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DIAGNOSTIC YIELD OF COMBINED EPIDEMIOLOGICAL AND RADIOLOGICAL DATA IN MALIGNANT PLEURAL MESOTHELIOMA: A PILOT STUDY.

Byline: Zafar Iqbal, Mohammad Yousaf Khan, Jamshed Alam and Zia Ullah

ABSTRACT

Objective: To determine the diagnostic yield of epidemiological and radiological data in malignant pleural mesothelioma (MPM) patients.

Methodology: It was a survey of 56 patients between January 2014 to June 2017 who presented to chest clinic with gradual onset of pulmonary symptoms and had specific abnormal chest radiology. Computerized tomography (CT) guided biopsies were done and samples were sent for analysis for diagnostic yield of MPM. SPSS version 20 was used for statistical analysis.

Results: Among the study cases, 30 (53.6%) were male and mean age was 58.79+-14.383 years). MPM was found in 28 (50%) cases. The diagnostic yield of epidemiological and radiological data showed sensitivity of (82.1%), specificity (14.3%), positive predictive value (48.9%) and negative predictive value (44.4%). The most commonly found marker was Cytokaratin which was present in 71.4% of the mesothelioma patients, followed by Calretinin (57.1%), and WT1 (50%).

Conclusion: Mesothelioma was found in half of the study participants. The diagnostic yield of epidemiological and radiological data showed increased sensitivity but low specificity regarding diagnosis of MPM.

KeyWords: Asbestos, Mesothelioma, Pleural malignancies, Khyber Pakhtunkhwa, District Swabi.

INTRODUCTION

Malignant pleural mesothelioma (MPM) is a very aggressive tumor, which arises from the mesothelial cells of the pleura. The most significant factor for the development of malignant mesothelioma is airborne asbestos fibers. MPM is no longer considered as un-common, as the use of asbestos is very much common these days. Asbestos is used as insulator against heat, fires and corrosions. It is mainly used in material for home construction, cement, ceiling, tiles, gas kits, car bracers, jewelry and even in toys. Due to the diverse use and exposure of asbestos results in high incidence of mesothelioma in Pakistan, particularly in Khyber Pakhtunkhwa (KPK)1. Besides occupational history, environmental exposure to asbestos fibers commonly found in northern districts of the province of KPK, is presumed to be the main causative agent for MPM.

Though human beings have been using asbestos for ages2,3, but the potentially carcinogenic airborne asbestos fibers in the environment have not come under consideration till recent past4,5. The major rock belts containing rich amount of asbestos are located in KPK and adjacent Federally Administered Tribal Areas (FATA). Overall in Pakistan, about 90% of asbestos is found in KP region. Asbestos fibers find their way into the environment and become airborne during the process of quarrying, cutting and freeing it from rocks by blowing and crushing6. The concentration of respirable airborne fiber in the mining area in Pakistan are much higher than the permissible limits7. It has been reported in a study by Jehan8 that asbestos fibers in surrounding field was more than 100 times than its permissible amount. Unfortunately, in KPK, the workers are not aware of the concept of occupational safety and industrial hygiene, mainly because of poverty9.

These people are working in marble/mining rocks using shovels for extraction and using bare hands for the spread of asbestos for drying, without considering the possible release of associated fibrous asbestos in the environment. It was observed in a study by Jehan et al9 that people working there or nearby residents have a lot of medical issues like skin allergies, chronic bronchitis, pleural thickening and calcified pleural plaques on radiology10. The developed countries have already banned the use of asbestos due its proven health hazards, but the developing countries like Pakistan is still facing the threat from this fatal dust i.e. micro-fibers of asbestos. Because of this un-regulated asbestos business, unfortunately a significant increase in number of mesothelioma patients in KPK is expected11.

When this environmental asbestos fibers go into the respiratory tract, it pierces its parenchyma, ends up in the pleura, inducing cytotoxicity, DNA changes and chronic inflammatory response resulting in abnormal mitosis, which leads to development of mesothelioma12,13. Clinico-radiological features play an important role in the diagnostic process as the histopathological diagnosis is often difficult due to variety of reasons including the nodular nature of disease, difficulty in selection of histochemical stain and the associated pleural effusion. CT and chest X-ray both play an important role in the diagnosis. The most common mesothelioma findings are pleural plaques, nodular pleural thickening and concentric pleural thickening, resulting in encasement of the lung parenchyma. This research was conducted as a pilot study to assess the role of combined epidemiological and radiological data in the diagnosis of mesothelioma.

We assessed the suspected patients of mesothelioma belonging to District Swabi. This study will help in creating awareness among clinicians regarding mesothelioma development due to environmental asbestos exposure and guidance regarding diagnostic modality for MPM.

METHODOLOGY

This study was conducted in chest clinic in District Swabi, KPK, Pakistan, between January 2014 to June 2017. All the patients enrolled in this study belonged to District Swabi who presented to chest clinic with gradual onset of pulmonary symptoms such as chest pain, dyspnea, cough. They were assessed with chest X-ray and CT thorax for findings consistent with mesothelioma (encasement, nodularity and pleural thickening on chest X-ray and CT thorax). Chest X-ray was considered positive when there was unilateral, concentric, plaque like or nodular pleural thickening. Positive CT thorax was defined when there was concentric pleural thickening or nodular pleural thickening or pleural thickening more than 1cm and or involvement of mediastinal pleura (Figure 1). Epidemiological data was definedIt as the data collected from patients from District Swabi to find out distribution (frequency, pattern) and determinants (causes, risk factors) of mesothelioma especially asbestos exposure.

Ultrasound chest was done to exclude large effusion; and patients not fit for CT guided biopsy because of desaturation were excluded from study. The enrolled patients were then referred for image guided biopsy to an experience radiologist and the specimens were sent to Shaukat Khanum Memorial Cancer and Research Hospital Laboratory for histpathology and immunohistochemial staining. All the patients were biopsied after a verbal and written informed consent. Three to four pieces of biopsies were taken, using tru cut biopsy needle. Two percent (2%) lignocain was used as local anesthetic. Intravenous midazolam and/or tramadol was used in excessively apprehensive cases. No serious complications were observed except for mild localized pain and occasional faintness in over apprehensive patients. None of the patients needed an invasive intervention to treat a complication of the procedure.

Data were collected, coded and entered to a computer before being analyzed using the software, SPSS version 20. Qualitative data (gender, radiological findings, presence of mesothelioma ) were presented as frequency and percentage; while quantitative data (age) were presented as means and standard deviation. Comparisons of qualitative data were performed using Chisquared test while validation tests were applied for determining the diagnostic yield. P-values of 0.05

Female###26###46.4###10###35.8

Total###56###100###28###100

Table 3: Age distribution of Mesothelioma patients (n=28)

Age group(Years)###Frequency###Percentage

30 - 40###01###3.5

40 - 50###03###10.7

Above 50###24###85.7

Total###28###100

Table 4: Histopathological diagnosis (n=56)

Findings###Frequency###Percentage

Mesothelioma###28###50

Other Malignancy###20

###Metastatic Adenocarcinoma###10

###Small Cell Lung Carcinoma###2###35.7

###Poorly Differentiated Adenocarcinoma###6

###Moderately Differentiated Adenocarcinoma###2

Negative for Malignancy###08

###Non -diagnostic Biopsy###2

###Solatiry Fibrous Tumor###2###14.3

###Anthracosis###1

###Chronic Pyogenic Inflammatory Infection###3

Total###56###100

Table 5: Presence of markers in mesothelioma cases (n=28)

Markers###Frequency###Percentage

Cytokeratin###20###71.4

Calretinin###16###57.1

WT1###14###50

D240###10###35.7

HBME###10###35.7

Table 6: Diagnostic yield compared to histopathological diagnosis of MPM (n=56)

Tests Report###Mesothelioma###Total

###Present###Not Present

Positive###23###24###47

Negative###05###04###09

Total###28###28###56

RESULTS

The common findings on X-ray and CT thorax were unilateral concentric nodular pleural thickening with pleural plaques in 83.9% of the total cases. There was no significant statistical difference between chest X-ray and CT thorax findings. However, on CT thorax, mediastinal pleura was also involved in 46.4% which is pathognomonic of mesothelioma (Table 1). Among total cases, 30 (53.6%) were male and 26 (46.4%) were female whereas majority of the patients with mesothelioma were males (64.2%, Table 2). Minimum age of the patients was 32 whereas maximum age was 80 and mean age was 58.79 +-14.383 years. Most (78.6%) were older than 50 years. Age distribution is shown in Table 3. Among study patients, 26 (46.4%) were house wives, 18 (32.2%) farmers, 10 (7.8%) shopkeepers and 2(3.5%) were school teachers by occupation. There was no occupational exposure to asbestosis in any case and only 6 (10.7%) had history of smoking.

The main presenting complaints were chest pain (89.2%), followed by cough (71.4%), shortness of breath (35.7%) and fever 8 (14.2%) cases. Mesothelioma was found in 28 (50%) of the study cases, whereas other 28 cases (50%) were negative for mesothelioma (Table 4). The most common marker was Cytokaratin which was present in 71.4% of cases followed by Calretinin in 57.1% cases (Table 5). Diagnostic yield of MPM revealed sensitivity as (23/28x100=82.1%); specificity (04/28x100)=14.3%; positive predictive value (23/47x100)=48.9%; and negative predictive value (04/09x100)=44.4% (Table 6).

DISCUSSION

Many studies have mentioned the presence of asbestos reserves in the north-west of Pakistan14-17. A study was conducted in Mohmand Agency and it was found that there is vast reserves of chrysotile, tremolite and anthophyllite asbestos deposits. It was noted that the physical size of asbestos fibers in the area was well within the potentially carcinogenic asbestos-fiber size (i.e. within the range of 5 micrometer in length). The amount of the airborne asbestos fibers was more than 100-times the permissible level of 0.1f/cc18. A cause and effect relation between environmental asbestos exposure and mesothelioma in the FATA and the KPK province of Pakistan was first established in the 1990s and was published in the year 200119. The histological diagnosis of mesothelioma reported in that study was questioned because immunohistochemical (IHC) markers were not applied.

Biopsy specimens obtained via closed pleural biopsies are small and pose difficulty in reaching a definitive diagnosis of mesothelioma. Moreover, the three histological types of mesothelioma; namely epithelioid, sarcomatoid and mixed variety can resemble other malignancies. This issue can be resolved by simultaneously applying positive IHC-markers for confirmation of mesothelioma and negative IHC-markers for ruling out other malignancies20-24. In our study, various IHC-markers were applied to the histopathology specimens. Thus a definitive diagnosis of malignant mesothelioma was made and relationship between environmental asbestos exposure and mesothelioma was shown. Swabi, one of the district in KPK, in North West of Pakistan, has the highest prevalence of MPM14 and environmental exposure is thought to be the cause of the disease.

Due to this reason, it can affect the younger age group as well without any occupational exposure as it is evident in our study (about 15% of our patients were less than 50 years old). Usually mesothelioma occurs in late ages as evident from our study and the study done by Jehan et al25. Usually after exposure it takes 20-30 years to develop mesotherlioma, because of long latent period between onset and symptoms26. However, in this locality mainly its seems to be environmental exposure in childhood. Moreover, the females who worked mostly at home developed mesothelioma as well. So from our study it is quite evident that there is something in the environment and the question arises here whether something is present at home or is airborne or genetic in origin. Of note, the males were 88% farmers by occupation and this raises question if our farms are rich in asbestos as mentioned by Jehan et al25. But if we look at our females cohort they were 100% housewives.

One explanation would be that as they live near farms, they could potentially get asbestos exposure and the second possibility will be the presence of something household or which they share indoor. Because of the limited resources and interest we are still not confident that whether this is something in the gene, in the farms nearby at homes or airborne from nearby mining industry. For this further work need to be done. Malignant pleural mesothelioma was found in 50% of our patients, which is quite significant. Interestingly it was followed by adenocarcinoma (32%) which could potentially be peripheral lung tumor involving pleura. Regarding diagnostic yield, the sensitivity was high (82.1%), though the specificity was very low (14.3%). Although epidemiological and radiological data can not establish the diagnosis of MPM, but these may provide substantial evidence to suggest MPM.

Therefore, anyone from the mention endemic area need to be suspected for MPM with typical radiological pattern on chest X-ray or CT thorax without pleural effusion, regardless of the occupation or history of asbestos exposure28.

LIMITATIONS

Critic could ask potentially the deficiency in history regarding the use of asbestos in buildings, houses near the mining industries, information about the farms nearby and mining industries and family history of the mesothelioma. As this study was conducted in a peripheral primary care setting clinics, there was no dedicated radiologists available onsite. And we feel that we could possibly bring down the number of non-mesothelioma cases to increase the sensitivity of our study for diagnosing MPM if these were collaborated with tertiary care radiology team.

CONCLUSION

Mesothelioma was found in half of the study participants. It was significantly more common in males aged 50 years and above. The most commonly found biomarkers was Cytokaratin followed by Calretinin. The diagnostic yield of epidemiological and radiological data showed increased sensitivity but low specificity.

RECOMMENDATIONS

Malignant pleural Mesothelioma is a common and rapidly fatal and aggressive tumor. The diagnosis is often delayed, due to a long latent period between onset and symptoms and the common, nonspecific clinical presentation. There should be a considerably high level of index of suspicion in mind, when an irregular pleural thickening or encasement on X-ray chest or CT Thorax is seen. High prevalence of the MPM in the district Swabi warrants further investigation and any abnormal radiology should be promptly investigated for MPM.

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Author:Igbal, Zafar; Khan, Mohammad Yousaf; Alam, Jamshed; Ullah, Zia
Publication:Journal of Postgraduate Medical Institute
Article Type:Report
Geographic Code:9PAKI
Date:Sep 30, 2018
Words:3233
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