How much exposure is there for mesothelioma

Malignant pleural mesothelioma

Background: The incidence of malignant mesothelioma in Germany is around 20 diseases per million population. The association between a mostly occupational exposure to asbestos and the development of mesothelioma is clearly proven. Despite the long-term asbestos processing ban, the number of cases of mesothelioma is rising steadily due to the long latency period (mean 50 years). The diagnosis and therapy of malignant mesothelioma are currently and will continue to be a challenge in everyday clinical and outpatient care.

Method: The present work is based on a selective literature review including the data of the German Mesothelioma Register.

Results: The number of deaths caused by mesothelioma was 1,397 in Germany in 2010. The number of illnesses is expected to reach a plateau between 2015 and 2030. The majority of mesotheliomas manifests in the pleura. The histological subtype and the Karnofsky index represent the relevant prognostic factors. There are only limited data on the best combination of treatment options (chemotherapy, surgery, radiation). The prognosis with mean survival times of 12 months is still unfavorable. Thus, symptom control and maintaining quality of life are essential aspects of follow-up care.

Conclusion: In terms of prognosis, it is not to be expected in the medium term that the number of cases of mesothelioma will decrease. In addition to surgical intervention, chemotherapy and radiation are available as forms of therapy. Multimodal approaches are increasingly used in the treatment of mesothelioma in specialized clinics.

Malignant diffuse mesothelioma is a tumor that originates from the mesothelial or submesothelial cells of the pleura, the peritoneum or the pericardium. The majority (> 80%) of mesotheliomas originate in the pleura (1). Pleural mesothelioma affects men in more than 80% of cases (1, 2). Compared to lung carcinomas, malignant mesotheliomas are comparatively rare, with a mortality rate of 1,397 deceased in 2010. Among the malignant tumors recognized as occupational diseases, mesotheliomas are signal tumors of occupational exposure to asbestos (graphic). Only after the period from 2015 to 2030 is a decline in the currently relatively constant number of illnesses expected. Currently and in the future, mesothelioma represents a diagnostic and therapeutic challenge in everyday clinical and outpatient care.

Mesothelioma now recognized as an occupational disease according to No. 4105 of the Occupational Diseases Ordinance (BKV) in Germany

method

The literature search for this article was Medline-based using search terms that were used in the preparation of the S2 guideline (3) of the European Respiratory Society and European Society of Thoracic Surgeons. Additional quantitative data on the occupational disease according to No. 4105 were generated using the database of the German Mesothelioma Register.

Association of Mesothelioma and Asbestos

The pioneering study from 1960 on the correlation between mesothelioma diseases and crocidolite asbestos (4) led to the coining of the term "asbestos-related signal tumor" (5) in 1965. Up to 90% of mesothelioma diseases can be traced back to asbestos exposure and there is a clear correlation between the level of asbestos consumption in a country and the frequency of mesothelioma diseases (6) (eBox). There is no official information on how many workers in Germany were exposed to asbestos at work. According to estimates for Germany, the values ​​have been between 1.5 and 2.5 million workers since the Second World War. In 2011, 561 277 people who work with asbestos-containing materials were included in the health care system (GVS) of the statutory accident insurance. The proportion of people with mesothelioma diseases in this group cannot be validly derived from these data.

In addition to occupational exposure to asbestos, exposure due to the following circumstances can also be considered (7):

  • private activities
  • physical proximity to asbestos-processing factories
  • Stay in areas with natural asbestos deposits
  • improper renovation of asbestos-containing components in old buildings.

Incidence and latency

While 1 to 2 cases per 1,000,000 inhabitants have been described in the normal population (6), occupational exposure to asbestos increases the disease by a factor of> 40 (1). Although the use of asbestos has been banned in many industrialized countries, an increase in the annual incidence of the disease is expected. The incidence is age-dependent (tenfold with an age of onset> 60 compared to < 40="" jahre)="" und="" steigt="" auch="" jahrzehnte="" nach="" expositionsende="" weiter="" an="" (6).="" es="" zeichnet="" sich="" ein="" anstieg="" (tabelle="" 1)="" der="" erkrankungszahlen="" in="" europa,="" japan="" und="" australien="" ab="" und="" ein="" rückgang="" in="" den="" vereinigten="" staaten="" (1).="" die="" ursachen="" für="" diese="" unterschiedlichen="" entwicklungen="" sind="" unklar.="" während="" zunächst="" eine="" mittlere="" latenzzeit="" von="" 30="" jahren="" veranschlagt="" wurde,="" liegen="" die="" aktuellen="" latenzzeiten="" bei="" einem="" mittelwert="" von="" 50="" jahren="" (1,="" 8).="">

Diagnostics and clinical symptoms

The clinical symptoms are usually uncharacteristic. Due to the heterogeneous picture, there can be up to six months between the first clinical symptoms and a final diagnosis (9).

Often (90%) the first symptom of patients with pleural mesothelioma is dyspnoea (3). Symptoms of pain in pleural mesothelioma can result from irritation of the intercostal nerves or from infiltration of the chest wall. Symptoms such as elevated diaphragm, dry cough, paraneoplastic symptoms or spontaneous pneumothorax occur rarely (10). Symptomatic metastases are uncommon.

Mesothelioma disease must be considered in patients with unilateral pleural effusions or pleural thickening - especially if there is chest pain (11). In the differential diagnosis, inflammatory-infectious pleural effusions (e.g. tuberculosis, pneumonia, thoracic trauma) or congestion genesis should be excluded.

If mesothelioma is suspected, a detailed professional history should be taken and the person should be referred to an experienced lung center. Imaging methods such as ultrasound, computed tomography (CT) and magnetic resonance tomography (MRT) are initially suitable as non-invasive methods to confirm the suspected diagnosis and to enable an assessment of the extent of the tumor. A final confirmation is ultimately only possible through a histological-pathological examination of tumor tissue.

Imaging procedures

In the case of a pleural effusion, transthoracic ultrasound allows the pleura to be assessed and, in particular, is considered the gold standard for visual control of the puncture (12).

The CT examination is the gold standard for assessing the extent of the tumor and detecting lymph node metastases (11).

The MRI examination is superior to the question of whether there is an invasion of the diaphragm or the chest wall.

Positron emission tomography (PET) is being used increasingly and has the advantage of being able to diagnose distant metastases (11).

Pleural puncture and cytological diagnosis

Depending on the mesothelioma subtype, tumor cells are released into the pleural effusion in more than 50% of pleural mesothelioma diseases. Since cytological features occur in both reactive and malignant events, negative cytology does not rule out mesothelioma (13). The guidelines (3, 13) indicate the limited sensitivity of purely cytological diagnostics.

Percutaneous needle biopsy and radiologically-guided percutaneous pleural biopsy

In studies, the sensitivity of percutaneous needle biopsy without imaging support is 7–47% (specificity 100%) (14). Since malignant and benign pleural changes are not evenly distributed pleurally, ultrasound and CT-guided techniques with sensitivities of 77–87% (specificity 100%) are used to obtain biopsies (15).

Thoracoscopy and Thoracotomy

Guidelines (3) recommend thoracoscopy (VATS = Video Assisted Thoracoscopic Surgery) for the diagnosis of pleural effusions of unknown origin. Using VATS (sensitivity 95–98%; specificity 100%), samples can be taken under visual control and pleurodesis can be performed at the same time (14). The use of VATS enables the site to be depicted more precisely, which enables a better assessment of the operability of the tumor to be achieved (16).

Pathological-anatomical diagnostics

The mesothelioma diagnosis is a challenge due to the variability of the histological appearance. The diagnosis should be made by a specialized pulmonary pathologist (if necessary a reference center). It requires close cooperation between surgeons and pathologists (3, 13, 17).

Epithelioid, biphasic and sarcomatoid mesothelioma subtypes are distinguished on the basis of the histomorphologically leading growth patterns. Additional immunohistochemical examinations are mandatory (13, 17). There is no single specific marker for mesothelioma, which is why different marker combinations are used depending on the differential diagnostic question (13, 17).

Staging

A unilateral pleural effusion is usually visible on the chest X-ray (11). A chest CT is the gold standard for assessing the extent of the tumor and possible lymph node involvement.

MRI or mediastinoscopy may be necessary to assess infiltration of the chest wall and mediastinal organs (mediastinal lymph nodes) (11). Supplementary abdominal sonography, bone scintigraphy and, if necessary, an MRI (neurocranium) can be indicated to rule out distant metastases (11). A classification according to the tumor node metastasis (TNM) classification of the Union internationale contre le cancer (UICC) (18) is recommended by the European Pneumological Society (3). The staging results from the summary of the pathological-anatomical and intraoperative findings and the clinical staging examinations.

Survival time and prognostic factors

The prognosis for patients with malignant pleural mesothelioma is poor. Median survival times of 4 to 12 months have been described (3). Only 12% of patients with negative prognostic factors survive the first year.

Age, gender, tumor subtype and tumor stage are essential prognostic factors. The epithelioid tumor subtype is associated with a more favorable prognosis. Subordinate factors for a favorable prognosis are a younger age of onset (< 75)="" und="" das="" weibliche="" geschlecht.="">

Another clinically relevant prognostic factor (3) is the percentage classification of the symptom-related limitation of activity, self-care and self-determination in patients with malignant tumors based on the Karnofsky index.

Other additional prognostic factors (low hemoglobin content, high LDH level or a high leukocyte and platelet content) are only relevant in the context of clinical studies. Potential blood serum markers such as soluble mesothelin or osteopontin are currently being clinically researched, but so far do not allow any valid conclusions to be drawn about the prognosis (3).

therapy

Since mesothelioma is a rare tumor disease, its treatment in specialized centers, which are pioneers in new curative, palliative or pain therapy approaches, is particularly important. Such specialized clinics should have close interdisciplinary cooperation between oncology, radiology and surgery, which is characterized by regular specialist meetings. Participation in clinical trials and cooperation with clinical registries are also characteristic.

The desired therapy goals - such as a life-prolonging effect and the improvement of quality of life - have so far only been partially achieved in the case of mesothelioma diseases. Curative treatment is currently not available.

The initial situation with a palliative therapy regimen includes the following criteria:

  • reduced general and nutritional condition
  • all stages of biphasic and sarcomatoid mesothelioma
  • Stages 3 and 4 in epithelioid mesothelioma
  • N2 stage and / or M1 situation.

For palliative therapy, thoracoscopy with pleurodesis can be used to control symptomatic pleural effusions and to reduce pain. Recurrent pleural effusions can be treated with talc pleurodesis with an effectiveness of 93% (19).

Multimodal strategies that pursue a putative curative therapeutic approach are currently in use. However, there is little data that can show which combination is effective for which patients (3).

The starting point for a putative curative approach includes the following criteria:

  • Patient < 70="">
  • no significant cardiopulmonary restrictions
  • no relevant comorbidities
  • epitheloid mesothelioma (stage 1 or 2)
  • N0 situation (mediastinoscopy).

In the following, the presentation is limited to long-term proven and resilient therapy modalities for which studies are available that achieve the necessary level of evidence to be taken into account in a guideline-compliant assessment (Table 2). Experimental approaches that have not been tried and tested cannot be additionally discussed here due to the limited space available.

Study overview of various forms of therapy for the treatment of malignant pleural mesothelioma

Surgical intervention

Complete macroscopic tumor removal is the goal of surgical intervention. With the diffuse growth of mesotheliomas, complete removal of the tumor is usually not possible. What remains are residual parts of the tumor that can often only be detected microscopically. The aim of adjuvant therapy (chemotherapy) is to eliminate all residual tumor components (20).

Pleurectomy / decortication

Pleurectomy / decortication with en bloc resection of the parietal and visceral pleura is an effective method of preventing pleural effusions (20). This intervention is suitable for symptom control for patients who do not benefit from pleurodesis. This is particularly the case in patients with a lung that can be expanded to a limited extent (“tied lung”), which results from fibrous restrictions (for example due to malignancies or inflammatory conditions) of the visceral pleura and possibly its adhesion to the pleura. This cytoreduction is characterized by a lower mortality (1.5–5%) and faster recovery time compared to extrapleural pleuropneumectomy. There is an increased risk of local recurrences (morbidity rate 2.5–5.9%) and an effect on median survival (10–17 months) without a significant effect on long-term survival is observed (21).

Extrapleural pleuropneumectomy

Pleurectomy and pneumectomy - including resection of the pericardium and diaphragm (EPP) - should only be performed in highly specialized centers in the context of clinical trials as part of multimodal therapy. In experienced centers, mortality from this extensive procedure can be limited to 3.4 to 10%. The morbidity rate is up to 50% and a second intervention is often necessary due to complications (20). Even in the context of multimodal therapy, EPP does not lead to an advantage in terms of survival rates (22). The number of local recurrences after EPP varies significantly (0 to 37%) (3, 23, 24).

chemotherapy

A pioneering publication from 1999 (25) and follow-up studies (26, 27) showed the possibility of effective chemotherapy (cisplatin / pemetrexed). Studies with a randomized approach are not often feasible with a small number of cases. A randomized study (chemotherapy versus placebo) showed no significant effect on survival times (28). Randomized studies on the use of chemotherapy as a second-line therapy are not available. Existing studies indicate that second-line therapy, compared with purely symptomatic therapy, can lead to an increase in survival time (29). The decision to use chemotherapy should be made on a case-by-case basis with the patient and their relatives against the background of limited efficiency. In any case, a Karnofsky index of> 60% should be given. In palliative care, chemotherapy can be indicated in the case of rapid tumor progression or severely debilitating symptoms (30).

radiotherapy

Radiation is used prophylactically in mesothelioma patients in the area of ​​puncture canals and after surgical interventions to prevent local recurrences and for palliative pain control. Radical irradiation of the entire tumor is currently not feasible due to the complex tumor spread and the resulting dose load due to the collateral damage to the lungs and heart (24).

According to the guidelines (3), prophylactic radiation after decortication / pleurectomy is not recommended and use in clinical studies after EPP is advised. Radiation therapy for pain control should be discussed in patients with chest pain and chest wall infiltration (3).

Multimodal concepts

With the multimodal therapy concepts, surgical interventions are combined with chemotherapy and, if necessary, radiation.By combining neoadjuvant chemotherapy with pleuropneumectomy and subsequent radiation treatment, an improvement in 3-year survival rates (76%) (31) and longer median survival times (22 months, stage I) (32) could be achieved in relation to non-multimodal therapy concepts.

The combination of a cytoreductive pleurectomy with an intraoperative hyperthermic chemotherapy, in which the temperature is increased to 42 ° C and thus an increased penetration and effect of the chemotherapeutic agents is achieved, is currently being tested as a multimodal approach in clinics.

Screening procedure

Attempts to record mesothelioma diseases in the early stages of the disease using serum markers (33), high-resolution CT images (HRCT) or PET have unfortunately not yet achieved a breakthrough (34, 35). Even with pleural ultrasonography, which is less sensitive than CT, no decisive advances in early detection are to be expected (11, 36). When comparing the prevalence, prognosis and treatment options of mesothelioma diseases with the efficiency of potential screening methods, no valid method for the early diagnosis of mesothelioma diseases is available, even with close-knit check-ups (3).

The international guidelines of the ERS / EST Task Force (3), the Mesothelioma Interest Group (37) and the Falkensteiner Recommendation of the DGUV (38) and the AWMF-S2 provide a more detailed description of the relevant aspects of diagnosis, therapy and the insurance-medical evaluation of mesothelioma diseases Guideline (39).

Occupational health aspects

If a malignant mesothelioma disease is diagnosed, there is always a suspicion of an occupational disease and, according to § 202 SGB VII, there is an obligation to report the suspicion of an occupational disease, even if the patient does not remember occupational exposure to asbestos. In the case of latency periods of sometimes over 60 years, qualified surveys of the work history by experienced experts are necessary. It should be noted that mesotheliomas can also be triggered by short-term and low exposure (40, e1) (eBox).

The work history is often difficult in older and often multimorbid patients and can be supported by a catalog with photos of former asbestos-contaminated workplaces (questionnaire from the Munich Tumor Center [e2]).

With the continued commercial use of asbestos, the number of mesothelioma diseases in the emerging markets of Asia will continue to increase. A worldwide asbestos ban (e3) must be demanded in order to prevent the further increase in the number of victims.

Asbestos-producing countries and their customers must be urged to give up the use of asbestos due to international pressure. Lobbyists in the chrysotile industry who question the carcinogenicity of chrysotile - especially in lung cancer - must be contradicted in the scientific discussion (e4).

Conflict of Interest Form

Dipl.-Biol. Neumann, Dr. Löseke, Prof. Nowak and Prof. Tannapfel received fees for expert work on pathological-anatomical diagnostics and contextual assessment of mesothelioma diseases for accident insurance carriers.

Prof. Herth declares that there is no conflict of interest.

Manuscript dates
submitted: November 19, 2012, revised version accepted: February 21, 2013

Address for the authors
Dipl.-Biol. Volker Neumann
German mesothelioma registry at the Institute for Pathology
of the Ruhr University Bochum on the employer's liability insurance association
Bergmannsheil University Hospital
Bürkle-de-la-Camp-Platz 1
44789 Bochum, Germany
[email protected]

Citation style
Neumann V, Löseke S, Nowak D, Herth FJF, Tannapfel A: Malignant pleural mesothelioma-incidence, etiology, diagnosis, treatment and occupational health. Dtsch Arztebl Int 2013; 110 (18): 319-26.
DOI: 10.3238 / arztebl.2013.0319

@Literature marked with "e":
www.aerzteblatt.de/lit1813

eBox under:
www.aerzteblatt.de/13m0319

The German version of this article is available online:
www.aerzteblatt-international.de

Delgermaa V, Takahashi K, Park E, Le G, Hara T, Sorahan T: Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008. Bull World Health Organ 2011; 89: 716-24 CrossRefMEDLINE PubMed Central
Woitowitz H, Hillerdal G, Galvarezos A, Berghäuser K, Rödelsperger K, Jöckel K: Risk and influencing factors of diffuse malignant mesothelioma (DMM) research report series FB 698 Federal Institute for Occupational Safety and Health 1993.
Scherpereel A, Astoul P, Baas P, et al .: Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleura mesothelioma. Eur Repir J 2010; 35: 479-95. CrossRefMEDLINE
Wagner J, Sleggs C, Marchand P: Diffuse pleural mesothelioma and asbestos exposure in the north western cape province. Brit J Ind Med 1960; 17: 260-71. MEDLINEPubMed Central
Selikoff I, Churg J, Hammond E: Relation between exposure to asbestos and mesothelioma. N Eng J Med 1965; 272: 560-5. CrossRefMEDLINE
Craighead J: Epidemiology of mesothelioma and historical background. Rec Res Cancer Res 2011; 189: 13-25. CrossRefMEDLINE
Hain E, Calavrezos A, Koschel G: Asbestos and asbestos-related tumors - clinic and diagnostics. Atemw Lungenerkrkh 1984; 10: 145-50.
Neumann V, Löseke S, Tannapfel A: Mesothelioma and analysis of tissue fiber content. Rec Res Cancer Res 2011; 189: 79-95. CrossRefMEDLINE
Champbell N, Kindler H: Update on malignant pleural mesothelioma. Semin Respir Crit Care Med 2011; 32: 102-10. CrossRefMEDLINE
Neumann V, Günther S, Müller K, Fischer M: Malignant mesothelioma - German mesothelioma register 1987-1999. Int Arch Occup Health 2001; 74: 383-95. CrossRefMEDLINE
Gill R: Imaging of mesothelioma. Recent Res Cancer Res 2011; 189: 27-55. CrossRefMEDLINE
Reus J: Sonography of the pleura. Ultrasound Med 2010; 31: 8-22. CrossRefMEDLINE
Husain A, Colby T, Ordonez N, et al .: Guidelines for pathologic diagnosis of malignant mesothelioma. Arch Pathol Lab Med 2012; 136: 1-21. MEDLINE
Attanous R, Gibbs A: The comparative accuracy of different pleural biopsy techniques in the diagnosis of malignant mesothelioma. Histopathol 2006; 53: 340-4. CrossRefMEDLINE
Hopper C, Lee Y, Maskell N: Investigation of a unilateral pleural effusion in adults. British Thoracic Society pleural disease guideline. Thorax 2010; 65; 4-17.
Hasegawa S, Kondo N, Matsumoto S, et al .: Practical approaches to diagnose and treatment T0 malignant pleual mesothelioma: a proposal for diagnostic total parietal pleurectomy. Int J Clin Oncol 2012; 17: 33-9. CrossRefMEDLINE
Tischoff I, Neid M, Neumann V, Tannapfel A: Pathological diagnosis and differential diagnosis of mesothelioma. Rec Res Cancer Res 2011; 189: 57-77. CrossRefMEDLINE
Wittekind C, Meyer H: TNM classification of malignant tumors. 7th edition. Weinheim: Wiley-VCH 2010. MEDLINE
Bielsa S, Hernandez P, Rodriguez-Pandero F, Taberna T, Salud A, Porcel J: Tumor type influence the effectiveness of pleurodesis in malignant effusions. Lung 2011; 189: 151-5. CrossRefMEDLINE
Rice D: Surgical therapy of mesothelioma. Recent Results Cancer Res 2011; 189: 97-125. CrossRefMEDLINE
Soysal O, Karaoglanoglu N, Demiracan S: Pleurectomy / decortication for palliation in malignant pleural mesothelioma. Results of surgery. Eur J Cardiothorac Surg 1997; 11: 210-3. CrossRefMEDLINE
Treasure T, Lazdunski LL, Waller D, Bliss JM, Tan C, et al .: Extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomized feasibility study. Lancet Oncol 2011; 12: 763-72. CrossRefMEDLINE
Gupta V, Krug L: Patterns of local and nodal failure in malignant pleural mesothelioma after extrapleural pneumectomy and photon electron radiotherapy. J Thorac Oncol 2009; 4: 746-50. CrossRefMEDLINE
Dhalluin X, Scherpereel A: Chemotherapy and Radiotherapy for mesothelioma. Rec Res Cancer Res 2011; 189: 127-47. CrossRefMEDLINE
Thödtmann R, Depenbrock H, Dumez H, et al .: Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin. J Clin Oncol 1999; 17: 3009-16. MEDLINE