Malignant pleural mesothelioma: A scourge of a disease – An audit of a single South African tertiary center

INTRODUCTION

Malignant pleural mesothelioma (MPM) is not rare and is considered a silent and invisible epidemic.^[1] On the contrary, it is on the rise, including the incidence of asbestos-related diseases, thus making it a rising global public health issue.^[1-6] Occupational and non-occupational asbestos exposure is the leading cause of MPM, and its incidence is understated globally because some countries do not have specific cancer registries.^[5]

Most MPM longitudinal studies were conducted in the United Kingdom (UK) which has been monitoring MPM mortality rates since 1968, and it’s showing an upward trend despite the ban on asbestos mining in 51 countries, including the UK, which showed an increase from 153 in 1969, 2360 in 2010, and 2291 in 2011. Russia, Indonesia, Pakistan, Brazil, and Nigeria had not imposed such bans. Therefore, it is unsurprising for other countries not to have MPM data, skewing the global incident data, which contributes to underestimating the true disease burden.^[7] The increase in MPM cases is significantly observed in low-income regions, and the incidence is declining in developed countries like Sweden, following the total ban two to three decades later.^[8]

Rising poverty and unemployment levels contribute to continued mining and use of asbestos despite the bans. Russia, Zimbabwe, Brazil, India, China, and Canada continued mining asbestos.^[8] Approximately 1300–3000 cases of MPM are diagnosed in the US and UK annually, and attempts to estimate the global burden are ongoing.^[9-11] The reporting status of mesothelioma by national income reflects medical resource capacity, explaining the absence of reports from low-income countries.^[5] Despite this, there has been an improvement in MPM-related mortality data in recent years, but data quality varies across countries.^[5]

The male-to-female ratio for the risk of MPM is 3:1, with the median age at 73. The median survival period is 6–15 months, despite the stage of the disease. Most mortality data are from Europe and America.^[4] By applying gender- and age-specific MPM mortality rates to all other countries, the estimated global burden ranges between 36 300 and 38 400 annual deaths.^[4]

There are two types of asbestos fibers: (1) Amphibole, with the following subtypes: Amosite, Crocidolite, Anthophyilite, Tremolite, and Actinolite, and (2) Serperntile, with Chrysotile as the only subtype.^[2,3] Amphibole exposure leads to MPM and there is still controversy on the causality of MPM from Chrysotile.^[2] The ReNam case series revealed that 80.5% of MPM were exposed to asbestos and ionizing radiation, smoking, and genetic predisposition were other identified risk factors.^[2,12] Symian virus 40, exposure from contaminated polio vaccine is a controversial risk factor for MPM and is believed to be declining. Several other risk factors include exposure to erionite, a mineral fiber commonly found in the stones used for building houses in some Turkish villages, and High Aspect Ratio Nanoparticles.^[2,3,13]

There are three sub-types of MPM, which are (1) epitheloid (epithelial), found in 50% of cases with longer survival rate, compared to (2) biphasic (mixed), and (3) sarcomatous, with poor survival rates.^[2,13] MPM is difficult to diagnose and requires an adequate biopsy specimen for histology and relevant clinical, radiologic, and surgical findings.^[11] Identifying actionable gene mutations is challenging, and current treatment options are mainly ineffective and becoming increasingly complex.^[3]

Non-invasive diagnostic modalities include blood biomarkers in the form of the soluble mesothelin-related peptide, methylation-specific real-time polymerase chain reaction analysis, oligonucleotide array-based (cGH), and micro-RHA; additionally, positron emission tomography scan can be done to confirm the diagnosis.^[13]

Invasive modalities include pleural biopsy done through minimal thoracotomy or video-assisted thoracic surgery; the specimen is sent for histology and immunohistochemistry.^[13]

Epithelial markers such as monoclonal and polyclonal carcinoembryonic antigen (CEA) and Ber-EP4 assist in excluding mesothelioma from other carcinomas, and mesothelial markers such as cytokeratin 5/6 and calretinin confirm MPM diagnosis.^[14]

Historically, there are three modes of treatment (Trimodal), and the first is surgery, which includes extrapleural pneumonectomy, extended pleurectomy decortication, pleurectomy decortication, or partial pleurectomy.^[3] The second modality is adjuvant radiation therapy, where intensity-modulated radiation therapy or external beam radiation therapy is given following surgery. The last modality is chemotherapy in the form of intravenous administration of Alimta plus Alkylating agent.^[3]

In the mesothelioma and radical surgery (MARS) 1 trial, although heavily criticized, patients who underwent extrapleural pneumonectomy fared worse than patients who underwent extended pleurectomy decortication.^[15]

MARS 2 has not shown any benefits of combining surgery with chemotherapy and radiation therapy over no surgery. Patients who did not undergo surgery survived better than those who had surgery.^[16]

Future treatment modalities include immune check-point inhibitors and chemoimmunotherapy, the results of which are currently still too early to conclude. Other future options include cellular therapy, molecular stratified therapy, and genomic and epigenomic landscapes.^[17]

However, the survival rate after the diagnosis of MPM is dismal, regardless of the stage of the disease or treatment modality undertaken, with an average of 9 months survival after the initial diagnosis.^[18]

MATERIALS AND METHODS

RESULTS

MPM was the second most diagnosed tumor at 23% (21 of 91 patients) after adenocarcinoma at 34% (31 of 91 patients) that underwent some surgery [Table 1].

The most affected age group was those above 55, at 61.9%, followed by those 36–55 years of age, at 33.33%, and those above 19 but below 36, at 4.76% [Figure 1a].

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Figure 1:

Breakdown of mesothelioma by (a) age and (b) gender.

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Males were diagnosed more than females at 76.19% and 23.81%, respectively [Figure 1b].

About 52.38% of MPM were diagnosed from decortication, 47.62% from pleural biopsy, and none following pulmonary resection and lung biopsy [Table 1].

DISCUSSION

MPM remains challenging and complex in terms of diagnosis, staging, and treatment. An optimal strategy for tackling MPM has yet to be clearly defined.^[13] An estimated 200 mesothelioma cases are diagnosed in South Africa (SA) each year.^[19,20] The country may have the greatest frequency of malignant mesothelioma worldwide because SA has more than a century of asbestos mining in the Northern Cape, North-West, Limpopo, and Mpumalanga provinces, and this impacts the incidence of the disease.^[21] Lack of data, however, may be affecting the demonstration of this increasing incidence and frequency of the disease. In our audit, mesothelioma was the second most frequently diagnosed tumor at 23%. Our audit revealed that 62% of patients diagnosed with MPM were 55 years and older, and 38% were younger than 55 years, which feeds into the fallacy that mesothelioma is a disease of the elderly. This undermines its known long latency period.^[22,23] Environmental factors such as exposure to mining dumps, asbestos roofing, and asbestos fibers brought home on family members’ clothing professionally exposed to asbestos may facilitate early exposure, leading to early MPM.^[24]

MPM is not a gender-exclusive cancer; however, it affects more men than women, and this is most likely because men have greater likelihood of being exposed to asbestos in their line of work compared to women.^[25,26] This was consistent with our findings, where 76% of our patients were males. However, recent studies cite an increase in MPM among women.^[22,23] This is critical for reducing gender disparity in diagnosing and caring for MPM. Of interest, those diagnosed with empyema thoracis were patients suspected to be infected with tuberculosis (TB) who subsequently underwent decortication. However, MPM was the confirmed diagnosis and the cause of empyema thoracis in these cases. This is critical in SA, a country with the highest prevalence and incidence of TB, which could be a precursor for misdiagnosis due to the low index of suspicion compounded by the limited access to specialist thoracic surgery services.

MPM does not yet have a recognized cure. The US Food and Drug Administration approved pharmaceutical drugs (Opdivo plus Yervoy) for the first-line treatment for adult patients who will not benefit from surgical treatment.^[27,28] In SA, the treatment of mesothelioma generally consists of aggressive surgery, chemotherapy, and radiotherapy; however, there is a high fatality rate: 50% of patients die within a year of diagnosis, and about 2 years for the remaining patients, with few exceptions.^[21] Although there are several cancer treatment centers where patients with mesothelioma can access treatment in SA, not all cancer centers have medical professionals with expertise in managing mesothelioma. Considering that MPM is regarded as uncommon, medical professionals can misdiagnose patients and fail to recognize the illness, delaying diagnosis and care.^[19,20] Long waiting times are a barrier to accessing care for patients that we refer to the oncology center. By the time patients reached their turn, they either had a poor performance status or had succumbed to the disease.

CONCLUSION

The lack of MPM databases worldwide enables under-reporting, which undermines investment in resources to tackle the scourge. The difficulty posed by the disease in terms of diagnosis, treatment, and aftercare of patients qualifies it to be called a scourge. The health inequity contributes to the difficulty with the diagnosis. Poor access to specialized care requires moral reflection. Justice should underpin multistakeholder interventions from policymakers, employers, health experts, and health advocates.