Pulmonary Diseases

Malignant Tumors of the Lung

and Pleura
Fadi W. Karim MD MEd
Professor Emeritus- CWRU and CCLCM
University of Balamand

Pathologic Basis of Disease – 10th Edition- Chapters 15

Lung Tumors: General

•90% to 95% are carcinomas.

•About 5% are bronchial carcinoid tumors.
•2% - 5% are mesenchymal and other
miscellaneous neoplasms (example
bronchial hamartoma).
Lung Cancer
• The most frequently diagnosed major and the most common cause of
cancer mortality worldwide.

• Since the early 1990s, lung cancer incidence and mortality rates have been
decreasing in men, due to the decreased smoking rates. However,
decreases in smoking patterns among women lag behind those of men.
• Since 1987 more women have died each year of lung cancer than of breast
cancer, which for > 40 years had been the major cause of cancer death.
• Occurs most often between ages 40 and 70 years, with a peak incidence in
the 50s or 60s. Only 2% of all cases appear before the age of 40.
Tobacco Smoking
• About 80% of lung cancers occur in active smokers or those who
stopped recently, and there is a nearly linear correlation between the
frequency of lung cancer and pack-years of cigarette smoking. The
increased risk is 60 times greater in habitual heavy smokers (two
packs a day for 20 years) than in nonsmokers.

• However, since lung cancer develops in only 10% to 15% of smokers,

there are likely to be other factors that interact with smoking to
predispose individuals to this deadly disease.
Tobacco Smoking
• Women are more susceptible to carcinogens in tobacco than men.

• Pipe and cigar smokers also incur an elevated risk, albeit only
modestly. Chewing tobacco is not a safe substitute.

• The long-term effects of electronic cigarette aerosols are not known,

as “vaping” is a relatively recent phenomenon.

• Each year about 3000 nonsmoking adults die of lung cancer as a

result of breathing secondhand smoking.
What of heavy smokers who never develop
cancer?
• “Chance”

• Modified by genetic variants. Specific P-450 variants have an

increased capacity to activate procarcinogens in cigarette smoke.

• Individuals whose peripheral blood lymphocytes show more

numerous chromosomal breakages after exposure to tobacco related
carcinogens (mutagen sensitivity genotype) have a greater than 10-
fold higher risk of developing lung cancer.
Lung Cancer: Risk factors: Industrial and Occupational
risk of lung cancer
Occupational carcinogens Risk

Asbestos Insulation and shipyard workers, increase in

risk of lung cancer after 10 years of exposure,
with concurrent smoking increases risk 90 fold.
Arsenic Smelters and vineyard workers,
Upper lobe predominance.
Nickel Squamous cell carcinoma-MC
Radiation Uranium mining, Oat cell carcinoma -MC
Haematite mining Due to radon exposure
Hard rock mining Chromium exposure, Squamous cell- MC
Chloromethyl Oat cell -MC
Ethers and mustard gas Squamous and undifferentiated -MC

Soots , Tars Coke oven workers

Oils and cokes Gas house workers, roofers
IACM Journal April-June 2012
Lung Cancer: Risk factors- Air Pollution

• Chronic exposure to air particulates in smog may cause lung

irritation, inflammation and repair which increases the risk of
cancers.

- Radon is a ubiquitous radioactive gas that has been linked

epidemiologically to increased lung cancer in uranium miners,
particularly those who smoke. Low-level exposure (e.g., in
well-insulated homes in areas with naturally high levels of
radon in soil) may also increase the incidence of lung cancers,
but this point remains unsettled.
Lung Cancer: Risk factors: Molecular Genetics
• Smoking-related carcinomas of the lung arise by a stepwise
accumulation of oncogenic “driver” mutations that result in the
neoplastic transformation of pulmonary epithelial cells- step wise
progression from normal.

• “ Field effect” Those few cells that accumulate a sufficient panoply of

complementary driver mutations to acquire all of the hallmarks of
cancer develop into invasive carcinomas
Lung cancer: Non-smokers

• The WHO estimates that 25% of lung cancer worldwide occurs in

never smokers. This percentage is probably closer to 10% to 15% in
Western countries.
• These cancers occur more commonly in women and most are
adenocarcinomas.
• Cancers in nonsmokers are more likely to have EGFR mutations, and
almost never have KRAS mutations; TP53 mutations are not
uncommon, but occur less frequently than in smoking-related
cancers.
Malignant Epithelial Lung Cancers
The relative proportions of the major
categories are:
• Adenocarcinoma (50%)
• Squamous cell carcinoma (20%)
• Small cell carcinoma (15%)
• Large cell carcinoma (2%) • Other (13%)

Combinations of squamous cell carcinoma

and adenocarcinoma or small cell and
squamous cell carcinoma occur in about
14% and 5% of patients, respectively.
LUNG CANCER: Location- Central/hilar region (more often
squamous cell carcinomas) vs. peripheral lung (more often
adenocarcinoma)
(A) Gland-forming adenocarcinoma; inset shows thyroid transcription factor 1 (TTF-1) expression, as detected by
immunohistochemistry. (B) Well-differentiated squamous cell carcinoma showing keratinization (arrow). (C) Small cell
carcinoma. There are islands of small, deeply basophilic cells and areas of necrosis. (D) Large cell carcinoma. The tumor cells are
pleomorphic and show no evidence of squamous or glandular differentiation.
LUNG CANCER
Squamous Cell Adenocarcinoma

Small Cell Carcinoma Large cell

Squamous Cell Carcinoma
• 40–70-year-old smoker
• May present with: Cough, Weight loss, Chest pain, Dyspnea
• Squamous cell carcinoma more likely to arise in central/hilar region
Precursor lesions of squamous cell carcinomas. Some of the earliest (“mild”) changes in smoking-damaged respiratory epithelium include goblet
cell hyperplasia (A), basal cell (or reserve cell) hyperplasia (B), and squamous metaplasia (C). More ominous changes include the appearance of
squamous dysplasia (D), characterized by the presence of disordered squamous epithelium, with loss of nuclear polarity, nuclear hyperchromasia,
pleomorphism, and mitotic figures. Squamous dysplasia may progress through the stages of mild, moderate, and severe dysplasia. Carcinoma-in-
situ (CIS) (E), the stage immediately preceding invasive squamous carcinoma (F), by definition has not penetrated the basement membrane and
has cytologic features similar to those in frank carcinoma.
 Squamous Cell Carcinoma of the Bronchus
Pathology

Normal Cartilage of Bronchus

Squamous Cell Carcinoma: Highly atypical nuclei with nucleoli,

moderate amounts cytoplasm with dyskeratosis, invading normal
structures
Normal Respiratory Epithelium
Dyskeratosis: Keratinization (bright pink) in
Oviedo, Original Photographs, Pathpresenter,
2019 all areas, not just surface
Molecular features: Squamous cell carcinoma
Highly associated with exposure to tobacco smoke and harbors diverse
genetic aberrations, many of which are chromosome deletions involving
tumor suppressor loci.
Losses, especially those involving 3p, 9p (site of the CDKN2A gene),
and 17p (site of the TP53 gene), are early events in tumor evolution (
can be detected in histologically normal mucosal cells of smokers.
Most have mutations in TP53, and p53 protein overexpression: 10%
to 50% of squamous dysplasia and 60% -90% of carcinoma in situ.
The CDKN2A tumor suppressor gene, which encodes the cyclin-
dependent kinase inhibitor p16, is mutated in 65% of tumors. Many
squamous cell carcinomas also have amplification of FGFR1, a gene
encoding the fibroblast growth factor receptor tyrosine kinase
Adenocarcinoma Pathology
 Adenocarcinoma of the Lung
Precursor Lesions

Adenocarcinoma in situ:

Atypical adenomatous hyperplasia is a small Adenocarcinoma in situ (formerly called

precursor lesion (≤5 mm) characterized by
dysplastic pneumocytes lining alveolar walls that
are mildly fibrotic (Fig. 15.41). It can be single or
multiple and can be in the lung adjacent to invasive
tumor or away from it.
bronchioloalveolar carcinoma) is a lesion that is less than
3 cm in size and is composed entirely of dysplastic cells
growing along pre-existing alveolar septa. The cells have
more dysplasia than atypical adenomatous hyperplasia
and may or may not have intracellular mucin
Molecular features: Adenocarcinoma
• Associated with tobacco smoking, but less so than other histologic
subtypes; as a result, it is the most common subtype in never-smokers.
1/3 of adenocarcinomas have oncogenic gain-of-function mutations
involving components of growth factor receptor signaling pathways
Gain-of-function mutations in genes encoding several different
receptor tyrosine kinases: EGFR (10%-15% of tumors in Caucasians
and a higher percentage of nonsmoking Asian women; ALK ( 3% to
5%); ROS1 (1% ); MET (2% t- 5%); RET (1%-2%).
Gain-of-function mutations in serine/threonine kinases: BRAF (2%) ,
PI3K (2%) or in KRAS gene (roughly 30%), all of which encode
signaling molecules that lie downstream of receptor tyrosine kinases
in growth factor signaling pathways.
Large Cell Carcinoma
 Bronchial Carcinoid (5%)
- NET/Low Grade
• Resemble intestinal carcinoids
showing neuroendocrine
differentiation of Kulchitsky cells
containing neurosecretory
granules. Often resectable and
curable (50-95%).

 Obstruction polypoid mass

 Mucosal infiltrating plaque
 Spread to local lymph nodes
 Bronchial Carcinoid Tumor

Normal Cartilage from Bronchus Bronchial Carcinoid Tumor: Groupings of cells with uniformly round nuclei
with salt and pepper chromatin and moderate amounts pink cytoplasm
Bronchial Carcinoid
Typical Carcinoid
- NET/Low Grade
Atypical Carcinoid
NET/Intermediate Grade
Small Cell carcinoma
• Cigarette smoking
• Most patients have distant metastases at diagnosis
• Sensitive to radiation and chemotherapy
• Mean survival with treatment is one year
• Most commonly associated with paraneoplastic syndromes:
• ACTH (Adrenocorticotropic Hormone): Can produce Cushing syndrome
• ADH (Antidiuretic Hormone): Can produce hyponatremia due to inappropriate
ADH secretion
Small Cell carcinoma
Molecular features: Small cell carcinoma
Shows the strongest association with smoking and despite its divergent
histologic features shares many molecular features with squamous cell
carcinoma.

This includes frequent loss-of-function aberrations involving TP53 (75%

to 90% of tumors), RB (close to 100% of tumors), and chromosome 3p
deletions. Also common is amplification of genes of the MYC family.
Lung cancer – Clinical course
The most insidious and aggressive neoplasms in the realm of oncology.

In the usual case it is discovered in patients in their 50s or older whose

symptoms are of several months' duration.

The major presenting complaints are cough (75%), weight loss (40%), chest
pain (40%), and dyspnea (20%).

Symptoms of metastases depend on the site, for example, back pain in bone
metastases, headache, hemiparesis, cranial nerve damage, and seizures in
brain metastases.
Lung cancer: Local effects
Clinical Features NETs

• The clinical manifestations of bronchial carcinoids emanate from their

intraluminal growth, their capacity to metastasize, and the ability of
some of the lesions to elaborate vasoactive amines.
• Intraluminal growth :Persistent cough, hemoptysis, secondary infections,
bronchiectasis, emphysema, and atelectasis

• Capable of producing the classic carcinoid syndrome (intermittent attacks of

diarrhea, flushing, and cyanosis). Approximately, 10 % of bronchial carcinoids
give rise to this syndrome.

• Most carcinoids do not have secretory activity, do not metastasize to distant

sites and follow a relatively benign course for long periods and are resectable.
Lung cancer: Paraneoplastic Syndromes (1-10%)
• Antidiuretic hormone (ADH), inducing hyponatremia due to inappropriate
ADH secretion –Small cell carcinoma
• Adrenocorticotropic hormone (ACTH), producing Cushing syndrome – Small
cell carcinoma
• Parathormone, parathyroid hormone-related peptide, prostaglandin E, and
some cytokines, all implicated in the hypercalcemia often seen with
lSquamous cell cancer
• Calcitonin, causing hypocalcemia
• Gonadotropins, causing gynecomastia
• Serotonin and bradykinin, associated with the carcinoid syndrome.
Lung cancer: Paraneoplastic Syndromes (1-10%)
• Lambert-Eaton myasthenic syndrome (muscle weakness is caused by
autoantibodies directed to the neuronal calcium channel;
• Peripheral neuropathy, usually purely sensory.
• Dermatologic abnormalities, including acanthosis nigricans.
• Hematologic abnormalities, such as leukemoid reactions.
• Hypercoagulable states, such as Trousseau syndrome (deep vein
thrombosis and thromboembolism)
• hypertrophic pulmonary osteoarthropathy, associated with clubbing
of the fingers.
Lung cancer: Immunohistochemical stains

IHC VanderLaan P. Surgical Pathology 11 (2018) 515–522

 METASTATIC LUNG CANCER

Metastases (more common)

to Lung from:
1. breast
2. colon
3. kidney
4. skin (melanoma)

Metastases from Lung to:

1. bone
2. liver
3. brain
4. pleura
Lung Cancer TNM staging
 KEY CONCEPTS CARCINOMAS OF THE LUNG
• The three major histologic subtypes are adenocarcinoma (most common),
squamous cell carcinoma, and small cell carcinoma.

• Each of these is clinically and genetically distinct. Small cell lung carcinomas are
best treated by chemotherapy because almost all are metastatic at presentation.
The other carcinomas may be curable by surgery if limited to the lung.
Combination chemotherapy also is available along with tyrosine kinase inhibitors
for those with EGFR, ALK, ROS, and MET mutations.

• Smoking is the most important risk factor for lung cancer; the most common
subtype related to smoking in men and women is adenocarcinoma.
Adenocarcinoma also is the most common subtype in non-smokers.
KEY CONCEPTS CARCINOMAS OF THE LUNG
• Precursor lesions include atypical adenomatous hyperplasia and
adenocarcinoma in situ (formerly bronchioloalveolar carcinoma) for
adenocarcinomas and squamous dysplasia for squamous cell
carcinoma.
• Tumors 3 cm or less in diameter characterized by pure growth along
pre-existing structures (lepidic pattern) without stromal invasion are
now called adenocarcinoma in situ.
• Lung cancers, particularly small cell lung carcinomas, often cause
paraneoplastic syndromes.
What are the various lung biopsy methods?
What are the various lung biopsy methods?

1. Sputum cytology
2. Transthoracic- CT guided
3. Transbronchial: obtains
alveoli*
4. Endo-bronchial: visible lung
lesion*
5. EBUS

*BAL – Broncho-alveolar
lavage/BW-Bronchial washing/BB-
Bronchial brushing
EBUS

• Endobronchial Ultrasound (EBUS) - an

ultrasound probe on the tip of a bronchoscope
• A bronchoscope has a camera and can have a
needle inserted into the sheath of the scope
• Can be done in EBUS suite or new cone beam
procedure room with a 360o x-ray image
EBUS: Endobronchial Ultrasound
 Utility of EBUS- Fine Needle Aspiration (FNA)
• Originally used in the nodal
staging of non-small cell lung
cancer
• Determines tumor repsectability and
prognosis
• Eliminates the need for surgical
staging in up 70% of patients
• Mediastinal lymphadenopathy
• Sarcoidosis
• Lymphoma
• Other mediastinal masses
• Germ cell tumors
• Thymoma
• Amyloid deposition
• Ectopic thyroid
• Central lung lesions
Adapted from the American Thoracic Society
mapping scheme, radiologyassistant.com
EBUS- ROSE(Rapid on site evaluation) : Diff Quik
Stain
Adenocarcinoma: TTF-1 (thyroid transcription factor), Napsin-A
positive (aspartic proteinase of the pepsin family involved in
maturation of surfactant protein B)
Lung cancer
Squamous cell carcinoma: p63 (member of p53
family at 3q27-29 but not a tumor suppressor gene
that encodes at least 6 different proteins) and p40
positive
Small cell carcinoma: TTF-1,
synaptophysisn , chromogranin, CD56
positive
 Clinical application of targeted therapies depends on
……………

accurate histological sub-classification of NSCLC. This information is

particularly important in patients with advanced NSCLC (stage III and IV NSCLC) and
in patients with metastatic lung cancers, since the majority of these patients are not
candidates for surgical resection of the tumor and in those patients fine needle
aspiration (FNA) biopsy of the tumor/lesion is frequently performed to obtain tumor
tissue for the diagnosis, histologic and molecular testing of the tumor .
• The need to accurately subtype lung cancers initially stemmed from
chemotherapy protocols, which discriminated between SCLC and NSCLC.

• NSCLC were generally treated with similar chemotherapy regimens.

• That is why distinction between Squamous cell carcinoma, and

Adenocarcinoma was deemed irrelevant for clinical purposes.

However, differentiating between AC and SCC

is important.
•
Non-small-cell lung cancer (NSCLC) genetics
Frequency of molecular aberrations in lung adenocarcinomas

Tsao et al, Journal of Thoracic Oncology, 2016, Vol. 11 No. 5

A history of never smoking or low smoking

Strongest predictor of EGFR mutation followed by ALK rearrangement

▫ Generally associated with never smokers or light smokers.
▫ Younger patient age.
▫ Found almost exclusively in adenocarcinomas no cases have been
identified in pure SCC.
 https://www.cancer.gov/about-
cancer/treatment/types/immun
Immunotherapy PDL-1 testing otherapy/checkpoint-inhibitors
PD-1 and PD-L1 inhibitors
PD-1 inhibitors
 Pembrolizumab (Keytruda)
 Nivolumab (Opdivo)
 Cemiplimab (Libtayo)
PD-L1 inhibitors
 Atezolizumab (Tecentriq)
 Avelumab (Bavencio)
 Durvalumab (Imfinzi)
CTLA-4 inhibitors
Ipilimumab (Yervoy)
LAG-3 inhibitors

Relatlimab This drug is given along with the PD-1

https://www.cancer.org/treatment/treatments-and-side-effects/treatment- inhibitor nivolumab ( Opdualag).
types/immunotherapy/immune-checkpoint-inhibitors.html
Lung Cancer: Treatment- Adenocarcinima
• Activating mutations in EGFR (15% of all cases) or in other tyrosine kinases
with specific kinase inhibitors prolongs survival. Many tumors that recur
carry new mutations that generate resistance .

• Activating KRAS mutations (30% of cases) appear to be associated with a

worse prognosis, regardless of treatment.

• Adenocarcinoma and squamous cell carcinoma respond in subsets of cases

to checkpoint inhibitor therapy, which has produced improvements.

• Antibody-drug conjugates that deliver chemotherapy selectively to tumor

cells and immune checkpoint inhibitors are being tested
Key points

• The diagnosis, staging, and

selection of therapy for patients
with lung cancer are increasingly
reliant on cytology and small biopsy
specimens obtained via minimally
invasive means.
• Combining cytomorphologic
features with immunohistochemical
testing can provide the accurate
and specific lung cancer diagnosis
required for clinical decision
making.
Lung Cancer: Treatment
• The best “treatment” for lung cancer is smoking prevention.

• Early detection trials in high-risk individuals using low-dose computed

tomography, which is capable of detecting some early (resectable) non–
small cell lung cancers: High cost and false-positive (noncancer) findings.

• Overall 5-year survival rate is only 18.7%: 52% for localized, 22% for
regional metastasis, 4% with distant metastases.

• Small cell carcinoma: Radiation therapy and chemotherapy, however, most

patients present with advanced stage disease, the median survival is
approximately 10 months and the cure rate is close to zero.
Pleural Tumors
Pleural Tumors
• Secondary metastatic involvement is far more common than are
primary tumors.
• Metastasis from primary neoplasms of the lung and breast.
• Malignancy from any organ of the body may spread to the pleural spaces.

In most metastatic involvements, a serous or serosanguineous effusion follows

that often contains neoplastic cells - Cytologic examination
Malignant Mesothelioma
Malignant Mesothelioma
• The lifetime risk in heavily exposed individuals is 7% to 10%
• There seems to be no increased risk of mesothelioma in asbestos
workers who smoke. Asbestos exposure is the only known cause
of mesothelioma, while smoking is by far the leading cause of lung
cancer. But asbestos exposure causes six times more cases of lung
cancer than mesothelioma
• Cytogenetic abnormalities: Homozygous deletion of the tumor suppressor
gene CDKN2A/INK4a, which occurs in about 80% of mesotheliomas.
Deletion (FISH) involving ch. 9p can helpful distinguish it from reactive
mesothelial lesions.
 Mesothelioma: Malignant cells
Malignant Mesothelioma forming tubular structures

H and E and Immunohistochemistry : Calretinin, D2–40,

WT1, and CK5/6 as mesothelial markers.
Electron Microscopy: Long TTF-1, Napsin-A, CEA as lung adenocarcinoma markers
slender villi- left ( not used p40, p63, CK5/6, MOC-31 as squamous cell markers.
for diagnosis at present)