Summary
The claimant was diagnosed in 2023 with mesothelioma, after attending his general practitioner complaining of shortness of breath. Initially, the treating hospital considered he was suffering from lung cancer but later, after further consideration, they revised their diagnosis to mesothelioma. The court found that when the expert for the claimant suggested molecular testing, he was seeking to explore the possibilities of resolving the diagnosis, while the court was troubled by the defedant's expert's view that it was not necessary to go on to consider molecular testing when the results of the immunohistology were available.
Learning points:
Case
In this case breach of duty was admitted and the sole issue was causation, more properly diagnosis.
The claimant was a painter and decorator who worked for the local authority in Sunderland for the whole of his working life. He was also a heavy smoker. He is now 66 years old. He was diagnosed in 2023 with mesothelioma, after attending his general practitioner complaining of shortness of breath. Initially, the treating hospital considered he was suffering from lung cancer but later, after further consideration, they revised their diagnosis to mesothelioma. He was treated with immunotherapy which has had a positive outcome but as there is no cure for mesothelioma, there will come a time when his condition deteriorates, and the illness will become terminal.
Issue
The issue on diagnosis was whether Mr McNally had proved, on the balance of probabilities, that the disease from which he is suffering is mesothelioma. It was agreed that if the court found that Mr McNally is suffering from mesothelioma, then he would recover damages of £250,000. If he has not, then the claim would be dismissed. The options were binary, either Mr McNally is suffering from mesothelioma or lung cancer. Other cancers have been considered by the experts and excluded.
Dr Moore-Gillon, the distinguished respiratory physician, stated in his report that this was the most difficult case that he ever had to consider in his long career as an expert on mesothelioma. He concluded that he was not satisfied that the medical evidence proved that Mr McNally was suffering from mesothelioma. Professor A, histopathologist, considered that Mr McNally is suffering from lung cancer. Dr Rudd, an equally eminent respiratory physician, considers that Mr McNally is suffering from mesothelioma. Professor N, histopathologist, also considers that this is a case of mesothelioma. The respiratory physicians agreed that the outcome of this case would depend upon which histopathologist's evidence which the court accepted.
The case turned on the test results in histopathology and molecular analysis. The court had to reconcile the results of the immunohistochemistry and molecular analysis to arrive at a conclusion.
Literature
From the literature provided, the court could see that it is well-recognised that cases of primary lung cancer can closely mimic cases of malignant pleural mesothelioma clinically. The court observed that in one paper, where Professor A was the lead author, it said in 2003 that Calretinin is the most reliable specific marker for malignant mesotheliomas. It cautions that tumour misdiagnosis may have medicolegal implications in asbestos-related claims. Ae Ri An et al have published a paper (2020) in which they said: "the tumour growth pattern makes it difficult to differentiate PLC [lung cancer] from MM [mesothelioma] based on radiologic findings and histologic confirmation is needed. IHC [immunohistochemistry] provides an adequate sensitivity and specificity for distinguishing PLC from MM." It goes on to refer to the absence of reports of genetic alterations in PLC. Dagogo-Jack et al have published a paper (2022) in which they recorded that the following genes were altered in MPM [malignant pleural mesothelioma]: CDNK2A 49%. BAP1 44%, MTAP 34% and NF2 33%. Table 1 broke the cases down into epithelioid and nonepithelioid cases of mesothelioma. The research confirmed that the mesothelioma somatic mutational landscape is largely defined by inactivation of tumour suppressor genes. Epithelioid mesothelioma is one of three types of mesothelioma. The court was not concerned with the other two.
Before turning to the evidence, there was an issue between the pathologists as to how the court should treat the molecular analysis. Professor A's position was that the Guidelines for Pathologic Diagnosis of Mesothelioma 2023 Update (published November 2024) set out the appropriate testing to be undertaken for a diagnosis of mesothelioma.
In the RCP Standards and Datasets for Reporting Cancer, (March 2024), two of the four authors were Professor N and Professor A. The foreword said that those guidelines were developed for the most common circumstances and recognised that they: "cannot anticipate every pathological specimen type and clinical scenario. Occasional variation from the practice recommended in this guideline may therefore be required to report a specimen in a way that maximises benefit to the patient."
Later in the paper, under Considerations for Microscopy the guidelines state that: "The distinction between EM [Epithelioid mesothelioma] and MAC [lung cancer] cannot be made with confidence on morphological grounds alone and immunohistochemistry is mandatory. Currently, no single antigen indicative of mesothelial or adenocarcinoma differentiation is sufficiently sensitive or specific, so a panel is recommended." It also refers to referral to regional or national experts in complex and difficult cases.
The Guidelines for Pathologic Diagnosis of Mesothelioma (November 2024), where again Professor N and Professor A are named as authors, relate primarily to immunohistochemistry but also refer to molecular assays. The evolving role of diagnostic molecular assays is addressed, where it states: "regardless of site, a diagnosis of mesothelioma should always be based on compatible morphologic and immunohistochemical results obtained from an adequate tissue sample. … a history of asbestos exposure should not be taken into consideration by the pathologist when confirming or excluding mesothelioma. Molecular studies might be necessary in a minority of cases."
The Guidelines state that: "Since none of these markers are perfectly sensitive or specific, it is recommended that, in addition to broad spectrum cytokeratin, 2 mesothelial and 2 epithelial markers be included in a first line immunopanel to establish mesothelial lineage. If the results are concordant, the diagnosis can be considered established. If discordant, the immunopanel can be expanded for a second round of staining …".
The Guidelines go onto state that: "in the authors experience, Claudin-4 is sufficiently reliable to serve as the sole epithelial marker in most differentials. It states: "Tables 1 and 2 list markers that are useful in distinguishing epithelioid pleural mesothelioma from adenocarcinoma and squamous cell carcinoma of the lung ….".
In a section on Molecular Sequencing In Routine Diagnosis And Management, it refers to the potential for tumour profiling to provide diagnostic, prognostic and therapeutic information in a single assay. It states that: "at present routine genomic sequencing of mesotheliomas is performed only in select referral or academic centres and it is not currently recommended for routine clinical use. Immunohistochemical studies remain the ancillary assay of choice, with targeted molecular studies … in select cases".
The Guidelines conclude that: "Molecular studies … are useful in challenging cases with nondiagnostic morphologic and immunophenotypic findings. Importantly the pathologist must always correlate morphology and ancillary findings with clinical, radiographic and operative findings". They finish by referring to the rapid evolution in the field of mesothelioma diagnosis.
There were also two further papers which consider the relationship between NF2 and BAP1. I refer to the Fanaroff paper (2025), where it states that: "Immunohistochemistry is widely available for the detection of the most frequent molecular alterations in DPM including BAP1, MTAP, NF2 and TP53 and may be used in resource limited settings where molecular testing is not available.". The paper concludes that: "the findings of this study suggest that histologic features and molecular findings can be complementary in providing prognostic information for patients with pleural mesothelioma."
The histopathologists agreed that molecular analysis is part of a developing science, however, the difference between them was that Professor A did not accept that there was sufficient provenance for a more general application for use in diagnosis. They were agreed that the facilities to carry out molecular analysis would only be found in large tertiary hospitals and regional centres.
It seemed to the court that the molecular analysis in this case should be treated as adding to the sum of knowledge which is available for the purposes of the differential diagnosis. It was not suggested that there is any inaccuracy with the results of the molecular analysis carried out in this case. Professor N drew the distinction between the histology which tested for proteins and the molecular analysis examining the genes, which, in fact cause the cancer. In the court’s view, once that analysis had been undertaken, it would be artificial to disregard the results. It had, however, to be given proper weight as part of the collective information that had been obtained.
The molecular analysis showed that NF2 was inactive, which it is in 40% of mesothelioma cases. The pathologists were agreed that based on the molecular analysis alone, the probable diagnosis is mesothelioma. There is, however, a stark difference between the NF2 and Claudin-4 test results. Claudin-4 has a 99% specificity and is positive for lung cancer. Each being the highwater mark of the parties' respective cases. It was, therefore, necessary to examine the tests which were undertaken. The other histopathology and molecular results were not conclusive.
The results
In summary, the immunohistology produced positive results in Claudin-4 testing at Cardiff, which was not undertaken at Brompton. The CEA, TTF-1, Napsin A tests were negative at all hospitals, The MOC-31 test was positive at Cardiff. The BER-EP4 tests were positive at all hospitals. The Cytoplasmic Mucin test was positive at Freeman. The BAP 1 and MTAP were non-mutated at Cardiff and not inactivated at Brompton. It followed that, if Mr McNally's disease is epithelioid mesothelioma, he would fall within a very small percentage of cases, where the result of the Claudin-4 was positive. The results of the tests in MOC31, BER EP4, Cytoplasmic Mucin, BAP1 and MTAP would also support that he has lung cancer.
The support for epithelioid mesothelioma came in immunohistology from the Calretinin test. The result of the tests at the Freeman Hospital were cytoplasmic + nuclear (occasional cells) weak staining, at Brompton and Cardiff, isolated cell positivity. And the Cytokeratin tests where the results were positive at the Freeman Hospital, (occasional cells), and uncertain at Brompton and Cardiff. The WT-1 and D2-40 test was negative.
The molecular testing showed that NF2 was mutated, CDKN2A/B and TP53 were also mutated. The other molecular tests, ALK, KRAS, and MET were not mutated.
Expert evidence
The joint statement of Professor N and Professor A set out the issue the court had to decide in these terms:
"[Professor N] places greater reliance on the tumour mutational profile. He is of the opinion that the molecular analysis changes the balance of probability, as NF2 mutations (~30% versus ~2%) (https://www.cbioportal.org, PMID: 35704798, 39788204, 34580349) and, to a lesser extend CDKN2A mutations, are more frequently seen in mesothelioma than NSCLC. In the context of a primarily pleural presentation of disease, Professor N is of the opinion that the molecular profile favours mesothelioma on the balance of probabilities."
"[Professor A] places greater reliance on conventional diagnostic modalities which have been fully validated. He recognises the evolving role of molecular analysis in diagnostics although considers that presently for mesothelioma, as a diagnostic tool, it is insufficiently validated and does not overturn a diagnosis concluded using conventional diagnostic methods as listed above. He remains in favour that Mr McNally has contracted NSCLC and not pleural epithelioid mesothelioma, on the balance of probabilities."
The court was impressed by all four experts and fully accepted that they were all seeking to assist the court. Dr Rudd and Dr Moore-Gillon have considerable experience in mesothelioma cases and recognise the complexities of this particular case, as indeed do both Professor N and Professor A.
In the court’s view, there was a difference between Dr Rudd and Dr Moore-Gillon as to how they had expressed their opinions.
Dr Rudd was satisfied that Mr McNally is suffering from mesothelioma. Indeed, at the outset when he prepared his first report, he did not consider that the diagnosis was likely to be disputed. A diagnosis of mesothelioma had already been reached by Dr Jones, the treating oncologist, and the other members of the MDT in October 2023. Dr Rudd accepted, however, that the radiology, which pointed to mesothelioma was not conclusive, and could only be seen as part of the material available. He, ultimately, deferred to the opinion of Professor N, whilst maintaining his own opinion that this was a case of mesothelioma.
Dr Moore-Gillon's opinion was more nuanced in favour of lung cancer. He recognised the finely balanced nature of this case. Albeit that he came down on the side of lung cancer, the impression from both his report and oral evidence was that he did not believe that the case for mesothelioma had been proved, which was, of course, a decision for the court.
The court was impressed by the evidence given by Professor N, who was less familiar with giving evidence than Professor A. His evidence was refreshingly candid, thoughtful, and considered in its delivery. The court rejected the suggestion made to him in cross-examination that he was departing from his duties as an expert and seeking to promote Mr McNally's case. The court found that when he suggested molecular testing, he was seeking to explore the possibilities of resolving the diagnosis. The court was troubled by Professor A's view that it was not necessary to go on to consider molecular testing when the results of the immunohistology were available. There might be comfort in that conclusion in clearcut cases, however, all the experts were agreed that this was not such a case. They recognised the difficulty in diagnosis.
The court was not satisfied that Professor A engaged sufficiently with the results of the molecular testing, once obtained. The court did not accept his criticism that molecular testing in mesothelioma cases is not sufficiently validated to be relied upon. Where it has been obtained, and there is no criticism of the results themselves, then, it forms part of the material, which is before the court in reaching an opinion as to whether Mr McNally is suffering from mesothelioma or lung cancer. The court accepted Professor N's evidence that the role of molecular testing has evolved rapidly in the past three years since the guidelines were written in 2023.
Nevertheless, the court had to reconcile the result of the molecular testing with that of the Claudin 4 test. The court concluded that Mr McNally is one of those very rare individuals who come within a very small percentage of cases where the positive result is not indicative of lung cancer. In reaching that decision the court considered the totality of the immunohistology and molecular results, particularly NF2, and to a lesser extent CDKN2A/B and TP53, which are both less conclusive. It seems that the results in the tests in Calretinin and Cytokeratin were not sufficiently certain to be relied upon. It also seemed that the radiology, pointing towards mesothelioma, is a relevant consideration. Finally, the court did not place significant weight on the opinion of Dr Jones and the treating consultants, that this is a case of mesothelioma, it was, however, another piece in this complex jigsaw that fits with a diagnosis of mesothelioma.
Accordingly, the court concluded, on the balance of probabilities, that Mr McNally is suffering from mesothelioma and, in those circumstances, the claim succeeded.
References
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Attanoos, R L, Gibbs, A R (2003) ‘Pseudomesotheliomatous’ carcinomas of the pleura: a 10-year analysis of cases from the Environmental Lung Disease Research Group, Cardiff Histopathology 43(5)
Dagogo-Jack I, Madison RW, Lennerz JK, Chen KT, Hopkins JF, Schrock AB, Ritterhouse LL, Lester A, Wharton KA Jr, Mino-Kenudson M, Danziger N, Hung YP, Mata DA, Ross JS. Molecular Characterization of Mesothelioma: Impact of Histologic Type and Site of Origin on Molecular Landscape. JCO Precis Oncol. 2022 Jun;6:e2100422. doi: 10.1200/PO.21.00422. Erratum in: JCO Precis Oncol. 2022 Aug;6:e2200389. doi: 10.1200/PO.22.00389. PMID: 35704798.
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Royal College of Pathologists Standards and datasets for reporting cancers: Dataset for the histopathological reporting of mesothelioma, March 2024.