Int J Colorectal Dis (2015) 30:1–10 DOI 10.1007/s00384-014-2029-1
REVIEW
Advances in malignant peritoneal mesothelioma Shoubo Cao & Shi Jin & Jingyan Cao & Jing Shen & Jing Hu & Dehai Che & Bo Pan & Jiawen Zhang & Xiaoxi He & Dian Ding & Feifei Gu & Yan Yu
Accepted: 9 October 2014 / Published online: 21 October 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background Malignant mesothelioma is a rare, insidious, and aggressive tumor arising from the mesothelial surface of pleural and peritoneal cavities, the pericardium, or the tunica vaginalis, with an increasing incidence worldwide, high misdiagnosis rate, and overall negative prognosis. A total of 20 % of all cases is peritoneum in origin. Methods The present study is a review of literatures focusing on the advances in epidemiology, clinical presentations, radiological features, diagnosis, misdiagnosis, management, and prognostic factors of malignant peritoneal mesothelioma (MPM) occurred in the past decades. Results Asbestos, SV40, and radiation exposures have been demonstrated to be correlated with the pathogenesis of MPM. The main presentations are abdominal distension and pain. Computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) play an important role in the preoperative imaging and staging. Definitive diagnosis is made on the basis of immunohistochemistry. Prognostic factors have been identified and verified. Negative indicators include advanced age, male gender, poor performance status, non-epithelial histology, and absence of Shoubo Cao and Shi Jin contributed equally to this work and should be considered co-first authors. S. Cao : S. Jin : J. Cao : J. Shen : J. Hu : D. Che : B. Pan : J. Zhang : X. He : D. Ding : F. Gu : Y. Yu (*) Department of Medical Oncology, Harbin Medical University Cancer Hospital, No.150 Haping Road, Harbin 150081, China e-mail: [email protected] Y. Yu e-mail: [email protected] S. Cao e-mail: [email protected] S. Jin e-mail: [email protected]
surgery. The management of MPM has evolved from single chemotherapy to multimodality treatment of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), chemotherapy, radiotherapy, and immunotherapy. Promising results have been achieved after a combined treatment of CRS and HIPEC, with an elevated median survival time of 29.5–92 months and a 5-year survival rate of 39–63 %. Conclusions CRS and HIPEC represent the standard treatment strategy for selected patients with MPM, and patients with unresectable tumors can benefit from the combined treatment of chemotherapy, radiotherapy, and immunotherapy. Keywords MPM . CRS . HIPEC . Diagnosis . Management
Introduction Malignant peritoneal mesothelioma (MPM) is a fatal, treatment-resistant, and asbestos-related neoplasm of the serosal lining of the peritoneum, with an incidence of one per million [1]. However, due to the extensive usage of asbestos materials in building and the long latent between asbestos exposure and development of MPM, which can be ranged 25–71 years [2], the incidence of MPM is increasing worldwide in recent decades [2–6]. The main presentations are abdominal distension and pain resulted from the accumulation of tumors and ascites. The median time between symptoms initially presented and definitive diagnosis is 122 days, indicating the insidious characteristic of this disease [7]. Most cases died of intestinal obstruction or terminal starvation within 12 months with the progression of disease. Given the increasing frequency, limited understanding of its natural history, and dismal prognosis, timely and effectively treatment is urgently needed. Unfortunately, scarcely advances in therapies have been achieved in the last century since the relationship between
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asbestos exposure and MPM was clearly clarified in 1960 on the basis of data from South Africa [8]. The roles of palliative surgery, chemotherapy, and radiotherapy remain unsatisfactory. Recently, the prevalence of CRS and HIPEC has reformed the management of MPM in selected patients, with an increased median survival of 29.5–92 months and a 5-year overall survival rate of 39–63 % [9–15]. At present, more and more attention has been paid to MPM, not only because of the widely exposure to asbestos especially occupational exposure but also for the increasing economic burdens caused by MPM. This review article focuses on the main advances in epidemiology, diagnosis, management, and prognostic factors of MPM occurred in the past decades.
Epidemiology Malignant mesothelioma, firstly described by Miller and Wynn in 1908 [16], was rarely seen before 1950. However, the widely use of asbestos after World War II directly induced the discovery of the relationship between asbestos exposure and development of MPM in 1960 [8]. The incidence of MPM was increasing since the 1970s. Although some developed countries had abandoned the usage of asbestos materials in the 1980s, the long latency between asbestos contact and onset of mesothelioma, which can be ranged 25–71 years, indicated that the frequency of MPM would be still increasing [2, 3]. In the USA, annual mesothelioma death had peaked in 2000– 2004 with a statistic of 2,000, while the incidence of other countries (Table 1) would still be rising until a reached peak [17–25]. Russia, China, India, and Brazil, as the giant manufacture places, have not paid enough attention to it, which may be a thorny issue in the following decades. MPM is also a lethal disease characterized as multiple etiologies. The main carcinogen leading to the development of MPM is asbestos, and 90 % MPM is associated with asbestos exposure [17]. However, exposures to radiation, talc,
mica, erionite, thorotrast, Hodgkin’s disease, and SV40 have also been reported to be correlated with MPM [26–30].
Clinical features Male predominance of MPM has been well established with a preference for cases in their fifth to seventh decades, which can be interpreted by more chances of occupational and environmental asbestos contact [4, 31]. MPM is usually diagnosed in advanced stage due to its non-specific manifestations. Median time between symptoms presented to diagnosis is about 4 months, highlighting the insidious feature of this disease [7]. The most common presentations are abdominal distension and pain caused by the accumulation of ascites and tumors, ranging 41–86 and 31–87 %, respectively [7, 31]. The less common initial complaints including weight loss, abdominal mass, fever, diarrhea, vomiting, and new onset hernia can be seen in 32, 30, 22, 17, 15, and 12 % patients [31, 32]. In addition, approximately 8 % patients can be diagnosed incidentally during a diagnostic workup for another conditions such as exploratory laparoscopy for infertility and laparotomy for a gynecological lesion [31]. Recently, Manzini Vde P et al. [7, 31] prompted a new clinical classification of MPM based on variable presentations which can be divided into three groups (classical, surgical, and medical group), and each group carried a different clinical course. Classical group is characterized as abdominal distension or abdominal pain. Medical group is characterized by fever, diarrhea, weight loss, and acute-phase reactant changes and surgical emergency in surgical group (such as acute appendicitis and intestinal obstruction). MPM is confined to the peritoneal cavity in most cases and seldom involves intra- and extra-abdominal organs because the typical growth pattern of MPM is extensive, not infiltrative [33]. Swelling lymph node induced by local involvement can cause the obstruction of superior vena cava, cardiac tamponade, and compression of some important organs (Fig. 1). Physical examination is helpful with the presence of peritoneal fluid or abdominal mass.
Table 1 Epidemiologic characteristics of malignant mesothelioma Country
Year of peak incidence
Annual death at peak
Trends of mesothelioma death (year)
Italy [17]
2012–2024
800
1,218 (1970–1974)
3,313 (1995–1999)
Greece [18] Japan [19] German [20] Britain [21] Spain [22] France [23] Australia [24]
no data 2027 2020 2020 At least 2016 2030 2020
No data No data No data 2,700–3,300 No data 820–1,630 No data
9 (1983–1985) 710 (2000) 992 (2000) 153 (1968) 270 (1977–1981) 1,229 (1980–1984) 16 (1980)
53 (2001–2003) 1,156 (2009) 1,392 (2010) 1,009 (1991) 520 (1997–2001) 1,614 (1985–1989) 289 (1990)
1,848 (2001)
490 (2000)
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Computed tomography
Fig. 1 Rectum compression induced by swelling lymph nodes in patients with MPM
CT is the primary imaging modality for suspected MPM. The dominant signs revealed on CT are ascites (69 %), peritoneal thickening (59 %), abdominal mass (37 %), and mesenterial thickening (27 %) [32]. Three types of MPM have been described according to variable CT presentations: dry-painful, wet, and mixed type [1, 36], as shown in Table 2. Metastasis is rarely seen during its natural history and in most cases, MPM is confined to the peritoneal cavity for the special growth pattern of extension rather than infiltration. However, rare cases of liver, colon, lung, bone, and lymph node involvement have already been reported [33, 37–39]. High inspection of MPM should be made with the presence of ascites, peritoneal thickening, and a localized tumor in peritoneal cavity in the procession of disease.
Diagnosis A precise diagnosis of MPM is made on basis of accurate medical history, laboratory, radiological, and pathological examinations. Typical clinical presentations including abdominal distension/abdominal pain combined with history of asbestos exposure is essential for leading us to the right direction, and radiography provides concrete information for the stage of this disease, while pathology can confirm the diagnosis.
Magnetic resonance imaging MRI has not been used routinely in the assessment of MPM, and only few articles refer to this issue. However, MRI shows an advantage over CT scan in the evaluation of tumor involvement, especially with the presence of ascites, which can be interpreted by the high contrast between the enhanced tumor and the non-enhanced ascites [40]. MRI can provide precise information of stage, and it is essential for selected patients accepting the therapy of surgery.
Laboratory examinations High levels of serum CA125, CA153, hyaluronic acid, osteopontin, and mesothelin-related protein (SMRP) have been referred to be as useful serum markers for MPM [4, 34]. A study performed recently including 13 MPM patients and 45 individuals with asbestos-related diseases showed that expressions of serum high-mobility group box 1 (HMGB1) were significantly higher in MPM compared with the population who had been exposed to asbestos but did not develop MPM [35]. The data suggested that serum HMGB1 concentration could be a useful marker for MPM. However, these positive serum markers are also important for the monitoring of treatment response in patients with MPM.
Positron-emission tomography PET is available in the distinguishability of malignant and benign mesothelioma due to the significant diversity in the standardized uptake value (SUV) of ( 18 Ffluorodeoxyglucose (FDG) [41]. FDG is the most common tracer used in clinical practice. PET has been widely used in the evaluation of stage for preoperative patients and shows an advantage for lymph node involvement, which may be negative on CT scan [4]. In addition, PET can also be used to assess the efficiency of management and is essential for the guide of treatment in next step [41, 42]. Table 2 Classifications of MPM due to variable CT presentations
Radiological characteristics Radiology plays an important role in the diagnosis, stage, and follow-up of this disease. Computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) are the main protocols used for the evaluation of MPM.
Types
Features on CT scan
Dry-painful type Wet type
Abdominal pain and peritoneum-based masses Abdominal distension, ascites, and multiple small nodules and plaques The combination of dry-painful and wet type
Mixed type
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Biopsy A long delayed time between symptoms initially presented and definitive diagnosis is a thorny problem facing both physicians and patients. The role of cytological examination of ascites was contradictory, which is known to be either useless [1], or with a high mesothelioma positive rate of 51 % [32]. Ascite cytology is suggested because it can not only alleviate abdominal distension but have a diagnostic function. Experiment laparotomy and laparoscopy with biopsy are the main diagnostic manners used at present. However, deficits of laparotomy are also remarkable, such as physical and mental injuries developed during surgery. Laparoscopy, for its minor wounds and clearly detection of intraoperative condition, represents a better diagnostic choice for patients [32, 43]. Ultrasound or CT-guided biopsies have become more popular and accepted in clinics for its low incidence of injury, high diagnostic accuracy, and absence of serious complications [34, 44]. The study of Wang J et al. [44] indicated that ultrasound-guided biopsy for peritoneal lesions revealed a high satisfactory rate and overall diagnostic accuracy of 91.5 and 92.8 %, respectively [44]. However, there is still one troublesome question that we should pay enough attention to, that is, the scanty or inadequate of tissue samples. To ensure the diagnostic accuracy, enough tissue biopsies are necessary.
Pathology MPM can be divided into three types, epithelioid, sarcomatoid, or biphasic, and the epithelioid type is the most common type which can be seen in 75–90 % patients [34]. Immunohistochemistry has been the most valuable and available modality for the diagnosis of MPM. However, no standard markers providing absolute specificity and high sensitivity have been identified at present [45]. It is widely accepted that calretinin, CK5/6, WT-1, HBME-1, thrombomodulin, podoplanin, mesothelin, and D2-40 (Fig. 2) are mainly expressed in mesothelioma, while TTF1, CEA, Ber-Ep4, B72.3, MOC31, CD15 are commonly expressed in adenocarcinoma instead of mesothelioma [45–47]. The most common
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used positive markers are calretinin, WT-1, CK5/6, HBME-1, and vimentin. Recently, a new marker PAX8 has been found to be effective in the differential diagnosis of ovarian cancer and malignant mesothelioma, which can be seen in all ovarian cancer patients, non-malignant pleural mesothelioma, and 9 % MPM [48]. The combination of two or more positive and negative markers is suggested for a precise diagnosis.
Differential diagnosis MPM is also a fatal malignancy with high misdiagnosis rate, which can be misdiagnosed as ovarian cancer, colon cancer and tuberculous peritonitis. High index of suspicion and precise examinations are essential for the early diagnosis of MPM, for the management and prognosis of these disease are significantly variable. MPM and ovarian cancer MPM is easy of being diagnosed as ovarian cancer due to the congenerous symptoms of extensive peritoneal spread, widely presence of ascites, and predilection for serosal cavities. So, the first step is to make clear which condition it belongs to: a primary peritoneal tumor involving ovaries or a primary ovarian tumor widely spreading peritoneum. A recent research found that clinical distinction of MPM from ovarian cancer is difficult, and differential diagnosis relies on the immunohistochemical markers mentioned above [47]. MPM and colon cancer With the progression of MPM, intestinal obstruction and cachexia can be the terminal presentations, and it is easily misdiagnosed as gastroenteric tumor especially with abdominal pain and a peritoneal cavity mass closely adjacent to colon on CT scan (Fig. 3a, b). There is less than ten patients with colonic invasion of MPM reported at present. Colonoscopy can also be misleading in the diagnosis if the tumor had penetrated structures of colon (Fig. 4). Intestinal obstruction
Fig. 2 Positive immunohistochemical markers of calretinin, CK5/6, and HBME-1 for patients with MPM
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Fig. 3 A 3D-enhanced CT revealed an irregular thickening wall of hepatic flexure of colon (a) and an infiltrating mass closely adjacent to intestine (a, b), which is easily misdiagnosed as colon cancer on radiography. This atypical radiological presentations should be considered in the differential diagnosis of MPM
combined with tumor located adjacent to colon, as the atypical manifestation of MPM, should be considered in the differential diagnosis of MPM.
MPM and tuberculous peritonitis Approximately 70 % MPM patients presented with exudative ascites with or without elevated tumor markers and fever, so it is necessary to distinguish MPM from tuberculous peritonitis [32]. Elevated ascitic or serum tumor markers of CA125, CA153 and hyaluronic acid, visible tumor, or mesothelial cells in peritoneal fluid cytology are helpful for diagnosis of MPM [49, 50].
Fig. 4 If MPM had penetrated the structures of colon, the results of colonoscopy could be an infiltrating lesion located in the colon, ruptured in the surface and easily bled when touched. A high inspection of MPM should be made and definitive diagnosis is made on basis of immunohistochemistry
Advances in management MPM was once considered a preterminal condition with little attention paid to it. However, with the widely contact to asbestos, increasing incidence as well as enormous economic burdens caused by MPM, it has become a focus of researches and has made a significant progress in the aspect of treatment in recent years. The management of MPM has evolved from single chemotherapy to multiple modality treatment including CRS plus HIPEC, systemic chemotherapy, radiotherapy, and immunotherapy. Radiotherapy The role of radiotherapy in the management of MPM remains unclear in spite of few reported long-term survivals related to it [51, 52]. Radiotherapy has been used as an adjuvant therapy of surgery and chemotherapy. A pilot study with limited ten patients enrolled showed an improved disease-free survival of 19–78 months when treated with surgical debulking, chemotherapy, and whole abdominal irradiation [53]. In addition, a single-institution phase I or II trial performed by Hesdorffer ME et al. [54] revealed a median overall survival of 70 months and a 3year survival of 67 % with the presence of surgery, intraperitoneal chemotherapy, and immunotherapy, followed by whole abdominal radiotherapy. The combination of radiotherapy and intraperitoneal chemotherapy can also be beneficial to the remission of locally advanced MPM and improvement of quality of life [55]. However, tolerated dose of some important abdominal organs, low responsive rate, and adverse reactions of adhesions and intestinal obstruction are the main reasons blocking the popularity of radiotherapy [33, 53].
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Systemic chemotherapy Limited clinical trials have been performed to assess the role of chemotherapy in patients with MPM due to the rarity of this disease [56]. Single-agent chemotherapy or combinations remains unsatisfactory, with a poor response rate of less than 15–20 % [4]. A randomized trial with 43 patients enrolled indicated that the early usage of chemotherapy presented a long-term symptoms control and survival, with a median survival and 1-year survival of 14 months, 66 % compared with 10 months, 36 % in the delayed treatment group [57]. Chemotherapeutic regimens can also be drawn lessons from the treatment of malignant pleural mesothelioma and pemetrexed combined with cisplatin has become the new standard for unresectable patients with a median survival time of 12.1 months [6, 56]. Currently, a phase II trial revealed that the management of pemetrexed plus gemcitabine provide an increased median survival time to 26.8 months in spite of a low response rate of 15 % [58]. Intraperitoneal chemotherapy Intraperitoneal chemotherapy was used for the treatment of peritoneal surface-spreading malignancies, aiming to deliver a high dose of chemotherapy where the tumor cells reside and reducing the occurrence of side effects [59–61]. Few studies have been performed on MPM, and no survival benefit has been verified for the single usage of intraperitoneal chemotherapy before 2009 [34]. A retrospective study performed recently revealed that the larger surface areas and smaller
volumes of patients receiving intraperitoneal chemotherapy were associated with an improved survival of 48 months and decreased mortality [60]. In addition, computed tomography peritoneography is suggested for the evaluation of the distribution of intraperitoneal chemotherapy and patients with poor distribution should be adjusted to systemic chemotherapy. A vitro trial found that intrapleural chemotherapy was more effective when using two drug combinations (cisplatin/ gemcitabine and cisplatin/pemetrexed) compared with cisplatin alone and showed no particular sensitivity to heat [61], which may be meaningful for the further research of MPM. CRS and HIPEC MPM is typically localized in the abdominal cavity during its clinical course and only few cases of intra- or extra-abdominal invasion have been reported at present [33, 37–39]. Effective and timely treatment strategies, aiming to remove tumors and control disease progression within peritoneal cavity, have been well established in recent years. CRS plus HIPEC, regarded as the standard therapeutic intervention for selected patients with MPM, have been examined by a series of studies [11–15, 62–68]. Details can be seen in Table 3. The goals of CRS and HIPEC are to achieve a complete resection of all grossly identified tumors and deliver high dose of regional chemotherapy to the micrometastatic residual sites of disease [56, 69]. CRS is the primary step and plays a fundamental role in multiple modality management. Large tumors within the abdomen and pelvis can be removed through peritonectomy or visceral organ resection if
Table 3 Efficiency of CRS plus HIPEC in patients with MPM and variable origins of peritoneal carcinomas Studies
N
MPM [62] 2000 33 [68] 2003 49 [63] 2006 49 [13] 2009 20 [14] 2009 401 [65] 2013 211 [66] 2013 112 [12] 2013 108 [11] 2014 65 Peritoneal carcinomasb
MSTa (months)
Survival rate and perioperative mortality and morbidity (%) 1 year
2 years
3 years
5 years
10 years
Perioperative mortality and morbidity
31 92 – 29.5 53 38.4 63.2 63.2 46.2
77 86 88 78.2 81 – – – 77
– 77 74 – – – – – 57
56 59 65 46.3 60 – – – –
47 59 57 – 47 41 91.3 52.4 39
– – – – – 26 – 44.6 –
3.0 – – 5.0 2.0 2.3 2.7 1.9 6.0
33 25 15 35 46 39.4 24.1 38.9 35
[15] 2012
57
–
Over 80
–
Over 60
–
–
0.0
51
[64] 2013 [67] 2014
100 1,000
– 29.4
91.7 72.3
– –
59.1 44.6
50.9 31.5
– 18.1
0.0 3.8
56 42
a
Median overall survival time
b
Peritoneal carcinomas derive from MPM and ovarian, colorectal, gastric, and appendiceal cancers
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necessary, whereas argon beam or other types of electrofulguration can be a choice for smaller tumor implants on the mesentery or solid organ surfaces [56]. HIPEC usually with mitomycin C or cisplatin is the most effective strategy of distributing high-dose intraperitoneal chemotherapy to all peritoneal surfaces with available hyperthermia, which can enhance the cytotoxic of chemotherapeutic agents in both temperature- and timedependent manners [31, 70]. However, not all patients are suitable for this standard treatment, evidence of disease outside the peritoneal cavity, poor performance status, and severe cardiac, pulmonary, hepatic, or renal dysfunction are the main contraindications to CRS and HIPEC [56]. The earliest study for this combined treatment revealed that the median survival of 33 patients was 31 months, with a 5year survival rate of 47 % [62]. A phase II study with 49 patients enrolled showed that median survival was an encouraging 92 months, and 5-year survival rate was 59 % [68]. In addition, a multi-institutional registry study with the largest number of patients enrolled indicated that median survival of all 401 patients was 53 months, with a 3- and 5-year survival rate of 60 and 47 %, respectively [14]. Based on these promising results, CRS plus HIPEC had been widely used and numbers of studies had been performed in recent 3 years, with a median survival and 5-year survival rate of 38.4– 63.2 months and 39–91.3 %, respectively [11, 12, 65, 66]. CRS and HIPEC were also effective in the management of variable origins of peritoneal carcinomas and malignant ascites [15, 64, 66, 67, 71–73]. Votanopoulos KI et al. [72] found that iterative CRS and HIPEC were valuable in the treatment of recurrent MPM, with a median survival of 52.9 and 21.8 months after the second cytoreduction, while the mortality (3.2 %) and 30-day morbidity (48.4 %) were similar to initial cytoreduction. Same results can also be reached in Chua TC et al. [73], with a median survival and 3- and 5-year survival rates of MPM of 57 months and 80 and 27 %, respectively. Despite the favorable results of CRS and HIPEC compared with the traditional therapies in recent studies, high perioperative mortality and morbidity ranging 0.0–6.0 and 15–56 % were a thorny question facing clinicians and patients, as shown in Table 3. The criteria for patients enrolled should be more careful. Immunotherapy Both studies of animals and small sample clinical trials indicated that malignant mesothelioma was sensitive to immunotherapy. TNFα, IL6, IFN, and GM-CSF had been shown to be effective in the management of mesothelioma [4, 74, 75]. However, limited data had been received at p r es e n t a n d t h i s c o n s t r i c t e d t he p r e va l e nc e o f
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immunotherapy. Tani M et al. [76] found that activated cytotoxic T lymphocytes (CTL) plus chemotherapy were an effective strategy for MPM, exhibiting a high cytotoxicity against mesothelioma cells and all two patients received a status of partial response. In mice models, pulsed dendritic cells had been demonstrated to be powerful in controlling growth of mesothelioma and may be used as adjuvant to control local recurrence, which is known to be associated with strong tumor-specific cytotoxic T lymphocyte responses [77]. Mesothelin is a tumor differentiation antigen highly expressed on the cell surface of mesothelioma, ovarian cancer, and some malignancies. HN1 IgG, a fully human IgG with an immuntoxin, had been shown with the ability of killing mesothelin-expressing tumor cells with high cytotoxic activity, and this may have significant potential for the treatment of mesothelinexpressing tumors [78]. More evidences of phase II/III clinical trials are needed for the promising treatment of immunotherapy. Targeted therapy Targeted therapy had made a significant progress in the management of lung, breast, gastric, and other cancers, but it had not found its direction in malignant mesothelioma at present. A phase II study of gefitinib on patients with previously untreated malignant mesothelioma indicated that gefitinib was not active in spite of a EGFR overexpression of 97 % mesothelioma patients [79]. Of all 43 patients enrolled, 1-year survival is 32 %. Disease control rate (DCR) is 53 % (2 % CR, 2 % PR, 49 % SD), while PD and death can be seen in 35 and 12 %, respectively. Effective targets are urgently essential for the further study and improved survival.
Prognostic factors Due to the rarity of MPM and variable treatment strategies, prognostic factors had not been well identified in the past century. However, a combined treatment of CRS and HIPEC has been demonstrated to be correlated with a promising improved survival compared with traditional therapies in recent 10 years [11–14, 63, 65, 66]. The increasing numbers of patients enrolled with the uniform regimen made the analysis for clinical, radiological, and pathological prognostic parameters more precise and credible. Female gender has been previously demonstrated to be a favorable prognostic factor of MPM with limited patients in each group [62, 80]. Recently, a large multi-institutional study with 294 MPM patients enrolled indicated that under the uniform strategy of CRS and HIPEC, female patients had a significant improved survival than male patients [81]. Less
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asbestos exposure and extensive peritoneal involvement, favorable epithelial pathological type, and the expression of ER-β (oestrogen receptors, nuclear) commonly induced the positive prognosis of female patients [31, 82, 83]. However, advanced age can be seen as a negative prognostic indicator for MPM [12], which may be accounted for the surgical injury or poor ability of recovering after surgery. Lymph node metastasis is rarely seen in MPM but is definitely related to an extremely poor prognosis [84, 85]. In one study with 100 patients enrolled, seven patients were found with lymph node metastasis. Median survival of these seven patients was 6 months with a 1- and 2-year survival rate of 43 and 0 %, respectively, while another 93 patients without lymph node metastasis showed a median survival of 59 months with a 5and 7- survival rate of 50 and 43 %, respectively [85]. Similar results were also obtained in a recent study with 83 MPM patients enrolled: 5-year overall survival of pathologically negative and positive nodes group was 82.5 and 16.7 %, respectively [85]. Careful assessment of node-containing sites is recommended during CRS, and all suspicious nodes should be submitted separately for a definitive pathological examination [85]. In addition, completeness of cytoreduction and epithelial type of pathology, as favorable prognostic indicators, have been widely accepted by both clinicians and patients since the beginning of this century [12–14, 62, 63].
Conclusions MPM is a rare and lethal disease characterized as multiple etiologies, variable presentations, high misdiagnosis rate, and overall negative prognosis if left untreated. Patients with unresctable tumors can benefit from the systemic chemotherapy using pemetrexed and cisplatin. CRS and HIPEC represent the standard strategy for selected patients, with a promising increased median survival of 29.5–92 months and a 5year overall survival rate of 39–63 %. With the further research and new understandings of molecular biology and immunology, more efficacious strategies indicating a longterm survival and high quality of life are worthy of being expected. Acknowledgments This work was supported by Wujieping Foundation (No. 320.6750.12204), Young People Research Fund for the grant National Natural Scientific Foundation of China (No. 81201828), Young People Foundation of Heilongjiang Provincial of China (No. QC2012C013), National Natural Scientific Foundation of China (No. 81101758), Health Department of Heilongjiang Provincial of China (No: 2011-124) and Harbin Medical University Cancer Hospital major project Foundation (No: JJZ-2010-01). Conflict of interest None.
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9 46. Suster S, Moran CA (2006) Applications and limitations of immunohistochemistry in the diagnosis of malignant mesothelioma. Adv Anat Pathol 13:316–329 47. Taşkın S, Gümüş Y, Kiremitçi S et al (2012) Malignant peritoneal mesothelioma presented as peritoneal adenocarcinoma or primary ovarian cancer: case series and review of the clinical and immunohistochemical features. Int J Clin Exp Pathol 5:472–478 48. Laury AR, Hornick JL, Perets R et al (2010) PAX8 reliably distinguishes ovarian serous tumors from malignant mesothelioma. Am J Surg Pathol 34:627–635 49. Krasuski P, Poniecka A, Gal E (2002) The diagnostic challenge of peritoneal mesothelioma. Arch Gynecol Obstet 266:130–132 50. Chen LY, Huang LX, Wang J et al (2011) Malignant peritoneal mesothelioma presenting with persistent high fever. J Zhejiang Univ Sci B 12:381–384 51. Rogoff EE, Hilaris BS, Huvos AG (1973) Long-term survival in patients with malignant peritoneal mesothelioma treated with irradiation. Cancer 32:656–664 52. Cain J, Nori D, Huvos A et al (1983) The role of radioactive colloids in malignant peritoneal mesothelioma. Gynecol Oncol 16:263–274 53. Lederman GS, Recht A, Herman T et al (1987) Long-term survival in peritoneal mesothelioma. The role of radiotherapy and combined modality treatment. Cancer 59:1882–1886 54. Hesdorffer ME, Chabot JA, Keohan ML et al (2008) Combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for the treatment of malignant peritoneal mesothelioma. Am J Clin Oncol 31:49–54 55. Takeuchi K, Fujimoto M, Tsujino T et al (2007) Impressive remission of locally advanced malignant peritoneal mesothelioma treated with combination of radiotherapy and intraperitoneal paclitaxel. Eur J Gynaecol Oncol 28:322–323 56. Turner K, Varghese S, Alexander HR Jr (2012) Current concepts in the evaluation and treatment of patients with diffuse malignant peritoneal mesothelioma. J Natl Compr Cancer Netw 10:49–57 57. O’Brien ME, Watkins D, Ryan C et al (2006) A randomised trial in malignant mesothelioma (M) of early (E) versus delayed (D) chemotherapy in symptomatically stable patients: the MED trial. Ann Oncol 17:270–275 58. Simon GR, Verschraegen CF, Jänne PA et al (2008) Pemetrexed plus gemcitabine as first-line chemotherapy for patients with peritoneal mesothelioma: final report of a phase II trial. J Clin Oncol 26:3567– 3572 59. Verschraegen CF (2001) Intracavitary therapies for mesothelioma. Curr Treat Options Oncol 2:385–394 60. Leinwand JC, Zhao B, Guo X et al (2013) Quantitative X-ray computed tomography peritoneography in malignant peritoneal mesothelioma patients receiving intraperitoneal chemotherapy. Ann Surg Oncol 20:S553–S559 61. Cameron RB, Hou D (2013) Intraoperative hyperthermic chemotherapy perfusion for malignant pleural mesothelioma: an in vitro evaluation. J Thorac Cardiovasc Surg 145:496–504 62. Sebbag G, Yan H, Shmookler BM et al (2000) Results of treatment of 33 patients with peritoneal mesothelioma. Br J Surg 87:1587–1593 63. Deraco M, Nonaka D, Baratti D et al (2006) Prognostic analysis of clinicopathologic factors in 49 patients with diffuse malignant peritoneal mesothelioma treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Ann Surg Oncol 13:229–237 64. Teo MC, Tan GH, Tham CK et al (2013) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in Asian patients: 100 consecutive patients in a single institution. Ann Surg Oncol 20: 2968–2974 65. Alexander HR Jr, Bartlett DL, Pingpank JF et al (2013) Treatment factors associated with long-term survival following cytoreductive surgery and regional chemotherapy for patients with malignant peritoneal mesothelioma. Surgery 153:779–786
10 66. Haslinger M, Francescutti V, Attwood K et al (2013) A contemporary analysis of morbidity and outcomes in cytoreduction/hyperthermic intraperitoneal chemoperfusion. Cancer Med 2:334–342 67. Levine EA, Stewart JH 4th, Shen P et al (2014) Intraperitoneal chemotherapy for peritoneal surface malignancy: experience with 1, 000 patients. J Am Coll Surg 218:573–587 68. Feldman AL, Libutti SK, Pingpank JF et al (2003) Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. J Clin Oncol 21:4560–4567 69. Alexander HR Jr (2010) Surgical treatment of malignant peritoneal mesothelioma: past, present, and future. Ann Surg Oncol 17:21–22 70. Los G, Smals OA, van Vugt MJ et al (1992) A rationale for carboplatin treatment and abdominal hyperthermia in cancers restricted to the peritoneal cavity. Cancer Res 52:1252–1258 71. Randle RW, Swett KR, Swords DS et al (2014) Efficacy of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in the management of malignant ascites. Ann Surg Oncol 21: 1474–1479 72. Votanopoulos KI, Ihemelandu C, Shen P et al (2012) Outcomes of repeat cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal surface malignancy. J Am Coll Surg 215:412–417 73. Chua TC, Quinn LE, Zhao J et al (2013) Iterative cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent peritoneal metastases. J Surg Oncol 108:81–88 74. Soulié P, Ruffié P, Trandafir L et al (1996) Combined systemic chemoimmunotherapy in advanced diffuse malignant mesothelioma. Report of a phase I-II study of weekly cisplatin/interferon alfa-2a. J Clin Oncol 14:878–885 75. Bielefeldt-Ohmann H, Marzo AL, Himbeck RP et al (1995) Interleukin-6 involvement in mesothelioma pathobiology: inhibition
Int J Colorectal Dis (2015) 30:1–10 by interferon alpha immunotherapy. Cancer Immunol Immunother 40:241–250 76. Tani M, Tanimura H, Yamaue H et al (1998) Successful immunochemotherapy for patients with malignant mesothelioma: report of two cases. Surg Today 28:647–651 77. Hegmans JP, Hemmes A, Aerts JG et al (2005) Immunotherapy of murine malignant mesothelioma using tumor lysate-pulsed dendritic cells. Am J Respir Crit Care Med 171:1168–1177 78. Ho M, Feng M, Fisher RJ et al (2011) A novel high-affinity human monoclonal antibody to mesothelin. Int J Cancer 128:2020–2030 79. Govindan R, Kratzke RA, Herndon JE 2nd et al (2005) Gefitinib in patients with malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B. Clin Cancer Res 11:2300–2304 80. Yan TD, Brun EA, Cerruto CA et al (2007) Prognostic indicators for patients undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma. Ann Surg Oncol 14:41–49 81. Cao C, Yan TD, Deraco M et al (2012) Importance of gender in diffuse malignant peritoneal mesothelioma. Ann Oncol 23:1494– 1498 82. Wolf AS, Richards WG, Tilleman TR et al (2010) Characteristics of malignant pleural mesothelioma in women. Ann Thorac Surg 90: 949–956 83. Pillai K, Pourgholami MH, Chua TC et al (2013) Oestrogen receptors are prognostic factors in malignant peritoneal mesothelioma. J Cancer Res Clin Oncol 139:987–994 84. Yan TD, Yoo D, Sugarbaker PH (2006) Significance of lymph node metastasis in patients with malignant peritoneal mesothelioma. Eur J Surg Oncol 32:948–953 85. Baratti D, Kusamura S, Cabras AD et al (2010) Lymph node metastases in diffuse malignant peritoneal mesothelioma. Ann Surg Oncol 17:45–53
REVIEW
Advances in malignant peritoneal mesothelioma Shoubo Cao & Shi Jin & Jingyan Cao & Jing Shen & Jing Hu & Dehai Che & Bo Pan & Jiawen Zhang & Xiaoxi He & Dian Ding & Feifei Gu & Yan Yu
Accepted: 9 October 2014 / Published online: 21 October 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background Malignant mesothelioma is a rare, insidious, and aggressive tumor arising from the mesothelial surface of pleural and peritoneal cavities, the pericardium, or the tunica vaginalis, with an increasing incidence worldwide, high misdiagnosis rate, and overall negative prognosis. A total of 20 % of all cases is peritoneum in origin. Methods The present study is a review of literatures focusing on the advances in epidemiology, clinical presentations, radiological features, diagnosis, misdiagnosis, management, and prognostic factors of malignant peritoneal mesothelioma (MPM) occurred in the past decades. Results Asbestos, SV40, and radiation exposures have been demonstrated to be correlated with the pathogenesis of MPM. The main presentations are abdominal distension and pain. Computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) play an important role in the preoperative imaging and staging. Definitive diagnosis is made on the basis of immunohistochemistry. Prognostic factors have been identified and verified. Negative indicators include advanced age, male gender, poor performance status, non-epithelial histology, and absence of Shoubo Cao and Shi Jin contributed equally to this work and should be considered co-first authors. S. Cao : S. Jin : J. Cao : J. Shen : J. Hu : D. Che : B. Pan : J. Zhang : X. He : D. Ding : F. Gu : Y. Yu (*) Department of Medical Oncology, Harbin Medical University Cancer Hospital, No.150 Haping Road, Harbin 150081, China e-mail: [email protected] Y. Yu e-mail: [email protected] S. Cao e-mail: [email protected] S. Jin e-mail: [email protected]
surgery. The management of MPM has evolved from single chemotherapy to multimodality treatment of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), chemotherapy, radiotherapy, and immunotherapy. Promising results have been achieved after a combined treatment of CRS and HIPEC, with an elevated median survival time of 29.5–92 months and a 5-year survival rate of 39–63 %. Conclusions CRS and HIPEC represent the standard treatment strategy for selected patients with MPM, and patients with unresectable tumors can benefit from the combined treatment of chemotherapy, radiotherapy, and immunotherapy. Keywords MPM . CRS . HIPEC . Diagnosis . Management
Introduction Malignant peritoneal mesothelioma (MPM) is a fatal, treatment-resistant, and asbestos-related neoplasm of the serosal lining of the peritoneum, with an incidence of one per million [1]. However, due to the extensive usage of asbestos materials in building and the long latent between asbestos exposure and development of MPM, which can be ranged 25–71 years [2], the incidence of MPM is increasing worldwide in recent decades [2–6]. The main presentations are abdominal distension and pain resulted from the accumulation of tumors and ascites. The median time between symptoms initially presented and definitive diagnosis is 122 days, indicating the insidious characteristic of this disease [7]. Most cases died of intestinal obstruction or terminal starvation within 12 months with the progression of disease. Given the increasing frequency, limited understanding of its natural history, and dismal prognosis, timely and effectively treatment is urgently needed. Unfortunately, scarcely advances in therapies have been achieved in the last century since the relationship between
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asbestos exposure and MPM was clearly clarified in 1960 on the basis of data from South Africa [8]. The roles of palliative surgery, chemotherapy, and radiotherapy remain unsatisfactory. Recently, the prevalence of CRS and HIPEC has reformed the management of MPM in selected patients, with an increased median survival of 29.5–92 months and a 5-year overall survival rate of 39–63 % [9–15]. At present, more and more attention has been paid to MPM, not only because of the widely exposure to asbestos especially occupational exposure but also for the increasing economic burdens caused by MPM. This review article focuses on the main advances in epidemiology, diagnosis, management, and prognostic factors of MPM occurred in the past decades.
Epidemiology Malignant mesothelioma, firstly described by Miller and Wynn in 1908 [16], was rarely seen before 1950. However, the widely use of asbestos after World War II directly induced the discovery of the relationship between asbestos exposure and development of MPM in 1960 [8]. The incidence of MPM was increasing since the 1970s. Although some developed countries had abandoned the usage of asbestos materials in the 1980s, the long latency between asbestos contact and onset of mesothelioma, which can be ranged 25–71 years, indicated that the frequency of MPM would be still increasing [2, 3]. In the USA, annual mesothelioma death had peaked in 2000– 2004 with a statistic of 2,000, while the incidence of other countries (Table 1) would still be rising until a reached peak [17–25]. Russia, China, India, and Brazil, as the giant manufacture places, have not paid enough attention to it, which may be a thorny issue in the following decades. MPM is also a lethal disease characterized as multiple etiologies. The main carcinogen leading to the development of MPM is asbestos, and 90 % MPM is associated with asbestos exposure [17]. However, exposures to radiation, talc,
mica, erionite, thorotrast, Hodgkin’s disease, and SV40 have also been reported to be correlated with MPM [26–30].
Clinical features Male predominance of MPM has been well established with a preference for cases in their fifth to seventh decades, which can be interpreted by more chances of occupational and environmental asbestos contact [4, 31]. MPM is usually diagnosed in advanced stage due to its non-specific manifestations. Median time between symptoms presented to diagnosis is about 4 months, highlighting the insidious feature of this disease [7]. The most common presentations are abdominal distension and pain caused by the accumulation of ascites and tumors, ranging 41–86 and 31–87 %, respectively [7, 31]. The less common initial complaints including weight loss, abdominal mass, fever, diarrhea, vomiting, and new onset hernia can be seen in 32, 30, 22, 17, 15, and 12 % patients [31, 32]. In addition, approximately 8 % patients can be diagnosed incidentally during a diagnostic workup for another conditions such as exploratory laparoscopy for infertility and laparotomy for a gynecological lesion [31]. Recently, Manzini Vde P et al. [7, 31] prompted a new clinical classification of MPM based on variable presentations which can be divided into three groups (classical, surgical, and medical group), and each group carried a different clinical course. Classical group is characterized as abdominal distension or abdominal pain. Medical group is characterized by fever, diarrhea, weight loss, and acute-phase reactant changes and surgical emergency in surgical group (such as acute appendicitis and intestinal obstruction). MPM is confined to the peritoneal cavity in most cases and seldom involves intra- and extra-abdominal organs because the typical growth pattern of MPM is extensive, not infiltrative [33]. Swelling lymph node induced by local involvement can cause the obstruction of superior vena cava, cardiac tamponade, and compression of some important organs (Fig. 1). Physical examination is helpful with the presence of peritoneal fluid or abdominal mass.
Table 1 Epidemiologic characteristics of malignant mesothelioma Country
Year of peak incidence
Annual death at peak
Trends of mesothelioma death (year)
Italy [17]
2012–2024
800
1,218 (1970–1974)
3,313 (1995–1999)
Greece [18] Japan [19] German [20] Britain [21] Spain [22] France [23] Australia [24]
no data 2027 2020 2020 At least 2016 2030 2020
No data No data No data 2,700–3,300 No data 820–1,630 No data
9 (1983–1985) 710 (2000) 992 (2000) 153 (1968) 270 (1977–1981) 1,229 (1980–1984) 16 (1980)
53 (2001–2003) 1,156 (2009) 1,392 (2010) 1,009 (1991) 520 (1997–2001) 1,614 (1985–1989) 289 (1990)
1,848 (2001)
490 (2000)
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Computed tomography
Fig. 1 Rectum compression induced by swelling lymph nodes in patients with MPM
CT is the primary imaging modality for suspected MPM. The dominant signs revealed on CT are ascites (69 %), peritoneal thickening (59 %), abdominal mass (37 %), and mesenterial thickening (27 %) [32]. Three types of MPM have been described according to variable CT presentations: dry-painful, wet, and mixed type [1, 36], as shown in Table 2. Metastasis is rarely seen during its natural history and in most cases, MPM is confined to the peritoneal cavity for the special growth pattern of extension rather than infiltration. However, rare cases of liver, colon, lung, bone, and lymph node involvement have already been reported [33, 37–39]. High inspection of MPM should be made with the presence of ascites, peritoneal thickening, and a localized tumor in peritoneal cavity in the procession of disease.
Diagnosis A precise diagnosis of MPM is made on basis of accurate medical history, laboratory, radiological, and pathological examinations. Typical clinical presentations including abdominal distension/abdominal pain combined with history of asbestos exposure is essential for leading us to the right direction, and radiography provides concrete information for the stage of this disease, while pathology can confirm the diagnosis.
Magnetic resonance imaging MRI has not been used routinely in the assessment of MPM, and only few articles refer to this issue. However, MRI shows an advantage over CT scan in the evaluation of tumor involvement, especially with the presence of ascites, which can be interpreted by the high contrast between the enhanced tumor and the non-enhanced ascites [40]. MRI can provide precise information of stage, and it is essential for selected patients accepting the therapy of surgery.
Laboratory examinations High levels of serum CA125, CA153, hyaluronic acid, osteopontin, and mesothelin-related protein (SMRP) have been referred to be as useful serum markers for MPM [4, 34]. A study performed recently including 13 MPM patients and 45 individuals with asbestos-related diseases showed that expressions of serum high-mobility group box 1 (HMGB1) were significantly higher in MPM compared with the population who had been exposed to asbestos but did not develop MPM [35]. The data suggested that serum HMGB1 concentration could be a useful marker for MPM. However, these positive serum markers are also important for the monitoring of treatment response in patients with MPM.
Positron-emission tomography PET is available in the distinguishability of malignant and benign mesothelioma due to the significant diversity in the standardized uptake value (SUV) of ( 18 Ffluorodeoxyglucose (FDG) [41]. FDG is the most common tracer used in clinical practice. PET has been widely used in the evaluation of stage for preoperative patients and shows an advantage for lymph node involvement, which may be negative on CT scan [4]. In addition, PET can also be used to assess the efficiency of management and is essential for the guide of treatment in next step [41, 42]. Table 2 Classifications of MPM due to variable CT presentations
Radiological characteristics Radiology plays an important role in the diagnosis, stage, and follow-up of this disease. Computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) are the main protocols used for the evaluation of MPM.
Types
Features on CT scan
Dry-painful type Wet type
Abdominal pain and peritoneum-based masses Abdominal distension, ascites, and multiple small nodules and plaques The combination of dry-painful and wet type
Mixed type
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Biopsy A long delayed time between symptoms initially presented and definitive diagnosis is a thorny problem facing both physicians and patients. The role of cytological examination of ascites was contradictory, which is known to be either useless [1], or with a high mesothelioma positive rate of 51 % [32]. Ascite cytology is suggested because it can not only alleviate abdominal distension but have a diagnostic function. Experiment laparotomy and laparoscopy with biopsy are the main diagnostic manners used at present. However, deficits of laparotomy are also remarkable, such as physical and mental injuries developed during surgery. Laparoscopy, for its minor wounds and clearly detection of intraoperative condition, represents a better diagnostic choice for patients [32, 43]. Ultrasound or CT-guided biopsies have become more popular and accepted in clinics for its low incidence of injury, high diagnostic accuracy, and absence of serious complications [34, 44]. The study of Wang J et al. [44] indicated that ultrasound-guided biopsy for peritoneal lesions revealed a high satisfactory rate and overall diagnostic accuracy of 91.5 and 92.8 %, respectively [44]. However, there is still one troublesome question that we should pay enough attention to, that is, the scanty or inadequate of tissue samples. To ensure the diagnostic accuracy, enough tissue biopsies are necessary.
Pathology MPM can be divided into three types, epithelioid, sarcomatoid, or biphasic, and the epithelioid type is the most common type which can be seen in 75–90 % patients [34]. Immunohistochemistry has been the most valuable and available modality for the diagnosis of MPM. However, no standard markers providing absolute specificity and high sensitivity have been identified at present [45]. It is widely accepted that calretinin, CK5/6, WT-1, HBME-1, thrombomodulin, podoplanin, mesothelin, and D2-40 (Fig. 2) are mainly expressed in mesothelioma, while TTF1, CEA, Ber-Ep4, B72.3, MOC31, CD15 are commonly expressed in adenocarcinoma instead of mesothelioma [45–47]. The most common
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used positive markers are calretinin, WT-1, CK5/6, HBME-1, and vimentin. Recently, a new marker PAX8 has been found to be effective in the differential diagnosis of ovarian cancer and malignant mesothelioma, which can be seen in all ovarian cancer patients, non-malignant pleural mesothelioma, and 9 % MPM [48]. The combination of two or more positive and negative markers is suggested for a precise diagnosis.
Differential diagnosis MPM is also a fatal malignancy with high misdiagnosis rate, which can be misdiagnosed as ovarian cancer, colon cancer and tuberculous peritonitis. High index of suspicion and precise examinations are essential for the early diagnosis of MPM, for the management and prognosis of these disease are significantly variable. MPM and ovarian cancer MPM is easy of being diagnosed as ovarian cancer due to the congenerous symptoms of extensive peritoneal spread, widely presence of ascites, and predilection for serosal cavities. So, the first step is to make clear which condition it belongs to: a primary peritoneal tumor involving ovaries or a primary ovarian tumor widely spreading peritoneum. A recent research found that clinical distinction of MPM from ovarian cancer is difficult, and differential diagnosis relies on the immunohistochemical markers mentioned above [47]. MPM and colon cancer With the progression of MPM, intestinal obstruction and cachexia can be the terminal presentations, and it is easily misdiagnosed as gastroenteric tumor especially with abdominal pain and a peritoneal cavity mass closely adjacent to colon on CT scan (Fig. 3a, b). There is less than ten patients with colonic invasion of MPM reported at present. Colonoscopy can also be misleading in the diagnosis if the tumor had penetrated structures of colon (Fig. 4). Intestinal obstruction
Fig. 2 Positive immunohistochemical markers of calretinin, CK5/6, and HBME-1 for patients with MPM
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Fig. 3 A 3D-enhanced CT revealed an irregular thickening wall of hepatic flexure of colon (a) and an infiltrating mass closely adjacent to intestine (a, b), which is easily misdiagnosed as colon cancer on radiography. This atypical radiological presentations should be considered in the differential diagnosis of MPM
combined with tumor located adjacent to colon, as the atypical manifestation of MPM, should be considered in the differential diagnosis of MPM.
MPM and tuberculous peritonitis Approximately 70 % MPM patients presented with exudative ascites with or without elevated tumor markers and fever, so it is necessary to distinguish MPM from tuberculous peritonitis [32]. Elevated ascitic or serum tumor markers of CA125, CA153 and hyaluronic acid, visible tumor, or mesothelial cells in peritoneal fluid cytology are helpful for diagnosis of MPM [49, 50].
Fig. 4 If MPM had penetrated the structures of colon, the results of colonoscopy could be an infiltrating lesion located in the colon, ruptured in the surface and easily bled when touched. A high inspection of MPM should be made and definitive diagnosis is made on basis of immunohistochemistry
Advances in management MPM was once considered a preterminal condition with little attention paid to it. However, with the widely contact to asbestos, increasing incidence as well as enormous economic burdens caused by MPM, it has become a focus of researches and has made a significant progress in the aspect of treatment in recent years. The management of MPM has evolved from single chemotherapy to multiple modality treatment including CRS plus HIPEC, systemic chemotherapy, radiotherapy, and immunotherapy. Radiotherapy The role of radiotherapy in the management of MPM remains unclear in spite of few reported long-term survivals related to it [51, 52]. Radiotherapy has been used as an adjuvant therapy of surgery and chemotherapy. A pilot study with limited ten patients enrolled showed an improved disease-free survival of 19–78 months when treated with surgical debulking, chemotherapy, and whole abdominal irradiation [53]. In addition, a single-institution phase I or II trial performed by Hesdorffer ME et al. [54] revealed a median overall survival of 70 months and a 3year survival of 67 % with the presence of surgery, intraperitoneal chemotherapy, and immunotherapy, followed by whole abdominal radiotherapy. The combination of radiotherapy and intraperitoneal chemotherapy can also be beneficial to the remission of locally advanced MPM and improvement of quality of life [55]. However, tolerated dose of some important abdominal organs, low responsive rate, and adverse reactions of adhesions and intestinal obstruction are the main reasons blocking the popularity of radiotherapy [33, 53].
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Systemic chemotherapy Limited clinical trials have been performed to assess the role of chemotherapy in patients with MPM due to the rarity of this disease [56]. Single-agent chemotherapy or combinations remains unsatisfactory, with a poor response rate of less than 15–20 % [4]. A randomized trial with 43 patients enrolled indicated that the early usage of chemotherapy presented a long-term symptoms control and survival, with a median survival and 1-year survival of 14 months, 66 % compared with 10 months, 36 % in the delayed treatment group [57]. Chemotherapeutic regimens can also be drawn lessons from the treatment of malignant pleural mesothelioma and pemetrexed combined with cisplatin has become the new standard for unresectable patients with a median survival time of 12.1 months [6, 56]. Currently, a phase II trial revealed that the management of pemetrexed plus gemcitabine provide an increased median survival time to 26.8 months in spite of a low response rate of 15 % [58]. Intraperitoneal chemotherapy Intraperitoneal chemotherapy was used for the treatment of peritoneal surface-spreading malignancies, aiming to deliver a high dose of chemotherapy where the tumor cells reside and reducing the occurrence of side effects [59–61]. Few studies have been performed on MPM, and no survival benefit has been verified for the single usage of intraperitoneal chemotherapy before 2009 [34]. A retrospective study performed recently revealed that the larger surface areas and smaller
volumes of patients receiving intraperitoneal chemotherapy were associated with an improved survival of 48 months and decreased mortality [60]. In addition, computed tomography peritoneography is suggested for the evaluation of the distribution of intraperitoneal chemotherapy and patients with poor distribution should be adjusted to systemic chemotherapy. A vitro trial found that intrapleural chemotherapy was more effective when using two drug combinations (cisplatin/ gemcitabine and cisplatin/pemetrexed) compared with cisplatin alone and showed no particular sensitivity to heat [61], which may be meaningful for the further research of MPM. CRS and HIPEC MPM is typically localized in the abdominal cavity during its clinical course and only few cases of intra- or extra-abdominal invasion have been reported at present [33, 37–39]. Effective and timely treatment strategies, aiming to remove tumors and control disease progression within peritoneal cavity, have been well established in recent years. CRS plus HIPEC, regarded as the standard therapeutic intervention for selected patients with MPM, have been examined by a series of studies [11–15, 62–68]. Details can be seen in Table 3. The goals of CRS and HIPEC are to achieve a complete resection of all grossly identified tumors and deliver high dose of regional chemotherapy to the micrometastatic residual sites of disease [56, 69]. CRS is the primary step and plays a fundamental role in multiple modality management. Large tumors within the abdomen and pelvis can be removed through peritonectomy or visceral organ resection if
Table 3 Efficiency of CRS plus HIPEC in patients with MPM and variable origins of peritoneal carcinomas Studies
N
MPM [62] 2000 33 [68] 2003 49 [63] 2006 49 [13] 2009 20 [14] 2009 401 [65] 2013 211 [66] 2013 112 [12] 2013 108 [11] 2014 65 Peritoneal carcinomasb
MSTa (months)
Survival rate and perioperative mortality and morbidity (%) 1 year
2 years
3 years
5 years
10 years
Perioperative mortality and morbidity
31 92 – 29.5 53 38.4 63.2 63.2 46.2
77 86 88 78.2 81 – – – 77
– 77 74 – – – – – 57
56 59 65 46.3 60 – – – –
47 59 57 – 47 41 91.3 52.4 39
– – – – – 26 – 44.6 –
3.0 – – 5.0 2.0 2.3 2.7 1.9 6.0
33 25 15 35 46 39.4 24.1 38.9 35
[15] 2012
57
–
Over 80
–
Over 60
–
–
0.0
51
[64] 2013 [67] 2014
100 1,000
– 29.4
91.7 72.3
– –
59.1 44.6
50.9 31.5
– 18.1
0.0 3.8
56 42
a
Median overall survival time
b
Peritoneal carcinomas derive from MPM and ovarian, colorectal, gastric, and appendiceal cancers
Int J Colorectal Dis (2015) 30:1–10
necessary, whereas argon beam or other types of electrofulguration can be a choice for smaller tumor implants on the mesentery or solid organ surfaces [56]. HIPEC usually with mitomycin C or cisplatin is the most effective strategy of distributing high-dose intraperitoneal chemotherapy to all peritoneal surfaces with available hyperthermia, which can enhance the cytotoxic of chemotherapeutic agents in both temperature- and timedependent manners [31, 70]. However, not all patients are suitable for this standard treatment, evidence of disease outside the peritoneal cavity, poor performance status, and severe cardiac, pulmonary, hepatic, or renal dysfunction are the main contraindications to CRS and HIPEC [56]. The earliest study for this combined treatment revealed that the median survival of 33 patients was 31 months, with a 5year survival rate of 47 % [62]. A phase II study with 49 patients enrolled showed that median survival was an encouraging 92 months, and 5-year survival rate was 59 % [68]. In addition, a multi-institutional registry study with the largest number of patients enrolled indicated that median survival of all 401 patients was 53 months, with a 3- and 5-year survival rate of 60 and 47 %, respectively [14]. Based on these promising results, CRS plus HIPEC had been widely used and numbers of studies had been performed in recent 3 years, with a median survival and 5-year survival rate of 38.4– 63.2 months and 39–91.3 %, respectively [11, 12, 65, 66]. CRS and HIPEC were also effective in the management of variable origins of peritoneal carcinomas and malignant ascites [15, 64, 66, 67, 71–73]. Votanopoulos KI et al. [72] found that iterative CRS and HIPEC were valuable in the treatment of recurrent MPM, with a median survival of 52.9 and 21.8 months after the second cytoreduction, while the mortality (3.2 %) and 30-day morbidity (48.4 %) were similar to initial cytoreduction. Same results can also be reached in Chua TC et al. [73], with a median survival and 3- and 5-year survival rates of MPM of 57 months and 80 and 27 %, respectively. Despite the favorable results of CRS and HIPEC compared with the traditional therapies in recent studies, high perioperative mortality and morbidity ranging 0.0–6.0 and 15–56 % were a thorny question facing clinicians and patients, as shown in Table 3. The criteria for patients enrolled should be more careful. Immunotherapy Both studies of animals and small sample clinical trials indicated that malignant mesothelioma was sensitive to immunotherapy. TNFα, IL6, IFN, and GM-CSF had been shown to be effective in the management of mesothelioma [4, 74, 75]. However, limited data had been received at p r es e n t a n d t h i s c o n s t r i c t e d t he p r e va l e nc e o f
7
immunotherapy. Tani M et al. [76] found that activated cytotoxic T lymphocytes (CTL) plus chemotherapy were an effective strategy for MPM, exhibiting a high cytotoxicity against mesothelioma cells and all two patients received a status of partial response. In mice models, pulsed dendritic cells had been demonstrated to be powerful in controlling growth of mesothelioma and may be used as adjuvant to control local recurrence, which is known to be associated with strong tumor-specific cytotoxic T lymphocyte responses [77]. Mesothelin is a tumor differentiation antigen highly expressed on the cell surface of mesothelioma, ovarian cancer, and some malignancies. HN1 IgG, a fully human IgG with an immuntoxin, had been shown with the ability of killing mesothelin-expressing tumor cells with high cytotoxic activity, and this may have significant potential for the treatment of mesothelinexpressing tumors [78]. More evidences of phase II/III clinical trials are needed for the promising treatment of immunotherapy. Targeted therapy Targeted therapy had made a significant progress in the management of lung, breast, gastric, and other cancers, but it had not found its direction in malignant mesothelioma at present. A phase II study of gefitinib on patients with previously untreated malignant mesothelioma indicated that gefitinib was not active in spite of a EGFR overexpression of 97 % mesothelioma patients [79]. Of all 43 patients enrolled, 1-year survival is 32 %. Disease control rate (DCR) is 53 % (2 % CR, 2 % PR, 49 % SD), while PD and death can be seen in 35 and 12 %, respectively. Effective targets are urgently essential for the further study and improved survival.
Prognostic factors Due to the rarity of MPM and variable treatment strategies, prognostic factors had not been well identified in the past century. However, a combined treatment of CRS and HIPEC has been demonstrated to be correlated with a promising improved survival compared with traditional therapies in recent 10 years [11–14, 63, 65, 66]. The increasing numbers of patients enrolled with the uniform regimen made the analysis for clinical, radiological, and pathological prognostic parameters more precise and credible. Female gender has been previously demonstrated to be a favorable prognostic factor of MPM with limited patients in each group [62, 80]. Recently, a large multi-institutional study with 294 MPM patients enrolled indicated that under the uniform strategy of CRS and HIPEC, female patients had a significant improved survival than male patients [81]. Less
8
asbestos exposure and extensive peritoneal involvement, favorable epithelial pathological type, and the expression of ER-β (oestrogen receptors, nuclear) commonly induced the positive prognosis of female patients [31, 82, 83]. However, advanced age can be seen as a negative prognostic indicator for MPM [12], which may be accounted for the surgical injury or poor ability of recovering after surgery. Lymph node metastasis is rarely seen in MPM but is definitely related to an extremely poor prognosis [84, 85]. In one study with 100 patients enrolled, seven patients were found with lymph node metastasis. Median survival of these seven patients was 6 months with a 1- and 2-year survival rate of 43 and 0 %, respectively, while another 93 patients without lymph node metastasis showed a median survival of 59 months with a 5and 7- survival rate of 50 and 43 %, respectively [85]. Similar results were also obtained in a recent study with 83 MPM patients enrolled: 5-year overall survival of pathologically negative and positive nodes group was 82.5 and 16.7 %, respectively [85]. Careful assessment of node-containing sites is recommended during CRS, and all suspicious nodes should be submitted separately for a definitive pathological examination [85]. In addition, completeness of cytoreduction and epithelial type of pathology, as favorable prognostic indicators, have been widely accepted by both clinicians and patients since the beginning of this century [12–14, 62, 63].
Conclusions MPM is a rare and lethal disease characterized as multiple etiologies, variable presentations, high misdiagnosis rate, and overall negative prognosis if left untreated. Patients with unresctable tumors can benefit from the systemic chemotherapy using pemetrexed and cisplatin. CRS and HIPEC represent the standard strategy for selected patients, with a promising increased median survival of 29.5–92 months and a 5year overall survival rate of 39–63 %. With the further research and new understandings of molecular biology and immunology, more efficacious strategies indicating a longterm survival and high quality of life are worthy of being expected. Acknowledgments This work was supported by Wujieping Foundation (No. 320.6750.12204), Young People Research Fund for the grant National Natural Scientific Foundation of China (No. 81201828), Young People Foundation of Heilongjiang Provincial of China (No. QC2012C013), National Natural Scientific Foundation of China (No. 81101758), Health Department of Heilongjiang Provincial of China (No: 2011-124) and Harbin Medical University Cancer Hospital major project Foundation (No: JJZ-2010-01). Conflict of interest None.
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