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Pathologic Anatomy

Lung Cancer

Prof. Pier Paolo Piccaluga

Department of Experimental, Diagnostic and Specialty Medicine, Bologna University

Department of Pathology JKUAT, Nairobi

Estimated age-standardized incidence and mortality rates (Europe and World) in 2018,

worldwide, both sexes, all ages

EUCAN, IARC/WHO November 2014

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Cancer Word Incidence

Breast 46,3

Prostate 29,3

Lung 22,5

Colorectum 19,7

Cervix uteri 13,1

Stomach 11,1

Liver 9,3

Corpus uteri 8,4

Thyroid 6,7

Ovary 6,6

Cancer World Mortality

Lung 18,6

Breast 13

Colorectum 8,9

Liver 8,5

Stomach 8,2

Prostate 7,6

Cervix uteri 6,9

Thyroid 4,2

Ovary 3,9

Corpus uteri 1,8

IARC/WHO

Estimated number of incident cases and deaths worldwide, both sexes, all ages

IARC/WHO

Estimated number of incident cases and deaths, both sexes, all ages in Italy

IARC/WHO

Epidemiology

• Most common cancer in both men and women

– 2nd in USA (In men, prostate cancer is more common, while in women breast cancer is more common.

– 3rd in Europe (prostate, breast, colorectal)

• About 13% of all new cancers are lung cancers in USA.

• Leading cause of cancer: more people die of lung cancer than of colon, breast, and prostate cancers combined.

American Cancer Society, 2019

Epidemiology

• Lung cancer mainly occurs in older people.

• Most people diagnosed with lung cancer are 65 or older;

• A very small number of people diagnosed are younger than 45.

• The average age of people when diagnosed is about 70.

American Cancer Society, 2019

Risk factors

Risk factors you can change

• Tobacco smoke

– 80% of deaths in smokers

– Number of cigarettes/day

– Total time of exposure

– Cigar and pipe = cigarettes

– Light cigarettes = standard cigarettes

• Secondhand smoke

• Exposure to radon

– Second cause and first in non-smokers

• Exposure to asbestos

– Synergistic with tobacco smoke

Risk factors 2

Risk factors you can change

• Exposure to other cancer-causing agents in the workplace– Radiocatives (uranium)

– Inhaled chemicals such as arsenic, beryllium, cadmium, silica, vinylchloride, nickel compounds, chromiumcompounds, coal products, mustard gas, and chloromethyl ethers

– Diesel exhaust

• Taking certain dietary supplements– Avoid Beta carotene in smokers

• Arsenic in drinking water– Asia, South America

Risk factors 3

Risk factors you cannot change

• Previous radiation therapy to the lungs

• Air pollution– 5% of lung cancer deaths

• Personal or family history of lung cancer

Factors with uncertain or unproven effects on lung cancer risk

• Smoking marijuana

• Talc mills

• E-cigarettes

Direct effects of nicotine on cell proliferation

Classificazione WHOWHO Classification 2015

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Epithelial tumors

1.Adenocarcinoma

•Lepidic adenocarcinoma

•Acinar adenocarcinoma

•Papillary adenocarcinoma

•Micropapillary adenocarcinoma

•Solid adenocarcinoma

•Invasive mucinous adenocarcinoma

– Mixed invasive mucinous and non-mucinous adenocarcinoma

•Colloid adenocarcinoma

•Fetal adenocarcinoma

•Enteric adenocarcinoma

•Minimally invasive adenocarcinoma

– Nonmucinous

– Mucinous

•Preinvasive lesions

– Atypical adenomatous hyperplasia

– Adenocarcinoma in situ

• Nonmucinous

• Mucinous

2. Squamous cell carcinoma

• Keratinizing squamous cell carcinoma

• Nonkeratinizing squamous cell carcinoma

• Basaloid squamous cell carcinoma

• Preinvasive lesion

– Squamous cell carcinoma in situ

3. Neuroendocrine tumors

• Small cell carcinoma

– Combined small cell carcinoma

• Large cell neuroendocrine carcinoma

– Combined large cell neuroendocrine carcinoma

• Carcinoid tumors

– Typical carcinoid tumor

– Atypical carcinoid tumor

• Preinvasive lesion

– Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

4. Other types

• Large cell carcinoma

• Adenosquamous carcinoma

• Sarcomatoid carcinomas

• Salivary gland-type tumors

– Mucoepidermoid carcinoma

– Adenoid cystic carcinoma

– Epithelial-myoepithelial carcinoma

– Pleomorphic adenoma

• Papillomas

• Adenomas

Mesenchymal tumors

Lymphohistiocytic tumors

Tumors of ectopic origin

Metatstatic tumors

Staging

• Stage I: cancer is located only in the lungs and has not spread to any lymph nodes.

• Stage II: The cancer is in the lung and nearby lymph nodes.

• Stage III: Cancer is found in the lung and in the lymph nodes in the middle of the chest, (locally advanced disease)

– stage IIIA: cancer has spread only to lymph nodes on the same side of the chest where the cancer started.

– stage IIIB: cancer has spread to the lymph nodes on the opposite side of the chest, or above the collar bone.

• Stage IV: advanced disease. Cancer has spread to both lungs, to fluid in the area around the lungs, or to another part of the body, such as the liver or other organs.

• Limited stage: In this stage, cancer is found on one side of the chest, involving just one part of the lung and nearby lymph nodes.

• Extensive stage: In this stage, cancer has spread to other regions of the chest or other parts of the body.

Non small cell lunga cancer (NSCLC) Small cell lunga cancer (SCLC)

Staging and Survival

SEER stage 5-year relative survival rate

Localized 60%

Regional 33%

Distant 6%

All SEER stagescombined

23%

EER stage 5-year relative survival rate

Localized 29%

Regional 15%

Distant 3%

All SEER stages combined

6%

Non small cell lunga cancer (NSCLC) Small cell lunga cancer (SCLC)

J Thorac Oncol. 2015;10: 1243–1260

Adenocarcinoma

Adenocarcinoma

• Def: invasive, malignant, epithelial tumor with glandular differentiation or mucin production

• 2° in the world by frequency; 1st in USA

Atypical adenomatous hyperplasia

Smll lesion (<5mm): dysplastic

pneumocytes lining alveolar walls,

that are mildly fibrotic.

It can be single or multiple

(sometimes close to a cancer area)

Adenocarcinoma

Adenocarcinoma Morphology

• Different growth patterns

– Acinar

– Lepidic

– Papillary

– Micropapillary

– Solid

With mucin

production

Adenocarcinoma Morphology

• From well differentiated

(obvious glandular

elements) to papillary

(resembling other

cancers) or solid masses

with occasional mucin

production

Colloid adenocarcinoma

• Tissue architecture effaced by large mucous «lakes»

• Small aggregates of neoplastic cells

• DD vs. metastatic lesions

Minimally invasive adenocarcinoma (MIA)

J Thorac Oncol. 2015;10: 1243–1260

Adenocarcinoma in situ (AIS)

J Thorac Oncol. 2015;10: 1243–1260

Spread Through Air Spaces

• An additional pattern of invasion is now clearly recognized consisting of spread through air spaces (STAS).

• STAS consists of micropapillary clusters, solid nests, or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma

• It probably contributes to the significantly increased recurrence rate for patients with small stage 1 adenocarcinomas who undergo limited resections and the worse prognosis observed by others.

• STAS is now incorporated into the definition of invasion that is used to separate lepidic adenocarcinomas from MIA and AIS.

• STAS is a pattern of invasion to be reported similar to visceral pleural and vascular invasion

Spread Through Air Spaces

Invasion of adenocarcinoma in the pattern of spread through air spaces (STAS).

A, Tumor cells are presentwithin airspaces in the lung parenchyma beyond the edgeof the tumor (arrows).

B, These consists of micropapillaryclusters and single cells (arrows).

J Thorac Oncol. 2015;10: 1243–1260

Squamous cell Carcinoma

Squamous cell Carcinoma

• Def: invasive, malignant, epithelial tumor with squamous differentiation

• Most commonly in males

• Strong association with tobacco smoke

• Central lesion (segmental/subsegmental)

Sqamous cell metaplasia/dysplasia

• Squamous metaplasia of the airway epithelium is characterized by replacement of bronchiolar or bronchial epithelium with squamous epithelium

• Squamous metaplasia of the alveolar epithelium is characterized by replacement of type I and type II pneumocytes with squamous epithelium.

• Mild, moderate, severe

Squamous cell carcinoma in situ

• Asymptomatic

• Not detectable at imaging

• Atypical cells at cytology (sputum, BAL)

• Eventually followed by invasive carcinoma

Epithelial cytological atypia is severe with mitoses seen at all

levels. Cell maturation is absent.

Squamous cell carcinomaGross pathology

• Different growth patterns

1.Exophytic

– Into the bronchial lumen

– Distal atelectasia

– Infections

2.Infiltrating peribronchial tissues

3.Dislocating lung tissue forming large, caulilflower like masses

Squamous cell carcinomaHistology

• SqCC is characterized by:

1.Keratinization

– Squamous pearls

– Individual cells with markedly eosinophilic dense cytoplasm

2.Intercellular bridges

• Well, moderately, and scarcely differentiated became keratinizing and nonkeratinizing

keratinizing

nonkeratinizing

Basaloid SqCC

• Uncommon histological variant composed of cells exhibiting cytological and tissue architectural features of both squamous cell lung carcinoma and basal cell carcinoma

TTF-1 positiveCD56 positiveChromogranin positiveSynaptophysin positive

CK5/6 positiveCK7 negative

Large cell carcinoma

Large cell carcinoma

• Indifferentiated large cell tumor (anaplastic)

• No glandular/squamous differentiation

• Aboundant cytoplasm

• Vescicular chromatin

• Evident nucleulus

Other types of epithelial tumors

Salivary gland-type tumors

• Rare

• All ages, no gender preference

• More often endoluminal

• Morphologically analogue to those arising in salivary glands

• Origin: bronchial, submucosal glands

• DD vs. metastasis from salivary glands

• Overall indolent behavior

– Adenoid cystic carcinoma: poor response to radiotherapy and chemotherapy

Adenosquamous carcinoma• Association of the two histological variants

• At leat 10% constituted by each type

• Sual overlap between the histological types

• Possibly more aggressive

Adenosquamous

carcinoma

Sarcomatoid carcinoma

• Morphologically simulating a sarcoma

• Fusated cells

• Vorticoid/spindle cell appearnce

• IHC necessary for diagnosis

Neuroendocrine tumors

Neuroendocrine cells in the lung

• Kultscitsky cells (Feyrter cells/APUD ssystem)

– Basal layer bronchial epithelium

– Sub-bronchial glands

• Single elemnts or groups (neuroepithelial bodies)

• Increasing from bronchus to bronchioles

– Rare in terminal bronchioles and alveoli

neuroepithelial body

Diffuse, Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH)

• Currently considered a possible pre- invasive lesion

• Generalizedproliferation of scattered single neuroendocrine cells, forming small nodules or linear proliferations

Neuroendocrine tumors

Generally characterized by:

• Organoid growth pattern

• Presence of neurosecretory

granules

• Positive staining for

neuroendocrine markers

Carcinoid tumors

• 5-10% of lung tumors

• Low grade malignancies

• Age often <40 y

• M=F

• Mostly 3-4 cm in the main bronchi

– Peripheral as solid nodules

– Infiltrating the brnchial wall

Carcinoid tumorsHistology

• Organoid

• Trabecular

• Palisanding

• Ribbon

• Rosette like

• Cells separated by thin fibrovascular stroma

• Uniform rounded shape

• Eosinophilic cytoplasm

Typical vs. atypical carcinoid

• Mitosis 2-10/10 HPF

• Spotss of necrosis

• Increased pleomorphism

• More prominent nucleoli

• More likely to have

– Disorganized growth

– Lymphoatic invasion

• Mitosis <2 /10 HPF

• Lack of necrosis

Carcinoid tumorsClinical features

Depends on:• Intraluminal growth (obstruction)• Capacity to give metastasis• Production and secretion of

vasoactive amines (carcinoid syndrome)(10%)– Diarrhea– Flushing– Cianosis

• 95% OS at 5y for typical vs. 70% for atypical

Lerge cell neuroendocrine carcinoma (LCNEC)

• Anaplastic

• Large cells

• Prominent nucleoli

• The differentiation between LCNEC and SCLC can be difficult in some cases

• 30% survival at 5y

Transl Lung Cancer Res. 2017 Oct; 6(5): 530–539.

Small cell lung carcinoma

Small cell lung carcinoma (SCLC)

• Most aggressive lung cancer

• 5y survival 5%

• Early metastasis

• Age: 50-70 years

• >98% in smokers

• Central or peripheral

Small cell carcinomaHistology

• Relatevily small cells with scant cytoplasm

• Ill-defined cell borders

• Granular chromatin

• No nucleoli

• Cells can be:

– Round

– Oval

– Spindle

• High mitotic rate

Small cell lung carcinomaHistology

• Cell growth in clusters

• Extensive necrosis

• Neurosecretory granules

• Neuroendocrine markers

• Hormone secretion (PTH)

• BCL2 expression (90%)

Immunophenotype of Lung Cancers

Immunohistochemistry 1

• Adenocarcinoma vs. Squamous cell carcinoma

– Adenocarcinoma: TTF-1 (NKX2-1)* and/or Napsin A

– Squamous cell carcinoma: p40, CK5/6, and TP63*

• * not very specific!

TTF1

NAP1

KRTSA

TP63

Immunohistochemistry 2

• Neuroendocrine markers: CHGA (chromogranin A), SYP (synaptophysin), NCAM1 (CD56), or INSM1.

INSM1

Immunohistochemistry 3

Carcinoid, Chromogranin A

Immunohistochemistry 4

ALK

ROS1

RET

EGFR

Markers of genetic lesions/therapeutic targets

PD1-PDL1 axis inhibitors

PD-L1 (CD274) is an immune modulator that promotes immunosuppression by

binding to PD-1 (PDCD1). PD-L1 on the surface of tumor cells inhibits an immune-

mediated attack by binding to PD-1 on cytotoxic T-cells

Genetics of lung cancer

Clinical relevance of genetic lesions

10-15%

Targeting EGF/EGFR-Erlotinib

- Gefitinib

Cell proliferation

Cell survival

Molecular subsets of lung adenocarcinoma

2%

ALK translocations in lung cancer

Prognosis and outcome

Extension/spread

• Extension to pleural surface and pericardium

• Bronchial, tracheal and mediastanil nodes most often involved

• Metastasis

– Lymphoatic

– Ematogenous

– Brain (20%), bone/bone marrow (20%), liver (30-50%), adrenal glands (>50%)…

– Early event (but not in SqCC)

Survival rates by stage and by hostology

http://dx.doi.org/10.1136/thoraxjnl-2013-203884

February 2015Oncology letters 9(2):563-568

Thank you

Q&A