- Email: [email protected]
Pathology of lung and pleural tumours
BASIC SCIENCE
Pathology of lung and pleural tumours
smoke, given that lung cancer risk has been shown to reduce on smoking cessation, the most effective preventative measure for an individual smoker is to stop! Pathological classification of malignant tumours of the lung Lung tumours are classified according to the World Health Organization (WHO) scheme (2004), with modification of the classification of adenocarcinomas based on a joint IASLC/ATS/ ERS consensus paper from 2011.2,3 The WHO classification is based on the morphological appearances of resected tumour specimens, whereas the consensus paper includes guidance on classification on small biopsy and cytology samples using ancillary techniques such as immunohistochemistry (an established means of identifying characteristics of a cell using antibodies directed against a target of interest). Broadly speaking, bronchial carcinomas can be divided into two groups, a heterogeneous group of ‘non-small cell carcinomas’ accounting for about 80% of cases and small cell carcinoma making up the remainder. Accurate subclassification is essential to guide oncology practice and appropriate molecular pathology testing.
Tim Andrews William AH Wallace
Abstract Lung and pleural malignancy is a major cause of morbidity and mortality. Approaches to diagnosis and management are evolving, based on both technological and scientific advances. A basic understanding of the classification of lung and pleural tumours and approaches to their pathological diagnosis is important for all those involved in managing these patients. To this end, we present an overview of the current classification of lung tumours, briefly discuss their aetiology and pathogenesis, describe pathological aspects of the diagnosis and staging of bronchial carcinoma (including an outline of the developing role of molecular approaches to refining oncological management), and finally review the pathology of mesothelioma and it differential diagnosis.
Keywords Classification; histopathology; lung cancer; molecular diagnostics; multidisciplinary team; staging
Non-small cell carcinoma Squamous cell carcinoma (Figure 1): these are typically large, centrally placed tumours arising in male patients with a long smoking history. The tumours may be necrotic and show extensive cavitation. The presence of keratinization and/or intercellular bridge formation (prickles), indicate the squamous nature of the tumour histologically. Papillary, small cell, basaloid and clear cell morphological variants are recognized, but are of no clinical significance.
Carcinoma of the lung Introduction Bronchial carcinoma is the most common cause of cancer-related death in the UK, with an annual incidence of around 42,000 and an over all 5-year survival rate less than 10%. Rates of the disease in women continue to rise in developed countries, and the potential for a lung cancer ‘epidemic’ in developing countries is acknowledged.1 Approaches to diagnosis, classification and management are evolving, based on technological and scientific advances. Patient management is determined by the tumour type, extent of disease and associated medical comorbidities. In the UK, management is discussed in the multidisciplinary team meeting (MDTM) setting and the pathologist plays a key role in this. An understanding of the classification of lung tumours and approaches used in their pathological diagnosis is important for all involved in these meetings.
Adenocarcinoma (Figure 2): this is now the most common subtype of lung cancer, with an as yet unexplained rise in the relative incidence of this tumour in men. Morphologically, glandular or papillary differentiation and/or mucin production are required for diagnosis. Lepidic, acinar, papillary, micropapillary, and solid with mucin production subtypes are described. The significance of detailed subtyping is a matter of debate, although there is evidence that pure solid or micropapillary tumours may do worse than pure lepidic types.3 There is a subgroup of in-situ/minimally invasive adenocarcinoma type lesions that would be expected to have 100% or near 100% 5year survival following resection. These have traditionally been grouped together using the term bronchioloalveolar carcinoma (BAC). There is a move away from this terminology in favour of more specific entities such as adenocarcinoma in-situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. It is beyond the scope of this article to discuss the intricacies and merits (or otherwise) of such a revised system, but it is important to be aware of the potentially changing terminology to ensure appropriate clinical management of these patients.
Aetiology Epidemiological studies demonstrate a causal association between tobacco (particularly cigarette smoking) and the development of bronchial carcinoma. Other risk factors including exposure to radiation, asbestos, and second-hand smoke are also recognized. Although efforts have been made to reduce environmental exposures to various agents, including second-hand
Tim Andrews FRCPath is a Consultant Histopathologist at the Royal Liverpool University Hospital, Liverpool, UK. Conflicts of interest: none declared.
Large cell carcinoma: resected tumours showing no specific features of either squamous or glandular differentiation fall into this category. They are poorly differentiated tumours with a poor prognosis. The most important subtype is large cell neuroendocrine carcinoma (LCNEC), which is a high-grade carcinoma
William AH Wallace PhD FRCPEd FRCPath is a Consultant Pathologist at the Royal Infirmary of Edinburgh, and Honorary Reader in Thoracic Pathology, University of Edinburgh, UK. Conflicts of interest: none declared.
SURGERY 32:5
228
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
a
b
c
Squamous cell carcinoma. (a) Macroscopic appearance of a large squamous carcinoma of the upper lobe. (b, high power, H&E) Demonstrating keratin formation within the tumour (arrows). (c, high power, H&E) Demonstrating intracellular bridge formation, ‘prickles’ (arrows). Figure 1
mm2 making the ‘atypical’ diagnosis. Differentiation from SCLC on biopsies can be difficult histologically, although some have advocated the use of Ki-67 immunohistochemistry to assess proliferation, as a discriminator, in problematic cases. The demonstration of neuroendocrine differentiation, by immunohistochemistry, in tumours which do not fall into the categories described above (SCLC, LCNEC, carcinoid) is reported, but is of no clinical significance.
showing morphological and immunohistochemical evidence of neuroendocrine differentiation. Sarcomatoid carcinomas: these are poorly differentiated tumours characterized by cells showing either a spindle cell or pleomorphic giant cell morphology, often admixed with more typical areas of squamous/adenocarcinoma. In some cases foci of true malignant mesenchymal differentiation may also been seen. Their prognosis tends to be poor.
Other tumours Other, rare, primary, lung malignancies include: salivary gland type tumours (e.g. adenoid cystic carcinoma), lymphoma, and sarcomas (e.g. synovial sarcoma).
Small cell carcinoma (Figure 3) This is the third most common type of carcinoma accounting for around 20% to 25% of cases. It is a poorly differentiated carcinoma with neuroendocrine features and is often disseminated with extensive nodal disease and/or distant metastases at the time of diagnosis. These tumours are composed of cells with little cytoplasm, easily identified mitotic figures, apoptotic debris and often extensive necrosis.
Pathogenesis and natural history of bronchial carcinomas Our understanding of the development of bronchial carcinoma is incomplete. There is a lack of a well-defined model for the development of the various cancer subtypes and no clear consensus regarding the optimum means of identifying so-called ‘premalignant’ lesions or how they should be managed. These gaps in knowledge provide challenges to both basic science research and also those wishing to devise screening and treatment strategies for patients at risk of lung cancer.
Carcinoid tumours These represent neuroendocrine tumours at the low and intermediate end of the malignant spectrum (compared to LCNEC and small cell lung carcinoma [SCLC]). They may present as wellcircumscribed peripheral lesions or polypoid endobronchial tumours. They are composed of uniform polygonal cells, which may show a packeted, trabecular, or spindle cell arrangement. Immunohistochemistry shows expression of neuroendocrine markers. A potentially important feature from the unwary clinicians’ viewpoint is the high vascularity of the tumour, which may result in haemorrhage on biopsy. The differentiation between carcinoid and atypical carcinoid usually requires examination of the resected tumour specimen with identification of either focal necrosis or 2e10 mitoses per 2
SURGERY 32:5
Squamous carcinoma (Figure 4): this is described as arising in a stepwise fashion with respiratory-type epithelium undergoing metaplasia to squamous epithelium which subsequently becomes dysplastic, and eventually frankly malignant. This hypothesis is supported by experimental work in animals, clinical work in humans, and by the genetic changes identified. However, epidemiological data challenge this hypothesis, with mild or moderate dysplasia apparently having virtually no
229
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
a
c
b
Adenocarcinoma. (a) Macroscopic appearance, typically a small peripherally placed tumour showing puckering and indrawing of the visceral pleura. (b, medium power, H&E) This is a well-differentiated example with obvious gland formation. (c, medium power, ABPAS). Mucin production is easily demonstrated (stained blue). Figure 2
change’ throughout the bronchial epithelium,4 and a recent microdissection study demonstrating clonality from multiple sites of dysplasia in the same patient provides further evidence for this.5
potential for progression to invasive carcinoma, whereas identification of severe dysplasia or carcinoma in-situ are very strong predicators for adjacent invasive carcinoma, or its development. This observation makes the argument for an effect of ‘field
b
a
Small cell lung carcinoma. (a, medium power, H&E) This is a poorly differentiated, high-grade tumour composed of cells with scanty cytoplasm. (b, medium power, immunohistochemistry) The neuroendocrine marker CD56 is positive in this tumour. This combined with other immunohistochemical satins may prove useful in differentiating small cell carcinoma from other poorly differentiated non-small cell carcinomas and crushed lymphoid tissue on biopsy. Figure 3
SURGERY 32:5
230
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
a
b
c
d
Pathogenesis of squamous cell carcinoma. This composite figure shows the morphological, stepwise progression from (a) benign metaplastic squamous metaplasia through (b) low-grade dysplasia to (c) carcinoma in-situ and finally (d) invasive squamous cell carcinoma. Figure 4
Adenocarcinoma (Figure 5): genome-wide expression profiling with subsequent clustering studies has suggested that there are two distinct groups of lung adenocarcinomas, corresponding to different pathways of development.6 Those in the ‘terminal respiratory unit phenotype’ group develop by a stepwise progression from atypical adenomatous hyperplasia (AAH), through adenocarcinoma in-situ (AIS) to invasive adenocarcinoma (although the rate of this is undetermined). In this pathway EGFR/K-Ras mutations and copy number aberrations are early events, and p53 mutations occur later. The second group of ‘non-terminal respiratory unit phenotype’ adenocarcinomas appear to show a less predictable sequence of genetic changes, and no definite morphological stepwise progression.
Natural history: the natural history of lung carcinomas is of initial local growth and invasion followed by distant metastases. The relative rate of progression is influenced by cell type, with SCLC tending to metastasize widely at an early stage. As the tumour grows within the lung, local effects such as obstructive pneumonia, lobar collapse and haemoptysis may be apparent. The tumour may involve the pleura giving rise to an effusion and invade adjacent structures (e.g. chest wall, mediastinum, diaphragm). The most common sites of metastases are regional nodes, liver, brain, bone and adrenal glands. Patients commonly present with symptoms relating to metastases rather than the primary tumour.
Neuroendocrine tumours: carcinoid and atypical carcinoid tumours may develop on a background of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). This biologically poorly understood entity is associated with a range of neoplastic and non-neoplastic conditions.7 No premalignant lesion of SCLC is known, and much of the genetic and karyotype data is based on cell lines and animal models e making its direct translation to the clinic problematic. Studies describe some similarities with non-small cell lung carcinoma (NSCLC) including obligate p53 and Rb mutations, and other, possibly more SCLC specific features including c-MYC mutations and loss of chromosome 3q.2
Diagnosis of bronchial carcinoma A multi-modality approach including clinical history/examination, radiological (CT-PET) and pathological evaluation is used in arriving at a diagnosis of bronchial carcinoma. The extent to which a particular patient is investigated is often determined by their fitness for further therapy. Multidisciplinary guidelines for the diagnosis of lung cancer, and its subsequent management have been produced (by NICE in the UK,8 and the American College of Chest Physicians in the USA9). The following section provides an overview (reviewed in Rivera et al, 201310) of the samples used to obtain a pathological diagnosis.
SURGERY 32:5
231
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
a
b
c
d
Pathogenesis of adenocarcinoma. This composite figure shows the morphological, stepwise progression from (a) type II pneumocyte hyperplasia to (b) atypical adenomatous hyperplasia (AAH), through (c) bronchioloalveolar carcinoma (BAC) to (d) invasive adenocarcinoma.
Figure 5
Biopsy: tissue biopsy for histological examination provides the optimal method for diagnosis and classification of lung tumours. Biopsies can be obtained from the primary tumour by bronchoscopy or percutaneously under CT guidance or from metastatic deposits (e.g. liver). Making the distinction between SCLC and NSCLC is robust, but studies have demonstrated that accurate distinction between squamous carcinoma and adenocarcinoma is potentially unreliable in small biopsy samples by morphology alone. This has lead to the use of the generic term ‘NSCLC e not otherwise specified (NOS)’. Recent developments in targeted chemotherapy have resulted in a requirement to classify these tumours with greater accuracy, and studies have suggested that with the use of immunohistochemistry around 85% of ‘NSCLC’ can be accurately classified as either adenocarcinoma or squamous carcinoma.11 This requirement is incorporated into current UK Pathology guidelines produced by the Royal College of Pathologists.12
on cytology specimens, especially those where a ‘cell block’ is prepared, which effectively results in a tissue microbiopsy being created. Sputum: sputum cytology should be restricted to patients not fit for more invasive investigations, with central tumour masses, and should not be sent routinely for examination.13 There has been some interest in its utility as a screening tool, but current trends are towards models of risk stratification and usage of repeat low-dose CT scanning in those identified as at highest risk of developing lung cancer. Frozen section (FS): in a proportion of patients, preoperative diagnosis and staging may not have been possible. In these situations, FS may be undertaken to obtain an intraoperative pathological diagnosis. The main roles of frozen section are to confirm malignancy, assess resection margins, examine unexpected intraoperative findings (e.g. pleural nodules), and assessment of lymph nodes. Used appropriately, FS may have a sensitivity for diagnosis of isolated pulmonary nodules >85%.14
Cytology: cytology samples are obtained from the lungs either as bronchial brushings or bronchial washings at bronchoscopy, or percutaneously as fine-needle aspirations (FNAs). Increasingly, FNAs from mediastinal and hilar lymph node metastases obtained by endobronchial ultrasound (EBUS) are being submitted for primary diagnosis. Subclassification with the aid of immunohistochemistry and molecular studies are feasible and reliable
SURGERY 32:5
Mimics of lung cancer (see Table 1 and Reference15) Metastases: the lung is a common site of metastasis. Distinction between primary and secondary tumours may be critical in
232
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
Mimics of lung cancer
TNM 7th edition for staging lung tumours
Malignancy Metastasis C Rare tumour (e.g. lymphoma or sarcoma)
TNM stage Descriptor
C
C C C
Benign tumour Mixed tumours of bronchial submucosal glands Leiomyoma Solitary fibrous tumours
C
Inflammatory/Infectious Pneumonia Tuberculosis Histoplasmosis/coccidiomycosis ‘Inflammatory nodule’
C
Vascular Infarct
C C C
C C
C C C
C C
C C C
Tumour T0 Tis T1
T2
T3
Nodular lesions associated with systemic disease Rheumatoid nodule Wegener’s granulomatosis T4
Nodular patterns of interstitial lung disease Sarcoidosis Cryptogenic organizing pneumonia (COP) Histiocytosis X
Nodes N0 N1 N2
Hamartoma e developmental and acquired Chondroid hamartoma Arteriovenous malformation Others Amyloid tumours Round atelectasis (folded lung) Encysted pleural fluid
N3
No regional lymph node metastases Involvement of ipsilateral peribronchial or hilar nodes Involvement of ipsilateral mediastinal or subcarinal nodes Involvement of contralateral mediastinal, contralateral hilar, contralateral scalene or supraclavicular lymph nodes
Metastases M0 No distant metastases M1a Separate tumour nodule(s) in a contralateral lobe, pleural nodules, or malignant pleural or pericardial effusion M1b Distant metastases
A range of diagnostic possibilities other than primary lung malignancy must be considered both clinically and histologically in patients presenting with a pulmonary nodule. Some of the common differential diagnoses are listed in this table.
Summary of TNM 7 Lung Cancer: This staging system is considered applicable to all tumour types including small cell lung carcinoma and carcinoid tumours. A stage grouping system may be used to combine various combinations of TNM parameters for inclusion of patients in clinical trials.
Table 1
determining optimal management. This requires an accurate history, including specific details of the previous tumour. Both morphology and immunohistochemistry may be helpful, but it has to be accepted that in some instances definite distinction is not possible and management has to be based on the clinical and radiological features of the disease.
Table 2
need to identify certain key components of the tumour (e.g. size, extent of local invasion, lymph node involvement etc). Preoperative staging: the staging of all lung cancers involves imaging in the first instance. It is important to remember that as resection rates for lung cancer are at best 10% to 15%, most patients will be managed on the basis of clinical stage alone. CTPET scanning is used to stage mediastinal nodes and look for occult distant metastases. Confirmation of the clinical stage can be obtained by biopsy (e.g. liver or adrenal biopsy) or FNA (e.g. EBUS FNA of mediastinal nodes) as appropriate if this is uncertain prior to a decision on management being taken.
Benign and inflammatory lung lesions: a proportion of patients presenting with symptoms suggestive of lung cancer will not have malignant disease. Table 1 gives a brief list of possible mimics of lung cancer, and is included as a reminder to consider carefully how the patient is being worked up. Staging lung cancer Staging, according to the TNM classification, represents the best way to predict the prognosis of a patient with lung cancer and for grouping patients together for inclusion in clinical trials. The TNM 7 classification is summarized in Table 2.16 This demonstrates the
SURGERY 32:5
No evidence of primary tumour Carcinoma in-situ Tumour 3 cm, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus) A 2 cm B >2 cme3 cm Main bronchus e 2 cm from carina, invades visceral pleura, partial atelectasis. A >3 cme5 cm or 3 cm satisfying above criteria B >5 cme7 cm Tumour >7 cm or with invasion of chest wall, diaphragm, pericardium, mediastinal pleura, main bronchus <2 cm from carina, total atelectasis, separate nodule(s) in same lobe Tumour of any size which invades mediastinum, heart, great vessels, carina, trachea, oesophagus, vertebra, separate nodule(s) in a different ipsilateral lobe
Postoperative staging of resection specimens: this is based on the examining the fixed resection specimen. Accurate dissection
233
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
and reporting of resection specimens requires the provision of good clinical information, including the demographic details for accession of the specimen to the laboratory, previous pathology reports, a brief description of the operation and resultant specimens, and any specific issues noted at the time of operation (e.g. intrapericardial resection performed). If radiologically there are multiple tumours or any suspicion of interstitial lung disease, this should be communicated on the request form. The pathologist slices the lung after fixation, measures the tumour and notes its relationship to the pleura and bronchial/ vascular resection margins. Blocks of tissue are taken for microscopic examination in order to determine the type of tumour, its extent including involvement of pleura, bronchus and adjacent structures, and any pathology of the background lung. Lymph nodes submitted are examined for evidence of metastatic disease. The final report will include the cell type of the tumour, the TNM stage and the adequacy of excision. Molecular pathology and targeted therapies Oncology practice in the field of lung cancer is changing with the development of agents that specifically target certain processes in specific types of tumour and the development of so called ‘small molecule inhibitors’ that are only effective against tumours harbouring specific genetic abnormalities. This provides a challenge to the pathologist with the need to obtain a refined morphological diagnosis competing with the need to conserve tissue to provide material for molecular assays. The possibility of taking a separate biopsy for molecular analysis (either simultaneously with the diagnostic procedure or subsequently), and re-biopsy of recurrent tumours for repeat genetic testing are becoming considerations in some patients. There is clearly a need within the MDTM setting to discuss the most appropriate management of the limited tissue available in a given case and balance the potential benefits of tailored oncology treatments against the risks associated with the biopsy procedure. In practice, this requires the subdivision of NSCLC into squamous and non-squamous subtypes in as many cases as possible. This will have a direct impact on therapy since some agents (e.g. the antifolate pemetrexed) are only effective in those with ‘non-squamous histology’; others (e.g. the angiogenesis inhibitor bevacizumab) have an unacceptable side effect profile if administered to those with squamous carcinoma Only tumours showing ‘non-squamous’ histology will be referred on for genetic testing to determine EGFR mutation status and thus their suitability for EGFR-TKI inhibitors (e.g. gefitinib). Drugs effective against tumours with an EML-4/ALK translocation are also available and it is likely that agents targeting ‘MET’ and other pathways will become commercially available in the near future.
Figure 6 Macroscopic appearance of mesothelioma. The thickened and malignant pleura forms a ‘rind’ around the lung leading to a distinctive radiological appearance. Such specimens are likely to become extremely rare as there is a move away from radical surgery for this disease.
vaginalis within the scrotum), closely associated with exposure to asbestos fibres. While this usually relates to direct occupational exposure, secondary environmental exposure from living in proximity to industrial facilities using asbestos or from contact with contaminated work clothes at home is recognized to occur. In a small number of cases no evidence of exposure can be identified and the absence of this should not preclude consideration of the diagnosis if the clinical and radiological features are suggestive. Mesothelioma has a long latent period of at least 20 years from exposure until the development of the tumour. Following statutory restrictions on asbestos use in the western world that were imposed in the 1970s and 1980s, the incidence is expected to start to fall within the next 5e10 years. In other parts of the world where asbestos is still widely used, however, the incidence is likely to remain high. The biology of mesothelioma is not well understood, but evidence suggests that asbestos may interact with a variety of cell signalling pathways, including EGFR and PI3K/AKT, and inflammatory cells/the tumour microenvironment to bring about tumourogenesis.17 These observations, coupled with reduced enthusiasm for radical surgical approaches (radical pleuropneumonectomy), mean that decortication and various chemotherapy regimes now provide the mainstays of treatment, and small molecule/immunomodulatory therapies are on the horizon. Regardless of the approach adopted, the disease has a very
Pleural malignancy Mesothelioma (Figure 6) Mesothelioma is an important clinical and medicolegal problem, and in many centres will be managed through the thoracic oncology MDT. Although this tumour is considerably rarer than bronchial carcinoma (around 2200 new cases annually in the UK) it presents challenges in diagnosis and management. Mesothelioma is a primary tumour of the pleural space (although more rarely can be seen in the peritoneal cavity or the tunica
SURGERY 32:5
234
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
opinion is helpful for all those involved in the care of these patients as it allows informed discussion regarding investigations and therapeutic options. A
poor prognosis, and in the vast majority of cases palliation is the only option with a median survival in the order of 11 months. Mesotheliomas are classified according to their morphological appearances as epithelioid, spindle cell/sarcomatoid or mixed (biphasic). The diagnosis of mesothelioma represents a challenge to the pathologist, as differentiating between reactive and neoplastic mesothelial cells may be problematic. The only definitive marker of a malignant proliferation of mesothelial cells, rather than a reactive one, is the demonstration of infiltration into the underlying connective tissue. The epithelioid component of a mesothelioma can show a wide variety of morphological patterns and as such in biopsy specimens from the pleura the differential diagnosis of mesothelioma includes metastatic adenocarcinoma, metastatic sarcomatoid (spindle cell) carcinoma and even sarcoma depending on the morphology. Mesothelioma typically presents with a large pleural effusion that may be blood stained an aspiration. In more advanced cases there may be chest wall pain from infiltration. Imaging may show evidence of pleural thickening but this is not always seen. Aspiration cytology may demonstrate the presence of atypical mesothelial cells, but a definitive diagnosis of mesothelioma solely on cytology is rarely, if ever, possible given that reactive proliferations may also show marked atypia and confirmation of an infiltrative process is not possible cytologically. Definitive diagnosis therefore requires pleural biopsy, either image-guided core biopsies of pleural based masses or ideally specimens obtained at thoracoscopy. Such specimens should ideally be full thickness to take in the parietal pleura and underling chest wall tissue so that invasion can be confirmed. Differentiation of mesothelioma from metastatic carcinoma and other tumours is carried out using a panel of immunohistochemical stains although it should be noted that none of these are 100% specific and in some cases, particularly with small biopsies, there may be a degree of uncertainty around the diagnosis. It should also be remembered that all cases of proven or suspected mesothelioma, given the close link to occupational asbestos, are regarded as an occupational disease and in the UK deaths must be notified to HM Coroner in England/Wales and the Procurator Fiscal in Scotland.
REFERENCES 1 For example statistical data on UK Cancer is provided by Cancer Research UK (CR-UK), reference: http://www.cancerresearchuk.org/ cancerstats/ (accessed 23/09/13). 2 Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, eds. WHO classification of tumours e pathology and genetics of tumours of the lungs, pleura, thymus and heart. Lyon: IARC Press, 2004. 3 Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung Cancer/American thoracic Society/European respiratory Society International multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6: 244e85. 4 Ishizumi T, McWilliams A, MacAulay C, et al. Natural history of bronchial preinvasive lesions. Cancer Metastasis Rev 2010; 29: 5e14. 5 McCaughan F, Pipinikas CP, Janes SM, et al. Genomic evidence of preinvasive clonal expansion, dispersal and progression in bronchial dysplasia. J Pathol 2011; 224: 153e9. 6 Yatabe Y, Borczuk AC, Powell CA. Do all lung adenocarcinomas follow a stepwise progression? Lung Cancer 2011; 74: 7e11. 7 Davis SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax 2007; 62: 248e52. 8 CG121 Lung Cancer: NICE Guideline. Available at: http://guidance. nice.org.uk/CG121/NICEGuidance/pdf/English (accessed 23/09/13). 9 Andrews TD, Wallace WA. Diagnosis and staging of lung and pleural malignancy e an overview of tissue sampling techniques and the implications for pathological assessment. Clin Oncol R Coll Radiol 2009; 21: 451e63. 10 Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer. Chest 2013; 143(suppl 5). 11 Loo PS, Thomas SC, Nicolson MC, Fyfe MN, Kerr KM. Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. J Thorac Oncol 2010; 5: 442e7. 12 Dataset for lung cancer histopathology reports. 3rd edn. April 2011. London: Royal College of Pathologists. Available through, www. rcpath.org (accessed 23/09/13). 13 Practice guideline e histopathology of limited or no clinical value. 2nd edn. 2005. London: Royal College of Pathologists. Available through, www.rcpath.org (accessed 23/09/13). 14 Marchevsky AM, Changsri C, Gupta I, et al. Frozen sections diagnosis of small pulmonary nodules: accuracy and clinical implications. Ann Thorac Surg 2004; 78: 1755e9. 15 Mayer NJ, Wallace WAH, Kamel HM. Nodular lesions of the lung: a practical approach to histological diagnosis. Curr Diagn Pathol 2003; 9: 188e98. 16 Sobin L, Gospodarowicz M, Wittekind C, eds. TNM classification of malignant tumours. 7th edn. Chichester UK: UICC. Wiley-Blackwell, 2009. 17 Heintz NH, Janssen-Heininger YMW, Mossman BT. Asbestos, lung cancers and mesotheliomas: from molecular approaches to targeting tumour survival pathways. Am J Respir Cell Mol Biol 2010; 42: 133e9.
Metastatic malignancy The pleura is a common site of metastatic malignancy from a wide variety of tumours arising at other sites and the development of a pleural effusion related to this may be the initial presentation. Metastatic adenocarcinoma from lung and breast are the most commonly seen. Clinically and radiologically these may on occasion mimick mesothelioma (pseudo-mesothelioma) with the tumour encasing the lung, emphasizing the need for histological/cytological assessment to obtain an accurate diagnosis.
Conclusion Lung and pleural malignancy are common clinical problems. Accurate pathological diagnosis, classification, and staging of tumours are essential to guide patient management. A basic understanding of the pathological classification of these tumours and the means by which the pathologist reaches their diagnostic
SURGERY 32:5
235
Ó 2014 Elsevier Ltd. All rights reserved.
Pathology of lung and pleural tumours
smoke, given that lung cancer risk has been shown to reduce on smoking cessation, the most effective preventative measure for an individual smoker is to stop! Pathological classification of malignant tumours of the lung Lung tumours are classified according to the World Health Organization (WHO) scheme (2004), with modification of the classification of adenocarcinomas based on a joint IASLC/ATS/ ERS consensus paper from 2011.2,3 The WHO classification is based on the morphological appearances of resected tumour specimens, whereas the consensus paper includes guidance on classification on small biopsy and cytology samples using ancillary techniques such as immunohistochemistry (an established means of identifying characteristics of a cell using antibodies directed against a target of interest). Broadly speaking, bronchial carcinomas can be divided into two groups, a heterogeneous group of ‘non-small cell carcinomas’ accounting for about 80% of cases and small cell carcinoma making up the remainder. Accurate subclassification is essential to guide oncology practice and appropriate molecular pathology testing.
Tim Andrews William AH Wallace
Abstract Lung and pleural malignancy is a major cause of morbidity and mortality. Approaches to diagnosis and management are evolving, based on both technological and scientific advances. A basic understanding of the classification of lung and pleural tumours and approaches to their pathological diagnosis is important for all those involved in managing these patients. To this end, we present an overview of the current classification of lung tumours, briefly discuss their aetiology and pathogenesis, describe pathological aspects of the diagnosis and staging of bronchial carcinoma (including an outline of the developing role of molecular approaches to refining oncological management), and finally review the pathology of mesothelioma and it differential diagnosis.
Keywords Classification; histopathology; lung cancer; molecular diagnostics; multidisciplinary team; staging
Non-small cell carcinoma Squamous cell carcinoma (Figure 1): these are typically large, centrally placed tumours arising in male patients with a long smoking history. The tumours may be necrotic and show extensive cavitation. The presence of keratinization and/or intercellular bridge formation (prickles), indicate the squamous nature of the tumour histologically. Papillary, small cell, basaloid and clear cell morphological variants are recognized, but are of no clinical significance.
Carcinoma of the lung Introduction Bronchial carcinoma is the most common cause of cancer-related death in the UK, with an annual incidence of around 42,000 and an over all 5-year survival rate less than 10%. Rates of the disease in women continue to rise in developed countries, and the potential for a lung cancer ‘epidemic’ in developing countries is acknowledged.1 Approaches to diagnosis, classification and management are evolving, based on technological and scientific advances. Patient management is determined by the tumour type, extent of disease and associated medical comorbidities. In the UK, management is discussed in the multidisciplinary team meeting (MDTM) setting and the pathologist plays a key role in this. An understanding of the classification of lung tumours and approaches used in their pathological diagnosis is important for all involved in these meetings.
Adenocarcinoma (Figure 2): this is now the most common subtype of lung cancer, with an as yet unexplained rise in the relative incidence of this tumour in men. Morphologically, glandular or papillary differentiation and/or mucin production are required for diagnosis. Lepidic, acinar, papillary, micropapillary, and solid with mucin production subtypes are described. The significance of detailed subtyping is a matter of debate, although there is evidence that pure solid or micropapillary tumours may do worse than pure lepidic types.3 There is a subgroup of in-situ/minimally invasive adenocarcinoma type lesions that would be expected to have 100% or near 100% 5year survival following resection. These have traditionally been grouped together using the term bronchioloalveolar carcinoma (BAC). There is a move away from this terminology in favour of more specific entities such as adenocarcinoma in-situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. It is beyond the scope of this article to discuss the intricacies and merits (or otherwise) of such a revised system, but it is important to be aware of the potentially changing terminology to ensure appropriate clinical management of these patients.
Aetiology Epidemiological studies demonstrate a causal association between tobacco (particularly cigarette smoking) and the development of bronchial carcinoma. Other risk factors including exposure to radiation, asbestos, and second-hand smoke are also recognized. Although efforts have been made to reduce environmental exposures to various agents, including second-hand
Tim Andrews FRCPath is a Consultant Histopathologist at the Royal Liverpool University Hospital, Liverpool, UK. Conflicts of interest: none declared.
Large cell carcinoma: resected tumours showing no specific features of either squamous or glandular differentiation fall into this category. They are poorly differentiated tumours with a poor prognosis. The most important subtype is large cell neuroendocrine carcinoma (LCNEC), which is a high-grade carcinoma
William AH Wallace PhD FRCPEd FRCPath is a Consultant Pathologist at the Royal Infirmary of Edinburgh, and Honorary Reader in Thoracic Pathology, University of Edinburgh, UK. Conflicts of interest: none declared.
SURGERY 32:5
228
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
a
b
c
Squamous cell carcinoma. (a) Macroscopic appearance of a large squamous carcinoma of the upper lobe. (b, high power, H&E) Demonstrating keratin formation within the tumour (arrows). (c, high power, H&E) Demonstrating intracellular bridge formation, ‘prickles’ (arrows). Figure 1
mm2 making the ‘atypical’ diagnosis. Differentiation from SCLC on biopsies can be difficult histologically, although some have advocated the use of Ki-67 immunohistochemistry to assess proliferation, as a discriminator, in problematic cases. The demonstration of neuroendocrine differentiation, by immunohistochemistry, in tumours which do not fall into the categories described above (SCLC, LCNEC, carcinoid) is reported, but is of no clinical significance.
showing morphological and immunohistochemical evidence of neuroendocrine differentiation. Sarcomatoid carcinomas: these are poorly differentiated tumours characterized by cells showing either a spindle cell or pleomorphic giant cell morphology, often admixed with more typical areas of squamous/adenocarcinoma. In some cases foci of true malignant mesenchymal differentiation may also been seen. Their prognosis tends to be poor.
Other tumours Other, rare, primary, lung malignancies include: salivary gland type tumours (e.g. adenoid cystic carcinoma), lymphoma, and sarcomas (e.g. synovial sarcoma).
Small cell carcinoma (Figure 3) This is the third most common type of carcinoma accounting for around 20% to 25% of cases. It is a poorly differentiated carcinoma with neuroendocrine features and is often disseminated with extensive nodal disease and/or distant metastases at the time of diagnosis. These tumours are composed of cells with little cytoplasm, easily identified mitotic figures, apoptotic debris and often extensive necrosis.
Pathogenesis and natural history of bronchial carcinomas Our understanding of the development of bronchial carcinoma is incomplete. There is a lack of a well-defined model for the development of the various cancer subtypes and no clear consensus regarding the optimum means of identifying so-called ‘premalignant’ lesions or how they should be managed. These gaps in knowledge provide challenges to both basic science research and also those wishing to devise screening and treatment strategies for patients at risk of lung cancer.
Carcinoid tumours These represent neuroendocrine tumours at the low and intermediate end of the malignant spectrum (compared to LCNEC and small cell lung carcinoma [SCLC]). They may present as wellcircumscribed peripheral lesions or polypoid endobronchial tumours. They are composed of uniform polygonal cells, which may show a packeted, trabecular, or spindle cell arrangement. Immunohistochemistry shows expression of neuroendocrine markers. A potentially important feature from the unwary clinicians’ viewpoint is the high vascularity of the tumour, which may result in haemorrhage on biopsy. The differentiation between carcinoid and atypical carcinoid usually requires examination of the resected tumour specimen with identification of either focal necrosis or 2e10 mitoses per 2
SURGERY 32:5
Squamous carcinoma (Figure 4): this is described as arising in a stepwise fashion with respiratory-type epithelium undergoing metaplasia to squamous epithelium which subsequently becomes dysplastic, and eventually frankly malignant. This hypothesis is supported by experimental work in animals, clinical work in humans, and by the genetic changes identified. However, epidemiological data challenge this hypothesis, with mild or moderate dysplasia apparently having virtually no
229
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
a
c
b
Adenocarcinoma. (a) Macroscopic appearance, typically a small peripherally placed tumour showing puckering and indrawing of the visceral pleura. (b, medium power, H&E) This is a well-differentiated example with obvious gland formation. (c, medium power, ABPAS). Mucin production is easily demonstrated (stained blue). Figure 2
change’ throughout the bronchial epithelium,4 and a recent microdissection study demonstrating clonality from multiple sites of dysplasia in the same patient provides further evidence for this.5
potential for progression to invasive carcinoma, whereas identification of severe dysplasia or carcinoma in-situ are very strong predicators for adjacent invasive carcinoma, or its development. This observation makes the argument for an effect of ‘field
b
a
Small cell lung carcinoma. (a, medium power, H&E) This is a poorly differentiated, high-grade tumour composed of cells with scanty cytoplasm. (b, medium power, immunohistochemistry) The neuroendocrine marker CD56 is positive in this tumour. This combined with other immunohistochemical satins may prove useful in differentiating small cell carcinoma from other poorly differentiated non-small cell carcinomas and crushed lymphoid tissue on biopsy. Figure 3
SURGERY 32:5
230
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
a
b
c
d
Pathogenesis of squamous cell carcinoma. This composite figure shows the morphological, stepwise progression from (a) benign metaplastic squamous metaplasia through (b) low-grade dysplasia to (c) carcinoma in-situ and finally (d) invasive squamous cell carcinoma. Figure 4
Adenocarcinoma (Figure 5): genome-wide expression profiling with subsequent clustering studies has suggested that there are two distinct groups of lung adenocarcinomas, corresponding to different pathways of development.6 Those in the ‘terminal respiratory unit phenotype’ group develop by a stepwise progression from atypical adenomatous hyperplasia (AAH), through adenocarcinoma in-situ (AIS) to invasive adenocarcinoma (although the rate of this is undetermined). In this pathway EGFR/K-Ras mutations and copy number aberrations are early events, and p53 mutations occur later. The second group of ‘non-terminal respiratory unit phenotype’ adenocarcinomas appear to show a less predictable sequence of genetic changes, and no definite morphological stepwise progression.
Natural history: the natural history of lung carcinomas is of initial local growth and invasion followed by distant metastases. The relative rate of progression is influenced by cell type, with SCLC tending to metastasize widely at an early stage. As the tumour grows within the lung, local effects such as obstructive pneumonia, lobar collapse and haemoptysis may be apparent. The tumour may involve the pleura giving rise to an effusion and invade adjacent structures (e.g. chest wall, mediastinum, diaphragm). The most common sites of metastases are regional nodes, liver, brain, bone and adrenal glands. Patients commonly present with symptoms relating to metastases rather than the primary tumour.
Neuroendocrine tumours: carcinoid and atypical carcinoid tumours may develop on a background of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). This biologically poorly understood entity is associated with a range of neoplastic and non-neoplastic conditions.7 No premalignant lesion of SCLC is known, and much of the genetic and karyotype data is based on cell lines and animal models e making its direct translation to the clinic problematic. Studies describe some similarities with non-small cell lung carcinoma (NSCLC) including obligate p53 and Rb mutations, and other, possibly more SCLC specific features including c-MYC mutations and loss of chromosome 3q.2
Diagnosis of bronchial carcinoma A multi-modality approach including clinical history/examination, radiological (CT-PET) and pathological evaluation is used in arriving at a diagnosis of bronchial carcinoma. The extent to which a particular patient is investigated is often determined by their fitness for further therapy. Multidisciplinary guidelines for the diagnosis of lung cancer, and its subsequent management have been produced (by NICE in the UK,8 and the American College of Chest Physicians in the USA9). The following section provides an overview (reviewed in Rivera et al, 201310) of the samples used to obtain a pathological diagnosis.
SURGERY 32:5
231
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
a
b
c
d
Pathogenesis of adenocarcinoma. This composite figure shows the morphological, stepwise progression from (a) type II pneumocyte hyperplasia to (b) atypical adenomatous hyperplasia (AAH), through (c) bronchioloalveolar carcinoma (BAC) to (d) invasive adenocarcinoma.
Figure 5
Biopsy: tissue biopsy for histological examination provides the optimal method for diagnosis and classification of lung tumours. Biopsies can be obtained from the primary tumour by bronchoscopy or percutaneously under CT guidance or from metastatic deposits (e.g. liver). Making the distinction between SCLC and NSCLC is robust, but studies have demonstrated that accurate distinction between squamous carcinoma and adenocarcinoma is potentially unreliable in small biopsy samples by morphology alone. This has lead to the use of the generic term ‘NSCLC e not otherwise specified (NOS)’. Recent developments in targeted chemotherapy have resulted in a requirement to classify these tumours with greater accuracy, and studies have suggested that with the use of immunohistochemistry around 85% of ‘NSCLC’ can be accurately classified as either adenocarcinoma or squamous carcinoma.11 This requirement is incorporated into current UK Pathology guidelines produced by the Royal College of Pathologists.12
on cytology specimens, especially those where a ‘cell block’ is prepared, which effectively results in a tissue microbiopsy being created. Sputum: sputum cytology should be restricted to patients not fit for more invasive investigations, with central tumour masses, and should not be sent routinely for examination.13 There has been some interest in its utility as a screening tool, but current trends are towards models of risk stratification and usage of repeat low-dose CT scanning in those identified as at highest risk of developing lung cancer. Frozen section (FS): in a proportion of patients, preoperative diagnosis and staging may not have been possible. In these situations, FS may be undertaken to obtain an intraoperative pathological diagnosis. The main roles of frozen section are to confirm malignancy, assess resection margins, examine unexpected intraoperative findings (e.g. pleural nodules), and assessment of lymph nodes. Used appropriately, FS may have a sensitivity for diagnosis of isolated pulmonary nodules >85%.14
Cytology: cytology samples are obtained from the lungs either as bronchial brushings or bronchial washings at bronchoscopy, or percutaneously as fine-needle aspirations (FNAs). Increasingly, FNAs from mediastinal and hilar lymph node metastases obtained by endobronchial ultrasound (EBUS) are being submitted for primary diagnosis. Subclassification with the aid of immunohistochemistry and molecular studies are feasible and reliable
SURGERY 32:5
Mimics of lung cancer (see Table 1 and Reference15) Metastases: the lung is a common site of metastasis. Distinction between primary and secondary tumours may be critical in
232
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
Mimics of lung cancer
TNM 7th edition for staging lung tumours
Malignancy Metastasis C Rare tumour (e.g. lymphoma or sarcoma)
TNM stage Descriptor
C
C C C
Benign tumour Mixed tumours of bronchial submucosal glands Leiomyoma Solitary fibrous tumours
C
Inflammatory/Infectious Pneumonia Tuberculosis Histoplasmosis/coccidiomycosis ‘Inflammatory nodule’
C
Vascular Infarct
C C C
C C
C C C
C C
C C C
Tumour T0 Tis T1
T2
T3
Nodular lesions associated with systemic disease Rheumatoid nodule Wegener’s granulomatosis T4
Nodular patterns of interstitial lung disease Sarcoidosis Cryptogenic organizing pneumonia (COP) Histiocytosis X
Nodes N0 N1 N2
Hamartoma e developmental and acquired Chondroid hamartoma Arteriovenous malformation Others Amyloid tumours Round atelectasis (folded lung) Encysted pleural fluid
N3
No regional lymph node metastases Involvement of ipsilateral peribronchial or hilar nodes Involvement of ipsilateral mediastinal or subcarinal nodes Involvement of contralateral mediastinal, contralateral hilar, contralateral scalene or supraclavicular lymph nodes
Metastases M0 No distant metastases M1a Separate tumour nodule(s) in a contralateral lobe, pleural nodules, or malignant pleural or pericardial effusion M1b Distant metastases
A range of diagnostic possibilities other than primary lung malignancy must be considered both clinically and histologically in patients presenting with a pulmonary nodule. Some of the common differential diagnoses are listed in this table.
Summary of TNM 7 Lung Cancer: This staging system is considered applicable to all tumour types including small cell lung carcinoma and carcinoid tumours. A stage grouping system may be used to combine various combinations of TNM parameters for inclusion of patients in clinical trials.
Table 1
determining optimal management. This requires an accurate history, including specific details of the previous tumour. Both morphology and immunohistochemistry may be helpful, but it has to be accepted that in some instances definite distinction is not possible and management has to be based on the clinical and radiological features of the disease.
Table 2
need to identify certain key components of the tumour (e.g. size, extent of local invasion, lymph node involvement etc). Preoperative staging: the staging of all lung cancers involves imaging in the first instance. It is important to remember that as resection rates for lung cancer are at best 10% to 15%, most patients will be managed on the basis of clinical stage alone. CTPET scanning is used to stage mediastinal nodes and look for occult distant metastases. Confirmation of the clinical stage can be obtained by biopsy (e.g. liver or adrenal biopsy) or FNA (e.g. EBUS FNA of mediastinal nodes) as appropriate if this is uncertain prior to a decision on management being taken.
Benign and inflammatory lung lesions: a proportion of patients presenting with symptoms suggestive of lung cancer will not have malignant disease. Table 1 gives a brief list of possible mimics of lung cancer, and is included as a reminder to consider carefully how the patient is being worked up. Staging lung cancer Staging, according to the TNM classification, represents the best way to predict the prognosis of a patient with lung cancer and for grouping patients together for inclusion in clinical trials. The TNM 7 classification is summarized in Table 2.16 This demonstrates the
SURGERY 32:5
No evidence of primary tumour Carcinoma in-situ Tumour 3 cm, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus) A 2 cm B >2 cme3 cm Main bronchus e 2 cm from carina, invades visceral pleura, partial atelectasis. A >3 cme5 cm or 3 cm satisfying above criteria B >5 cme7 cm Tumour >7 cm or with invasion of chest wall, diaphragm, pericardium, mediastinal pleura, main bronchus <2 cm from carina, total atelectasis, separate nodule(s) in same lobe Tumour of any size which invades mediastinum, heart, great vessels, carina, trachea, oesophagus, vertebra, separate nodule(s) in a different ipsilateral lobe
Postoperative staging of resection specimens: this is based on the examining the fixed resection specimen. Accurate dissection
233
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
and reporting of resection specimens requires the provision of good clinical information, including the demographic details for accession of the specimen to the laboratory, previous pathology reports, a brief description of the operation and resultant specimens, and any specific issues noted at the time of operation (e.g. intrapericardial resection performed). If radiologically there are multiple tumours or any suspicion of interstitial lung disease, this should be communicated on the request form. The pathologist slices the lung after fixation, measures the tumour and notes its relationship to the pleura and bronchial/ vascular resection margins. Blocks of tissue are taken for microscopic examination in order to determine the type of tumour, its extent including involvement of pleura, bronchus and adjacent structures, and any pathology of the background lung. Lymph nodes submitted are examined for evidence of metastatic disease. The final report will include the cell type of the tumour, the TNM stage and the adequacy of excision. Molecular pathology and targeted therapies Oncology practice in the field of lung cancer is changing with the development of agents that specifically target certain processes in specific types of tumour and the development of so called ‘small molecule inhibitors’ that are only effective against tumours harbouring specific genetic abnormalities. This provides a challenge to the pathologist with the need to obtain a refined morphological diagnosis competing with the need to conserve tissue to provide material for molecular assays. The possibility of taking a separate biopsy for molecular analysis (either simultaneously with the diagnostic procedure or subsequently), and re-biopsy of recurrent tumours for repeat genetic testing are becoming considerations in some patients. There is clearly a need within the MDTM setting to discuss the most appropriate management of the limited tissue available in a given case and balance the potential benefits of tailored oncology treatments against the risks associated with the biopsy procedure. In practice, this requires the subdivision of NSCLC into squamous and non-squamous subtypes in as many cases as possible. This will have a direct impact on therapy since some agents (e.g. the antifolate pemetrexed) are only effective in those with ‘non-squamous histology’; others (e.g. the angiogenesis inhibitor bevacizumab) have an unacceptable side effect profile if administered to those with squamous carcinoma Only tumours showing ‘non-squamous’ histology will be referred on for genetic testing to determine EGFR mutation status and thus their suitability for EGFR-TKI inhibitors (e.g. gefitinib). Drugs effective against tumours with an EML-4/ALK translocation are also available and it is likely that agents targeting ‘MET’ and other pathways will become commercially available in the near future.
Figure 6 Macroscopic appearance of mesothelioma. The thickened and malignant pleura forms a ‘rind’ around the lung leading to a distinctive radiological appearance. Such specimens are likely to become extremely rare as there is a move away from radical surgery for this disease.
vaginalis within the scrotum), closely associated with exposure to asbestos fibres. While this usually relates to direct occupational exposure, secondary environmental exposure from living in proximity to industrial facilities using asbestos or from contact with contaminated work clothes at home is recognized to occur. In a small number of cases no evidence of exposure can be identified and the absence of this should not preclude consideration of the diagnosis if the clinical and radiological features are suggestive. Mesothelioma has a long latent period of at least 20 years from exposure until the development of the tumour. Following statutory restrictions on asbestos use in the western world that were imposed in the 1970s and 1980s, the incidence is expected to start to fall within the next 5e10 years. In other parts of the world where asbestos is still widely used, however, the incidence is likely to remain high. The biology of mesothelioma is not well understood, but evidence suggests that asbestos may interact with a variety of cell signalling pathways, including EGFR and PI3K/AKT, and inflammatory cells/the tumour microenvironment to bring about tumourogenesis.17 These observations, coupled with reduced enthusiasm for radical surgical approaches (radical pleuropneumonectomy), mean that decortication and various chemotherapy regimes now provide the mainstays of treatment, and small molecule/immunomodulatory therapies are on the horizon. Regardless of the approach adopted, the disease has a very
Pleural malignancy Mesothelioma (Figure 6) Mesothelioma is an important clinical and medicolegal problem, and in many centres will be managed through the thoracic oncology MDT. Although this tumour is considerably rarer than bronchial carcinoma (around 2200 new cases annually in the UK) it presents challenges in diagnosis and management. Mesothelioma is a primary tumour of the pleural space (although more rarely can be seen in the peritoneal cavity or the tunica
SURGERY 32:5
234
Ó 2014 Elsevier Ltd. All rights reserved.
BASIC SCIENCE
opinion is helpful for all those involved in the care of these patients as it allows informed discussion regarding investigations and therapeutic options. A
poor prognosis, and in the vast majority of cases palliation is the only option with a median survival in the order of 11 months. Mesotheliomas are classified according to their morphological appearances as epithelioid, spindle cell/sarcomatoid or mixed (biphasic). The diagnosis of mesothelioma represents a challenge to the pathologist, as differentiating between reactive and neoplastic mesothelial cells may be problematic. The only definitive marker of a malignant proliferation of mesothelial cells, rather than a reactive one, is the demonstration of infiltration into the underlying connective tissue. The epithelioid component of a mesothelioma can show a wide variety of morphological patterns and as such in biopsy specimens from the pleura the differential diagnosis of mesothelioma includes metastatic adenocarcinoma, metastatic sarcomatoid (spindle cell) carcinoma and even sarcoma depending on the morphology. Mesothelioma typically presents with a large pleural effusion that may be blood stained an aspiration. In more advanced cases there may be chest wall pain from infiltration. Imaging may show evidence of pleural thickening but this is not always seen. Aspiration cytology may demonstrate the presence of atypical mesothelial cells, but a definitive diagnosis of mesothelioma solely on cytology is rarely, if ever, possible given that reactive proliferations may also show marked atypia and confirmation of an infiltrative process is not possible cytologically. Definitive diagnosis therefore requires pleural biopsy, either image-guided core biopsies of pleural based masses or ideally specimens obtained at thoracoscopy. Such specimens should ideally be full thickness to take in the parietal pleura and underling chest wall tissue so that invasion can be confirmed. Differentiation of mesothelioma from metastatic carcinoma and other tumours is carried out using a panel of immunohistochemical stains although it should be noted that none of these are 100% specific and in some cases, particularly with small biopsies, there may be a degree of uncertainty around the diagnosis. It should also be remembered that all cases of proven or suspected mesothelioma, given the close link to occupational asbestos, are regarded as an occupational disease and in the UK deaths must be notified to HM Coroner in England/Wales and the Procurator Fiscal in Scotland.
REFERENCES 1 For example statistical data on UK Cancer is provided by Cancer Research UK (CR-UK), reference: http://www.cancerresearchuk.org/ cancerstats/ (accessed 23/09/13). 2 Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, eds. WHO classification of tumours e pathology and genetics of tumours of the lungs, pleura, thymus and heart. Lyon: IARC Press, 2004. 3 Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung Cancer/American thoracic Society/European respiratory Society International multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6: 244e85. 4 Ishizumi T, McWilliams A, MacAulay C, et al. Natural history of bronchial preinvasive lesions. Cancer Metastasis Rev 2010; 29: 5e14. 5 McCaughan F, Pipinikas CP, Janes SM, et al. Genomic evidence of preinvasive clonal expansion, dispersal and progression in bronchial dysplasia. J Pathol 2011; 224: 153e9. 6 Yatabe Y, Borczuk AC, Powell CA. Do all lung adenocarcinomas follow a stepwise progression? Lung Cancer 2011; 74: 7e11. 7 Davis SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax 2007; 62: 248e52. 8 CG121 Lung Cancer: NICE Guideline. Available at: http://guidance. nice.org.uk/CG121/NICEGuidance/pdf/English (accessed 23/09/13). 9 Andrews TD, Wallace WA. Diagnosis and staging of lung and pleural malignancy e an overview of tissue sampling techniques and the implications for pathological assessment. Clin Oncol R Coll Radiol 2009; 21: 451e63. 10 Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer. Chest 2013; 143(suppl 5). 11 Loo PS, Thomas SC, Nicolson MC, Fyfe MN, Kerr KM. Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. J Thorac Oncol 2010; 5: 442e7. 12 Dataset for lung cancer histopathology reports. 3rd edn. April 2011. London: Royal College of Pathologists. Available through, www. rcpath.org (accessed 23/09/13). 13 Practice guideline e histopathology of limited or no clinical value. 2nd edn. 2005. London: Royal College of Pathologists. Available through, www.rcpath.org (accessed 23/09/13). 14 Marchevsky AM, Changsri C, Gupta I, et al. Frozen sections diagnosis of small pulmonary nodules: accuracy and clinical implications. Ann Thorac Surg 2004; 78: 1755e9. 15 Mayer NJ, Wallace WAH, Kamel HM. Nodular lesions of the lung: a practical approach to histological diagnosis. Curr Diagn Pathol 2003; 9: 188e98. 16 Sobin L, Gospodarowicz M, Wittekind C, eds. TNM classification of malignant tumours. 7th edn. Chichester UK: UICC. Wiley-Blackwell, 2009. 17 Heintz NH, Janssen-Heininger YMW, Mossman BT. Asbestos, lung cancers and mesotheliomas: from molecular approaches to targeting tumour survival pathways. Am J Respir Cell Mol Biol 2010; 42: 133e9.
Metastatic malignancy The pleura is a common site of metastatic malignancy from a wide variety of tumours arising at other sites and the development of a pleural effusion related to this may be the initial presentation. Metastatic adenocarcinoma from lung and breast are the most commonly seen. Clinically and radiologically these may on occasion mimick mesothelioma (pseudo-mesothelioma) with the tumour encasing the lung, emphasizing the need for histological/cytological assessment to obtain an accurate diagnosis.
Conclusion Lung and pleural malignancy are common clinical problems. Accurate pathological diagnosis, classification, and staging of tumours are essential to guide patient management. A basic understanding of the pathological classification of these tumours and the means by which the pathologist reaches their diagnostic
SURGERY 32:5
235
Ó 2014 Elsevier Ltd. All rights reserved.