The total number of patients referred to our Territorial Diagnostic, Therapeutic and Assistance Planning was 88. From there, the total number of patients that did not fit our inclusion criteria was 39. In our raw data, we looked at more than 30 parameters in 49 patients between 2017 and 2020. The male-to-female ratio we report is roughly 1.6, which is significantly lower than the national one as reported in the 6th edition of the ReNaM report (M:F ratio of 2.5) . This male predominance was expected as exposure to asbestos often occurred in and around industrial factories where most employees were men. Our ratio may have been lower though because our observational period was later than theirs and women increased longevity in comparison to men. The average age at diagnosis supports this concept: it was of 69 years, with a median age of 71. This data is broadly in line with that of the 6th ReNaM report, which shows an average age at diagnosis of 70 years. No cases of diagnosis under the age of 47 were found in our study, confirming what is contained in the ReNaM report "Up to 45 years the disease is very rare (only 2% of the total cases recorded)". Interestingly, the older patients were mostly women. Indeed, the youngest woman in our study was diagnosed at 58 (in comparison to 47 for men), and most of the diagnoses in women were after the age of 71. The advanced age makes sense due to the significant latency associated with the disease, but the even older age of women may have to do with the decreased concentration of exposure and increased longevity. Indeed, all 9 of the patients who reported workplace exposure (either directly from the factory or indirectly through various blue-collar work), were men. If the higher exposure led to an earlier disease, and the lower, environmental exposure led to a longer latency, then this would help explain why women seemed to be diagnosed later than men.
Studies have shown that cigarette smoking is associated with an increased risk of developing all types of lung cancer. Though smoking is not strictly causative of MPM, it shows some important synergistic activity with asbestos as both have a common pathogenesis which includes provoking inflammation and directly damaging DNA . Even with equal asbestos exposure, smoking has been correlated with increased risk of developing MPM . In the cohort analyzed, almost half of the patients were smokers or ex-smokers; this data is likely underestimated since about 10% of the patients observed had an uncertain smoking history.
The vast majority of patients were residents in the province of Pavia. However, the fact that we received patients from Italian provinces distant from Pavia shows how the organization of the interdisciplinary diagnostic-therapeutic pathway form MPM defined in the PDTA makes our institution attractive for a non-local population as well. A considerable rate of the initial, 88-patient cohort (14%) was found to be a resident of Broni (within a 10 km radius). This is explained by the fact that the vast majority of the Fibronit workers lived in the municipality of Broni and the neighboring towns. The significant environmental pollution and massive exposure during the company's peak activity period (1970s and 1980s) created this high incidence, as previously mentioned. Interestingly, our cohort showed a lower occupational exposure with just one patient having a certain exposure, as he worked for Fibronit. On the other hand, 7 patients had a probable professional exposure, as they were builders, mechanics, or working in some other field that deals with materials like cement and insulation that is laden with asbestos. This means our (certain/probable/possible) occupational exposure rate was around just 16%. Environmental exposure cases were significantly higher (37%) as the pollution from the factories had an effect on members of the town. There are a few reasons why our study has different occupational exposures to previous studies. The first issue may be because the cohort in the study includes diagnosis of MPM made relatively recently (i.e., in the last 5 years) compared to the observation period of the data contained in the ReNaM (1993–2015). It is possible that a large proportion of patients had occupational exposure were diagnosed in the years prior to the baseline time interval of the cohort in our study. Moreover, the area of Broni corresponds to high environmental pollution and we had a significant number of patients from the city of Broni, but also from surrounding cities.
Diagnostic And Therapeutic Approaches
In the study cohort, the majority of patients (57%) was subjected to medical thoracoscopy, while 20% were diagnosed by surgical pleural biopsy (both in VATS and thoracotomy). In our cohort, 23% of patients received a transthoracic CT-guided core-needle biopsy (CNB), while none received diagnosis through cytology on pleural fluid. The fact that 100% of the patients in the cohort have undergone diagnostic procedures approved by various guidelines enhances the quality and reliability of the information provided. In this study, the vast majority of diagnoses of MPM showed an epithelioid histotype (78% of cases); this result is in-line with the AIOM 2018 guidelines that showed a prevalence of the epithelioid histotype in 75–80% of cases, but is significantly higher than the percentage of epithelioid cases reported in the ReNaM (55% of cases). As expected, the epithelioid histotype was associated with an increased overall survival (p < 0.0001). Sarcomatoid and biphasic histotypes were found in 2% and 9% of cases respectively, being less represented than the data reported in ReNaM, where the biphasic histotype accounts for 10.5% of cases. These percentages are also slightly different from those reported in the AIOM guidelines, where the biphasic histotype is attested to 10–25% of cases and the sarcomatoid about 10%. No cases of desmoid mesothelioma were found in our cohort, confirming that this histotype is the least expressed (< 2% of cases). Finally, in 10% of our cases it was not possible to define a precise histotype even in the presence of certain MPM (defined as unspecified mesothelioma). This data is broadly in line with the ReNaM, where 12% of MPM are not otherwise specified (NOS).
Before a definite diagnosis was made and before a treatment regimen was established, many of our patients had a significant pleural effusion; indeed, dyspnea due to pleural effusion is a common presenting symptom. As a result, prior thoracentesis or past/current drain placement was available on roughly 16% of our radiologic reports. This number could be higher, but we believe it’s still small enough that it did not distort our analysis of pleural effusion levels. In addition, patients with significant levels of pleural effusion, who merit an early drainage, are known to often require repeated drainage. In the study cohort, 76% of patients have an early stage of disease (IA-B, II) developed on clinical data (TC and PET)  according to the TNM-8 Ed system. As a result, the majority of patients are susceptible to surgical therapy or a multimodal approach. The reliability of this data is quite robust as all patients had undergone contrast tomography with contrast media. We expected that this high number of early disease stages would correlate with an even poorer prognosis, but no statistically significant association can was identified between OS and TNM disease stage. The reason for this is not known but it’s possible that limited information on overall survival and disease-free progression could have skewed these results. Furthermore, less than a quarter of the patients had an advanced staging, which may not have been enough to find a significant association.
As previously mentioned, a very small amount of pleural fluid (roughly 10 mL) physiological, however a pathological pleural effusion is a common occurrence in mesothelioma and is a common cause of dyspnea. Support of the high prevalence is that only 4% of our patients had no pleural effusion. Our 96% pleural effusion prevalence is significantly higher than the 79% found by Dogan and colleagues in their CT analysis of 212 patients with MPM in Turkey . The different patient population and different time-period analyzed with different environmental and epidemiological factors could account for this difference. Pleural effusion can cause the lung to poorly ventilate and can be a cause of death, especially when bilateral. Thus, patients with a bilateral pleural effusion are at a bigger risk of complications and are associated with a higher progression of disease. Indeed, just 2 of our patients had evidence of bilateral pleural effusion on pre-treatment CT scans. This correlates with the Turkish study that found that 2.3% of their patients had bilateral pleural effusion . Measurements of pleural effusions on CT scan can estimate the amount of fluid the patient has in the lung(s). This estimation can be done with table 4 and is important to take into consideration when thoracentesis or drain placement is being considered. The posterior costo-phrenic recess at the level of the apex of the emi-diaphragm was determined to be the best for estimating the fluid amount as the increased dimensions at the lower thorax mean a larger amount of fluid can be collected there. This measurement was then used when we compared the amount of pleural effusion to the TNM staging. Here we found that no obvious differences in pleural fluid level existed between TNM stages. Although expected, it was interesting to find that there appeared to be a correlation between patients with a bilateral disease and patients with involvement of the mediastinum and diaphragm. This indicates that a sign, such as bilateral thickening of the parietal pleura on chest x-ray, warrants further and thorough investigation.
Surgery is an important treatment option for patients with MPM. This is demonstrated in our cohort by the fact that more than half of our patients received some type of surgery. This correlates with the fact that most of our patients had low-stage tumors (TNM stage I or II), which is necessary to be eligible for surgery. More than half of the patients who underwent surgery (35% of total patients) underwent pleurectomy and decortication (P/D). As mentioned, this procedure is favored to extrapleural pneumonectomy ( EPP,) due to its safety in an elderly population and better outcomes. Of the 17 patients who underwent P/D, we know that 11 of them had several months of survival without disease progression. From these 11 patients, we can say that on average, patients who underwent P/D surgery had 15 months free of disease. This is slightly higher than the average of 12.5 months free of disease and within the standard deviation (10 months). There is not enough data on the surgical procedures received to draw any statistically significant analysis about whether P/D showed superior outcomes. video-assisted thorascopic surgery was not discussed in the results because it was only used in 4 patients from our cohort and its use in comparison to more conservative measures is debatable, as mentioned in the introduction.
Chemotherapy was the most common therapeutic option for our patients. As mentioned, 67% of our patients received a chemotherapy regimen of pemetrexed and cisplatin, which is first-line therapy for mesothelioma. The timing of the treatment was not the same for all patients though: 6% of the 67% received neoadjuvant treatment and 18% underwent adjuvant treatment. Neoadjuvant treatment means that chemotherapy was given before another treatment, such as surgery (either open, or VATS) or radiotherapy, with the aim of shrinking the tumor as much as possible. This was the case for 3 of our patients. Of these three patients, one patient received surgery only while another patient received both surgery and radiotherapy. The third patient did not go on to receive any further treatment, likely because of poor tolerance to the treatment, worsening condition, or personal wishes which made surgery or radiotherapy contraindicated. Adjuvant therapy means the chemotherapy was started after another therapy, with the aim of destroying all remaining tumor cells, for example. Indeed, in every case in which adjuvant therapy was used (9/9), the patient had previously received a non- VATS pleurectomy/decortication. Of these 9 patients, we know that 7 of them had several months of disease-free progression. The average number of months free of disease in these patients was nearly a year (11.6 months), which is close to the total average for all patients with months free of disease (12.5 months) and certainly within the standard deviation (10 months). Side effects of the chemotherapy was not monitored, but it’s known that providing B12 and folate can help limit toxicity , and thus this combination may have contributed to the nearly one year free of disease in 7 of our patients.
The main role of radiotherapy was to reduce the size of the tumor so other treatment options can be more effective or to relieve symptoms.