following thoracal radiotherapy;
dissemination from pericardium to pleura
Hüseyin YILDIRIM, Muzaffer METİNTAŞ, Güntülü AK
Eskişehir Osmangazi Üniversitesi Tıp Fakültesi, Göğüs Hastalıkları Anabilim Dalı, Eskişehir.
ÖZET
Torakal radyoterapi sonrası gelişen malign perikardiyal mezotelyoma; perikarttan plevraya yayılım
Malign perikardiyal mezotelyoma nadir görülen mezodermal orijinli primer perikardiyal tümördür. Etyolojisine bakıldığın- da, asbest temas öyküsü net olarak belirlenememiştir. Malign perikardiyal mezotelyoma tanısı klinik şikayetlerin ve semp- tomların özgül olmaması nedeniyle tanısı zor bir hastalıktır. Bilinen etkili bir tedavisi yoktur ve prognozu kötüdür. Bu olgu sunumunda literatür bilgileri ışığında malign perikardiyal mezotelyomanın olası etyolojik nedenleri tartışılmıştır. Burada non-Hodgkin’s lenfoma nedeniyle evvelce kemoradyoterapi uygulanmış, asbest temas öyküsü olmayan ve tümörün peri- karttan plevraya yayılımını gözlemlediğimiz bir olgu rapor edilmiştir.
Anahtar Kelimeler: Asbestozis, malign mezotelyoma, perikart, plevra, radyoterapi.
SUMMARY
Malignant pericardial mesothelioma following thoracal radiotherapy; dissemination from pericardium to pleura
Hüseyin YILDIRIM, Muzaffer METİNTAŞ, Güntülü AK
Department of Chest Diseases, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey.
Yazışma Adresi (Address for Correspondence):
Dr. Hüseyin YILDIRIM, Eskişehir Osmangazi Üniversitesi Tıp Fakültesi, Göğüs Hastalıkları Anabilim Dalı, Meşelik 26480 ESKİŞEHİR - TURKEY
e-mail: [email protected]
Malignant mesothelioma is an aggressive and malignant tumor that is occurring throughout the world with an increasing prevalence; unfortuna- tely, there are limited treatment options for ma- lignant mesothelioma (1). Frequently, malignant mesothelioma develops through the mesothelial surfaces of the pleural and peritoneal cavities, and rarely, through the pericardium and tunica vaginalis (2). Although a relationship between asbestos exposure and the development of me- sothelioma has been clearly observed, not all pa- tients with malignant mesothelioma have a his- tory of asbestos exposure. Other possible causes of malignant mesothelioma include the simian 40 virus, non-asbestos mineral fibers, organic chemical substances, and radiotherapy (3).
Primary tumors of the pericardium are rarely ob- served. Malignant pericardial mesothelioma (MPeM) is the most frequent primary pericardial tumor and comprises approximately 50% of all primary pericardial tumors (4). In a Canadian epidemiologic study, the annual incidence of MPeM was reported to be 1 in 40 million (5). In another study which focused on 1785 cases of malignant mesothelioma detected between the years 1958 and 1996, only 6.1% of the cases we- re reported to be MPeM (6). Approximatelly 150 cases of MPeM have been described in the litera- ture, of which most have been reported as case studies. Today, the etiology of MPeM is not comp- letely known. The relationship between asbestos exposure and MPeM has not been clearly establis- hed (7). It has been reported that there is a pos- sibility for MPeM to develop after radiotherapy applied to the thorax for various reasons (8,9).
Our aim in reporting this case was to contribute information pertaining to the etiology of MPeM by describing a patient with no history of asbes- tos exposure in whom MPeM was assumed to have developed secondary to radiotherapy ad-
ministered in the treatment of non-Hodgkin’s lymphoma; detected to have spread through the pleural cavity as a result of treatment. The ca- usal relationship between radiotherapy and MPeM is discussed together with information existing in the literature. We also hoped to emp- hasize the many obstacles which occur during the diagnosis and treatment of MPeM.
CASE REPORT
A 40 year-old male patient was admitted to our clinic with dyspnea in October 2005. In addition to the dyspnea, there was chest pain. In 1978, non- Hodgkin’s lymphoma was diagnosed and the pa- tient was treated with radiotherapy; chemotherapy with the COPP regimen (cyclophosphamide, vinc- ristine, procarbazine, and prednisolone) was insti- tuted because of a relapse in 1983. The patient had a gastrectomy after a diagnosis of gastric lymphoma in 1998, for which he had chemothe- rapy with CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisolone). He was admitted to a chest clinic of another hospital in December 2004 with a complaint of dyspnea, which had existed for three months. With the assistance of the medical oncology-haematology and cardi- ology departments, pericardial fluid was identified.
In this period, a chest computerized tomography (CT) scan demonstrated a moderate pericardial effusions and mild left-sided pleural effusions.
There was no reliable evidence to speculate a di- agnosis of pleural or pericardial mesothelioma at that time. Assuming that the cause of the pericar- dial fluid was mediastinal drainage reduction, a pericardial-pleural window was recommended as a method of treatment, and a pericardial-pleural window was opened in July 2005. Non-specific findings were observed during the histopathologi- cal analysis of the obtained pericardial specimen, and a specific diagnosis was not established.
Malignant pericardial mesothelioma (MPeM) is a rare, primary pericardial tumor of mesodermal-origin. With respect to the etiology of MPeM, a history of exposure to asbestos has not been clearly demonstrated. MPeM is difficult to diagnose beca- use of the non-specificity of the clinical complaints and symptoms. A known effective treatment does not exist and the prog- nosis is poor. In this case study, the possible etiologies of MPeM are discussed based on the extant literature. We report he- rein a patient with MPeM and no history of asbestos exposure who had chemo-radiotherapy for non-Hodgkin’s lymphoma, and in whom a tumor spread from the pericardium through the pleura.
Key Words: Asbestosis, malignant mesothelioma, pericardium, pleura, radiotherapy.
The patient gave no history of consuming alco- hol or smoking cigarettes, he did not use any medication on a long-term basis, and he had no exposure to asbestos.
On physical examination at the time of admissi- on, the sound of the heart beat was deep, the breath sounds were diminished at the left lung base, and dullness was appreciated in the lower left lobe by percussion. The laboratory analysis was significant for a sedimentation rate of 48 mm/hour and a C-reactive protein of 7.9 mg/dL;
the hematological tests were within normal li- mits. A posteroanterior chest radiograph sho- wed a left pleural effusion and an enlarged car- diac shadow. Echocardiography (ECHO) reve- aled irregularly thickening pericardium invased to the epicardium with a small amount of fluid in the back walls of the left and right ventricles.
The pleural effusion was predominantly lymphocytic and had an exudate from the albumin gradient. The pleural fluid ADA value was 8 IU/L (ranges, 0-40 IU/L). A purified protein derivative (PPD) test had a 2 mm induration. The pleural ef- fusion lymphoma panels did not reveal a marked characteristic. The pleural effusion cytologic analysis showed atypical cells, suggesting malig- nancy. A CT scan of the thorax revealed irregular pericardial thickening and fluid, a pleural effusion on the left side, and fibrotic changes secondary to radiotherapy in the pulmonary parenchyma (Fi- gure 1). A magnetic resonance imaging (MRI) of the thorax showed an irregular, limited mass that entirely surrounded the pericardium, located on the anterior wall of the right ventricle adjacent to the apex, and on the inferior segment of the left ventricle, with invasion to the epicardium (Figure 2). The positron emission tomography (PET)/CT scans revealed pericardial and widespread incre- ased activity in the pleura (Figure 3). A CT scan of the abdomen revealed mild congestion in the li- ver. A closed pleural needle biopsy yielded reacti- ve mesothelial cells within the fibrous material.
Thus, the patient underwent a thoracoscopy. The entire parietal pleural surfaces were hyperaemic, and rare irregular thickening areas and nodules were also detected (Figure 4). As a result of the immunohistochemical analysis of the biopsy spe- cimens, epithelial-type malignant mesothelioma
was reported. Initially, the origin of the disease was the pericardial space, consequently we accepted the patient as MPeM. Following the diagnostic pro- cedures, the patient voluntarily left the clinic. We were informed that the patient had a partial peri- cardiectomy at another heart surgery center and died one month later.
DISCUSSION
MPeM is a rare type of tumor that originates from the mesothelial cells of the pericardium.
Frequently, it is often diagnosed late in its cour- se, is locally aggressive, and carries a poor prognosis (9). Although a relationship has been established with exposure to asbestos in pleural and peritoneal mesothelioma, the role of asbes- tos is not definite in MPeM (7). Radiation is the Figure 1. Chest CT scan shows large right-sided ple- ural effusion, and reveals diffuse and nodular thicke- ning of left parietal pleura. Note pericardial thicke- ning and effusion.
Figure 2. Magnetic resononce imaging showing peri- cardial effusion and pericardial thickening, with inva- sion to the epicardium.
most significant carcinogen for humans. It is ac- cepted to be one of the etiologic agents for me- sothelioma, with both a direct impact and a synergistic effect with asbestos. Radiation-indu- ced tissue injury is commonly classified as acu- te or late effects, according to the time before appearance of symptoms. Early or acute effects emerge during or immediately after the end of
therapy, while late side effects develop months to years after radiation exposure. Several biolo- gical mechanisms have been proposed to expla- in the late effects of radiation therapy. These inc- lude vascular injury, radiation-induced fibroge- nesis, chronic oxidative stress, increased pro- duction of reactive oxygen species and free ra- dicals, oxidation of DNA and proteins, and acti- vation of pro-inflammatory factors (10).
Cavazza et al. reported on 8 patients who had ra- diotherapy for cancer and developed malignant mesothelioma within the treatment area (11). In this study, the median time between the develop- ment of malignant pleural mesothelioma and ra- diotherapy was reported to be 21 years. Simi- larly, Pappo et al. reported that malignant pleural mesothelioma developed in 3 of their patients in 11 years who underwent radiotherapy for child- hood cancer within the treatment area (12). Des- pite these reports, Neugut et al. showed that ma- lignant pleural mesothelioma occurred in only 2 of approximately 251.000 female patients who were administered radiotherapy for breast can- cer, and also mentioned that there was no relati- onship between malignant pleural mesothelioma and radiotherapy (13). Only one case has been previously reported that radiotherapy for Hodg- kin’s lymphoma led to the development of MPeM during the follow-up period (8). According to our patient, he had no history of environmental or occupational asbestos exposure. He was admi- nistered thoracic radiotherapy 29 years prior to diagnosis with MPeM for non-Hodgkin’s lympho- ma, but then received chemotherapy (COPP) due to a relapse 5 years after the radiotherapy. A longer latent period is accepted to be characte- ristic of solid tumors developing secondary to ra- diotherapy. Another etiologic agent for this case was the use of an alkylating chemotherapeutic, such as cyclophosphamide, which is known to be carcinogen. The synergistic effect of radiation and an alkylating agent is a potential mechanism leading to MPeM in our patient.
The onset of symptoms in MPeM is generally insidious and specious. The basis for symp- toms in patients with MPeM, such as chest pa- in, cough, dyspnoea, and palpitations, are constrictive pericarditis developing due to the Figure 3. PET/CT image showing increased uptake
in the left pleural space and the pericardium.
Figure 4. The entire parietal pleural surfaces were hyperaemic, and nodular lesion was found to diffu- sely involve the parietal pleura.
Renkli
involvement of the pericardium, and pericardi- al effusion, cardiac tamponade, and heart failu- re due to myocardial infiltration (14). The diag- nosis of the disease is made as a result of the pathologic assessment of pericardial fluid or tissue generally obtained with the guidance of ECHO, ultrasonography, or CT scans. The fin- dings detected by electrocardiogram are a dec- rease in QRS and T wave voltage and ST-T changes. Chest radiography of patients with MPeM typically reveals cardiomegaly, pericar- dial fluid findings, an irregular cardiac silhouet- te, or diffuse mediastinal enlargement. While an irregular, diffuse pericardial thickening and pericardial effusion is established by thoracic CT, a MRI reveals that the heart is surrounded by a pericardial mass (15).
Today, a standard treatment approach does not exist for MPeM. Although there are various stu- dies assessing the efficiency of surgery, radiot- herapy, and chemotherapy, the results are far from encouraging (7). In localized cases, surgi- cal resection might be curative (14). Radiothe- rapy is not appropriate to control the disease be- cause of such side effects as pericarditis and myocarditis. A standard chemotherapy protocol does not exist to control the disease. In recent years, anti-folate agents, such as pemetrexed, have been reported to yield successful results in patients with MPeM (16). In order to prevent pe- ricardial tamponade or constrictive pericarditis, percutaneous balloon pericardiotomy or pericar- diectomy are recommended (9). The median survival time of patients with MPeM is approxi- mately 6-12 months (7,14).
This case shows that in patients who undergo ra- diotherapy to the thoracic area for cancer, deve- lopment of a pericardial effusion, even after many years, requires thorough evaluation. The pericardial region must be examined, and one should not accept limited biopsies until a defini- tive diagnosis is made before deciding on the treatment options. In this case, opening a win- dow from the pericardium to pleura made it pos- sible for the tumor to pass through this window to the pleura, complicated the treatment, and probably had a negative impact on the duration of survival of the patient.
REFERENCES
1. Robinson BWS, Musk AW, Lake RA. Malignant mesothe- lioma. Lancet 2005; 366: 397-408.
2. Sterman DH, Albelda SM. Advances in the diagnosis, evaluation, and management of malignant pleural me- sothelioma. Respirology 2005; 10: 266-83.
3. Hughes RS. Malignant pleural mesothelioma. Am J Med Sci 2005; 329: 29-44.
4. Maisch B, Seferovic PM, Ristic AD. The task force on the diagnosis and management of pericardial disease of the European Society of Cardiology. Guidelines on the diag- nosis and management of pericardial disease. Eur Heart J 2004; 25: 587-610.
5. Lagrotteria DD, Tsang B, Elavathil LJ, Tomlinson CW. A case of primary malignant pericardial mesothelioma.
Can J Cardiol 2005; 21: 185-7.
6. Murai Y. Malignant mesothelioma in Japan: analysis of registered autopsy cases. Arch Environ Health 2001; 56:
84-8.
7. Papi M, Genestreti G, Tassinari D, et al. Malignant peri- cardial mesothelioma. Report of two cases, review of the literature and differential diagnosis. Tumori 2005; 91:
276-9.
8. Velissaris TJ, Tang AT, Millward-Sadler GH, et al. Pericar- dial mesothelioma following mantle field radiotherapy. J Cardiovasc Surg (Torino) 2001; 42: 425-7.
9. Pasquotti B. Pericardial and tunica vaginalis mesothe- lioma. In: Pass HI, Vogelzang NJ, Carbone M (eds).
Malignant mesothelioma: advances in pathogenesis, diagnosis, and translational therapies. Springer Verlag, 2005: 755-61.
10. Stone HB, Coleman CN, Anscher MS, McBride WH. Ef- fects of radiation on normal tissue: consequences and mechanisms. Lancet Oncol 2003; 4: 529-36.
11. Cavazza A, Travis LB, Travis WD, et al. Post-irradiation malignant mesothelioma. Cancer 1996; 77: 1379-85.
12. Pappo AS, Santana VM, Furman WL, et al. Post-irradiati- on malignant mesothelioma. Cancer 1997; 79: 192-3.
13. Neugut AI, Ahsan H, Antman KH. Incidence of malig- nant pleural mesothelioma after thoracic radiotherapy.
Cancer 1997; 80: 948-50.
14. Suman S, Schofield P, Large S. Primary pericardial me- sothelioma presenting as pericardial constriction: a case report. Heart 2004; 90: e4.
15. Grebenc ML, Rosado de Christenson ML, et al. Primary cardiac and pericardial neoplasms: radiologic-pathologic correlation. Radiographics 2000; 20: 1073-103.
16. Maruyama R, Sakai M, Nakamura T, et al. Triplet che- motherapy for malignant pericardial mesothelioma: a ca- se report. Jpn J Clin Oncol 2006; 36: 245-8.
