patients with malignant mesothelioma

Abstract
OBJECTIVE: To identify and characterize the major symptoms, the clinical presentation and radiological abnormalities in patients with malignant mesothelioma (MM), admitted in a government institution specializing in diseases of the chest. MATERIAL AND METHODS: We performed a retrospective study which reviewed the medical records and radiological data of patients diagnosed with MM, admitted to the National Institute of Respiratory Diseases (INER) in Mexico City from 1991 to 1998. We included the following data: age, occupation, exposure to asbestos, onset, family history relative to other malignancies, clinical symptoms and radiological alterations. Percentages were calculated by sex and age group. RESULTS: There were 45 cases with MM and 80% were unable to document a history exposicional asbestos. The age group most often found among 51-60 years. Dyspnea and chest pain were the main symptoms. Radiological abnormalities constituted thickening and pleural effusion in 75% of patients. CONCLUSIONS: The clinical and radiological abnormalities in patients with MM without a history of exposure to asbestos were similar to those of patients with a history of exposure to asbestos.
Keywords: mesothelioma / clinical symptoms, mesothelioma / radiography; asbestos, genetic predisposition, Mexico



Abstract
OBJECTIVE: Our aim was to identify and describe the main symptoms, clinical presentation, and radiographic changes in malignant mesothelioma (MM) patients. MATERIAL AND METHODS: We reviewed the medical records and X-ray of all patients diagnosed with MM, admitted between 1991 and 1998 to the National Institute of Respiratory Diseases (INER), which is a governmental institution specialized in chest disease in Mexico City. The following data were collected: Age, occupation, asbestos exposure, latency, family history of cancer, clinical symptoms, and X-ray changes. Data are presented as percentages by sex and age group. RESULTS: We found 45 cases of MM, in 80% of them a history of asbestos exposure could not be documented. The 51-60 years age group had the highest frequency of MM. Dyspnea and chest pain were the presenting symptoms in most patients. Pleural thickening and pleural effusion were the X-ray abnormalities observed in 75% of the patients. CONCLUSIONS: The clinical and radiographic findings among patients with MM without asbestos exposure were similar to those with a history of asbestos exposure.
Key words: mesothelioma / diagnosis, clinical, mesothelioma / Radiography; asbestos, genetic predisposition, Mexico





Malignant mesothelioma (MM) is the most common malignant tumor in pleura.1, 2 The first histological description of this was made by E. Wagner in 1870, and it was not until 1960 when JC Wagner and colleagues have established a link between malignant mesothelioma and exposure to asbestos, thus described a disease with a long latency period, which affected mainly miners and mill workers exposed to 5-crocidolita.3

The incidence of MM in the global variable. In the United States of America (USA) 2 have been reported 200 new cases per year, an increase of approximately 50% in the last década.6, 7 In the UK, this neoplasm is responsible for 2 700 to 3 000 deaths year, and it is estimated that these figures continue to rise until the year 2020.8 after which predicts a decrease in incidence due to the implementation of regulatory measures on exposure and use of asbestos. In Mexico it is difficult to know the real impact of GM, since there is no recognized as an occupational disease case, and only 66 have been reported cases of asbestosis between 1995 and 1998 .* Gavira and collaborators in their work and health Asbestos in Mexico City, identified 52 cases of MM in the archives of the Pathology Department of the various national institutes of health, as well as the Instituto Mexicano del Seguro Social (IMSS) and the Institute of Security and Social Services of State Workers (ISSSTE) in the period 1980-1985.9

In the etiology of MM, 70% of cases can be established with a history or a history of direct or indirect exposure to asbestos, 10-12 however, could not be directly correlated to the intensity and duration of exposure to appearance of pleural disease. Exposure to asbestos is associated with the occurrence of chronic bronchitis, pulmonary fibrosis, and bronchogenic cancer. It is estimated that the risk of developing pleural disease secondary to such exposure is 8% -13% .1,3,4 radiation also appears to play an important role in the development of MM.13 Thus, in patients with seminoma, cervical cancer and Hodgkin's lymphoma treated with radiotherapy, there has been an increased incidence of MM.

From a genetic point of view, much remains unknown about this neoplasia. Analysis of histocompatibility antigens has not shown a correlation directa.14 Moreover, some reports mentioned that the lack of expression of GST-M1 gene (whose product acts on the detoxification of carcinogenic compounds), is associated with the appearance of neoplasia. Other players considered as probable inducers of GM are zeolita.15 and beryllium-17

Histologically, the MM is divided into three groups: epithelial, sarcomatoid and mixto.1 3.4 The sarcomatoid type is associated with large tumor masses, absence or minimal pleural effusion and increased frequency of blood-borne metastasis. The epithelial type is approximately 60% of the total and is divided into tubulopapilar, glandular and sólido.1, 2 mixed features common to the two.

The most frequent clinical manifestations in patients with MM are: characteristics without pleuritic chest pain (70%), dyspnea (25%), cough (20%), but some cases may be completely asintomáticos.1 radiological abnormalities are: pleural effusion (usually unilateral), thickening and mass pleural.2, 3 may be associated with mediastinal widening, for lymph node lymphatic, or invasion by tumor directa.1 3.4

The prognosis is bleak for the GM, the survival time is between 6 and 18 meses.2, 3 factors that are associated with a better prognosis are: age less than 55 years, absence of chest pain at presentation clinical presence of symptoms for more than six months at diagnosis, histologic type and high Karnowfsky epithelial. The presence of thrombocytosis, fever of unknown origin, or mixed sarcomatous histologic type and age over 65 years leads to a worse pronóstico.2 3.4

Because in recent years have seen at the National Institute of Respiratory Diseases (INER) a steady increase in the occurrence of this neoplasm, since in many cases the clinical behavior seems to be different than described in the literature, is decided to undertake this work in order to define the clinical and radiological features of MM patients who presented to the Institute.



Materials and methods

We reviewed medical records of all cases diagnosed with MM, and admitted to the INER within the period from January 1 1991 to December 31, 1998. In the data collection sheet included the following variables: age, occupation, time of evolution of symptoms (months), exposure to asbestos, smoke and other toxic.

Clinical data were: chest pain, cough, hemoptysis, weight loss and dyspnea. The radiological changes were grouped into: pleural thickening, pleural effusion, mediastinal shift and shrink. Were analyzed further diagnostic tests required in each case, taking the information recorded in the pleural fluid cytology and closed pleural biopsy or obtained by thoracoscopy. In the review of chest computed tomography, were assessed alterations in the lungs, as well as the presence of mediastinal lymph node masses and pleural thickening. As a method of extension study were included reports of liver and bone scan.

To determine the tumor stage was used the classification of the International Mesothelioma Interest Group (IMIG) 18 was also included in the data sheet information on the treatment and monitoring of the disease. Percentages were calculated by sex and age group.



Results

We studied 45 cases with a diagnosis of pleural mesothelioma, of whom 33 (73.3%) were males and 12 (26.7%) women. The age group with the highest frequency of MM in men was the 51-60 years, with a percentage of 42.4%, and the second group of higher frequency, ranged between 41 and 50 years (21.2%) and also in women the frequency was similar in the age groups 51-60 and 61-70 years, with a percentage of 33.3% in both groups (Figure 1). In males of 61-70 years, the observed frequency was 12.1%. In the age group 31-40 years were six cases in males and females only one in the group of 41-50 years, there were two cases of MM in women and seven men, while of the 18 cases MM in the age group 51-60 years, 14 were males and four females. For the remaining groups, the distribution of cases for each sex was similar.





These results differ somewhat from those reported by Yates and colleagues, 8 who reviewed 272 cases with MM and found that the average age of onset of this malignancy is 65.9 years, with no identified differences in the incidence of MM among both sexes . It is worth noting that in the present study the average age was 52.5 in men and women of 55 years.

Of the 45 patients, only 20% had a history of exposure to asbestos (eight men and one woman). This was primarily an industrial workforce. 80% of the cases studied did not have even indirect exposure to asbestos. Most cases without antecedent exposicional to asbestos occurred among males (69.4%), with an average age of 49 years, while 30.5% of cases with no history of asbestos exposicional were women, aged 59 and 75 years. Only 15 patients were history of smoking (eight males and seven females). It is worth mentioning that all data from the clinical file limitations inherent in any retrospective study, the absence of an association between exposure to asbestos and mesothelioma to be taken into account with some reservations.

With the aim of analyzing whether the GM without antecedent exposicional to asbestos showed the same clinical and radiological features in cases with history exposicional, patients were divided into two groups (Table I). In the first group, consisting of patients with evidence in the clinical history of exposure to asbestos, the most frequent symptoms were: chest pain, dyspnea, weight loss and cough. The incidence of these symptoms was similar in both sexes, with only the highest weight loss in women, but with no statistically significant difference. The most frequently observed radiological abnormalities were pleural effusion and thickening, as both disorders was higher than 75% of the mediastinal shift was observed in 37.5% of patients, while the retraction hemithorax was observed in only 25% of men .





In those patients in whom there was no antecedent exposicional to asbestos, the symptoms most frequently found at diagnosis were chest pain and dyspnea, which were found in more than 80% of cases in both men and women. Weight loss was present in more than 75% of patients. The most frequent radiological deterioration in this patient group was represented by the pleural effusion was found in more than 88% of cases. Occurrence of mediastinal displacement and retraction hemithorax was different in both sexes. Thus, 8% and 20% of men had decreased hemithorax and mediastinal shift, respectively, while in women the frequency of these alterations was 27.2% and 36.3% in the same order. Pleural thickening was different for each sex, as males were found in only 4% and women 72.7% (Table I).

From the detailed analysis of the family background of individual patients, they identified a group of patients referred at least one close relative with cancer. Due to the limited information on cases of familial predisposition to MM since it is not known the existence of a genetic component that may be important in the pathogenesis of neoplasia, it was decided to examine separately the group of patients.

Genetic load was defined as the group of patients with more than one close relative with any type of tumor. 80% of patients had no genetic load for malignancy, while 20% (nine cases) showed the antecedent itself. Thus, an analysis was, again, the presentation of clinical and radiological manifestations MM dividing the group between those patients who presented for genetic cancer and those who did not (Table II). Chest pain, breathlessness and weight loss were the most frequent clinical presentation in patients of both sexes and in both groups, with an incidence greater than 80%. The hemoptysis was present at diagnosis only in patients without genetic load, and its incidence was 12.5% in women and 3.5% in males. None of the patients with familial predisposition to malignancy was observed fever at diagnosis, but was present in more than 25% of patients without genetic load for neoplasia. Among the radiological abnormalities, over 75% of patients in both groups had pleural effusion, the pleural thickening was observed at a rate above 80% in cases with genetic loading for neoplasia. The frequency with which it was observed thickening and pleural effusion in patients without genetic load was above 42% and 85% respectively. Within the group of patients without a genetic load for malignancy was found hemithorax decreased to 14.2% in men and 37.5% of women, while in the group with this genetic alteration was detected in only 25% of women ( There were no cases in men).





Analyzing both the history of exposure to asbestos and the genetic load for malignancy (Table III), genetic males with and without exposure to asbestos had a mean age of 45.6 years, evolution time of symptoms of 1.4 months and a Symptoms at diagnosis similar to that described in the literature for the Anglo MM associated with asbestos. In this group the average age at diagnosis among women was 59.4 years. In the second group, comprising patients in whom no antecedent exposicional to asbestos showed no genetic load for neoplasia, the average age of presentation of MM was 48.6 years in men and women in 57 years, while the time elapsed between the onset of symptoms and diagnosis in both sexes was three months. The clinical and radiological had the same characteristics as the other groups. The third group of patients, consisting of cases in which there was precedent exposicional to asbestos but who had no genetic load for neoplasia, the mean age at diagnosis was 56.5 years in men and women in 35 years. Unfortunately, only one case could have female, who presented a very long time of evolution. Clinical symptoms observed in this patient at diagnosis were chest pain, breathlessness and weight loss. Thickening and pleural effusion were the most frequent radiological findings in this third group, but none has been observed retraction hemithorax or mediastinal shift. The fourth group, which includes cases where there was exposure to asbestos and presented for genetic cancer included only two men with a mean age of 52.2 years at diagnosis and with an interval of evolution, since the appearance of symptoms to diagnosis of 2.4 months, the clinical manifestation most frequently observed in this group was chest pain. Thickening and pleural effusion were present in both cases.





We also analyzed the interval between the onset of symptoms and the time of diagnosis (Table IV). In female patients without genetic load (66.6%), the range was 0.7-48 months, with an average of 4.1 months, whereas patients of the same sex with genetic load, the interval was 3-24 months with an average of 9.6 months. Of the 33 cases found in men, five (15.5%) had genetic load for neoplasia, and in them the interval between symptom onset and diagnosis ranged between 1 and 6 months, with an average of two months. In the remaining 28 cases (84.8%), duration between onset of symptoms and diagnosis was 0.5-18 months, with an average of 2.8 months. Therefore, the development of mesothelioma appears to be more aggressive in men, and among these, in which there is familial predisposition to cancer.





Finally, we separately analyzed the following variables: gender, genetic load and the latency period between the onset of symptoms and the time of diagnosis in different age groups. This period was lower in women with ages ranging from 43-46 years and 58-59 years, without genetic load (range three months), while in women of 56-57 years, with genetic load for malignancy, the interval was 18 months. In male patients, this difference was not marked. In men with the greatest genetic load latency period occurred in patients 77 years (eight months), and the interval was reduced to one month in patients from 42 to 69 years. Moreover, men without genetic load, the group of 32-39 years had the shortest latency period (1.9 months), and 63-68 years of which was the largest interval (9.5 months).

Regarding the clinical stage, the majority of patients had an IV IMIG, and several of them were metastases, primarily in the liver and spleen. The advanced clinical stage of the tumor is probably due to the patients when entering the INER pulmonary symptoms. Notably, the index Karnowfsky showed that the majority of patients was higher than 70%, and only one case was identified with a value of 40%.



Discussion

The results of this analysis correspond to a retrospective study of 45 cases admitted to the INER GM, the only tertiary center specializing in respiratory diseases in Mexico City.

Since 1960 was established as the main factor involved in the genesis of MM exposure to both direct and indirect asbestos.10, 17 In this review, cases in which there was documented exposure to asbestos were scarce. In the overall distribution by sex, the MM primarily affects males (83.3%), with a peak incidence in those who were between 51 and 60 years of age. The incidence of MM in women was not different in groups of 51 to 70 years. Yates and colleagues, in a review of 272 cases with MM, had a higher incidence in patients 65 years of both sexos.8

In our series, dyspnea, chest pain and cough were the most common clinical presentation of patients in both groups (with and without exposure to asbestos), and these results are similar to those reported in most series with a history of MM Exposure to asbestos.7, 17 In the series published by Yates and colleagues also found significant differences between the clinical presentation of MM associated with exposure to asbestos and those who had no history exposicional.8

Among the most common radiographic abnormalities associated with MM (x-ray postero-anterior chest) include pleural effusion, retraction hemithorax, mediastinal shift and thickening pleural.1, 2 In this paper, the pleural effusion was the most common radiological abnormality, together with pleural thickening. Although there are no pathognomonic nor tomographic findings of MM, Yilmaz and colaboradores19 studied retrospectively tomographic features of 46 cases of MM associated with exposure to asbestos, hence pleural thickening was the most common finding (99%), while the spill pleural involvement of the mediastinal pleura and the interlobar fissure, were presented in 91%, 57% and 54% of cases, respectively. Pleural calcifications and retraction of the hemithorax was affected in 26% and 30% of cases in the same order. In our series, only 25 of the 45 patients had CT scan done as part of the study protocol, the most common finding was pleural thickening, present in 44% of cases, followed by pleural effusion (36%).

Among the diagnostic procedures used in most patients the initial approach included thoracocentesis with pleural fluid cytology and closed pleural biopsy. Several authors have recognized the limited value of cytologic examination of pleural fluid for establishing the diagnosis of MM, as calculated 3,18,20,21 a diagnostic sensitivity of approximately 26%.

Boutin and colleagues reviewed 137 patients diagnosed with MM and compared the diagnostic efficacy of thoracoscopy in relation to closed pleural biopsy and cytologic analysis of pleural fluid. This study reported a sensitivity of 26% for cytologic examination of pleural fluid and 21% for closed pleural biopsy, with a cumulative sensitivity between the two procedures only 38.7%, and it was attributed to a material obtained by thoracoscopy diagnostic sensitivity of 80% .20 Our findings are consistent with those reported in series.

In this study, the diagnosis of MM could only be established definitively in the analysis of pleural fluid in one case, and the diagnosis was the most common inflammatory disorders. Of the 45 patients diagnosed with MM in the series presented here only 17 (37.5%) patients underwent thoracoscopy for diagnostic and staging. The most frequent histological type was epithelial Sarcomatoid followed.

At present, guidelines have been established in the field of management internacional18, 21 for the study, diagnosis and treatment of patients with suspicion of MM, which, in addition to an emphasis on detailed questioning and to identify exposure asbestos, highlighting the importance of completing the clinical diagnosis and supported in obtaining multiple biopsies through thoracoscopy. Although the diagnostic efficiency is increased by this method, you must not forget that this is an invasive procedure, not without complications, and that in most cases treatment is only palliative and MM with a poor prognosis in the short term; For this reason, the decision to perform thoracoscopy should be taken before evaluating the characteristics and circumstances of each patient.

Currently there is a tendency to classify exposure to asbestos: a) occupational (work) b) indirect or family, and c) environment, the latter is that which occurs in the vicinity of mines, factories or sites of natural asbestos, 22 and is more difficult to obtain, and therefore excluded. It is also known that the incidence of asbestos related not only to the duration of exposure, but also with its intensity. For some authors, short periods of exposure may be able to determine the onset of MM, as seems the case for the niños.22 The latency period between exposure to asbestos fibers and the appearance of the pleural neoplasia ranges from 5 and 70 years, so it is often difficult to establish in retrospect that exposición.10, 12.22

Unfortunately, in Mexico there are few studies focused on analyzing the incidence, characteristics and survival of patients with MM, so that despite the data obtained in our series, it is difficult to say that the old axiom, "Exposure to incidence of mesothelioma-asbestos "is not applicable. Thus, it is necessary to perform clinical and epidemiological studies on the possible contact of patients and their families, to provide an enhanced and comprehensive access to information for patients with MM.

The results obtained in this series show that 80% of cases had no exposure to asbestos, and that the clinical symptoms and radiographic abnormalities present at diagnosis are similar to those described in the Anglo-American literature for MM associated with exposure to asbestos. It is worth noting that because this study is retrospective, it was not possible to obtain a complete record of environmental and occupational exposure to asbestos of patients, so the data presented here should be considered with reservation.

Most series indicate that the antecedent to exposicional asbestos is present in 60% -80% of cases of MM, and given the high rate of exposure to asbestos (eg in the USA is estimated at 21 million Persons exposed only in the construction area) and the low incidence "relative" for this neoplasm, it is necessary to search for other etiologies that can influence the occurrence of this malignancy.

In this series, we found that only 20% of patients had family history of cancer. Huncharek and colaboradores23 studied 39 cases of MM, of whom 71% had family history of cancer. Although in this series did not find such a high percentage, this seems to be the only parameter to consider, as the number of patients with exposure to snuff, wood smoke or other inhalants was very low.

Comparison of clinical and radiographic findings between cases with and without antecedent exposicional to asbestos and between those with and without genetic load, showed no significant differences. However, it was a partnership with the time between the onset of symptoms and diagnosis.

Other factors have been implicated in the genesis of mesothelioma. Thus, for some authors the chronic inflammation in the pleural cavity could be one of them, 11 cases have been reported for recurrent pleural effusion and subsequently developed MM.22 Another officer involved in the pathogenesis of MM is radiation. Moreover, the latter's association with exposure to asbestos presents a synergistic effect for the development of mesotelioma.11 It is important to note that none of the patients in this series showed some of this background.

Several authors mention the existence of a familial predisposition or increased susceptibility gene in patients with MM. However, this work has not yet been carefully analyzed the role of familial or genetic predisposition in the genesis of MM. In the series presented here, clinical symptoms and radiologic abnormalities showed that both patients with positive genetic load as those in which there was no family history of malignancy, were common to those described for MM associated with asbestos. Thus, only differences in the time between the onset of symptoms and diagnosis, as well as the age at presentation of disease.

There are several works that mention a higher incidence of cancer in parents and relatives of patients with MM, but its meaning is still desconocido.23-26 Studies in Turkey found a higher frequency of histocompatibility antigens of B-41, HLA B-58 and DR-16 in patients with MM, in relation to population control groups and normal donor renales.14 were also described various chromosomal abnormalities in patients with mesothelioma. Especially frequent is a deletion of the long arm of chromosome 6.26 Other abnormalities described include monosomy on chromosomes 13 and 17 and, less frequently, on chromosomes 14 and 22. However, at present still unknown the implication of these findings in the development of GM and the predictive value of this still needs to be evaluated.