PATHOLOGY OF LUNG CANCER

•Walid AL-SALEH MD, D.E.S, Ph.D, MIAC, FIAPth

•AL-BAIROUNI UNIVERSITY HOSPITAL

•May 2010

‘Biopsy’ techniques in lung cancer

diagnosis

•Sputum cytology

•Bronchial brushings and washings

•Fluids

•FNA cytology – primary or mets

•Transbronchial biopsy

•Bronchial biopsy

•Core biopsy – primary or mets

•Liver biopsy

•Mediastinoscopy

•Lymph node excision

•VATS biopsy / resection

•Thoracotomy tumour excision

Increase in

Cell number

and

Tissue architecture

AAH LNMBAC

AdCISInvasive

adenocarcinoma

Large cell

Undifferentiated

&

Sarcomatoid

carcinomas

Bronchial

Squamous

Dysplasia

Squamous

CIS

Invasive

Squamous Cell

carcinoma

De novo development from

unknown precursor ?

?

?

Adenocarcinoma, gross

appearance

Bronchioloalveolar ca, subtypes

Squamous cell carcinoma,

gross appearance

Large cell carcinomaAn undifferentiated malignant epithelial tumour that lacks the

cytologic features of small cell, squamous or adenocarcinoma.

The cells typically have large nuclei, prominent nucleoli and a

moderate amount of cytoplasm

•VariantsLarge cell Neuroendocrine carcinoma (LCNEC)

Basaloid carcinoma

Lymphoepithelioma-like carcinoma

Clear cell carcinoma

Large cell carcinoma with rhabdoid phenotype

•This diagnosis CANNOT be made on small biopsy samples or cytology

•It is only a diagnosis for surgically resected tumours

or (perhaps) large tumour samples

Undifferentiated large cell ca

Adenosquamous

carcinoma(x20)

Bronchial

Squamous

Dysplasia

Squamous

CIS

Invasive

Squamous Cell

carcinoma

Molecular progression of disease in bronchial squamous carcinogenesis

8p21-23 LOH

3p14.2 (FHIT) inactivation *

3p12 (DUTT1) LOH

17p13 (P53) LOH

P53 mutation *5q (APC-MCC)

loss

* Smoking-related

EGFR, HER2/neu,

p53, MCM2,

Bcl2, VEGF all increased

Fhit, p16, RAR-beta

all decreased

Bcl2:bax ratio >1

P63 overexpressed

K-RAS mutations ?

Altered MMP expression

Insulin Growth Factor pathways

p16 INK4A-Cyclin D1-CDK4-RB pathway

Disruption by

P16 loss and

Cyclin D1 increase

13q14 (RB) loss or Rb inactivation less common

The evolving role of

histology and molecular biology

in non-small cell lung cancer

Non-small cell carcinoma is NOT one diseaseDiverse histological types

Multiple tissue origins; myriad molecular characteristics

Prognostic factors poorly understood

Selective therapies being developed

Predictive factors emerging, including histological type

Diagnostic challenges posed

The right drug for the right patient at the right time

Prognostic factors in NSCLC:Likely natural history of tumour

in the absence of clinical intervention

•Stage

•Influence of histology?

•Individual molecular markers

•Gene expression

….amongst many others!

Adenocarcinoma

Squamous cell ca

Large cell carcinoma

Kerr et al, JTO 2007; 2:s4,801-802

n = 202

P<0.05

J Clin Pathol 2006; 59,790-800

Poor prognosis?

HER2 VEGF

CCNE MMP2

Ki67 MMP9

P53 CD44v6

Good Prognosis?

P27 Ecadherin

P16 β-catenin

bcl2

☻

☻☻

☻ ☻

Over-expression results in……

Meta analysis

None convincing

Histology and prognosis:

Squamous carcinomas

•Not all cases behave in the same way

•Better prognosis

–Well differentiated

–Papillary endobronchial

–‘Creeping’ squamous carcinoma (Nakamoto et al,

1993)

•Worse prognosis

–Poorly differentiated

–Basaloid variants

Adenocarcinomas

•Pure BAC – 100% 5YS

•% pattern combinations in mixed adenocarcinoma

–High ‘BAC’ is good

–High Solid is bad

–Papillary ??

•Multifocal disease is biologically different

Large cell carcinomas

• Generally more aggressive

• Basaloid variant is bad

• LCNEC is bad

Sarcomatoid carcinomas

• Highly invasive

• Rapidly growing

• Poor prognosis

Relatively fewlarge studiescontrolled for stage with good pathologicalclassification

Conclusion

•The role of the pathologist is to help the oncologist in providing the right drug for the right patient at the right time!!