Pathology of lung tumours

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Pathology of lung tumoursTim Andrews

William Wallace

AbstractLung cancer is a major cause of morbidity and mortality. Approaches to

diagnosis and management are evolving, based on both technological

and scientific advances. In the UK setting, patient management is deter-

mined by a multidisciplinary team (MDT). A basic understanding of the

classification of lung tumours, and the approaches to their pathological

diagnosis is important for all those involved in the lung cancer MDT. To

this end, we present an overview of the current World Health Organization

classification of lung tumours, briefly discuss the aetiology and pathogen-

esis, and then describe pathological aspects of the diagnosis and staging

of lung cancer.

Keywords classification; histopathology; lung cancer; multidisciplinary

team; staging

Introduction

Lung cancer is a major cause of morbidity and mortality in both

the developed and developing world.1 Approaches to diagnosis

and management are evolving, based on both technological and

scientific advances. Patient management is determined by the type

of tumour, extent of disease and associated medical co-morbid-

ities, with (in the UK) treatment decisions taken in the setting of

a multidisciplinary team (MDT) meeting. The pathologist plays

a key role in this process, and an understanding of both the

classification of lung tumours and the approaches used in their

pathological diagnosis is important for all involved in the MDT.

The aim of this article is to briefly review the aetiology of lung

cancer, discuss the World Health Organization (WHO) classifica-

tion of lung tumours, and describe recent advances in our under-

standing of the pathogenesis. We will then discuss pathological

aspects of the diagnosis and staging of lung cancer and their

importance in determining management and prognosis.

Aetiology

Epidemiological studies have demonstrated a strong association

between tobacco, in particular cigarette smoking, and the devel-

opment of bronchial carcinoma. It is, however, important to note

that other risk factors including radiation and asbestos exposure are

recognized and that these tumours can arise in ‘never’ smokers.

Tim Andrews BSc MBChB FRCPath is a Specialist Registrar in Pathology at

the Royal Infirmary of Edinburgh, UK. Conflicts of interest: none

declared.

William Wallace PhD FRCPEd FRCPath is a Consultant Pathologist at the

Royal Infirmary of Edinburgh, and Honorary Senior Lecturer, University

of Edinburgh, UK. Conflicts of interest: none declared.

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The potential role of passive smoking has received considerable

attention in the last few years, although the effect remains difficult

to quantify. It is also recognized that these factors may be syner-

gistic, for example asbestos exposure in smokers results in a much

higher incidence of lung carcinoma than in non-smokers.

Pathological classification of malignant tumours of the lung

Lung tumours are classified according to the WHO scheme

(2004).2 This classification is based on the morphological

appearances of resected tumour specimens, when multiple blocks

of tissue can be examined. This means that for many patients with

bronchial carcinoma, who have diagnosis based on a small biopsy

or cytology specimen, a definitive application of this classification

may not be possible. Broadly tumours can be divided into small

cell carcinoma (SCLC) and non-small cell (NSCLC) subgroups

with the latter having a number of subdivisions.

Non-small cell lung cancer

Squamous cell carcinoma (Figure 1): historically this has been the

commonest tumour in men accounting for around 50% of cases.

They are typically large, centrally placed tumours arising in

patients with a long smoking history. The tumours may be

necrotic and show extensive cavitation. The key histological

features allowing classification as squamous carcinoma are the

presence of keratinization and/or intracellular bridge formation

(prickles). Papillary, small cell, basaloid and clear cell variants

are recognized, although these features are often focal and of no

direct clinical significance.

Adenocarcinoma (Figure 2): these are commonly peripheral in

location and tend to be seen at higher prevalence in women and

in the Far East. Their incidence in men is rising in the West and

the USA for reasons which are not fully understood.

Morphologically the features required for diagnosis are either

glandular or papillary differentiation and/or mucin production.

There is a wide range of sub-types of adenocarcinoma described,

but most tumours are a mixture of the various patterns.

One subtype of note is bronchioloalveolar carcinoma (BAC).

These tumours can be divided into non-mucinous and mucinous

in type. The cells grow along the alveolar walls and particularly

in the mucinous form may be multifocal. The current WHO

classification stipulates that BAC should show no evidence of

stromal invasion and current thinking is that it is a form of ‘in

situ’ adenocarcinoma which may precede the development of an

invasive tumour (see pathogenesis below).

Large cell carcinoma: resected tumours showing no specific

features of either squamous or glandular differentiation can fall

into this category. These by definition are poorly differentiated

tumours and have a poorer prognosis. The most important sub-

type is large cell neuroendocrine carcinoma (LCNEC), which is

a high-grade carcinoma showing morphological and immuno-

histochemical evidence of neuroendocrine differentiation.

Sarcomatoid carcinomas: these are poorly differentiated

tumour characterized by cells showing either a spindle cell or

pleomorphic giant cell morphology, often admixed with more

typical areas of squamous carcinoma, adenocarcinoma or large

cell carcinoma. In some cases foci of true malignant mesen-

chymal differentiation may also been seen. Their prognosis tends

to be poor.

� 2011 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.mpsur.2011.02.010

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 (arrow). (c, high power, H&E) Demonstrating intracellular bridge formation, ‘prickles’ (arrow).

Figure 1

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

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SURGERY 29:5 205 � 2011 Elsevier Ltd. All rights reserved.


Small cell lung carcinoma. (a, medium power, H&E) This is a poorly differentiated, high-grade tumour composed of cells with scanty cytoplasm.

(b,mediumpower, immunohistochemistry) The neuroendocrinemarker CD56 is positive in this tumour. This combinedwith 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

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Small cell lung cancer (Figure 3)

This is the third most common type of carcinoma accounting for

around 20e25% of cases and is sometimes referred to as small

cell undifferentiated carcinoma. It is a very poorly differentiated

carcinoma with neuroendocrine features and is often dissemi-

nated with extensive nodal disease and/or distant metastases at

the time of diagnosis. These tumours are very poorly differenti-

ated being composed of cells with little cytoplasm and are often

extensively necrotic.

Carcinoid tumours

These represent neuroendocrine tumours of the lung at the low

and intermediate end of the malignant spectrum (compared to

LCNEC and SCLC). They may present as well circumscribed

peripheral lesions or polypoid endobronchial tumours. These

tumours are composed to 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 clini-

cians’ 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/

2mm2. Tumours with a mitiotic count of >10/2mm2 are classi-

fied as LCNEC. Differentiation from SCLC on small biopsies is

also important due to therapeutic and prognostic implications,

and can be difficult histologically.

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.

Other tumours

Other, rare, primary lungmalignancies include: salivary gland type

tumours such as adenoid cystic carcinomas arising from the

submucosal glands; lymphoma (usually non-Hodgkin’s lymphoma

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extranodal marginal zone type); and sarcomas such as angio-

sarcomas, leiomyosarcomas and synovial sarcomas.

Pathogenesis and natural history of bronchial carcinomas

In the following section, we present an outline of our current

understanding of the pathogenesis of the main types of bronchial

carcinoma.

Squamous carcinoma (Figure 4): this is described as arising

in a stepwise fashion with respiratory type epithelium

undergoing metaplasia to squamous epithelium which subse-

quently 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

potential for progression to invasive carcinoma, whereas identi-

fication of severe dysplasia or carcinoma in situ are very strong

predicators for adjacent invasive carcinoma, or its development.

As such, an argument for an effect of ‘field change’ throughout

the bronchial epithelium is made,3 with the suggestion that those

with severe dysplasia or worse should be screened for the

development of invasive carcinoma, whereas those with lower

levels of dysplasia should be approached in a different manner. A

greater understanding of the process of carcinogenesis in the

setting is important to allow the development of effective

screening strategies for lung cancer.

Adenocarcinoma (Figure 5): once again a morphological and

molecular progression is described from atypical adenomatous

hyperplasia (AAH), through bronchioloalveolar carcinoma

(BAC) to invasive adenocarcinoma. EGFR and K-Ras mutations

and copy number aberrations are early events in this pathway,

with p53 mutations a later event. While morphologically, AAH

and BAC often co-exist in specimens with invasive adenocarci-

noma, the rate of progression between these preinvasive lesions

and frank carcinoma is difficult to define.4



Pathogenesis of squamous cell carcinoma. This composite figure shows the morphological, step-wise progression from benign metaplastic

squamous metaplasia a, through low-grade dysplasia b, to carcinoma in situ c, and finally invasive squamous cell carcinoma d.

Figure 4

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Neuroendocrine tumours

Carcinoid and atypical carcinoid tumours may develop on

a background of diffuse idiopathic pulmonary neuroendocrine

cell hyperplasia (DIPNECH). This, relatively recently defined and

biologically poorly understood entity, is associated with a range

of neoplastic and non-neoplastic conditions.5

SCLC: no premalignant lesion is known. Study of this disease has

been hampered by a lack of resected tumourmaterial and advanced

disease at time of diagnosis.Much of the genetic and karyotype data

are based on cell lines and animal models e making its direct

translation to the clinic problematic. Itmay be for these reasons that

a clear genetic marker of prognosis in SCLC has failed to emerge.

Studies describe some similarities with NSCLC including obligate

p53 and Rb mutations, and other, possibly more SCLC-specific

features including c-MYC mutations and loss of chromosome 3q.2

SCLC seems to be a more aggressive disease than NSCLC and

typically presents with lymph node involvement or metastases,

arising from a very small primary tumour.

Natural history

Regardless of their mode of development, the natural history for

lung carcinomas is of initial local growth and invasion followed

by distant metastases. The relative rate of progression is influ-

enced 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

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haemoptysis may be apparent. The tumour may involve the

pleura giving rise to an effusion and invade adjacent structures

such as the chest wall, mediastinal structures and diaphragm.

The most common sites of metastases are regional nodes, liver,

brain, bone and adrenal glands. Patients commonly present

with symptoms relating to these rather than the primary

tumour.

Diagnosis of lung cancer (reviewed in6)

Biopsy: tissue biopsy for histological examination provides the

optimal method for diagnosis and classification of lung cancer.

Biopsies can be obtained from the primary tumour by bron-

choscopy or percutaneously under computed tomography (CT)

guidance, depending on the tumours anatomical location, or

from metastatic deposits (e.g. liver). In general, distinction

between SCLC and NSCLC is robust, but studies have demon-

strated that accurate distinction between squamous carcinoma

and adenocarcinoma is unreliable by morphological criteria. This

has lead to the use of the generic term ‘NSCLC e not otherwise

specified’. Recent developments in targeted chemotherapy have,

however, led to 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 accu-

rately classified as either adenocarcinoma or squamous

carcinoma.7



Pathogenesis of adenocarcinoma. This composite figure shows the morphological, step-wise progression from type II pneumocyte hyperplasia

a, to atypical adenomatous hyperplasia (AAH) b, through bronchioloalveolar carcinoma (BAC) c, to invasive adenocarcinoma d.

Figure 5

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Cytology: cytology samples are obtained from the lungs either

as bronchial brushings or bronchial washings at bronchoscopy,

or percutaneously as fine-needle aspirations (FNAs). Increas-

ingly, FNAs from sites of suspected lymph node metastases are

being submitted for primary diagnosis.

Cytology is a reliable diagnostic tool in confirming malignancy,

although the diagnostic yield is less than that for histology. It also

allows distinction between SCLC and NSCLC. Subclassification of

NSCLC can be more difficult as tumour architecture is less

obvious. Immunohistochemistry may, however, be used if suffi-

cient material is obtained.

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.8

Frozen section (FS ): in a proportion of patient’s, preoperative

diagnosis and staging may not have been possible. In these situa-

tions, FS may be undertaken to obtain an intraoperative patholog-

ical diagnosis. The main roles of frozen section are to confirm

malignancy, assess resection margins, examine unexpected intra-

operative findings, for example pleural nodules or nodules in

another lobe, and assessment of lymph nodes. Used appropriately,

FS may have a sensitivity for diagnosis of isolated pulmonary

nodules >85%.9

FS is a resource intensive technique, and therefore its use

should be limited to legitimate cases, as opposed to being

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a surrogate for poor preoperative work-up. Ideally, cases strongly

suspected to harbour specific ‘high-risk’ infections e tuberculosis

or blood-borne viruses e should either not be submitted for FS,

or the laboratory warned in advance to make appropriate facili-

ties available.

Mimics of lung cancer (see Table 1)10

Metastases: the lung is a common site of metastases from

tumours at other sites. Distinction between primary and

secondary tumours may be critical in determining optimal

management. From the pathologists perspective this requires an

accurate history including specific details of the previous tumour.

Both morphology and immunohistochemistry (e.g. oestrogen

receptors may be expressed on metastatic carcinoma of the

breast) may be helpful in this distinction, 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.

Benign and inflammatory lung lesions: a proportion of

patients presenting with symptoms suggestive of/being investi-

gated for lung cancer will not have malignant disease. Table 1

gives a brief list of possible mimics of lung cancer in these

situations, and is included as a reminder to consider carefully

how the patient is being worked up.



Mimics of lung cancer

Malignancy

Primary lung cancer

Metastasis

Rare tumour, e.g. lymphoma or sarcoma

Benign tumour

Mixed tumours of bronchial submucosal glands

Leiomyoma

Solitary fibrous tumours

Inflammatory/infectious

Pneumonia

Tuberculosis

Histoplasmosis/coccidiomycosis

‘Inflammatory nodule’

Vascular

Infarct

Nodular lesions associated with systemic disease

Rheumatoid nodule

Wegener’s granulomatosis

Nodular patterns of interstitial lung disease

Sarcoidosis

Cryptogenic organizing pneumonia (COP)

Histiocytosis X

Hamartoma e developmental and acquired

Chondroid hamartoma

Arteriovenous malformation

Others

Amyloid tumours

Round atelectasis (folded lung)

Encysted pleural fluid

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 consid-

ered in this table.

Table 1

TNM 7th edition for staging lung tumours

TNM stage Descriptor

Tumour

T0 No evidence of primary tumour

Tis Carcinoma in situ

T1 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 <2cm

B >2 cme3 cm

T2 Main bronchus d 2 cm from carina, invades

visceral pleura, partial atelectasis.

A >3 cme5 cm or <3 cm satisfying above

criteria

B >5 cm e 7 cm

T3 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.

T4 Tumour of any size which invades

mediastinum, heart, great vessels, carina,

trachea, oesophagus, vertebra, separate

nodule(s) in a different ipsilateral lobe

Nodes

N0 No regional lymph node metastases

N1 Involvement of ipsilateral peribronchial or

hilar nodes

N2 Involvement of ipsilateral mediastinal or

subcarinal nodes

N3 Involvement of contralateral mediastinal,

contralateral hilar, contralateral scalene or

supraclavicular lymph nodes.

Nx Regional lymph nodes cannot be assessed,

e.g. previously removed.

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.

Summary of TNM 7 Lung Cancer: stages T1, T2, and M have been subdi-

vided; and multiple ipsilateral tumours moved from M to T4, compared to

TNM 6. Furthermore, this staging system is considered applicable to all

tumour types including small cell lung cancer and carcinoid tumours.

It is important to be aware of the TNM system which is being used in a given

institution to avoid confusion in communication.

A stage grouping system may be used to combine various combinations of

TNM parameters for inclusion of patients in clinical trials. TNM, tumour/

node/metastasis.

Table 2

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Staging lung cancer

Staging, according to the tumour/node/metastasis (TNM) clas-

sification, 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 recently published TNM 7 clas-

sification is summarized in Table 2, including notes of changes

made from the previous edition.11 This demonstrates the need to

identify certain key components of the tumour such as size,

extent of local invasion, lymph node involvement etc. The

staging may be clinical (i.e. based on examination of the patient

and imaging studies) or pathological when this is supported by

the results of histological or cytological evaluation.

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 10e15%, most

patients will bemanaged on the basis of imaging techniques alone.

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One major recent advance is the use of CT-positron emission

tomography (CT-PET) scanning to stage mediastinal nodes and

look for occult distant metastases. This has been shown to be

prone to significant false-positive rates for mediastinal node



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.

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involvement, thus tissue sampling for confirmation is often

required where feasible. This may be achieved by mediastino-

scopy with lymph node biopsy for histological assessment or,

increasingly, endobronchial ultrasound-guided (EBUS) node

aspiration with the generation of specimens for cytological

examination.

Postoperative staging of resection specimens: this is based on

the examining the fixed lobectomy or pneumonectomy spec-

imen. Accurate dissection and reporting of resection specimens

require the provision of good clinical information. In addition

to the demographic details required for accession of the spec-

imen to the laboratory, reference to previous pathology should

be made, the operation and resultant specimens described

briefly, and any specific issues noted at the time of operation

(e.g. intra-pericardial 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 at the hilum. 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 should be labelled as to their site of origin

and 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.

Screening for lung cancer

A screening test must fulfil a number of defined criteriae brieflye

it is sensitive and specific for answering the question posed, it is

safe and acceptable to the patient undergoing the procedure, and it

is cost effective. Although a large number of studies have looked at

means of screening for lung cancer including sputum analysis,

interval high-resolution CT scanning12 and addition of auto-

fluorescence techniques to standard bronchoscopy,13 all have

failed, as yet, to be incorporated into mainstream clinical practice.

Whether these failings are related to methodological weaknesses

in the studies or a failure to fully appreciate the biology of lung

cancer as a disease remains to be seen. Pragmatically, encour-

agement of smoking cessationmay be themost effective approach,

at least at the population level.

Future developments

Molecular studies in lung cancer are starting to identify specific

biomarkers that will predict responses to given chemotherapeutic

agents. Specific mutations in exons 18e21 of the EGFR gene are

associated with clinical response to tyrosine kinase receptor

inhibitors and up-regulation of ERCC1may confer a better response

to platinum-based chemotherapy.14 These findings suggest that

future pathological assessment of lung cancer will become

increasingly sophisticated and that in time the tumours may be

classified more on a molecular basis and less on morphology. With

these developments come technical challenges, including a need to

determine reproducible threshold values for semi-quantitative

assays, and an ability to perform tests on the small diagnostic

biopsy and cytology specimen available in the majority of lung

cancer patients.

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Mesothelioma (Figure 6)

This is a tumour of the pleural space, associated with exposure to

asbestos fibres. Although not strictly a ‘lung tumour’, mesothe-

lioma is an important clinical and medicolegal problem, and in

many centreswill bemanaged through the thoracic oncologyMDT.

The biology of mesothelioma is not well understood, but recent

evidence suggests that asbestos may interact with a variety of cell

signalling pathways, including EGFR and PI3K/AKT to bring about

tumourogenesis.15 These observations, coupled with reduced

enthusiasm for radical surgical approaches (radical pleuro-

pneumonectomy), mean that the surgical and clinical oncology

approaches to mesothelioma are changing, with decortication and

various chemotherapy regimes now proving the mainstays of

treatment. Regardless of the approach adopted, the disease has

a very poor prognosis, and in many cases palliation is the only

option.

The diagnosis of mesothelioma represents a challenge to the

pathologist, as differentiating between reactive and neoplastic

mesothelial cells may be problematic in histology sections and

almost impossible on cytology. Ideally thoracoscopic pleural biop-

sies should be provided for assessment. Mesotheliomas are classi-

fied according to their morphological appearances as epithelioid,

spindle cell/sarcomatoid or mixed (biphasic). The differential

diagnosis of mesothelioma often includes metastatic adenocarci-

noma, but may also include sarcomatoid carcinoma or sarcomas.



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Conclusion

Lung cancer is amajor cause ofmorbidity andmortality, and looks

likely to remain so for many years. Currently, treatment decisions

are taken in the MDT setting and are based on the subtype of the

tumour, extent of disease and fitness of the patient. Pathological

assessment plays an important role in this process, and an

understanding of the classification of lung tumours and the tech-

niques used to arrive at amorphological diagnosis are important to

improve clinical decision-making. A

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Pathology of lung tumours