台 灣 癌 症 醫 誌 (J. Cancer Res. Pract.) 2(1), 83-92, 2015 DOI: 10.6323/JCRP.2015.2.1.11 Case Report journal homepage:www.cos.org.tw/web/index.asp Malignant Peritoneal Mesothelioma Zhong-Yi Lin 1,2, Cheng-Hsin Chu 1,2,3, Horng-Yuan Wang 1,2,3, Shou-Chuan Shih 1,2,3, Ming-Jen Chen 1,2,3 * 1 Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan 2 Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan 3 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan Abstract. Malignant peritoneal mesothelioma (MPM) is rare. It is difficult to diagnose early and responds poorly to treatment. There is no optimal and effective treating consensus so far. We report three patients of MPM treated at Mackay Memorial Hospital in recent 3 years. They were two men and one woman without asbestos exposure related to their occupations. Due to failure in early diagnosis of MPM, none of them survived for more than 5 months. We make a brief review from the previous literature. These three cases were compared with the reviewing data in many aspects including the risk factor, clinical presentation, diagnostic options, and management. Besides, some latest clinical trials are introduced in this report. 病 例 報 告 Keywords : malignant peritoneal mesothelioma, peritoneal tumor, abdominal carcinomatosis 腹 膜 惡 性 間 皮 細 胞 瘤 林 仲 一 1,2 朱 正 心 1,2,3 王 鴻 源 1,2,3 施 壽 全 1,2,3 陳 銘 仁 1,2,3 * 1 馬 偕 紀 念 醫 院 肝 膽 腸 胃 內 科 2 馬 偕 醫 護 管 理 專 科 學 校 3 馬 偕 醫 學 院 醫 學 系 中 文 摘 要 腹 膜 惡 性 間 皮 細 胞 瘤 相 當 罕 見 它 很 難 早 期 被 診 斷, 並 且 對 於 治 療 的 反 應 也 不 好 至 今 仍 然 未 見 有 效 的 治 療 共 識 我 們 收 集 到 馬 偕 醫 院 這 三 年 發 現 的 三 個 病 例, 包 含 不 同 職 業 的 兩 位 男 性 與 一 位 女 性 患 者 由 於 無 法 早 期 診 斷, 他 們 存 活 都 沒 有 超 過 五 個 月 我 們 回 顧 從 前 發 表 之 相 關 文 章, 在 危 險 因 子 臨 床 症 狀 診 斷 策 略 與 相 關 治 療 這 幾 方 面 來 與 我 們 發 表 的 病 例 相 比 較 此 外, 有 關 最 新 的 治 療 研 究 也 在 這 篇 文 章 中 介 紹 關 鍵 字 : 腹 膜 惡 性 間 皮 細 胞 瘤 腹 膜 腫 瘤 腹 膜 內 癌 轉 移 擴 散 INTRODUCTION Malignant mesothelioma is a malignancy arising from the serosal membranes of the pleura, peritoneum, pericardium, and tunica vaginalis testes. The pleural mesothelioma is the most common type followed by peritoneal type [1]. There is a strong relationship between asbestos exposure and the development of mesothelioma at any location [2]. One study pointed out
84 Z. Y. Lin et al./jcrp 2(2015) 83-92 that the link between exposure to asbestos and peritoneal mesothelioma is less strong than it is for pleural mesothelioma, particularly among women [3]. But no reason has been found to explain this difference. Asbestos exposure-induced MPM generally required a higher cumulative dose than malignant pleural mesohtelioma [3]. In the United States, the overall prevalence is 1-2 cases per million, with an estimated incidence of 200-400 new cases annually [4]. In Taiwan Lee et al. reported a total of 423 cases of malignant mesothelioma which were registered from 1979 to 2005 [5]. Up to 91% of these patients in their study were diagnosed as peritoneal or pleural mesothelioma. The median survival of malignant mesothelioma was 7.6 and 13.5 months for males and females, respectively. The male to female ratio is 1.5:1. MPM is a fatal disease without specific initial clinical presentations. No serum marker or typical image criteria have been established to diagnose this disease early [6, 7]. One study for proposal of the TMN staging system for peritoneal mesothelioma enrolled 294 patients, of whom 242 patients (82.3%) were classified as stage II or III. The TMN staging for peritoneal mesothelioma has three stages with 5-year-survial rate as 87, 53, and 29%, respectively. Therefore most cases were diagnosed at the advanced stage at the time of diagnosis [8]. We share three cases of MPM in the present communication. CASE REPORTS Case 1 A 57-year-old man, a retired taxi driver, had a history of hepatitis B, diabetes mellitus, and hypertension. He visited the emergency department of Mackay Memorial Hospital because of abdominal pain and distention for two weeks. The chief complaints were poor appetite, abdominal distention and dyspnea on exertion for about one month. Leukocytosis (15400/ ul) and anemia (Hemoglobin: 8.5g/dl) were noted. Physical examination detected peritoneal signs (diffuse rebounding pain without specific location). Then computed tomography of the whole abdomen revealed a large right liver tumor (more than 10 cm in diameter) and carcinomatosis (Figure 1A). Moderate amount of ascites was also seen. Under the impression of liver tumor rupture with peritonitis, he was transferred to the intensive care unit. A series of examinations including of abdominal echo, cytological analysis of ascites, esophagogastroduodenalscopy (EGD) and serum tumor marker were performed in turn in order to discover the nature of the abdominal tumors. The positive findings were elevated serum, CA-125 (297u/mL), and β2-microglobulin (9360μg/mL). Diagnostic laparoscopy for taking an omental specimen was performed. Under microscopic investigation, high-grade, poorly differentiated carcinoma cells were found (Figure 1B). The tumor cells were positive for some immunohistochemical staining including CK7, vimentin, calretinin, D2-40, thrombomodulin (Figure 2A-2D), and negative for CEA, RCC, CK20, HepPar, and mucicarmine. Hepatocellular carcinoma and metastatic adenocarcinoma were therefore excluded. The pathological diagnosis was epithelioid type, pleomorphic subtype of MPM. This patient died of profound septic shock leading to multiple organ failure after admission for 15 days. Due to rapid progression, no active treatment such as chemotherapy or radiotherapy could be arranged for this patient. *Corresponding author: Ming-Jen Chen M.D. * 通 訊 作 者 : 陳 銘 仁 醫 師 Tel: +886-2-25433535 ext.3993 Fax: +886-2-25433642 E-mail: mingjen.ch@msa.hinet.net Case 2 A 71-year-old woman, a housewife, had a history of diabetes mellitus. She suffered from abdominal pain and body weight loss of up to 5 kg within one month, and looked for medical advice at the hemato-
Z. Y. Lin et al./jcrp 2(2015) 83-92 85 Figure 1. (A) Contrast computed tomography of abdomen presents with large liver tumor (red arrows) in Segments 7, 6, and 1. Carcinomatosis, celiac trunk lymphadenopathy, and much ascites are also noted (white arrows). (B) Under microscopy hematoxylin and eosin stain, the omental tissue is effaced by clusters of high-grade epithelioid neoplastic cells with increased mitotic figures, including abnormal form logical outpatient service. Two liver tumors were found in segment 6 and 7 on abdominal sonography. Abdominal computed tomography demonstrated massive ascites and carcinomatosis (Figure 3). Differential diagnosis included hepatocellular carcinoma, metastatic tumor from the alimentary tract or urogential tract. The serum CA-125 level was elevated (530.2 u/ml). However, no tumor formation was found by gynecological echo. The ascites cytology revealed atypical reactive mesothelial cells with prominent nucleoli. Due to the failure of finding out the origin of peritoneal tumors by noninvasive examinations, diagnostic laparoscopy was performed. The final diagnosis from biopsy specimen was epithelioid type, solid subtype MPM. After receiving two cycles of pemetrexed with cisplatin, she developed of intra-abdominal infection with septic shock, which progressed to death. We had no time to perform further image studies to evaluate the response to treatment. Refractory ascites, however, implied that the disease was under progression. We are in lined to think that she died of progressive MPM and the complication of septic shock. The survival period after diagnosis was only 4 months. Case 3 A 73-year-old man, a retired labor, had a past history of coronary artery disease post-bypass graft and right renal stone post-extracorporeal shock wave lithotripsy (ESWL). Investigation was started at the Mackay Memorial Hospital urological outpatient clinic because of right flank pain and hemospermia. One 1.2 cm right renal stone was found. A second session of ESWL was suggested. Three months later, he was still afflicted with intermittent right flank pain. Double colon series, pan-endoscopy, and small bowel series showed negative findings. Abdominal echo revealed a hypo-echoic mass, suspecting a large subcapsular hematoma in the right liver with blood clot in Morrison s pouch. The hematoma was regarded as the side effect of ESWL at that time. Abdominal computed tomography was arranged on account of unresolved symptoms including hematuria. The report confirmed a hematoma covering the right liver and one right renal stone (Figure 4A). Two months later, he was transferred to the emergency department with the complaint of severe abdominal pain and body weight loss of up to 8 kg. Abdominal computed tomography subsequently discovered the peritoneal carcinomatosis
86 Z. Y. Lin et al./jcrp 2(2015) 83-92 Figure 2. The tumor cells under special immunohistological stain are positive for CK7, vimentin, calretinin, and D2-40 (Figure 4C,4D). A series of non-invasive examinations including serum tumor markers could not help in finding out the tumor origin. By way of diagnostic laparoscopy an omental specimen was obtained for pathological study. The diagnosis was epithelioid-type, tubulopapillary-subtype MPM. The gallium-67 whole body scan performed before the first cycle of systemic chemotherapy revealed rapid progression of the tumor into pelvic cavity compared with last abdominal computed tomography one month before. No further image examination was performed after chemotherapy. Therefore it was difficult to evaluate the efficacy of the treatment. The patient suffered from persistent fever and leukocytosis after the first cycle of chemotherapy. Finally, septic shock led the patient to his death. We are of the opinion that he died of progressive MPM and the complication of septic shock. The survival period after the diagnosis of the tumors found by abdominal echo was 5 months, or only two months after final diagnosis. DISCUSSION According to epidemiologic data, exposure to asbestos is an established risk factor for developing
Z. Y. Lin et al./jcrp 2(2015) 83-92 87 Figure 3. Contrast computed tomography of abdomen presents with prominent carcinomatosis (arrows) MPM [2]. The relation of relative risk to the exposure dose for MPM is not linear; while that for pleural mesothelioma is nearly linear [3]. It is presumably related to the dynamics controlling the distribution of asbestos fibers around the body which partially lodge into the peritoneal membrane. It is more complex than the absorbing mechanism of direct inhalation in pleural mesothelioma [3]. Besides asbestos, other risk factors including radiation and mineral fibers have also been reported [9,10]. With respect to the patients mentioned in our report, one was a taxi driver, another a labor, and the last a housewife. To the best of our acknowledge, none of them had a history of any exposure to asbestos. According to the occupation risk factors in Sweden for MPM, bricklayers and plumbers had the highest risk. Farmers and self-employees had a relatively low risk [2]. There are no specific clinical presentations for diagnosis of MPM [4]. Most cases were asymptomatic until the tumors occupied most of the abdominal cavity [4]. The most frequent complaint is abdominal pain (35%), and the second, abdominal swelling (30%) [4]. According to the initial clinical presentations of the patients in our report, their pain were often diffuse and nonspecific. This kind of unspecific pain often leads to a delay in diagnosis and till the time when these patients were afflicted with refractory ascites. There are some diagnostic strategies including laboratory findings and image examinations. However, those examinations except the histological study are short of high specificity and sensitivity [6,7]. Elevated serum levels of hyaluronan, CA-125, alpha fetoprotein, CEA, and mesothelin were found in some patients, but these levels are poorly correlated to the disease progression [6,7]. Elevated CA-125 was found in case 1 and case 2 in our report. None of them had elevated serum CEA or alpha fetoprotein. Radiological examination such as computed tomography or magnetic resonance cannot offer adequate accuracy for differential diagnosis [7]. Combined image guiding biopsy and immunohistochemical staining can help in diagnosing MPM precisely [11]. Cytologic analysis of ascites has its limitations in differential diagnosis of malignant or benign reactive peritoneal mesothelioma because it lacks the evidence of stromal invasion to peritoneum [11,12]. In the beginning, the contrast computed tomography failed to detect a peritoneal lesion in case 3 until the disease progressed to peritoneal carcinomatosis. It is difficult to distinguish MPM from some peritoneal tumors which mimic MPM in the clinical and image patterns by the histological appearance. Those
88 Z. Y. Lin et al./jcrp 2(2015) 83-92 Figure 4. (A,B) Pictures of first contrast abdominal computer tomography. In Figure 4A, the hypodense area (arrow) covering right liver surface is thought to be a hematoma. However, omental thickening (arrow) is also noted in the right lower abdominal quadrant in Figure 4B. (C,D) These are pictures of subsequent liver dynamic computed tomography (arterial phase) 2 months afterward. Obvious abdominal carcinomatosis is found (arrow) tumors are: sarcoma, melanoma, primary papillary serous carcinoma of the peritoneum, serous ovarian carcinomas, colorectal adenocarcinoma diffusely involving the peritoneum, and borderline serous tumors [4]. A panel with immunohistochemical markers has been suggested for diagnostic aid [13]. Most mesotheliomas stain positively for antimesothelial cell antibody-1, D2-40, calretinin, cytokeratins5/6, Wilms tumor-1, thrombomodulin, and mesothelin which are absent in those serous carcinoma mentioned above. Cytokeratin statins are absent in sarcoma and melanoma. Mesotheliomas usually stain negative for other adenocarcinoma markers, including carcinoembryonic antigen (CEA), thyroid transcription factor-1, LeuM1, Ber-Ep4, B72.3, Bg8, and MOC-31. Mesotheliomas have three basic histologic forms: epithelioid (the most frequent), sarcomatoid (least frequent), and mixed (biphasic). In most cases, all three type features will be encountered in a single tumor [13]. The morphological category is based on the 2004 World Health Organization (WHO) criteria (less than 10% sarcomatoid component defined as epithelioid type; otherwise defined as biphasic type) [14]. The pure sarcomatoid type peritoneal mesothelioma is very
Z. Y. Lin et al./jcrp 2(2015) 83-92 89 rare. In general, the epithelioid type has the best prognosis, followed by the biphasic type [14]. According to the 2004 WHO classification, the malignant epithelioid mesothelioma have five histological subtypes, that is, trabecular, tubulopapillary, micropapillary, solid, and pleomorphic [14]. There is no published paper in the literature discussing the prognostic difference of each epithelioid subtype in malignant peritoneal mesothelioma. One research, however, reported this difference with malignant pleural mesothelioma [14]. In that study, the trabecular and tubulopapillary subtypes had a longer overall survival time than the micropapillary and pleomorphic subtypes. The pleomorphic subtype, in particularly, was an independent predictor for worse overall survival in the multivariate analysis setting. The pleomorphic subtype showed no significant difference in overall survival compared with biphasic (p=0.96) and sarcomatoid type (p=0.15). The authors defined the solid and micropapillary as high-grade subtype in epithelioid mesothelioma. With regard to the pleomorphic subtype which had aggressive clinical and biologic behavior such as prominent lymphatic, vascular invasion, and rapid recurrence, the authors proposed that it was best regarded as a sarcomatoid pattern rather than an epithelioid one. There were some histological features belonging to epithelioid mesothelioma, namely, microcystic, clear cell, deciduoid, and small cell types. That study did not demonstrate any association of those histological features with prognosis. Multicytic peritoneal mesothelioma and well-differentiatedpapillary mesothelioma are two rare subgroups which are nearly always encountered in peritoneal mesothelioma of females. They are variants of epithelioid mesothelioma and have excellent prognosis [13]. Due to rarity and lack of prospective large scale clinical trials, there is still no consensus for optimal treatment so far. Localized MPM can be resected by surgical intervention. However, the diffuse-type of invasive mesothelioma was managed with chemotherapy and even radiotherapy after palliative surgery in the past [9]. The median survival period was uniformly less than one year, and long-term survival was uncommon [15]. The median survival for untreated patients was approximately 6 months [15]. Over the past 5 years, experiences in cytoreductive surgery (CRS) and hyperthemic intraperitoneal chemotherapy (HIPC) were accumulated gradually. Markedly improved outcomes including the survival rate have been reported. Some papers reported their phase II and observation experiences with CRS and HIPC in the US and Europe reaching the satisfied outcome with an overall fiver-year survival rates ranging from 29% to 57%, and median survival time of up to 70 months [16, 17]. The advantages of CRS combined with HIPC over the conventional systemic chemotherapy are that they remove macroscopic tumors, decreasing tumor burden [16,17]. Heated and direct-contact chemotherapy drugs provide higher concentration and penetration into mesentery nodules [17, 18]. However not all patients are candidates for CRS and HIPC; patients with poor performance and extra-peritoneal metastasis are not suitable for such treatment [17]. Moreover the skill of the surgeon plays an important role in completeness of cytoreduction surgery [19]. Based on the best knowledge and a report in the literature, a research by Pubmed et al, there is no published report from Taiwan on the application of HIPC and cytoredutive surgery in MPM. In our report, these three patients did not undergo cytoreductive surgery and HIPC. This was due either to advanced disease with liver metastasis and our lacking of experience. This approach may be adopted in the future with gathering more evidence and increased experience in cytoreduction surgery. In 2004, pemetrexed was approved worldwide to be used in combination with cisplatin for the treatment of malignant pleural mesothelioma in patients whose disease was not resectable [20]. However, up to now no chemotherapeutic agent, either alone or in combination, has demonstrated a consistent survival advantage in peritoneal mesothelioma. Currently, there is
90 Z. Y. Lin et al./jcrp 2(2015) 83-92 no approved treatment for peritoneal mesothelioma [20]. Many researches on evaluating the efficacy profile when peritoneal mesothelioma patients were treated with pemetrexed with or without a platinum agent demonstrate that pemetrexed or cisplatin alone is inferior to pemetrexed combined with cisplatin or carboplatin in the response rate [20]. One study reported this difference among these regimens in the response rate [20] (pemetrexed, pemetrexed with cisplatin, and pemetrexed with carboplatin): 12.5%, 20.0%, and 24.1%, respectively. Pemetrexed combined with cisplatin is still thought to be more efficient in treating MPM. Recently molecularly targeted therapy agents have been introduced to treat advanced malignant mesothelioma (including pleural type). Tremelimumab in a small single arm, phase II study reported positive treating outcome [21]. Tremelimumab is a monoclonal antibody of cytotoxic T-lymphocyte antigen 4 (CTLA4), which is a powerful negative regulator of T cell activation. By means of blockage of CTLA4, the activated cytotoxic T lymphocyte can eliminate the tumor cells more efficiently. This study enrolled only 29 participants. Though none-attained a complete response, two patients (7%) had a durable partial response (one lasting 6 months and the other lasting 18 months). However nine patients (31%) had a median progression-free survival of only 6.2 months. The author recognized that tremelimumab seemed to have encouraging clinical activity in previously treated patients with advanced malignant mesothelioma. Other experimental approaches with immunotherapeutic agents including bevacizumab, thalidomide, sorafenib, sunitinib, imatinib, vatalanib, cediranib, and vorinostat [22-29] have been reported, but no established role has yet been found in the treatment of mesothelioma. In conclusion, MPM is a rare, highly lethal, and rapidly progressive malignancy. There is no consensus for established treatment so far. Further researches for MPM are ongoing and we hope that they will offer us a better, feasible treatment in the future. REFERENCES 1. Boffetta P. Epidemiology of peritoneal mesothelioma: a review. Ann Oncol 18: 985-990, 2007. 2. Hemminki K, Li X. Time trends and occupational risk factors for peritoneal mesothelioma in Sweden. J Occup Environ Med 45: 451-455, 2003. 3. Hodgson JT, Darnton A. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Ann Occup Hyg 44: 565-601, 2000. 4. Borrida A, Padoan I, Mencarelli R, et al. Peritoneal mesothelioma: a review. MedGenMed 9: 32-35, 2007. 5. Lee LJ, Chang YY, Wang JD. Impact of malignant mesothelioma in Taiwan: a 27-year review of population-based cancer registry data. Lung Cancer 68: 16-19, 2010. 6. Baratti D, Kusamura S, Martinetti A, et al. Circulating CA125 in patients with peritoneal mesothelioma treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Ann Surg Oncol 14: 500-508, 2007. 7. Kebapci M, Vardareli E, Adapinar B, et al. CT findings and serum ca 125 levels in malignant peritoneal mesothelioma: report of 11 new cases and review of the literature. Eur Radiol 13: 2620-2026, 2003. 8. Yan TD, Deraco M, Elias D, et al. A novel tumornode-metastasis (TNM) staging system of diffuse malignant peritoneal mesothelioma using outcome analysis of a multi-institutional database. Cancer 117: 1855-1863, 2011. 9. Yan TD, Edwards G, Alderman R, et al. Morbidity and mortality assessment of cytoreductive surgery and perioperative intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma--a prospective study of 70 consecutive cases. Ann Surg Oncol 14: 515-525, 2007. 10. Chua TC, Yan TD, Morris DL. Outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma:
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