**Neoplastic Pericardial Disease**

## Mitja Letonja

*Medical Faculty Maribor, General Hospital Ptuj, Slovenia* 

#### **1. Introduction**

200 Inflammatory Diseases – Immunopathology, Clinical and Pharmacological Bases

[37] Petroianu A, Alberti LR, Zac RI. Assessment of the persistence of faecal loading in the

[38] Doria AS. Optimizing the role of imaging in appendicitis. Pediatr Radiol 2009; 39

[39] Poortman P, Oostvogel HJ, Bosma E et al. Improving diagnosis of acute appendicitis. J

[40] Parks NA, Schroeppel TJ. Update on imaging for acute appendicitis. Surg Clin North

[41] Krajewski S, Brown J, Phang T, Raval M, Brown CJ. Impact of computed tomography

[42] LeeSL, Islam S, Cassidy LD, Abdullah F, Arca MJ. Antibiotics and appendicitis in the

[44] Cobben LPJ, Otterloo AM, Puylaert JBCM. Spontaneously resolving appendicitis.

[45] Markides G, Subar D, Riyad K. Laparoscopic versus open appendectomy in adults

[46] Bhandarkar D, Shah RMC. A novel technique for extraction of the appendix in laparoscopic appendectomy. Surg Laparosc Endosc Percut Tech 2002; 12: 117-118. [47] Motson RW Kelly MD. Simplified technique for laparoscopic appendectomy. Aust

[48] Liu Z, Zhang P, Ma Y, et al. Laparoscopy or not. Surg Laparosc Endosc Percutan Tech

[49] Wang X, Zhang W, Yang X, Shao J, Zhou X, Yuan J. Complicated appendicitis in

[50] Howard C, Jen MD, Stephen B, Shew MD. Laparoscopic versus open appendectomy in

[51] Nakhamiyayev V, Galldin L, Chiarello M, Lumba A, Gorecki PJ. Laparoscopic

[52] Lee J, Baek J, Kim W. Laparoscopic transumbilical single-port appendectomy. Surg

[53] Vidal O, Valentini M, Ginestà C, Martí J, Espert JJ, Benarroch G, García-Valdecasas JC.

[54] Akgür FM, Olguner M, Hakgüder G, Ateş O. Appendectomy conducted with single

[55] Saber AA, Elgamal MH, Ghazaly TH, Dewoolkar AV, Akl A. Simple technique for

appendectomy is the preferred approach for appendicitis. Surg Endosc 2010; 24:

Laparoendoscopic single-site surgery appendectomy. Surg Endosc 2010; 24: 686-

port incisionless-intracorporeal conventional equipment-endoscopic surgery. J

single incision transumbilical laparoscopic appendectomy. Int J Surg 2010; 8: 128-

with complicated appenidicitis. World J Surg 2010; 34: 2026-40.

of the abdomen on clinical outcomes in patients with acute right lower quadrant

caecum in presence of acute appendicitis. Int J Surg. 2007; 5: 11-6.

(Suppl 2):S144–S148

Am 2011; 91: 141-54.

Am Coll Surg 2009; 208: 434-41.

pain. Can J Surg 2011; 54: 43-53.

Radiology 2000; 215: 349-352.

New Zeal J Surg 2002; 72: 294–295.

children. J Pediat Surg 2009; 44: 1924-1927.

Laparosc Endosc Percut Tech 2010; 20: 100-103.

children. J Surg Res 2010; 161: 13-17.

Pediat Surg 2010; 45: 1061-1063.

2010; 20: 362-70.

859-864.

691.

130.

pediatric population. J Pediatr Surg 2010; 45: 2181-5. [43] Khairy G. Acute appendicitis. Saudi J Gastroenterol 2009; 15: 167-70.

Malignant pericardial disease represents a common cause of morbidity and mortality in patients with cancer. Malignant tumours of the pericardium may occur as primary or secondary tumours. Primary tumours of the pericardium occur rarely, and secondary involvement of the pericardium constitutes the majority of the cases of malignant disease of the pericardium. In necropsy series, the pericardium is involved in 5 to 40% of patients with malignant disease (1-3). Autopsy studies overestimate the clinical problem because they mostly include terminally ill patients and also identify microscopic metastases even without pericardial effusion. For the majority of patients, a clinical manifestation of neoplastic pericarditis is absent or remains unrecognised during their lifetime. In a study comparing clinical and pathologic features of pericardial metastases, 60%-70% were clinically non significant (4). Clinically, neoplastic pericarditis presents itself as acute pericarditis, pericardial effusion, effusive-constrictive pericarditis or cardiac tamponade (5). In their retrospective analysis from the years 1979 to 2000, the Mayo Clinic reported a decrease of the prevalence of cancer among symptomatic pericardial effusion, mainly due to an increase of pericardial effusion due to postoperative procedures or perforations from invasive procedures, rather than to a decrease of malignant pericarditis cases (6). A Spanish study observing the years 1998-2002 and an Italian study observing the years 1996-2003, report a neoplastic etiology among pericardial effusion in 13% and 7.3%, respectively (7,8). The relative proportions of neoplastic pericarditis in particular population depends on the prevalence of cancer and the prevalence of other causes of effusion in particular populations.

#### **2. Clinical picture**

Clinically, neoplastic pericarditis can be presented as acute pericarditis where at least 2 criteria of the following 4 should be present: 1. characteristic chest pain; 2. pericardial friction rub; 3. suggestive electrocardiographic changes; and 4. new or worsening pericardial effusion (9). Neoplastic pericarditis is also manifested as effusive-constrictive pericarditis where the diastolic filling is limited by the by restricted inelastic pericardium, which is inflamed, scarred, or calcified and thicker than normal. Two other clinical pictures are pericardial effusions and cardiac tamponade (4,10). In rare cases, pericardial effusion is the initial manifestation of malignancy, and the first review of 29 isolated cases of cancer first manifested with pericardial effusion was published by Fraser in 1974

Neoplastic Pericardial Disease 203

importance. The gross appearance of the pericardial fluid is not useful in differentiating malignant from non-malignant effusion (20). A cytological examination of pericardial fluid confirmed the diagnosis of malignant pericardial effusion in 65% to 85% of cases (21). Even with accurate sampling and cytopreparatory techniques, the diagnosis is not always simple, and sometimes impossible. In cytology-negative samples of pericardial fluid the dosage of tumour markers such as carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), serum cytocheratin 19 fragments (CYFRA 21-1) and carbohydrate antigens CA 125, CA 15-3 and CA 19-9 may be helpful in the setting of an equivocal diagnosis (22). However, there is no tumor marker that alone has sufficient diagnostic accuracy in discriminating between malignant and benign pericardial diseases. Measuring a panel of tumor markers as was proposed for the diagnosis in pleural effusion also does not provide a much higher sensitivity. At present, for the confirmation of the diagnosis of malignant pericardial effusion, there is a firm recommendation for the assessment of CEA and CYFRA 21-1 (23- 26). Open pericardial biopsy or pericardoscopy with visualisation of the pericardial surface and guided biopsies of suspicious areas can identify most of the remaining cases (5). A search for the primary tumour must be undertaken because metastases to the pericardium are much more common than the primary tumour and furthermore, primary tumors of the heart are far less common than metastatic tumours to the heart. Primary tumours of the pericardium are usually sarcomas or mesotheliomas (27,28). The metastatic cancer is most often carcinoma of the lung (40%), breast (22%), leukemia and lymphoma (15%), sarcomas

The reason for the heart and the pericardium not being affected by primary cancer, and cardiac tissue mostly being invaded by the metastatic process can probably be explained with the concept of immune privilege which was first proposed in the 1940s by the Nobel laureate, P.B. Medawar and colleagues. At present, the eye, brain and reproductive organs are endowed with immune privilege where inflammation is self-regulated so as to preserve organ functions (29,30). There are also a lot of reports which might indicate self-regulated inflammation of the heart and pericardium as well. The reaction of cardiac tissue to acute injury involves interacting cascades of cellular and molecular responses that encompass inflammation, hormonal signalling, extracellular matrix remodelling, and compensatory adaptation of cardiomyocytes. There is a significant importance of acute inflammation occurring during acute myocardial infarction where the infarct scar is a dynamic tissue: cellular, vascularised, metabolically active and contractile. Although the induction of proinflammatory mediators is important for the clearance of the wound from dead cardiomyocytes and matrix debris, the activation of inflammatory pathways is transient and followed by the repression of inflammatory gene synthesis and the resolution of the leukocytic infiltrate (31). There is also evidence of heart specific cardiomyocytes apoptosis and changes in interstitial tissue of the heart in the progression of heart failure, as in hypertension, myocarditis and after myocardial infarction. Ongoing inflammation is of great importance in chronic heart failure. The marker of inflammation, the C-reactive protein (CRP), is elevated in chronic heart failure and is produced by the liver in response to cytokines such as IL-1, IL-6, and TNF-alpha. Inflammatory cytokines and chemokines plays an active role in cardiac deterioration in chronic heart failure through the induction of endothelial dysfunction and apoptosis of cardiomyocytes (32,33). Therefore, a chronic inflammatory response in heart and vessels also produces different end stage complications compared to other tissue and due to their close interaction with angiogenesis, apoptosis and

(3.5%) and melanoma (2.7%) (10).

(11,12). Reports of cardiac tamponade as an initial presentation of malignancy are even much less prevalent, but we report a patient with cardiac tamponade as the first manifestation of lung cancer, although the occurrence of malignant cardiac tamponade is underestimated due to non-specific signs and symptoms (13,14). Acute dyspnea is the most commonly presented symptom in a review of malignant tamponade pooling several series with an incidence of 78%. The other reported symptoms were cough (46%), chest pain (27%), orthopnea (26%), and weakness (19%). On physical examination the most frequently detected findings are sinus tachycardia (50%), jugular venous distention (45%), hepatomegaly (36%) and peripheral edema (35%). Classical findings of pericardial tamponade such as pulsus paradoxus, pericardial rub and Kussmaul's sign – occurred in only 30%, 12% and 5%, respectively (13-15). Despite the assumption that patient presented with tamponade have a worse prognosis than the patient with pericardial effusion without tamponade, no data are available to allow the stratification of the prognosis based on clinical presentation.

#### **3. Diagnosis**

The ECG changes were suggestive of pericardial involvement in some patients. There are reports of sinus tachycardia which is usual in terminal malignancy, but should also be considered as an important sign of cardiac involvement. The presence of low voltage in limb leads, non-specific T-wave abnormalities, ST-segment elevation, atrial fibrillation and electrical alternans are neither common nor specific findings for malignant pericardial effusion (5). The chest x-ray showed non-specific cardiomegaly and indicates at least 200 ml of pericardial fluid (16). Pleural effusion is presented in more than half of the patients in literature (5). The echocardiogram documented the presence and magnitude of pericardial effusion which is detected as an echo-free space between the left ventricular posterior wall and the lung. As effusion grows in size, we observed besides the echo-free space the swinging of the heart, and abnormal septal motion. Echocardiography differentiates cardiac tamponade from other causes of systemic venous hypertension and arterial hypotension, including constrictive pericarditis, cardiomyopathy and right ventricular infarction. Typical echocardiographic findings in tamponade include late diastolic collapse of the right atrium and early diastolic collapse of the right ventricle when the intrapericardial pressure exceeds intracavitary pressure. Left atrial collapse, which can occur in tamponade, is very specific but is not sensitive for tamponade. Abnormal septal motion is described with bulges of the intraventricular septum during inspiration into the left ventricle due to an increased systemic venous return to the right ventricle and a limited expansion of the right ventricular free wall due to the increase in intrapericardial pressure. With expiration, the transmitral pressure gradient increases and the systemic venous return decreases and we observe a reversal of diastolic flow in the hepatic veins (17). Echocardiography also guides pericardiocentesis (18). Cardiac computed tomography (CT) and cardiac magnetic resonance imaging (CMR) are increasingly being used in the diagnosis of pericardial diseases. Both imaging modalities are very sensitive in the detection of generalised or loculated effusions and can also be used to measure the pericardial thickness (19).

Pericardial effusions in patients with cancer are not always due to malignancy. Other causes of pericardial effusion are radiation-induced, idiopathic, hypoalbuminemic, drug-related or uremic (5). Defining the cause of a pericardial effusion in a patient with cancer is of vital

(11,12). Reports of cardiac tamponade as an initial presentation of malignancy are even much less prevalent, but we report a patient with cardiac tamponade as the first manifestation of lung cancer, although the occurrence of malignant cardiac tamponade is underestimated due to non-specific signs and symptoms (13,14). Acute dyspnea is the most commonly presented symptom in a review of malignant tamponade pooling several series with an incidence of 78%. The other reported symptoms were cough (46%), chest pain (27%), orthopnea (26%), and weakness (19%). On physical examination the most frequently detected findings are sinus tachycardia (50%), jugular venous distention (45%), hepatomegaly (36%) and peripheral edema (35%). Classical findings of pericardial tamponade such as pulsus paradoxus, pericardial rub and Kussmaul's sign – occurred in only 30%, 12% and 5%, respectively (13-15). Despite the assumption that patient presented with tamponade have a worse prognosis than the patient with pericardial effusion without tamponade, no data are available to allow the stratification of the prognosis

The ECG changes were suggestive of pericardial involvement in some patients. There are reports of sinus tachycardia which is usual in terminal malignancy, but should also be considered as an important sign of cardiac involvement. The presence of low voltage in limb leads, non-specific T-wave abnormalities, ST-segment elevation, atrial fibrillation and electrical alternans are neither common nor specific findings for malignant pericardial effusion (5). The chest x-ray showed non-specific cardiomegaly and indicates at least 200 ml of pericardial fluid (16). Pleural effusion is presented in more than half of the patients in literature (5). The echocardiogram documented the presence and magnitude of pericardial effusion which is detected as an echo-free space between the left ventricular posterior wall and the lung. As effusion grows in size, we observed besides the echo-free space the swinging of the heart, and abnormal septal motion. Echocardiography differentiates cardiac tamponade from other causes of systemic venous hypertension and arterial hypotension, including constrictive pericarditis, cardiomyopathy and right ventricular infarction. Typical echocardiographic findings in tamponade include late diastolic collapse of the right atrium and early diastolic collapse of the right ventricle when the intrapericardial pressure exceeds intracavitary pressure. Left atrial collapse, which can occur in tamponade, is very specific but is not sensitive for tamponade. Abnormal septal motion is described with bulges of the intraventricular septum during inspiration into the left ventricle due to an increased systemic venous return to the right ventricle and a limited expansion of the right ventricular free wall due to the increase in intrapericardial pressure. With expiration, the transmitral pressure gradient increases and the systemic venous return decreases and we observe a reversal of diastolic flow in the hepatic veins (17). Echocardiography also guides pericardiocentesis (18). Cardiac computed tomography (CT) and cardiac magnetic resonance imaging (CMR) are increasingly being used in the diagnosis of pericardial diseases. Both imaging modalities are very sensitive in the detection of generalised or

loculated effusions and can also be used to measure the pericardial thickness (19).

Pericardial effusions in patients with cancer are not always due to malignancy. Other causes of pericardial effusion are radiation-induced, idiopathic, hypoalbuminemic, drug-related or uremic (5). Defining the cause of a pericardial effusion in a patient with cancer is of vital

based on clinical presentation.

**3. Diagnosis** 

importance. The gross appearance of the pericardial fluid is not useful in differentiating malignant from non-malignant effusion (20). A cytological examination of pericardial fluid confirmed the diagnosis of malignant pericardial effusion in 65% to 85% of cases (21). Even with accurate sampling and cytopreparatory techniques, the diagnosis is not always simple, and sometimes impossible. In cytology-negative samples of pericardial fluid the dosage of tumour markers such as carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), serum cytocheratin 19 fragments (CYFRA 21-1) and carbohydrate antigens CA 125, CA 15-3 and CA 19-9 may be helpful in the setting of an equivocal diagnosis (22). However, there is no tumor marker that alone has sufficient diagnostic accuracy in discriminating between malignant and benign pericardial diseases. Measuring a panel of tumor markers as was proposed for the diagnosis in pleural effusion also does not provide a much higher sensitivity. At present, for the confirmation of the diagnosis of malignant pericardial effusion, there is a firm recommendation for the assessment of CEA and CYFRA 21-1 (23- 26). Open pericardial biopsy or pericardoscopy with visualisation of the pericardial surface and guided biopsies of suspicious areas can identify most of the remaining cases (5). A search for the primary tumour must be undertaken because metastases to the pericardium are much more common than the primary tumour and furthermore, primary tumors of the heart are far less common than metastatic tumours to the heart. Primary tumours of the pericardium are usually sarcomas or mesotheliomas (27,28). The metastatic cancer is most often carcinoma of the lung (40%), breast (22%), leukemia and lymphoma (15%), sarcomas (3.5%) and melanoma (2.7%) (10).

The reason for the heart and the pericardium not being affected by primary cancer, and cardiac tissue mostly being invaded by the metastatic process can probably be explained with the concept of immune privilege which was first proposed in the 1940s by the Nobel laureate, P.B. Medawar and colleagues. At present, the eye, brain and reproductive organs are endowed with immune privilege where inflammation is self-regulated so as to preserve organ functions (29,30). There are also a lot of reports which might indicate self-regulated inflammation of the heart and pericardium as well. The reaction of cardiac tissue to acute injury involves interacting cascades of cellular and molecular responses that encompass inflammation, hormonal signalling, extracellular matrix remodelling, and compensatory adaptation of cardiomyocytes. There is a significant importance of acute inflammation occurring during acute myocardial infarction where the infarct scar is a dynamic tissue: cellular, vascularised, metabolically active and contractile. Although the induction of proinflammatory mediators is important for the clearance of the wound from dead cardiomyocytes and matrix debris, the activation of inflammatory pathways is transient and followed by the repression of inflammatory gene synthesis and the resolution of the leukocytic infiltrate (31). There is also evidence of heart specific cardiomyocytes apoptosis and changes in interstitial tissue of the heart in the progression of heart failure, as in hypertension, myocarditis and after myocardial infarction. Ongoing inflammation is of great importance in chronic heart failure. The marker of inflammation, the C-reactive protein (CRP), is elevated in chronic heart failure and is produced by the liver in response to cytokines such as IL-1, IL-6, and TNF-alpha. Inflammatory cytokines and chemokines plays an active role in cardiac deterioration in chronic heart failure through the induction of endothelial dysfunction and apoptosis of cardiomyocytes (32,33). Therefore, a chronic inflammatory response in heart and vessels also produces different end stage complications compared to other tissue and due to their close interaction with angiogenesis, apoptosis and

Neoplastic Pericardial Disease 205

chemotherapeutic agents are summarized in table 1. Lestuzzi et al. have suggested a "tumour specific" treatment algorithm for neoplastic pericardial effusion in which he preferred cisplatin in pericardial lung carcinoma metastases and bleomycin in pericardial breast carcinoma metastases. Authors reported a low complication rate and significant effectiveness of local chemotherapy. On the basis of personal experience and the review of literature, they conclude that sclerosing therapy should not be considered as the first choice

> Treatment success (%)

Immunomodulator 70 Fever (60%)

Current use

73-75 Severe pain (15-70%)

71-100 Constriction (2.4%)

79-91 Thrombocytopenia (0.9%)

70 Constriction after several

60 None

50-100 Nausea (6.7%)

100 Pain (% no report)

100 Nausea (% no report)

report)

Side effects and complications

Fever (7.5-50%) Infection (0.5%) Constriction (2%)

Pain (50%)

Fever (18%)

months (5%)

Atrial fibrillation (9%)

Leucopoenia (0.9%)

Atrial arrhythmias (4.4%) Constriction (1.1%) Myocardial ischemia (1%)

Nausea (% no report) Vomiting (% no report) Leucopenia (% no report) Fever (% no report)

Leucopenia (% no report) Premature beats (% no

Atrial arrhythmias (9-10%)

Itrapericardial treatment (references)

Tetracycline or Doxycyline (43-46)

OK-432 (47)

Bleomycin (45,48,49)

Thiotepa (50-52)

(58)

(59)

Cisplatin (41,42,53-57)

Nitrogen mustard (60,61)

5-Fluorouracil

(62)

Table 1. .

Mitomycin C

Mitoxantrone

Chemical natures and

Antineoplastic agent,

Inhibits synthesis of DNA and sclerosis

Antineoplastic agent, Alkylating agent

Antineoplastic agent,

Act like an alkylating

Antineoplastic agent, Anthracenedione Inhibits DNA and RNA synthesis

Antineoplastic agent, Alkylating agent Inhibits DNA synthesis

Antineoplastic agent, Alkylating agent Inhibits DNA and RNA synthesis

Antineoplastic agent, Pyrimidine analogue-Antimetabolite Interferes with DNA and RNA synthesis

action

Antibiotics sclerosis

Antibiotic

Antibiotic

agent

cell proliferation. Cardiac tissue specific immune response may also influence carcinogenesis (34). Plausible immune privilege of the heart and pericardium can also be due to the complex structure of the lymphatic system in the heart, which is a three-tiered structure: the subepicardial, the myocardial and the subendocardial nets and drain from the heart to the mediastinum. Considering that lymphatics represent the major route to cardiac metastases, a blockade of the common lymphatic node by neoplastic cells coming from the metastasised mediastinum lymph nodes is a key event leading to the formation of metastases (35). Immune privilege might explain the relatively low incidence of secondary tumors in the heart compared with other organs.

## **4. Treatment**

The ideal treatment for pericardial effusion ensures the complete removal of fluid, relives tamponade if present and therefore relives symptoms. Other goals in the treatment are to prevent recurrent effusion and treat the local neoplastic disease with the aim of prolonging survival.

Pericardiocentesis using the Seldinger technique is successful in removing fluid and alleviating symptoms in 97% of patients, with 3% of major complications (6,36). There is only a sporadic report on the rate of recurrence of pericardial effusion which was reported to be 40%, without additional treatment (36,37). The number of patients reported in literature not receiving any additional therapy is too small to make a firm conclusion of the spontaneous re-accumulation rate of malignant effusion after pericardiocentesis (38-41). Tsang et al. reported of reducing the rate of recurrence by extending the drainage for several days (6,37). The indwelling pericardial catheter was left in place in the study of Gatenbey et al. for 4.8 days (42), but in the majority of studies it was used in conjunction with systemic therapy or sclerosing agents.

The rationale for sclerosing therapy is to prevent the recurrence of effusion by creating adhesions of the visceral and parietal pericardium. Antibiotic agents doxycycline and previously tetracycline were first used as pure sclerosing agents for this purpose with shortterm efficacy in preventing early recurrences (43,44-46). It should be noted, however, that the effusion control of tetracyclines is only due to sclerosing activity and not to specific antineoplastic action. Tetracyclines have many adverse effects and a potential for the development of the constrictive pericarditis secondary to fibrosis in long-term survivors (table 1). The OK-432, an immunomodulator available in Japan has been used in small group of patients with neoplastic pericarditis. Despite that, the OK-432 has the ability to stimulate cell-mediated immunity and besides the direct cytotoxic effect against malignant cells it has no significant advantages over other agents. The OK-432 also has common side effects (47). Bleomycin and thiotepa are anticancer agents with sclerosing properties and are used for local therapy with good results and few side effects (45,48-52).

The rationale for intrapericardial instillation of the antineoplastic drug is to provide a high and long-lasting concentration of the intrapericardial drug. Various chemotherapeutic agents have been used for local chemotherapy with the purpose to prevent recurrent effusion or prolong the effusion-free period and prolong survival. The use of intrapericardial cis-platinum was first reported in 1985 and after that drug was often used (41,53-57). Nitrogen mustard, mitomycin C, mitoxantrone and 5-fluorouracil have also been used intrapericardially (58-62). The reported experiences with sclerosing agents and

cell proliferation. Cardiac tissue specific immune response may also influence carcinogenesis (34). Plausible immune privilege of the heart and pericardium can also be due to the complex structure of the lymphatic system in the heart, which is a three-tiered structure: the subepicardial, the myocardial and the subendocardial nets and drain from the heart to the mediastinum. Considering that lymphatics represent the major route to cardiac metastases, a blockade of the common lymphatic node by neoplastic cells coming from the metastasised mediastinum lymph nodes is a key event leading to the formation of metastases (35). Immune privilege might explain the relatively low incidence of secondary

The ideal treatment for pericardial effusion ensures the complete removal of fluid, relives tamponade if present and therefore relives symptoms. Other goals in the treatment are to prevent recurrent effusion and treat the local neoplastic disease with the aim of prolonging

Pericardiocentesis using the Seldinger technique is successful in removing fluid and alleviating symptoms in 97% of patients, with 3% of major complications (6,36). There is only a sporadic report on the rate of recurrence of pericardial effusion which was reported to be 40%, without additional treatment (36,37). The number of patients reported in literature not receiving any additional therapy is too small to make a firm conclusion of the spontaneous re-accumulation rate of malignant effusion after pericardiocentesis (38-41). Tsang et al. reported of reducing the rate of recurrence by extending the drainage for several days (6,37). The indwelling pericardial catheter was left in place in the study of Gatenbey et al. for 4.8 days (42), but in the majority of studies it was used in conjunction with systemic

The rationale for sclerosing therapy is to prevent the recurrence of effusion by creating adhesions of the visceral and parietal pericardium. Antibiotic agents doxycycline and previously tetracycline were first used as pure sclerosing agents for this purpose with shortterm efficacy in preventing early recurrences (43,44-46). It should be noted, however, that the effusion control of tetracyclines is only due to sclerosing activity and not to specific antineoplastic action. Tetracyclines have many adverse effects and a potential for the development of the constrictive pericarditis secondary to fibrosis in long-term survivors (table 1). The OK-432, an immunomodulator available in Japan has been used in small group of patients with neoplastic pericarditis. Despite that, the OK-432 has the ability to stimulate cell-mediated immunity and besides the direct cytotoxic effect against malignant cells it has no significant advantages over other agents. The OK-432 also has common side effects (47). Bleomycin and thiotepa are anticancer agents with sclerosing properties and are used for

The rationale for intrapericardial instillation of the antineoplastic drug is to provide a high and long-lasting concentration of the intrapericardial drug. Various chemotherapeutic agents have been used for local chemotherapy with the purpose to prevent recurrent effusion or prolong the effusion-free period and prolong survival. The use of intrapericardial cis-platinum was first reported in 1985 and after that drug was often used (41,53-57). Nitrogen mustard, mitomycin C, mitoxantrone and 5-fluorouracil have also been used intrapericardially (58-62). The reported experiences with sclerosing agents and

local therapy with good results and few side effects (45,48-52).

tumors in the heart compared with other organs.

**4. Treatment** 

therapy or sclerosing agents.

survival.

chemotherapeutic agents are summarized in table 1. Lestuzzi et al. have suggested a "tumour specific" treatment algorithm for neoplastic pericardial effusion in which he preferred cisplatin in pericardial lung carcinoma metastases and bleomycin in pericardial breast carcinoma metastases. Authors reported a low complication rate and significant effectiveness of local chemotherapy. On the basis of personal experience and the review of literature, they conclude that sclerosing therapy should not be considered as the first choice


Table 1. .

Neoplastic Pericardial Disease 207

[9] Khandaker MH, Espinosa RE, Nishimura RA, Sinak LJ, Hayes SN, Melduni RM, Oh JK.

[10] Wilding G, Green HL, Longo DL, Urba WJ. Tumors of the heart and pericardium.

[11] Fraser RS, Viloria JB, Wang N. Cardiac tamponade as a presentation of extra cardiac

[12] Fincher E. Case Report: Malignant pericardial effusion as the initial manifestation of

[13] Letonja M, Debeljak A. Cardiac tamponade as the initial manifestation of pulmonary

[14] Muir KW, Rodger JC. Cardiac tamponade as the initial presentation of malignancy: is it

[15] Press OW, Livingston R. Management of malignant pericardial effusion and

[17] Oh JK, seward JB, Tajik AJ, eds. The Echo Manual. 3rd ed. Philadelphia, PA: Lippincott,

[18] Chong HH, Plotnick GD. Pericardial effusion and tamponade: evaluation, imaging,

[19] Beek EJR, Stolpen AH, Khanna G, Thompson BH. CT and MRI of pericardial and

[20] Edoute Y, Malberger E, Kuten A, Moscovitcz M, Ben-Haim S. Symptomatic pericardial

[21] King DT, Nieberg RK. The use of cytology to evaluate pericardial effusions. Ann Clin

[22] Alatas F, Alatas O, Metintas M, Colak O, Harmanci E, Demir S. Diagnostic value of

[23] Szturmowicz M, Tomkowski W, Fijalkowska A, Kupis W, Cieslik A, Demkow U et al.

[25] Kobayashi M, Okabayashi T, Okamoto K, Namikawa T, Araki K. Clinopathological

[26] Koh KK, In HH, Lee KH, Kim EJ, Cho CH, Cho SK et al. New scoring system using

[27] Poole-Wilson PA, Farnsworth A, Brainbrige MW, Pambakian H. Angiosarcoma of the

[28] Sytman AL, MacAlpin RN. Primary pericardial mesothelioma: Report of two cases and

cancer. World J Gastroenterol 2005; Nov 28; 11(44): 899-904.

effusion in lung cancer patients: the role of fluid cytology. J Surg Oncol 1990; 45:

CEA, CA 15-3, CA 19-9, CYFRA 21-1, NSE, and TSA assay in plural effusion. Lung

Diagnostic utility of CYFRA 21-1 and CEA assays in pericardial fluid for the recognition of neoplastic pericarditis. Int J Biol Markers 2005 Jan-Mar; 20(1): 43-9. [24] Szturmowicz M, Tomkowski W, Fijalkowska A, Burakowski J, Sakowicz A, Filipecki S

et al. The role of carcioembryonic antigen (CEA) and neuron-specific enolase (NSE) evaluation in pericardial fluid for the recognition of malignant pericarditis. Int J

study of cardiac tamponade due to pericardial metastasis originating from gastric

tumor markers in diagnosing patients with moderate pericardial effusions. Int J

Cancer Treat Rev 1988; 5: 165-81.

malignancy. Cancer 1980; 45: 1697-704.

tamponade. JAMA 1987; 257: 1088-92.

Williams &Wilkins; 2007.

Lab Sci 1979; 9: 18-23.

Cancer 2001; 31: 9-16.

Biol Markers 1997 Jul-Sep; 12(3): 96-101.

pericardium. Br Heart J 1976; 38: 240-3.

review of the literature. Am Heart J 1971; 81: 760-9.

Cardiol 1997 29; 61(1): 5-13.

121-3.

malignancy. Am J Med Sci 1993; 305: 106-10.

adenocarcinoma. Radiol Oncol (Ljub) 2007; 41: 161-5.

as rare as previously supposed? Postcard Med J 1994; 70: 703-7.

[16] Spodic DH. Acute cardiac tamponade. N Engl J Med 2003; 349(7): 684-90.

modalities, and management. Compr Ther 1995; 21: 378-85.

cardiac neoplastic disease. Cancer Imaging 2007; 7 19-26.

Pericardial disease: diagnosis and management. Mayo Clin Proc 2010; 85(6): 572-93.

therapy for malignant pericardial effusion because the goal of treatment is not simply to mechanically prevent the accumulation of pericardial fluid, but trying to cure pericardial metastases (63).

Systemic chemotherapy and radiation therapy are successfully used in breast cancer and leukemia and lymphoma after the initial pericardiocentesis to prevent the recurrence of effusion and to treat primary cancer (37-39). In cases of recurrent effusion and persistent symptoms various surgical drainage procedures are available. Total pericardiectomy is seldom performed today for pericardial effusions associated with malignancy because the operative risks are too high. Recent literature favours the creation of a pericardial window either by thoracotomy, by a subxiphoid route, or by thoracoscopy (40).

The epidemiology, therapy, and prognosis of neoplastic pericarditis have changed over time. The comparison of many observational studies is misleading, since in the largest studies, different tumours and/or different treatments were analyzed together. The most important bias in the articles reporting the efficacy of various local treatments is the concomitant use of systemic chemotherapy.

## **5. Conclusion**

Clinical suspicion of pericardial involvement is crucial for the identification of a patient with neoplastic pericarditis because of non-specific symptoms and signs and because chest x-ray, ECG and even echocardiographic findings are not 100% sensitive or specific either. Pericardiocentesis provides the diagnosis and offers this group of patients immediate relief, but trials with various chemotherapeutic agents and radiotherapy, in addition to the new surgical procedure will hopefully change the survival rate for this group of oncologic patients.

#### **6. References**


therapy for malignant pericardial effusion because the goal of treatment is not simply to mechanically prevent the accumulation of pericardial fluid, but trying to cure pericardial

Systemic chemotherapy and radiation therapy are successfully used in breast cancer and leukemia and lymphoma after the initial pericardiocentesis to prevent the recurrence of effusion and to treat primary cancer (37-39). In cases of recurrent effusion and persistent symptoms various surgical drainage procedures are available. Total pericardiectomy is seldom performed today for pericardial effusions associated with malignancy because the operative risks are too high. Recent literature favours the creation of a pericardial window

The epidemiology, therapy, and prognosis of neoplastic pericarditis have changed over time. The comparison of many observational studies is misleading, since in the largest studies, different tumours and/or different treatments were analyzed together. The most important bias in the articles reporting the efficacy of various local treatments is the

Clinical suspicion of pericardial involvement is crucial for the identification of a patient with neoplastic pericarditis because of non-specific symptoms and signs and because chest x-ray, ECG and even echocardiographic findings are not 100% sensitive or specific either. Pericardiocentesis provides the diagnosis and offers this group of patients immediate relief, but trials with various chemotherapeutic agents and radiotherapy, in addition to the new surgical procedure will hopefully change the survival rate for this group of oncologic

[1] Mukai K, Shinkai T, Tomonaga K, Shimoto Y. The incidence of secondary tumors of the heart and pericardium: A ten-year study. Jpn J Clin Oncol 1998; 18: 195-201. [2] Butany J, Leong SW, Carmichael K, Komeda M. A 30-year analysis of cardiac neoplasms

[4] Adenle AD, Edwards JE. Clinical and pathologic features of metastatic neoplasms of the

[5] Posner MR, Cohen GI, Skarin AT. Pericardial disease in patients with cancer. The

[6] Tsang TS, Enriquez-Sarano M, Freeman WK, Barnes ME, Sinak LJ, Gersh BJ, Bailey KR,

[7] Sagrista-Sauleda J, Merce J, Permanyer-Miralda G, Soler-Soler J. Clinical clues to the

[8] Imazio M, Demichelis B, Parrini I, Favro E, Beqaraj F, Cecchi E et al. Relation of acute

causes of large pericardial effusions. Am J Med 2000; 109: 95-101.

pericardial disease to malignancy. Am J Cardiol 2005; 95: 1393-4.

differentiation of malignant from idiopathic and radiation-induced pericarditis.

Seward JB. Consecutive 1127 teherapeutic echocardiographically guided pericardiocenteses: clinical profile, practice patterns, and outcomes spanning 21

either by thoracotomy, by a subxiphoid route, or by thoracoscopy (40).

concomitant use of systemic chemotherapy.

at autopsy. Can J Cardiol 2005; 21: 675-80.

pericardium. Chest 1982; 81: 166-9.

years. Mayo Clin Proc 2002; 77: 429-36.

Am J Med 1981; 71: 407-13.

[3] Klatt EC, Heitz DR. Cardiac metastases. Cancer 1990; 65: 1456-9.

metastases (63).

**5. Conclusion** 

patients.

**6. References** 


Neoplastic Pericardial Disease 209

[46] Kitamura S, Wagai F, Izumi T, Sugiyava Y, Kosaka K. Tratment of carcinomatous

[47] Imamura T, Tamura K, Takenaga M, Nagamoto Y, Ishikawa T, Nagakawa S.

[48] van der Gaast A, Kok TC, van der Linden NH, Splinter TA. Intrapericardial installation

[49] Yano T, Yokoyama H, Inoue T, Takanashi N, Asoh H, Ichinose Y. A simple technique

[50] Bishiniotis TS, Antoniadau S, Katseas G, Mouratidou D, Litos AG, Balamoutsos N.

trethylenethiopshoposphoramide (thiotepa). Am J Cardiol 2000; 86: 362-4. [51] Coleoni M, Martinelli G, Bereta F. Intracavitary chemotheraphy with thiotepa in

[52] Martinoni A, Cipola MC, Cardinale D, Civelli M, Lamantia G, Colleoni M, Fiorentini C.

[53] Markman M, Howell SB. Intrapericardial instillation of cisplatin in a patient with a

[54] Pavon-Jimenez R, Garcia-Rubira JC, Garcia-Martinez JT. Intrapericardial cisplatin for

[55] Tomkowski WZ, Filipecki S. intrapericardial administration of cisplatin in treatment of

[56] Fiorentino MV, Daniale O, Morandi P. Intrapericardial instillation of platin in

[57] Tondini M, Rocco G, Bianchi C, Severi C, Corbellino D. Intracavitary cisplatin (CDDP)

[58] Lee LN, Yang PC, Chang DB, Yu CJ, Ko JC, Liaw YS, Wu RG, Luh KT. Ultrasound

[59] Norum J, Lunde P, Aasebo U, Himmelman A. Mitoxantrone in malignant pericardial

[60] Weisberger AS, Levine B, Storaasli JP. Use of nitrogen mustard in treatment of serious

[61] Terpening M, Orringer M, Wheeler R, Bull FE. Intrapricardial nitrogen mustard with

[62] Suhrland LG, Weisberger AS. Intracavitary 5-fluorouracil in malignant effusions. Arch

non-small cell carcinoma of the lung. Oncology 1994; 51: 507-9.

pericardiocentesis and intrapericardial administration of

pericardial effusions with thiotepa. CHEST 2004; 126: 1412-6.

large malignant effusion. Cancer Drug Deliv 1985; 2: 49-52.

malignant tamponade. Rev Esc Cardiol 2000; 53: 587-9.

malignant pericardial effusion. Cancer 1988; 62: 1904-6.

malignant pericardial effusion. Thorax 1994; 49: 594-95.

effusions of Neoplastic origin. JAMA 1955; 159: 1704-7.

Mondali Arch Chest Dis 1995; 50: 86-8.

effusion. J Chemother 1998; 10: 399-404.

pericardial effusion. Curr Therapeut Res 1981, 30: 589-96.

effusion. Cancer 1991; 68: 259-63.

Clin Oncol 1989; 25: 1505-6.

1998; 16: 2371-6.

1997; 52: 221-4.

Res 1979; 20: 286.

Intern Med 1965; 116: 431-3.

pericarditis with doxycycline: intrapericardial doxycycline for control of malignant

Intrapericardial OK-432 instalation for the management of malignant pericardial

of Bleomycin in the manegment of malignant pericardial effusion. Eur J Cancer

to manage malignant pericardial effusion with a local instillation of Bleomycin in

Malignant cardiac tamponade in women with breast cancer treated by

malignant pericardial effusion: an active and well-tolerated regimen. J Clin Oncol

Long-term results of intrapericardial chemotherapeutic treatment of malignant

metastatic pericardial involvement in adenocarcinoma of the lung. Arch Chest Dis

in the tratment of metastatic pericardial involvement from breast and lung cancer.

guided pericardial drainage and intrapericardial instillation of mitomycin C for

chateter drainage for the treatment of malignant effusion. Proc Am Assoc Cancer


[29] Khatami M. Inflamation, aging, and cancer: tumorocidal versus tumorigenesis of

[30] Hori J. mechanisms of immune privilege in the anterior segment of the eye: what we learn from corneal transplantation. J Ocul Biol Dis Inform 2008; 1: 94-100. [31] Frantz S, Bauersachs J, Ertl G. Post-infarct remodeling: contribution of wound healing

[32] Zorc-Pleskovič R, Alibegovič A, Zorc M, Milutinovič A, Radovanovič N, Petrovič D. Apoptosis of cardiomyocytes in myocarditis. Folia Biologica (Praha) 2006; 52:6-9. [33] Petrovič D. Cytopathological basis of heart failure – cardiomyocytes apoptosis,

[34] Khatami M. Unresolved inflammation: immune tsunami or erosion of integrity in

[36] Callahan JA, Seward JB, Nishimura RA, Miller FA, Reeder GS, Shub C et al. Two-

[37] Tsang TS, Seward JB, Barnes ME, Bailey KR, Sinak LJ, Urban LH, Hayes SN. Outcomes

[38] Vaitkus PT, Herrmann HC, LeWinter MM. Treatment of malignant pericardial

[39] Einama T, Sato K, Tsuda H, Mochizuki H. Successful treatment of malignant

[40] Martinoni A. Treatment of neoplastic pericardial effusions. Recenti Prog Med 2006; 97:

[41] Tomkowski WZ, Wisniewska J, Szturmowicz M, Kuca P, Burakowski J, Kober J et. al..

[42] Gatenbey RA, Hartz WH, Kessler HB. Percutaneus catheter drainage for malignant

[43] Davis S, Rambotti P, Grignani F. Intrapericardial tetracycline sclerosis in the treatment

[44] Shepherd FA, Morgan C, Evans WK, Ginsberg JF, WattD, Murphy K. Medical

[45] Liu G, Crump M, Gross PE, Dancey J, Sheperd FA. Prospective comparison of the

pericardial effusion. J Vasc Interv Radiol 1991; 2: 151-5.

inflammatory disease or cancer. Expert Opin Biol Ther Early Online [35] Bussani R, De-Giorgio F, Abbate A, Silvestri F. Cardiac metastases. J Clin Pathol 2007;

intersitnal fibrosis and inflammatory cell response. Folia Biologica (Praha) 2004;

immune-privileged and immune-responsive tissues and acute and chronic

dimensional echocardiographically guided pericardiocentesis: experience in 117

of primary and secondary treatment of pericardial effusion in patients with

pericardial effusion, using weekly paclitaxel, in a patient with breast cancer. Int J

Evaluation of intrapericardial cisplatin administration in cases with recurrent malignant pericardial effusion and cardiac tamponade. Support Care Cancer 2004;

of malignant pericardial effusion: an anylysis of thirty-three cases. J Clin Oncol

manegment of malignant pericardial effusion by tetracycline sclerosis. Am J

sclerosing agents doxycycline and bleomycin for the pimary management of malignant pericardial effusion and cardiac tamponade. J Clin Oncol 1996; 14: 3141-

immunity. Cell Biochem, Biophys 2009; 55: 55-79.

consecutive patients. Am J Cardiol 1985; 55: 476-9.

malignancy. Mayo Clin Proc 2000; 75: 248-53.

effusion. JAMA 1994; 272: 59-64.

Clin Oncol 2006; 11: 412-5.

50:58-62.

60. 27-34.

206-10.

12: 53-7.

1984; 2: 631-6.

7.

Cardiol 1987; 60: 1161-6.

and inflammation. Cardiovacular Research 2009; 81: 474-81.


**Therapeutic Approaches, Markers** 

**Identification and Applications** 

[63] Lestuzzi C, Viel E, Sorio R, Meneguzzo N. Local chemotherapy for neoplastic pericardial effusion. Am J Cardiol 2000; 86: 1292. **Part 2**  pericardial effusion. Am J Cardiol 2000; 86: 1292. **Part 2** 

**Therapeutic Approaches, Markers Identification and Applications** 

210 Inflammatory Diseases – Immunopathology, Clinical and Pharmacological Bases

[63] Lestuzzi C, Viel E, Sorio R, Meneguzzo N. Local chemotherapy for neoplastic

**10** 

 *Slovenia* 

**Tolerogenic Dendritic Cells for Therapy** 

Urban Švajger1,2 and Borut Štrukelj1 *1University of Ljubljana, Faculty of Pharmacy, 2Blood Transfusion Centre of Slovenia, Ljubljana,* 

**of Immune-Mediated Inflammatory Diseases** 

Within the complex array of numerous immunological processes that protect the host from invading pathogens and at the same time avoid excessive immune reactions with induction and maintenance of tolerance to self, the dendritic cells (DCs) have been designated as central players. Discovered and morphologically described by Steinman and Cohn almost 30 years ago, DCs have gained an ever-increasing interest from the scientific community (Steinman, Topliss et al. 1973). This has been even more pronounced throughout the last decade with the discovery that DCs not only serve as primary initiators of antigen (Ag) specific immune responses, but can also induce immunological tolerance and contribute to immune homeostasis maintenance by various mechanisms, including induction of regulatory T cells (Treg) (Steinman, Hawiger et al. 2003). Indeed, the DCs possess a unique set of biological tools that allows them to present Ag information to effector cells of the immune system in a way to promote tolerance induction by functional mechanisms such as T-cell anergy, deletion, apoptosis and instruction of different Treg types. Direct delivery of tolerogenic signals by DCs, most commonly to respective Ag-specific T cells, is in a great way determined by the DCs preliminary activation state, which itself is orchestrated by various environments that DCs find themselves in under both physiological and pathophysiological conditions. Today it is well-documented, that a number of immunosuppressive factors, either related to specific tissue microenvironments, microbial components or pharmacological immunosuppressants, can act on DCs in a way to cause their alternative activation or tolerogenic state (Weiner 2001; Hackstein and Thomson 2004; Rutella, Danese et al. 2006). In addition to immature (iDCs) which are known to act in an immunosuppressive fashion, the tolerogenic DCs (TDCs) can be said to do the same but in an even more efficient manner. Whereas tolerance induction by iDCs seems to rely mostly on insufficient delivery of co-stimulatory signals, TDCs express more elements of active tolerance induction, including surface inhibitory molecules and production of antiinflammatory cytokines, that are expressed depending on the nature of DC activation

With DCs able to achieve greatly opposing states regarding their immunostimulatory status, together with the notion of manipulating DC function in the lab, scientists have put ongoing efforts into resolving the underlying mechanisms of DC-mediated tolerance induction. The

**1. Introduction** 

and/or development.
