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1. Diagnostic Specialties Laboratory, Bremerton, Washington 98310, USA.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: We report a series of 196 cases of pseudomesotheliomatous neoplasms identified in one of our laboratories between 1983 and 2015. We also performed an extensive review of the literature. Most "pseudomesotheliomas" arise in the pleural tissue of the chest cavity and resemble pleural mesotheliomas, macroscopically and histologically, although some metastasize to the pleura from another site or can metastasize to other parts of the body.
Methods: The criteria for inclusion as a pseudomesotheliomatous neoplasm were: 1) presentation of the tumor as a diffuse pleural neoplasm confirmed radiographically, by video-assisted thoracoscopy, by thoracotomy, or at autopsy; 2) lack of a tumor outside of the lung/chest cavity; and 3) the microscopic, histologic, histochemical, immunohistochemical, and/or ultrastructural features of the neoplasm other than a mesothelioma, or a neoplasm other than a mesothelioma that showed histologic, histochemical, immunohistochemical features of a specific neoplasm.
Results: Of the 196 patients in our series, 183 were primary in the lung, 2 were primary in the peritoneum, and 11 were metastatic from another site. One hundred thirty-four (68.3%) had a known history of exposure to asbestos (130 occupational and 4 bystander/paraoccupational). Six (6) had no history of exposure to asbestos; and in 56 cases, the exposure history was unknown. Of the 196 cases, 109 (55%) had a history of cigarette smoking, 23 were nonsmokers, and in 64 cases the smoking history was unknown. Of the 196 cases of pseudomesotheliomatous neoplasms arising in the lung/pleura and peritoneum, 134 (68.3%) had historical exposure to asbestos in the workplace or as a result of paraoccupational and/or bystander exposure; 100 (51%) had radiographic and/or pathologic evidence of pleural plaques or pathologically definable asbestosis; and 56 of 59 cases evaluated for ferruginous bodies and/or asbestos fibers had above background levels in digested lung tissues.
Conclusions: We conclude there is a relationship between the development of pseudomesotheliomatous lung cancer and asbestos exposure based on radiological/pathological findings (including tissue burden of ferruginous bodies and/or uncoated asbestos fibers) as correlated with a background history in many individuals within this study.
Keywords: Pseudomesotheliomatous lung cancer, asbestos, cigarette smoke, asbestosis, fiber analysis
The purpose of our article is to report on the clinical and pathologic features of pseudomesotheliomatous lung cancer and to determine if there is a causal relationship between asbestos exposure and/or cigarette smoking. Most cases of pseudomesotheliomatous lung cancer are diagnosed clinically as mesotheliomas, but when the tissue is further evaluated by histochemistry, immunohistochemistry, and/or electron microscopy, the pathologic findings indicate these tumors are not mesotheliomas but are, in fact, primary lung cancers or metastatic cancers growing in a distribution that macroscopically resembles mesothelioma. The criteria for including a case as a pseudomesotheliomatous neoplasm in our study were: 1) presentation of the tumor as a diffuse pleural neoplasm confirmed radiographically, by video-assisted thoracoscopy, by thoracotomy, or by autopsy; 2) lack of a tumor outside of the lung or chest cavity; and 3) the microscopic, histologic, histochemical, immunohistochemical, and/or ultrastructural features of the neoplasm other than a mesothelioma, or a neoplasm other than a mesothelioma that showed histologic, histochemical, immunohistochemical features of a specific neoplasm. Some pseudomesotheliomatous lung cancers represented metastatic cancers from a site outside of the chest that grew in a diffuse pleural distribution macroscopically mimicking a diffuse pleural mesothelioma. We also performed an extensive review of the literature concerning pseudomesotheliomatous lung cancers, which are summarized in Table 1 [1-40].
Table 1 : Summary of peer-reviewed journal articles of pseudomesotheliomatous neoplasms.
Tissue samples were evaluated in 196 individuals who were diagnosed as having pseudomesotheliomatous neoplasms (194 pleural; 2 peritoneal). These neoplasms were received during the normal course of business by Diagnostic Specialties Laboratory, Inc., P.S., Bremerton, Washington (laboratory of Samuel P. Hammar, M.D.) between 1983 and 2015. These materials were considered discarded at the time of our study. No name identifiers were used. Of the 196 cases, thirty (30) were medical consultation cases; fourteen (14) were surgical cases from Harrison Medical Center, Bremerton, Washington; and 152 were medico-legal cases which were sent to one of our laboratory's (SPH) for possible asbestos-related litigation. Most were subtypes of primary pulmonary adenocarcinoma and other non-mesothelial cancers. When indicated, histochemical studies were performed on 4 μm thick sections for Periodic acid-Schiff (PAS), PAS-diastase, mucicarmine, and Alcian blue with and without hyaluronidase according to standard techniques. Immunohistochemical studies were performed on paraffin embedded tissue, if available, according to standard techniques using the Ventana Bench Mark System®. Positive and negative controls were run for each test performed. Because these cases involved diffuse malignant pleural mesothelioma in the differential diagnosis, a combination of positive and negative markers were used for differentiating epithelial mesothelioma from primary pulmonary adenocarcinoma. The antigens most commonly used as positive markers for epithelial mesothelioma (negative markers for primary pulmonary adenocarcinoma) were calretinin, cytokeratin 5/6, cytokeratin 7, mesothelin, D2-40 (podoplanin), and HBME-1. The most commonly used positive markers for primary pulmonary adenocarcinoma (negative markers for epithelioid mesothelioma) were carcinoembryonic antigen (CEA), LeuM1 (CD15), thyroid transcription factor-1 (TTF-1), B72.3 and BerEP4. In the event that ultrastructural evaluation was required to aid in the diagnosis, tissue specimens were fixed in Trump's fixative and in some instances neutral buffered formalin. In rare instances, tissue was removed from paraffin blocks and processed for ultrastructural evaluation.
In cases where formalin-fixed autopsy tissue was available, 5-gram samples of peripheral lung tissue were cut into small pieces and completely digested in commercial bleach at Diagnostic Specialties Laboratory in Bremerton, Washington. After complete digestion, the bleach was carefully decanted and the sediment at the bottom of the container was carefully extracted with equal volumes of chloroform and 50% ethyl alcohol. This solution was transferred to a test tube, shaken vigorously, and centrifuged at 1200 revolutions per minute (rpm) for ten minutes. After removal of as much carbonaceous material as possible, the solution was re-centrifuged and the sediment at the bottom of the test tube was extracted in 95% alcohol and passed through a Millipore filter of 0.5 micrometer diameter pore size. Ferruginous bodies (morphologically consistent with the appearance of asbestos-cored ferruginous bodies) on the filter were then counted. In our laboratories (SPH, RFD), persons in the general population may have between 0-20 asbestos bodies per gram of wet lung tissue, which we consider to be background levels [41].
Formalin-fixed lung tissue from 20 cases was submitted to the Tyler laboratory (Ronald F. Dodson's laboratory) and prepared for evaluation via a digestion procedure using a modified bleach procedure [42]. The extensive findings from this evaluation were published in a companion manuscript [43]. A synopsis of the methodology used was: "Dry weights were calculated based on a dry/wet ratio obtained for each digestion pool. All reagents were pre-filtered through 0.2 μm pored polycarbonate filter prior to use in the digestion procedure. Control blanks of filters and solution blanks were prepared and evaluated to provide quality assurance within the laboratory. Aliquots of the digestate from each sample were collected on 0.22 μm pored mixed cellulose ester filter for quantitation of ferruginous body content of the tissue samples, while additional aliquots were collected on 0.2 μm pored polycarbonate filters and prepared for evaluation by Analytical Transmission Electron Microscopy (ATEM) for the determination of uncoated asbestos fibers and assessment of core materials of any ferruginous bodies found in the areas evaluated. The preparation of the mixed cellulose filters used for determination of ferruginous body content of the tissue consisted of mounting a wedge of each filter on a glass slide, exposing the filter to acetone vapor (making the substrate transparent) and evaluation of the 'cleared' surface at 100x with magnification increased to 400x via a light microscope if additional morphological clarification was desired. Structures conforming to the definition of a ferruginous body as seen by light microscopy were counted. The definition of such a ferruginous body included elongated/transparent central core and a rust colored beaded surface. The polycarbonate filters were prepared for ATEM analysis by a direct method involving collection of the digestate on the filter surface followed by carbon coating of the dried filter. The carbon coated filter was cut into strips and mounted on 100 mesh copper grids. A modified Jaffe-Wick method [44] was used to remove the filter matrix, leaving the carbon film containing the entrapped fibers, ferruginous bodies, and other particulates. Random areas on the grids were evaluated at 16,000x for uncoated fibers in a JEOL 100CX transmission electron microscope which was interfaced with an EDAX DX Prime X-ray analyzer. An additional scan of other areas on the grids was conducted at 1,600x for the presence of additional ferruginous bodies. A fiber as defined in the present study consisted of an elongated entity ≥0.5μm with parallel sides for a majority of its length and an aspect ratio of greater than 5:1. Uncoated fibers as well as the core material of ferruginous bodies were analyzed as to elemental composition by X-ray energy dispersive spectrometry (XEDS) and for crystalline structure by selected area electron diffraction (SAED)".
Approximately 90% of the cases received for evaluation by one of us (SPH) were thought clinically to have diffuse malignant pleural mesothelioma and two were thought to be peritoneal mesotheliomas. The most common clinical symptom was dyspnea on exertion. Other common symptoms included chest pain/discomfort, cough, weight loss, and fatigue. Less frequent symptoms included abdominal pain/ distention, back pain, shoulder pain, fever, weakness, and anorexia. Many patients exhibited more than one symptom. The most frequent radiographic changes included pleural thickening/nodularity and a unilateral pleural effusion that often re-accumulated rapidly. Following pathologic evaluation by one of us (SPH), one-hundred eighty three (183) of the 196 cases were determined to be primary in the lung; 2 were primary in the peritoneum; and 11 were metastatic to the lung from another site (kidney-4; skin-3; mouth/tongue-2; Mullerian origin-1; and possibly larynx-1). Of the 196 cases, 173 were males, 21 were females, and in 2 cases the sex was unknown. The age-range was between 23 and 96 years with a mean age of 62.89 years.
A summary of the 196 cases evaluated in our laboratory (Diagnostic Specialties Laboratory, Inc. P.S.) is shown in Table 2. The various histologic types identified in our cases are shown in Table 3. The macroscopic and ultrastructural features of a pseudomesotheliomatous pulmonary adenocarcinoma are shown in Figures 1-5.
Table 2 : Case summary of 196 cases of pseudomesotheliomatous neoplasms.
Table 3 : Histologic types of 196 pseudomesotheliomatous carcinomas.
Figure 1 : This tumor has the macroscopic features of a pleural mesothelioma, being encased by a rind of tumor that when examined microscopically had features of a primary pulmonary adenocarcinoma.
Figure 2 : Cross-section of pseudomesotheliomatous pulmonary adenocarcinoma.
Figure 3 : This pseudomesotheliomatous adenocarcinoma surrounds the heart and lung.
Figure 4 : Ultrastructural evaluation of this pseudomesotheliomatous adenocarcinoma of lung shows short microvilli and a fuzzy glycocalyx.
Figure 5 : Ultrastructural evaluation of a pleural epithelioid mesothelioma showing long, sinuous microvilli that are not covered by glycocalyx.
One hundred thirty-four patients (68.3%) had a known history of exposure to asbestos (130 occupational and 4 bystander/paraoccupational); six (6) had no history of exposure to asbestos; and in 56 cases, the exposure history was unknown. It should be stated that in 6 cases where the occupational history was known (painter; welder in a steel mill; digester cooker in a pulp/paper mill; shipyard worker-2 cases; and crew boat captain/welder/fisherman) but the asbestos exposure history was stated to be "unknown," one has to wonder if there was possible exposure to asbestos based on their occupation/job title. Of the 62 cases where there was no known history or an unknown history of asbestos exposure, 25 (40.3%) had either pathologic or radiographic markers of asbestos exposure, e.g., pleural plaques, asbestosis, and/or ferruginous bodies/asbestos fibers in lung tissue.
Pleural plaque characteristic of plaque caused by asbestos was identified in 89 cases (56 pathologically, 12 radiographically, and 21 both pathologically and radiographically). Forty-six (46) cases had pathologically definable asbestosis (CAP-NIOSH 1982). Radiographic asbestosis was identified in 4 cases and 1 had probable asbestosis.
A total of 59 cases were evaluated in the laboratory of one of us (Samuel P. Hammar, M.D.) for ferruginous bodies that were morphologically characteristic of asbestos bodies (5 by iron stained sections and 54 using quantitative asbestos digestion analysis). In addition, asbestos fiber analysis was performed in Dr. Ronald F. Dodson's laboratory on 24 cases. These cases were evaluated using standardized techniques as described in the Materials and Methods section. Results are shown in Table 4. By quantitative asbestos digestion analysis, 47 of 54 cases had above background levels (over 20 ferruginous bodies per gram wet lung tissue) in at least one or more lobes of lung. It should be noted that in 4 cases where the results fell below background levels (20 or less ferruginous bodies per gram wet lung tissue in our laboratory), when fiber analysis was performed, those same four cases showed background levels at the upper limits of levels found in general populations (see cases #160, 163, 164, and 165) and often the burden in one lung would greatly exceed the average found in the general studies conducted by one of us (RFD). This illustrates that asbestos fibers are not evenly distributed in the lungs. Of the 20 cases studied by analytical transmission electron microscopy (ATEM) in the laboratory of Ronald F. Dodson, Ph.D., for ferruginous bodies and uncoated fibers [43], 19 cases contained tissue burden of asbestos in at least one of the lung samples in appreciable excess of the average background levels found in the general population studies [41,45]. The numbers of asbestos bodies identified in the right lung versus the left lung also varied, which further illustrates that asbestos fibers are not evenly distributed in the lungs.
Table 4 : Asbestos digestion and fiber analysis results.
Of the 196 cases, 109 (55.6%) were cigarette smokers, 23 (11.7%) were nonsmokers, and in 64 cases the smoking history was unknown. Of the 109 patients who were known smokers, 61 had a greater than 20-pack year history of cigarette smoking.
Pseudomesotheliomatous lung cancers are rare neoplasms, most of which are primary pulmonary carcinomas that macroscopically grow like diffuse pleural mesotheliomas. Some insist that only tumors growing in a pleural distribution in which there are no primary lung masses (tumors) be included as pseudomesotheliomas, although others would accept cases where the tumor is growing predominantly in a pleural distribution in which a mass in the lung exists which may be the source of the predominantly pleural tumor.
The most frequent forms of adenocarcinoma are mucinproducing, tubulodesmoplastic, acinar, and poorly differentiated. Less common adenocarcinomas include signet ring adenocarcinoma, adenocarcinoma of type 2 pneumocyte origin, and adenocarcinoma with a papillary/micropapillary morphology. Other primary carcinomas involving the lung and which may grow like a diffuse pleural mesothelioma include adenosquamous carcinoma, squamous cell carcinoma, deciduoid carcinoma, and rhabdoid carcinoma. Other rare/ unusual types of neoplasms that grow in a diffuse pleural distribution include metastatic melanoma, calcifying fibrous tumors of the pleura, small cell lung cancer, hemangioendothelioma, metastatic renal cell carcinoma, sarcomatoid carcinoma, basaloid carcinoma, and metastatic squamous cell carcinomas from the larynx and mouth, as well as combined adenocarcinomas and mesothelioma.
The primary differential diagnosis of pseudomesotheliomatous lung cancers include epithelial mesothelioma, sarcomatoid mesothelioma (sarcomatoid cases), and biphasic sarcomatoid mesothelioma. Also in the differential diagnosis is metastatic carcinoma from a site outside the chest and rare sarcomas that grow in a pleural distribution, such as synovial sarcomas. As shown in our report, the majority of pseudomesotheliomatous cancers are primary lung cancers; specifically, adenocarcinomas. Just as there is a wide range of variation of primary adenocarcinomas of the lung, there is also a wide variation of pseudomesotheliomatous adenocarcinomas of the lung. Pseudomesotheliomatous lung cancers can also metastasize to other parts of the body, including regional lymph nodes, opposite lung, liver, bone, and brain.
Pseudomesotheliomatous lung cancers usually present with the same signs and symptoms as diffuse pleural mesothelioma. Pleural effusions are common in both pseudomesotheliomatous lung cancers and pleural mesotheliomas. Pleural fluid can be evaluated for malignant cells using cytologic, histochemical, immunohistochemical and ultrastructural techniques. The same immunohistochemical analyses can be performed on cell block specimens. Electron microscopy can easily be performed on cytocentrifuged specimens.
The immunohistochemical features that characterize primary lung adenocarcinomas also characterize pseudomesotheliomatous adenocarcinomas. In addition, the ultrastructural features of pseudomesotheliomatous adenocarcinomas are those of a primary pulmonary adenocarcinoma; namely, a neoplasm that shows short microvilli with prominent glycocalyceal bodies, rootlets, and intracellular or extracellular mucin production. With respect to mucin production, one has to remember that epithelial mesotheliomas can show histochemical staining for PAS-diastase, mucicarmine, and Alcian blue/colloidal iron. Epithelial mesotheliomas that express mucin are usually ones that show extracellular crystalloid structures. The mucin positivity of epithelial mesotheliomas is thought to be related to hyaluronic acid production. It should also be pointed out that primary pulmonary adenocarcinomas and pseudomesotheliomatous adenocarcinomas of the lung can show expression of acidic mucous substances with the colloidal iron and Alcian blue stain that is resistant to hyaluronidase digestion.
Most people in the scientific community who are familiar with pseudomesotheliomatous neoplasms have come to the conclusion that most are made up of cells that form the chest cavity. One issue is where do the cells come from that form the pseudomesotheliomatous lung cancers? The answer to that is not precisely known, although some speculate these neoplasms come from lung tissue that is present in the lung, including bronchi, bronchioles, and alveoli. Some speculate that these cells come from the lung and penetrate through the lung and into the visceral and parietal pleura where they form neoplasms that resemble mesotheliomas, although they are actually formed by epithelioid cells in the lung. Another theory is that some cases of pseudomesotheliomatous lung cancers come from pleural tissue that contains structures such as epithelioid cells and cells that form squamous epithelial cells. In studying pseudomesotheliomatous lung cancers, most come to the conclusion based on the evidence available that the majority of pseudomesotheliomatous lung cancers are adenocarcinomas that directly invade the pleura and many are associated with a marked desmoplastic reaction.
There is some controversy as to whether scarring causes the cancer or whether the scarring already existed, such as scarring from tuberculosis or some other type of inflammatory condition. At this point in time, most scientists would state that, in most instances, the scarring that is associated with pseudomesotheliomatous lung cancers is not pre-existing but is actually caused by the tumor itself. That is also the case with most cancers; e.g., it is thought that the scarring in breast cancer is caused by the tumor and not by some pre-existing condition.
As shown in our case series, there appears to be a causal/historical link between persons exposed to asbestos and the development of pseudomesotheliomatous lung carcinomas, just as there is a link between asbestos and primary pulmonary carcinomas, mesothelioma, and other asbestos-related cancers. We conclude that when we evaluated asbestos as a potential cause in these cases of pseudomesotheliomatous neoplasms, correlation with asbestos-related changes or actual presence of biological markers of past exposure indicated a link between the development of this unique tumor and exposure to asbestos in most cases within the study. In the case of pseudomesotheliomatous lung carcinomas, there also appears to be a causal link to cigarette smoking in that 109 patients (55%) had a known history of cigarette smoking, although in 64 cases the smoking history was unknown. This causal relationship is not surprising in that most cases were primary pulmonary adenocarcinomas, which is a recognized cancer caused by cigarette smoke carcinogens. Furthermore, the combination of asbestos exposure and smoking is recognized to result in a synergistic effect on the risk for development of a lung cancer.
The authors declare that they have no competing interests.
| Authors' contributions | SPH | RFD |
| Research concept and design | √ | √ |
| Collection and/or assembly of data | √ | -- |
| Data analysis and interpretation | √ | -- |
| Writing the article | √ | √ |
| Critical revision of the article | √ | √ |
| Final approval of article | √ | √ |
| Statistical analysis | √ | √ |
We wish to thank Michaele Stoll for her editorial and research skills, which enabled us to finalize the complex data presented in this manuscript. We also wish to thank Teresa Bair and Hector Hallman for their assistance.
Editor: Jae Y. Ro, Houston Methodist Hospital, USA.
EIC: Markus H. Frank, Harvard Medical School, USA.
Received: 04-Jun-2015 Final Revised: 24-Jul-2015
Accepted: 14-Aug-2015 Published: 25-Aug-2015
Copyright © 2015 Herbert Publications Limited. All rights reserved.
