Context.—The International Collaboration on Cancer Reporting is a not-for-profit organization formed by the Royal Colleges of Pathologists of Australasia and the United Kingdom; the College of American Pathologists; the Canadian Association of Pathologists–Association Canadienne des Pathologists, in association with the Canadian Partnership Against Cancer; and the European Society of Pathology. Its goal is to produce common, internationally agreed upon, evidence-based datasets for use throughout the world.
Objective.—To describe a dataset developed by the Expert Panel of the International Collaboration on Cancer Reporting for reporting malignant mesothelioma of both the pleura and peritoneum. The dataset is composed of “required” (mandatory) and “recommended” (nonmandatory) elements.
Design.—Based on a review of the most recent evidence and supported by explanatory commentary.
Results.—Eight required elements and 7 recommended elements were agreed upon by the Expert Panel to represent the essential information for reporting malignant mesothelioma of the pleura and peritoneum.
Conclusions.—In time, the widespread use of an internationally agreed upon, structured, pathology dataset for mesothelioma will lead not only to improved patient management but also provide valuable data for research and international benchmarks.
Evidence-based, structured (synoptic) pathology reports with standardized definitions for each component have been shown to significantly enhance the completeness and quality of data provided to clinicians.1–4 During the past 2 decades, the United Kingdom,5 the United States,6 and other countries7 have produced standardized cancer reporting protocols or “datasets” for national use. Other minimum or comprehensive datasets have been developed around the world for reporting of a variety of cancers on an individual or institutional basis.
In 2011, the International Collaboration on Cancer Reporting (ICCR) was convened with a view to reducing the global burden of cancer dataset development and reduplication of effort by the different international organizations engaged in the development of standardized cancer-reporting datasets. The ICCR datasets are made freely available for use by organizations globally, and it is anticipated that, in time, this will enable the alignment and normalization of pathology cancer data around the world as producers of datasets adopt and incorporate the ICCR datasets.
To date, the ICCR collaboration has successfully published 5 datasets on cancers of the prostate, endometrium, lung, ovarian/fallopian tube/primary peritoneal sites, and malignant melanoma. All datasets are evidence based, have been produced by a panel of internationally renowned experts, have been subject to international open consultation, and are freely available for worldwide use at the following Web site: http://www.iccr-cancer.org (accessed February 19, 2016). The process of production for each of these datasets has been published in peer-reviewed journals.8–12
The ICCR datasets are designed to be as concise as possible to encourage uptake, facilitate future translation, limit the burden on reporting pathologists, and avoid jurisdictional pitfalls through the exclusion of nonessential information.
Given the interdependence of cancer datasets with the World Health Organization (WHO) Classification of Tumors, the ICCR has undertaken to develop datasets in synchrony with the update of the WHO classifications. In 2015, WHO released the fourth edition of its WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart.13 As a result, the ICCR commenced development of a series of thoracic datasets, including a dataset for malignant mesothelioma.
METHODS
Standardized cancer reporting protocols or “datasets” have been produced for national use for many years.5–7 Perforce, these datasets use the same peer-reviewed evidence as the basis of these protocols; however, each is constructed differently, uses different terminology, and similar elements may be based on different methodologies.
The adoption of a single international reporting standard avoids duplication of cancer pathology data-set development in many different jurisdictions, which reduces the burden on each country and improves opportunities for interoperability, international comparison, and research.
The ICCR conducted a pilot project in 2011 to standardize the initial 4 cancer datasets for lung, melanoma, prostate (radical prostatectomy), and endometrial carcinoma. By using different development processes for this initial collaboration, the ICCR has been able to optimize the development method for all further dataset efforts, as documented in the Guidelines for the Development of ICCR Datasets (http://www.iccr-cancer.org/datasets/dataset-development; accessed February 19, 2016).
For the construction of the mesothelioma dataset, a chair was selected by the ICCR Dataset Steering Committee, and a Dataset Authoring Committee (DAC), composed of pathologists with expertise in mesothelioma and one clinician, was then empanelled. The DAC also included an ICCR representative whose role was to provide guidance and support to the chair of the DAC regarding ICCR standards and committee participation and to undertake a quality-assurance role within the committee. A project manager was also appointed to streamline and standardize the data-set development process, reduce individual pathologists' time and effort, expedite the development timeline, and ensure implementation of, and adherence to, ICCR standards.
The dataset is composed of 2 types of elements: required and recommended. Required elements are defined as those that are unanimously agreed upon by the panel to be essential for the histologic diagnosis, clinical management, staging, or prognosis of mesothelioma. Recommended elements are nonmandatory and are defined as clinically important and recommended as good practice, which should ideally be included in the report but which are not yet validated or regularly used in patient management. Evidentiary support at level III-2 or above (based on prognostic factors in the National Health and Medical Research Council levels of evidence document and defined as “analysis of prognostic factors amongst persons in a single arm of a randomized controlled trial”)14 is required to support required (mandatory) elements. Rarely, where level III-2 evidence is not available, an element can be categorized as required with unanimous agreement of the Expert Panel. Required elements are mandatory, and the sum of these is the minimum information that should be included on the pathology report.
Commentary—that is, explanatory text, diagrams, or tables—is added where necessary to clarify the elements: to define the way an item should be reported, to ensure clarity and conformity, to explain why an item is included (eg, how an item assists with clinical management or prognosis of the specific cancer), to cite published evidence in support of the element, and to state any exceptions or issues that may be encountered by the reporting pathologist. Commentary is designed to provide contextual guidance to the reporting pathologist.
As a starting point, a search for all published mesothelioma datasets was undertaken. This scan included review of datasets from existing ICCR members and also of datasets, protocols, or checklists published in review articles or other international Web sites. This information formed the foundation for a comparative review, from which elements that are mandatory, required, or core in any one or more of these datasets was extracted for consideration by the DAC, along with all responses and commentary.
A proposed dataset was developed and circulated to the DAC for their initial thoughts. This initial feedback from the group enabled the chair to determine areas of concordance and dissent before a series of Web/teleconference discussions with the DAC regarding the proposed dataset.
Following agreement of the draft datasets by the DAC, the dataset was posted to the ICCR Web site for a period of 2 months for public comment. All feedback was reviewed, and final edits made.
RESULTS
Scope
The initial scope of the dataset was for resection specimens for malignant mesothelioma of the pleura. However, upon consideration, this was expanded to include peritoneal, as well as pleural, lesions because peritoneal mesothelioma had more in common with pleural mesothelioma in behavior and treatment than it did with gynecologic malignancies.
After the initial feedback from the DAC, a proposal to expand the scope to include biopsy specimens was discussed and agreed upon. A detailed review of biopsy for mesothelioma has recently been published.15
Required Elements
The required elements are shown in Table 1.
Operative Procedure
Documentation of the operative procedure is useful because correlation of the type of procedure with the material received can be important for patient safety. In resection specimens, the type of surgical procedure is important in determining the assessment of surgical margins.
Because of advanced age, clinical status, or extent of disease, few patients with mesothelioma are suitable for extrapleural pneumonectomy or radical pleurectomy/decortication; therefore, diagnosis is usually based on biopsy alone. Although the volume of tissue sampled is more restricted than it is for surgical resection specimens, biopsy assessment may contribute significant observations for clinical management and prognosis, in addition to the crucial distinction between secondary tumors affecting the serosal membranes and mesothelioma and between mesothelioma and benign-reactive mesothelial proliferations.
The type of biopsy is important because it affects the extent to which a diagnosis may be made with any certainty. Accurate typing of mesothelioma16–19 has been shown to vary by procedure—83% for open biopsy compared with 74% for video-assisted thoracoscopic surgery biopsy, and 44% for computed tomography–guided biopsy, when compared with the subtype assessed in a follow-up series of 83 extrapleural pneumonectomy specimens.19
Specimens Submitted
Specimen type varies according to the type of operation, and although the nature of the specimens submitted for pathologic assessment may be deduced from the procedure, specifying the nature of the specimen received provides complementary information and confirmation that an entire organ or organs have been resected and submitted.
Macroscopic Tumor Site
The macroscopic site of the tumor is an important component for pathologic staging.
Histologic Tumor Type
The major histologic tumor types of malignant mesothelioma, as recognized by the WHO classification (4th edition),13 are epithelioid, sarcomatoid, and biphasic or mixed. By convention, a biphasic mesothelioma is diagnosed if the lesser component reaches 10% of the tumor examined.
There are a number of histologic patterns of malignant mesothelioma that are important, primarily because of diagnostic confusion. For epithelioid mesothelioma, these include common patterns, such as solid, tubulopapillary, and trabecular, and less-common forms, such as micropapillary, adenomatoid (microcystic), clear cell, transitional, deciduoid, small cell, and pleomorphic mesothelioma. At present, there is no uniformity among pathologists for the definition of many of these patterns, and there is no clear prognostic significance to most of them; therefore, we do not recommend these names be included as part of a diagnosis—their importance lies in recognition by the pathologist that these are patterns seen in mesotheliomas.
For sarcomatoid mesothelioma, these histologic variants may comprise heterologous (osteosarcomatous, chondrosarcomatous, and rhabdomyosarcomatous) elements and desmoplastic mesothelioma. Desmoplastic mesothelioma is characterized by atypical spindle cells and dense, hyalinized fibrous stroma, the latter comprising at least 50% of the tumor.20
The conventional immunohistochemical panel of markers may require modification with some of these patterns to prevent misdiagnosis. Some of these patterns may have prognostic significance; however, until these prognostic patterns are clearly defined and accepted, the current recommendation is to diagnose mesotheliomas as epithelioid, sarcomatoid/desmoplastic, or biphasic/mixed, particularly because radical surgical approaches depend on these general classifications.
In some cases, such as small biopsy specimens, a definitive tumor type cannot be assigned, and in this situation, a value of “mesothelioma, not otherwise specified” would be used.
Margin Status
In extrapleural pneumonectomy specimens, the bronchial resection margin status is evaluated by intraoperative frozen section examination. In the surgical pathology specimen, the soft tissue margin status is difficult to assess because the entire pleura represents a margin. Usually, in patients with extrapleural pneumonectomy, the surgeon is performing a blind dissection beneath the endothoracic fascia between the pleura and chest wall.
Extent of Invasion
Extent of invasion is part of staging for radical pleural surgical specimens. In biopsies, the presence of invasion is the most important parameter for separating benign from malignant mesothelial proliferations.
Invasion into the endothoracic fascia is a staging parameter and should be determined only by the surgeon or radiologist because there are no characteristic pathologic features appreciable by gross or microscopic examination.
The endothoracic fascia represents a connective tissue plane that lies between the parietal pleura and the innermost intercostal muscle. Its histology is not well defined. Sections from parietal pleura that appose the chest wall showing histologic involvement of skeletal muscle are the best surrogate indicator that the endothoracic fascia has been breached.
Lymph Node Status
Thoracic or abdominal lymph nodes may be sampled to obtain a diagnosis or for the staging of an already diagnosed tumor. For thoracic lymph nodes, they should be identified by standard station; for abdominal lymph nodes, a suitable specimen identifier or descriptor should be used. A lymph node station should be regarded as positive for mesothelioma, regardless of the number of malignant mesothelial cells present or the number of lymph nodes involved, provided one node contains malignant mesothelial cells. However, the identification of mesothelial cells in lymph nodes does not necessarily indicate metastasis. Rarely, mesothelial cells in lymph nodes may represent incidental benign inclusions.21,22 The diagnosis of metastatic mesothelioma should only be made when there is good evidence of a serosa-based tumor, whether diffuse or, very rarely, localized.
Pathologic Staging (TNM, 7th edition)
Staging by TNM, 7th edition, is one of the most important prognostic factors.
Recommended Elements
The recommended elements are shown in Table 2.
Clinical History
Clinical information is essential to proper processing and evaluation of pathologic specimens because it can influence pretest probability of a particular diagnosis. This allows the pathology laboratory to accurately triage processing, including extent of sampling. It also informs the pathologist as to decisions ultimately influencing the number of slides to be examined (serial sections, levels) and potential ancillary studies to be performed,1 thus avoiding error.
For malignant mesothelioma, the radiologic growth pattern and history of previous cancer are important guides to further analysis of a particular specimen. A radiologic nodular growth pattern may prompt correlation with surgical thoracoscopic observations for nodule sampling, whereas a diffuse growth pattern may lead to a request for deeper or more-extensive samples. History of prior cancer could suggest a different panel of immunohistochemical stains to definitively rule out metastasis from a known tumor. A cancer history can prompt a request to review prior outside material or to review an archival in-house slide record.23 Other valuable clinical information includes presence of pleural effusion and its characteristics (eg, transudative, bloody, exudative), which can trigger review of, and correlation with, a concurrent cytologic specimen.
A history of asbestos exposure is not relevant for the diagnosis of samples in which malignant mesothelioma is a consideration because this history does not influence sample processing or ultimate diagnosis.20
Neoadjuvant Therapy
Tumor Size
For pleural mesotheliomas that are received as radical surgical (extrapleural pneumonectomy or pleurectomy/decortication) specimens, attempting to measure the dimensions of individual tumor nodules is neither simple (because the distinction between tumor and fibrotic reaction may be difficult to assess) nor informative. Rather, measuring the maximum thickness of tumor appears to be a more-useful indicator of tumor burden and can often be compared with radiologic measurements.6
For peritoneal mesotheliomas, the specimen is usually received in multiple parts, and dimensions of the dominant mass should be measured. Where multiple nodules are present, the dimensions of the largest nodule should be recorded.
Block Identification Key
The origin and designation of all tissue blocks should be recorded. This information should be documented in the final pathology report and is particularly important should the need for internal or external review arise. The reviewer needs to be clear about the origin of each block to provide an informed specialist opinion.
Recording the origin and designation of tissue blocks also facilitates retrieval of blocks for further immunohistochemical or molecular analysis, research studies, or clinical trials.
Mitotic Count
In pleural malignant mesothelioma, mitotic count has not been definitively established as an independent parameter in the diagnostic setting or as a determinant of prognosis. However, among epithelioid peritoneal malignant mesothelioma, increased mitotic count (>4 in 10 high-power fields)26 was reported as a poor prognostic indicator, and, more recently, was validated in a multiobserver study of an independent group of patients,27 establishing a lower cutoff of 5 mitoses in 50 high-power fields.
Ki-67 fraction may also have prognostic significance, but its use as an adjunct to mitotic count has not been investigated.
Response to Neoadjuvant Therapy
There is no recommended or agreed upon system for tumor regression grading of mesothelioma that has been treated with neoadjuvant therapy; however, a general indication of residual viable tumor of less than 50% and more than 50% may be useful.
Coexistent Pathology
It is recommended that pathologists comment on any coexistent, nonneoplastic findings present in the submitted materials. These include, for extrapleural pneumonectomy specimens, such findings as emphysema, small airways disease, respiratory bronchiolitis, asbestosis, asbestos bodies, talc granulomas, and pleural plaques.28 For diagnosing asbestosis, it is recommended that the criteria published by the asbestosis committee of the College of American Pathologists and the Pulmonary Pathology Society be used.29 For peritoneal resection specimens, additional findings, such as endometriosis, endosalpingiosis, and mesothelial inclusion cysts, should be noted.
Ancillary Studies
The 3 most-common molecular alterations in malignant mesothelioma are loss of neurofibromin 2 (merlin or NF2), cyclin-dependent kinase inhibitor 2A (CDKN2A, p16), and BRCA1–associated protein-1 (BAP1). Although, to date, NF2 loss has not been exploited diagnostically, p16 fluorescence in situ hybridization and BAP1 appear to be useful markers for separating benign from malignant mesothelial proliferations.30 Thus far, both of these markers have been reported as only lost in malignant mesotheliomas when strict cutoffs are applied. One outcome of the strict cutoff is the major problem of low sensitivity. Overall, studies reporting loss of p16 by fluorescence in situ hybridization in mesotheliomas show a sensitivity of around 50%, albeit significantly higher in pleural (67% ) than in peritoneal (25%) mesothelioma.30
Loss of p16 by fluorescence in situ hybridization in pleural mesothelioma is correlated with adverse survival rates.31,32 Retention of p16 by immunohistochemistry is a useful prognostic indicator in peritoneal epithelioid malignant mesothelioma, with significantly prolonged survival in that group.26
The sensitivity for loss of nuclear expression of BAP1 is not well defined but is probably about 50% to 70% for epithelioid mesotheliomas and very low for sarcomatoid mesotheliomas.30 These markers, however, are only useful when lost; positive staining does not rule out a mesothelioma.
BAP1 immunohistochemistry in addition is useful as a screening tool for BAP1 germline mutation syndromes, in which there are familial aggregations of mesotheliomas, melanomas, including ocular melanomas, renal cell carcinomas, and probably a variety of other tumors.33 Interestingly, patients with BAP1 germline mutation mesotheliomas are reported to have dramatically better survival rates.34 However, BAP1 immunohistochemistry is no more than a screening tool in this context, because most mesotheliomas that show BAP1 loss only have somatic mutations, and formal genetic analysis is required to confirm germline tumors.
Positive immunohistochemistry for epithelial membrane antigen (EMA), glucose transporter 1 (Glut1), human U3 small nucleolar ribonucleoprotein protein (IMP3), and cluster of differentiation 146 (CD146) have all been proposed as single markers for malignant mesothelioma when compared with benign proliferations.30 Because small, but significant, proportions of benign proliferations are positive for each of these markers, combinations of markers have been proposed, but the correlations are weak.35–38 Therefore, in the absence of morphologic invasion (cytology, small biopsy, or cellular atypia alone), these markers should not be relied upon as the sole determinant of malignancy.
DISCUSSION
A series of Web/conference calls were undertaken by the DAC to discuss each of the elements in the proposed dataset for the pathologic reporting of mesothelioma. Points of consideration included the following: (1) the publication of the 4th edition of the WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart13; (2) variation in local practice, both surgical and pathologic, among the international DAC; (3) the value of biopsy for the diagnosis of mesothelioma; (4) variation in terminology in use for element names and responses; and (5) whether localized mesothelioma should be included in the scope of the dataset. Localized malignant mesotheliomas are extremely uncommon tumors with the microscopic appearances of diffuse malignant mesotheliomas, but they are solitary and, by definition, do not show gross or microscopic evidence of diffuse pleural spread. Roughly half of localized malignant mesotheliomas are curable by wide surgical excision.39 It was agreed that localized malignant mesotheliomas are sufficiently different from ordinary diffuse malignant mesotheliomas that there was little value in including these lesions in the scope of this publication.
Each element and its value list or response—for example, present, not assessable, not indicated—were discussed and agreed upon by the DAC. Standardized terminology with definitions for common terms is used to avoid any ambiguity in the assessment or meaning of the element. The DAC was then assigned tasks for the writing of commentary for those elements requiring further explanatory text accounting for recent and pertinent literature.
The goal of the ICCR was to develop a set of data elements that will form the core of any pathology report on the specific cancer around the world. Adoption of the ICCR datasets will help facilitate recording of pathologic data in a consistent, standardized manner. The ICCR datasets need to include any element that is essential to include when reporting a cancer and which has either supporting evidence or unanimous agreement from the DAC to include as best practice. This dataset is, therefore, the core of any structured pathology report on mesothelioma. It is not, however, the intention that the dataset be restrictive, and additional data items may be included when reporting, according to local needs. All structured pathology reports must also include the facility for free-text comments to ensure that any clarification or nuance in reporting is captured.
This study was supported in part by cancer center support grant P30 CA008748 from the US National Institutes of Health/National Cancer Institute, Bethesda, Maryland (Dr Rusch). We thank Avril Kwiatkowski, BEng, for her considerable contributions to the development of the mesothelioma dataset.
References
Author notes
Drs Churg, Attanoos, Chirieac, Gibbs, and Roggli consult and provide medicolegal work for asbestos and mesothelioma litigation to both plaintiff and defense attorneys. Dr Henderson consults and provides medicolegal work for courts in Australia to both plaintiff and defense attorneys. The authors have no relevant financial interest in the products or companies described in this article.