MALIGNANT PLEURAL MESOTHELIOMA AND ITS DIFFICULT HISTOLOGICAL DIAGNOSIS

The diagnosis of pleural tumors, despite the progress in clinical, paraclinical and morphological methods, is still difficult. In this anatomic region develop a few primary tumors, and the most common of them is the malignant pleural mesothelioma (MPM). This is also the location of numerous metastases from different malignant tumors of various histogenesis. This diversity of malignant tumors requires first of all to differentiate them from the pleural mesothelioma – a tumor of high malignancy and unfavourable prognosis. Its difficult histological diagnosis is confirmed either rarely in life with reliable electronic microscopic study or after death with an autopsy.

The uncertain imaging diagnostics and the difficult interpretation of cytological material from the pleura require a necessary study of tissue biopsy material. The histological picture of the malignant mesothelioma and the metastatic tumors in most part are very similar and are often indistinguishable in routine colouring with hematoxylin and eosin. The only way to a correct diagnosis of pleural tumor remains the immunohistochemical study of biopsy material.

With its wide differential diagnosis, difficult therapy and unfavourable prognosis, the accurate diagnosis of the malignant mesothelioma nowadays is crucial. This led us to conduct this study, and our aim was to help improve its correct diagnosis.

Definition

Malignant mesothelioma is a rare, asbestos-associated tumor, which originates from the pleural mesothelium, peritoneum, pericardium and tunica vaginalis of testis. Its frequency is less than 1% of all malignancies. It most commonly affects the pleura (80-90%), the peritoneal cavity (10-20%) and there are only isolated cases of other locations. [23, pp. 1-11], [11, p. 3]

According to the WHO histological classification for 2004, it includes the following types of malignant mesothelioma:

epithelioid: includes tubulopapillary, deciduoid, clear cell, and small cell types
biphasic
sarcomatoid
desmoplastic

It is difficult to trace when the nosological unit mesothelium begins to be recognized as such. It is believed that Е. Wagner, in 1870, while describing a pleural tumor, most probably meant mesothelioma. [30, p. 107] In 1931, Klemperer and Rabin in the USA, described 5 cases and suggested that the term mesothelioma is used for a tumor of biphasic structure – carcinoma and sarcoma parts in different ratio, which originates in the mesothelium. [18, p. 385]

Today, it is considered that 90% of the people with mesothelioma were subjected to asbestos exposure. In most cases it happened at their workplace. In many countries around the world, it is included in the list of occupational diseases. In the past, asbestos was widely used in industry and households because of its very good insulating properties. It was mixed with concrete, stucco, gypsum plasterboards, wall and floor coating in millions of buildings all over the world. This means that too many people were exposed to it for years, unaware of the effect of asbestos dust or fibers from it. So today, the tumor is considered not only as occupational disease, but also as a disease involving a wide range of people, who seemingly have not worked with asbestos. Unlike lung carcinoma, there is no proven causal relationship between smoking and mesothelioma.

Although an early diagnosis has a relatively better prognostic significance, generally the MPM prognosis remains unfavourable. The average survival period is still within 8-30 months. [15] Reports for longer periods are rare and with some of them it was established that they concerned a wrong diagnosis. [36, p. 1485]

While with some lung tumors, breast cancer and lymphoproliferative diseases, the achievements of molecular biology and target therapy led to significant increase in the survival rate of the patients, with MPM there is still no significant progress in this area. Currently are being studied specific molecular mechanisms, which are involved in the tumor carcinogenesis and the effects of asbestos. [6, p. 364]

Epidemiology of malignant pleural mesothelioma

The existing data in literature shows an increase in the frequency of mesothelioma incidence over the last 20 years all over the world, but still, the disease remains rare. [24, p.197] The data cited by various national statistical registers is too diverse and contradictory. All authors accept this data with the reservation that it may be inaccurate, as the correct morphological diagnosis of mesothelioma remains difficult and the epidemiological data concerns comparatively few limited series of tumor. Average for the global statistics, the indicator of incidence is about 1 per million. The highest incidence rate is in the UK, Australia and Belgium – an average of 40 per million per year. Only for the period of 1974 – 2004 among the Caucasian race in these countries it increased with 300%. To compare we need to point out that the squamous cell lung cancer in a population with high percentage of smokers comprises 1000 per million. With MPM, the men/women ratio is 6:1 in the USA, whereas in Europe it is significantly lower – 3:1. According to data of the National Institute for Tumor Diseases and the official US government statistics, in the new cases of mesothelioma there is a significant increase in the group of men aged 74-84. It is more than double, from 10.0 to 20.4 per 100 000 population.

According to WHO /2004/, the tumor epidemiology includes its distribution around the world, but while the peak of incidence in the US will be reached within the following several years, in Europe it will happen about year 2025. [31, p. 107]

According to the latest data from June 2013 by the US National Cancer Registrars, the probability of suffering from mesothelioma in the next 30 years, considering the extrapolation of previous data, will rise nearly three times in the age group 50-60. [31, p. 107]

MPM usually occurs in patients aged over 60, but there are a few reported cases in children. It is estimated that in the USA, 90% of pleural mesothelioma in men is associated with asbestos exposure, whereas in women it was proven in only 20% of the tumors. A meta-analysis of the statistical data indicated that the prohibition of asbestos use almost equalized the risk of asbestos exposure and development of mesothelioma for people apparently unrelated to asbestos and those living near natural asbestos deposits. It is reported that it was related to the asbestos already used in almost all the buildings built before year 2000.

For Bulgaria, the data from the National Statistical Institute and the National Cancer Registry for new cases of mesothelioma and incidence per 100 000 population is presented in Table 1. [1 p. 14] In the eight-year period were found 352 cases of mesothelioma and the men:women ratio was 1.66:1. The most affected age group for both sexes was 60-69 years of age. In 2004 the incidence was 0.5 per 100 thousand, and in 2011 it reached 1.00 per 100 thousand. This represents a double increase in the incidence of mesothelioma within just 8 years.

Table 1

New cases of mesothelioma and incidence by years. National Cancer Registry 2004-2011 for Bulgaria

Year	2004		2005		2006		2007		2008		2009		2010		2011		Total
Age	M	F	M	F	M	F	M	F	M	F	M	F	M	F	M	F	M	F
20-29			1			1			1								2	1
30-39	1		1		3	1					1		2	2		1	8	4
40-49	1	1	6		2	5	3	2	3	4	4	4	1	2	5	3	25	21
50-59	9	3	5	3	8		9	5	5	6	6	4	6	7	5	6	53	34
60-69	5	2	6	5	6	4	14	4	8	4	7	11	13	5	14	8	73	43
70-79	3	3	4	2	3	2	9	2	3	3	8	4	8	5	10	4	48	25
80+	1		1					3			8		1		1		11	4
Total	20	9	24	10	22	13	35	16	23	17	34	23	31	21	35	22	220	132
Incidence per 100,000	0.5	0.2	0.6	0.2	0.6	0.3	0.9	0.4	0.6	0.4	1.0	0.6	0.9	0.5	1.0	0.6	0.7	0.4

Immunohistochemical diagnosis of malignant mesothelioma

The histological picture of the malignant mesothelioma and the metastatic tumors in most part are very similar and often indistinguishable in routine histological examination. The only way for an accurate diagnosis of pleural tumors remains the immunohistochemical examination of biopsy material. There are great difficulties in defining a unique reproductive immunophenotype of MPM, which we can use in differential diagnosis with metastatic pleural tumors.

The immunohistochemical study (ICH) has existed for more than 25 years. In the diagnostic practice for that time were offered various antibodies and combinations of them, but still the “gold standard“ for this study has not been found yet. There are many reasons for these, sometimes significant differences in the obtained results from the immunohistochemical study, but the main one is the phenotypical flexibility of the mesothelium typical for the embryonic differentiation of the mesoderm. Second are the objectively limited possibilities of the immunohistochemical method itself. Today there are dozens of companies offering different antibodies with different sensitivity and specificity. Despite the existing automated systems for IHC study, the records for processing the material are still too cumbersome and bulky. We shouldn’t also forget the very important subjective factor in assessing the results from this study. With its wide differential diagnosis, difficult therapy and bad prognosis, the accurate diagnosis of malignant pleural mesothelioma today is crucial. [28, p. 1-19]

The lack of absolutely specific and sensitive immunohistochemical markers for mesothelioma makes the differential diagnosis of this tumor very difficult. The recommended ICH panels are constantly changing as a result of introducing new markers and additional information about their specificity and sensitivity. [21, p. 1324]

The markers used in the diagnostic panels can be conditionally divided into 3 main groups:

Markers positive for mesothelioma
Markers negative for mesothelioma /positive carcinoma markers/
Organ-associated tumor markers /negative for mesothelioma/

Table 2

Markers positive for mesothelioma

MARKER

COMMENTARY

Calretinin

Very widely used, highly sensitive and mesothelioma-specific marker, which proves all types of mesothelioma and distinguishes them from pulmonary adenocarcinoma and renal carcinoma. [2, p. 662], [28, pp. 1-19]

Keratin 5/6

Very widely used to distinguish mesothelioma from lung adenocarcinoma or renal carcinomas, but more limited – in distinguishing from squamous cell lung carcinoma and breast carcinoma. [7, p. 140], [22, p. 150]

Podoplanin

Widely used to differentiate mesothelioma from lung adenocarcinoma and significantly less used for metastases of serous ovarian and squamous cell lung carcinomas. [13, p. 189], [28, pp. 1-19]

WT1 protein

Widely used in distinguishing epithelioid mesothelioma from lung adeno or squamous cell carcinomas. Good value for renal carcinomas, but hardly used in solving the dilemma mesothelioma/breast carcinoma or mesothelioma/lung adenocarcinoma. [32, p. 20], [10, p. 1217]

Thrombomodulin

Limited use in distinguishing mesothelioma from serous and mucinous lung adenocarcinomas. The results from various authors are contradictory from 60 to 100% sensitivity and specificity. It cannot be used to distinguish squamous cell lung carcinomas.

[17, p. 223], [8, p. 559]

Mesothelin

Limited use in distinguishing mesothelioma from adeno and squamous cell lung carcinomas, but also from renal carcinomas. This marker is with expressed sensitivity for mesothelioma and therefore can help a lot in cases of uncertain and doubtful results. The negative result indicates that the case is probably not a mesothelioma. [25, p. 192], [14, p. 838]

Table 3

Broad-spectrum positive carcinoma markers /negative for mesothelioma/

MARKER

COMMENTARY

MOC-31

Very widely used to distinguish MPM from lung squamous and adenocarcinomas, metastases of serous ovarian carcinomas and breast carcinomas. Malignant mesotheliomas express MOC-31 only in 2 to 15% of the cases. [28, p. 1-19], [26, p. 1407]

Ber-EP4.

Very widely used to distinguish mesothelioma from breast and lung carcinoma (serous adeno- and squamous cell carcinomas). It cannot be used to distinguish from renal carcinomas. It is equal in specificity and sensitivity to MOC-31. [26, p. 1412]

CEA

Widely used to distinguish mesothelioma from lung and breast carcinomas. It is not suitable to distinguish from serous ovary and renal carcinomas.

[33, p. 253], [17, p. 223]

CD15

Widely used to distinguish mesothelioma from metastatic renal carcinomas. Its application for distinguishing lung carcinomas is very limited.

[3, p. 237], [26, p. 1407]

Claudin-4

This marker still has a limited utility and there are only a few scientific publications on this issue. It can be used to distinguish mesotheliomas from lung, breast and renal carcinomas. [35, p. 250], [12, p. 669]

MUC4

The data on this marker is still limited but it is reported of the possibility to distinguish mesothelioma from lung adenocarcinomas. [29, p. 150], [9, p. 756]

Table 4

Organ—associated carcinoma markers /negative for mesothelioma/

MARKER

COMMENTARY

TTF-1

One of the most commonly used markers for distinguishing metastatic adenocarcinomas, which are 75-85% positive. It is not expressed in mesotheliomas and squamous cell lung carcinomas. [16, p. 1117], [27, p.429]

Napsin A

Very often used. 80-90% of lung adenocarcinomas, 40% of clear cell carcinomas and 75% of papillary renal carcinomas express this marker. It is not expressed in mesotheliomas and planocellular lung carcinomas.

[5, p. 163], [39, p. 313]

PAX 8

Very often used due to its expression in most renal carcinomas, serous ovarian carcinomas and thymic epithelial tumors. It is not expressed in mesotheliomas.

[29, p. 751], [19, p. 627]

PAX 2

Comparatively rarely used due to its similar expression as PAX 8, but strictly negative in mesothelioma [34, p. 494]

Mammaglobin

Often used to distinguish breast carcinomas /positive/ and totally negative in mesotheliomas. A highly specific and less sensitive marker. This gives reason to accept as true the reports for its uneven expression, which varies from 50 to 95%.

[37, p. 239], [3, p. 103]

CDX2

Very often used to distinguish metastases from gastrointestinal, biliary and pancreatic tumors. These adenocarcinomas are CDX2 positive. The mesotheliomas are negative in 100% for CDX2.

[38, p. 476]

Conclusions from the literature review:

The morphological diagnosis of MPM is difficult. The pleura is a place for metastasis of many malignant tumors from other organs, whose metastases are difficult to distinguish from MPM in a routine histological examination.
The differentiation of MPM from metastatic pleural tumors requires a biopsy and IHC examination. Since the occurrence of the first antibodies for this purpose, more than 25 years have passed, but even now the immunohistochemical examination panels are big, expensive and still not entirely reliable.
The most suitable tumor markers, positive for epithelioid mesothelioma are Calretinin (80-100%), D2-40 podoplanin (80-100%), WT1 (43-93%), CK5/6 (60-100%), Trombomodulin (50-90%), ЕМА (60-100%) and Mesothelin (65-85%). They are not expressed in other primary and metastatic pleural tumors or only very rarely.
First and most often it is required to distinguish the epithelioid mesothelioma from lung adenocarcinoma. The latter has the following positive immunohistochemical markers: СЕА (50-90%), CD15 (50–70%), Ber-EP4 (95–100%), TTF-1 (70–85%), Napsin A (70-80%).
The differential diagnosis of metastatic breast carcinoma is most easily performed with ЕR, which is never positive in mesotheliomas, whereas with breast carcinomas it has a 75% expression.
The differential diagnosis of metastatic ovarian tumors is performed with the positive carcinoma markers: MOC-31, Ber-EP4, PAX 8. Among the mesothelioma-positive markers, Calretinin seems most useful. Although this marker rarely but still can be expressed in serous ovarian carcinomas, its absence is a certain indication that it is not a case of mesothelioma.

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