myocardium and blockage of the lymphatic channels draining the heart. Myocardial damage may be compounded by chemotherapy and radiotherapy, often used to treat these disorders. (7,8)

Routes of metastatic growth to the heart include direct invasion, retrograde lymphatic extension, direct venous extension, and hematogenous spread. In this case of Merkel cell metastases, it is likely that the remote primary tumor hematogenously seeded the pericardium and then directly extended to the right atrium. Considering that the atria are in direct contact with the pericardium and are less muscular with weaker contractions, they are more likely than the ventricles to be involved in neoplastic spread. (9)

Diagnosis of cardiac metastases is most often made by echocardiography. However, pericardial lesions are better visualized on MRI or a high-resolution CT scan. Cardiac metastases may also manifest as abnormalities in electrocardiography, including ST-segment elevations, conduction disturbances, arrhythmias, or voltage changes. (9) In this case of metastatic Merkel cell carcinoma, in addition to the echocardiographic evidence of intracardiac tumor and pericardial effusion, there were electrocardiographic changes over the course of the disease. Voltage decreased with increasing tumor burden, atrial fibrillation developed secondary to right atrial irritation, and progressive conduction abnormalities were seen.

This case also highlights the critical decision-making that a physician must make when dealing with a patient with cardiac metastases. One must be able to quickly make a clinical diagnosis of cardiac tamponade and determine the most appropriate treatment strategy. Another critical issue is the timing of permanent pacemaker insertion in a patient with a clinical indication and coexisting terminal illness.

The diagnosis of cardiac tamponade must be done in a timely manner. Tamponade results from a rapid or slow compression of the heart due to the increasing intrapericardial pressure of accumulating fluid, often malignant effusion. It may be acute or chronic and can present anywhere on a hemodynamic continuum from mild (pericardial pressure lower than 10 mm Hg) to severe (pericardial pressure higher than 20 mm Hg). Symptoms include tachypnea, progressive dyspnea, and generalized fatigue, although mild tamponade is often asymptomatic. Key clinical findings are tachycardia, hypotension, jugular venous distension, muffled heart sounds, and pulsus paradoxus, which is defined as the inspiratory systolic drop in arterial pressure of 10 mm Hg or more. However, it is useful to note that there are several conditions in which a pulsus paradoxus will be absent in the presence of cardiac tamponade. Examples include extreme hypotension, pericardial adhesions, atrial septal defects, severe aortic regurgitation, right ventricular hypertrophy without pulmonary hypertension, and, in some cases, low-pressure tamponade. In this case, the patient's pericardial adhesions surrounding and infiltrating the right heart probably impeded volume changes throughout the cardiac cycle, making the pulsus paradoxus undetectable. (10)

Cardiac tamponade is diagnosed by Doppler echocardiography, which often shows the diastolic collapse of the right atrium and right ventricle. In some patients, the left atrium may also collapse, which is a very specific sign. The inferior vena cava is dilated with minimal respiratory variation. Cardiac catheterization will show elevation and equilibration of right atrial, pulmonary capillary wedge, and pulmonary artery diastolic pressures, usually between 10 and 30 mm Hg. (11) Pericardial pressure is also elevated, depending on the amount of effusion, and approximates the pressure in the right atrium. An electrocardiogram may show electrical alternans and reduced voltage. Chest radiography may show cardiomegaly, although this effect is not usually seen unless the effusion is greater than 200 mL.

When treating cardiac tamponade, the goals are to determine the cause of the effusion, relieve immediate symptoms, and prevent recurrence. In a hemodynamically unstable patient, initial relief of symptoms may be accomplished with percutaneous pericardiocentesis under echocardiographic guidance, a procedure with low morbidity and mortality rates. However, in patients with a possible malignant effusion, a subxiphoid pericardial window, which is also a fairly safe procedure, offers the additional benefit of biopsy and has been shown to be more effective in preventing recurrence. (12-14) Chemotherapy and radiotherapy are also effective in controlling metastases in sensitive tumors such as lymphomas and leukemias and in solid tumors such as breast cancer and Merkel cell carcinoma. Local sclerotherapy with tetracycline hydrochloride or bleomycin has also been used with good effect. (12)

Another clinical consideration in this case is the timing of permanent pacemaker placement in a patient with complete heart block due to metastatic disease. Although initially this patient had a hemodynamically stable escape rhythm, he eventually developed severe symptomatic bradycardia several days after admission but was too clinically unstable in noncardiac issues to undergo permanent pacemaker implantation. As this case illustrates, it can be very difficult to determine the optimal timing of pacemaker placement in a patient with multiple comorbidities. In many cases, however, the heart rate is not as important as the presence of signs or symptoms. A pacemaker may be recommended at a seemingly adequate rate if there is a high likelihood of progression of conduction system disease, profound bradycardia, or sinus pauses while awake or asleep, depressed left ventricular dysfunction, or limitation of activity due to chronotropic incompetence. In cases of AV block, the permanence of the block must be considered as well, particularly in cases of acute ischemia or reversible medication defects. (15)

The development of tumor lysis syndrome (TLS) in this patient also deserves some mention. Risk factors of TLS include large tumor burden, neoplasms with high sensitivity to chemotherapy, or high growth fraction and the presence of pre-existing renal impairment. Corticosteroids have also been shown to induce tumor lysis syndrome. (16,17) Possible causes of TLS in this patient include his baseline renal insufficiency, the treatment with prednisone, and the high tumor burden.

Conclusion

In summary, cardiac metastases should be considered in any patient with history of malignant tumors presenting with unexplained arrhythmias, pericardial effusion, new murmurs, or electrocardiographic changes. This case represents a wide spectrum of cardiac involvement from a rare neuroendocrine tumor. One should be aware of the diagnostic signs of cardiac tamponade and complete heart block in the setting of metastatic disease and be able treat the patient appropriately.

References

1. Jongbloed MRM, Kanen BLJ, Visser M, et al. Intracardiac metastasis from a Merkel cell carcinoma. J Clin Oncol 2004;22:1153-1156.

2. Goessling W, McKee PH, Mayer RJ. Merkel cell carcinoma. J Clin Oncol 2002;20:588-598.

3. Yamana N, Sueyama H, Hamada M. Cardiac metastasis from Merkel cell skin carcinoma. Int J Clin Oncol 2004;9:210-212.

4. Chao TC, Park, JM, Rhee H, et al. Merkel cell tumor of the back detected during pregnancy. Plast Reconstr Surg 1990;86:347-351.

5. Page E, Fric D, Barjhoux JL, et al. Cardiac metastasis from a Merkel cell skin carcinoma: A case report. Arch Mal Coeur Vaiss 2001;94:1423-1426.

6. Sarjeant JM, Butany J, Cusimano RJ. Cancer of the heart. Am J Cardiovasc Drugs 2003;3:407-421.

7. Roberts WC. Primary and secondary neoplasms of the heart. Am J Cardiol 1997;80:671-682.

8. Hall RJ, Cooley DA, McAllister HA Jr, et al. Neoplastic heart disease. In Fuster V, Alexander RW, O'Rourke RA, et al. (eds): Hurst's The Heart, 11th ed, New York, McGraw-Hill, 2004, pp. 2081-2096.

9. Salcedo EE, Cohen GI, White RD, et al. Cardiac tumors: diagnosis and management. Curr Probl Cardiol 1992;17:79-131.

10. Spodick DH. Acute cardiac tamponade. N Engl J Med 2003;349:684-690.

11. Hoit BD, Faul MD. Diseases of the pericardium. In Fuster V, Alexander RW, O'Rourke RA, et al. (eds): Hurst's The Heart, 11th ed, New York: McGraw-Hill, 2004, pp. 1985-1988.

12. Vaitkus PT, Herman HC, LeWinter MM, Treatment of malignant pericardial effusion. JAMA 1994;272:59-64.

13. Laham RJ, Cohen DJ, Kuntz RE, et al. Pericardial effusion in patients with cancer: outcome with contemporary management strategies. Heart 1996;75:67-71.

14. Allen KB, Faber LP, Warren WH, et al. Pericardial effusion: subxiphoid pericardiostomy versus percutaneous catheter drainage. Ann Thorac Surg 1996;67:437-440.

15. Gregoratoros G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 guideline update for the implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the ACC/AHA Task Force on practice guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines) Circulation 2002;106:2145-2161.

16. Sparano J, Ramirez M, Wiernik PH. Increasing recognition of corticosteroid-induced tumor lysis syndrome in non-Hodgkin's lymphoma. Cancer 1990;65:1072-1073.

17. Habib GS, Saliba WR. Tumor lysis syndrome after hydrocortisone treatment in metastatic melanoma: a case report and review of the literature. Am J Med Sci 2002;323:155-157.</p> <pre> A friend is a gift to give yourself --Robert Louis Stevenson </pre> <p>CAPT Maria Conley, USAF, MC, MAJ Karin Hawkins, USAF, MC, and LT COL David Ririe, USAF, MC

From the Departments of Internal Medicine, Oncology, and Cardiology, Wilford Hall Medical Center, Lackland Air Force Base, TX.

Reprint requests to Dr. Maria Conley, 2200 Bergquist Drive, Suite 1 759th MDOS/MMIMR, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, TX 78236.

The views expressed herein are those of the authors and do not reflect the official policy of the Department of Defense, the United States Air Force, or other departments of the US government.

Accepted August 15, 2005.

RELATED ARTICLE: Key Points

* One should be aware of the diagnostic signs of cardiac tamponade and complete heart block in the setting of metastatic disease and be able treat the patient appropriately.

* Presenting symptoms of cardiac metastases can mimic any type of heart disease and can vary, depending on the site of involvement.

* Echocardiography is a powerful tool for the diagnosis of pericardial effusion and cardiac tumors.

* Cardiac metastases should be considered in any patient with a history of malignant tumors presenting with unexplained arrhythmias, pericardial effusion, new murmurs, or electrocardiographic changes.