Pathology

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Lecture (5) : Lung tumors

Color Index :-
▪VERY IMPORTANT
▪Extra explanation
▪Examples
▪Diseases names: Underlined
▪Definitions ..‫وأنت لعلِة الُدنيا طبيُب ؟‬.. ‫* كيف تعُّلك الُدنيا بشيٍء‬
 \

1- Know the epidemiology of lung

cancer

2-Is aware of classification of

bronchogenic carcinoma which
include: squamous carcinoma,
adenocarcinoma, small cell and large
cell (anaplastic) carcinomas.

3- Understand the predisposing

factors of bronchogenic carcinoma.
Objectives :

4 -Understands the clinical features

and gross pathology of bronchogenic
carcinoma. Know the precursors of
squamous carcinoma (squamous
dysplasia) and adenocarcinoma
(adenocarcinoma in situ and atypical
adenomatous hyperplasia).

5- Have a basic knowledge about

neuroendocrine tumors with special
emphasis on small cell carcinoma
and bronchial carcinoid.

6- Is aware that the lung is a frequent

site for metastatic neoplasms.
LUNG TUMORS
Most lung tumors are malignant.

Primary lung cancer is a common disease BUT metastatic tumors are the
most common lung carcinoma seen in clinical practice.

95% of primary lung tumors are carcinomas

5% carcinoids, mesenchymal malignancies (fibrosarcomas,

leiomyomas) and lymphomas

The most common benign lesions are hamartomas

Epidemiology
1. Primary lung cancer is the most common fatal cancer in both men and
women worldwide.
a. Accounts for >30% of cancer deaths in men
b. Accounts for >25% of cancer deaths in women

2. Incidence of lung cancer is declining in men but increasing in women.

3. Peak incidence is at 55 to 65 years of age.

Classification of bronchogenic
carcinoma

Malignant epithelial tumors/ Miscellaneous

Malignant malignant tumor
bronchogenic carcinoma mesothelial tumor

1- Non-Small Cell Lung 2- Small cell lung 3-Combine 4- Carcinoid Malignant 1-

5- Others
Carcinoma (NSCC) : carcinoma (SCC) patterns tumor mesothelioma Carcinosarcoma

2- Pulmonary
1. Squamous cell Epithelial
carcinoma
blastoma

Fibrous (spindle
2. cell) 3- Melanoma
Adenocarcinoma

3. Large cell Biphasic 4- Lymphoma

carcinoma

5- Others
DR. RIKABI’S NOTES - HAMARTOMA
• Hamartomas are abnormal tissue growth in the lung that are normal
somewhere else. E.g. in the liver, or kidney…
• Hamartomas usually present as a coin like lesion.
• They represent 5% of all cases.
• 30 to 40% of hamartoma cases involve a mutation in the P53 gene.
• They usually have well defined outlines (Well circumscribed).
• The patient doesn’t complain or doesn’t know that it’s there.
• It’s called a ”Leave me alone” lesion due to the big operation to remove it by a
lobar or partial lobarsectomy.
• It consists of cartilage, C.T, fat, glandular tissue, and some inflammatory cells.
CLASSIFICATION OF MALIGNANT EPITHELIAL
TUMORS OF LUNG: (BRONCHOGENIC
CARCINOMA)
1. Non-Small Cell Lung Carcinoma (NSCC) (70%-75%)
1. Squamous cell carcinoma (25%-35%)
2. Adenocarcinoma, including bronchioloalveolar carcinoma
(30%-35%).
3. Large cell carcinoma (10%-15%).

2. Small cell lung carcinoma (SCC) (20%-25%).

3. Combine patterns (5%-10%).

- Most frequent patterns:
- Mixed squamous cell carcinoma and adenocarcinoma.
- Mixed squamous cell carcinoma and SCLC.

4. Carcinoid tumors

5. Others
Both small cell carcinoma and carcinoids are neuroendocrine
tumors as both arise from the neurendocrine cells normally present
in the lung

Bronchogenic carcinoma
It is important to differentiated NSCC from SCC because treatment are different

NSCC therapy SCC Therapy

• Surgical:- offers the best chance

for curing. Chemotherapy is very effective
• Radiation:- controls local because small cell carcinomas are
disease. Radiation therapy is highly responsive to chemotherapy
most commonly used to palliate
symptoms.
• Chemotherapy:- not effective.
PREDISPOSING FACTORS OF
BRONCHOGENIC CARCINOMA
1- Tobacco smoking:
• Some 85% of lung cancers occur in cigarette smokers.
• Most types are linked to cigarette smoking, but the strongest
association is with squamous cell carcinoma and small cell
carcinoma.
• The nonsmoker who develops cancer of the lung usually has an
adenocarcinoma.
• Is directly proportional to the number of cigarettes smoked
daily and the number of years of smoking.
• Cessation “‫ ”انقطاع تام‬of cigarette smoking for at least 15 years brings the
risk down.
• Passive smoking “inhaling of smoke from other people's cigarettes”
increases the risk to approximately twice than non-smokers.
• Cigarette smokers show various histologic changes, including squamous
metaplasia of the respiratory epithelium which may progress to
dysplasia, carcinoma in situ and ultimately invasive carcinoma.
2- Radiation:
• All types of radiation may be carcinogenic and increase the risk of
developing lung cancer. Tradium and uranium workers are at
risk

3- Asbestos:
• increased incidence of cancer with asbestos exposure, especially in
combination with cigarette smoking.

4- Industrial exposure:
• to nickel and chromates, coal, mustard gas, arsenic, iron etc.

5- Air pollution:
• May play some role in increased incidence.
• Indoor air pollution especially by radon “chemical element (noble gas
series)”

6- Scarring:
• sometimes old infarcts, wounds, scar, granulomatous infections
are associated with adenocarcinoma.
 PRECURSOR LESIONS
• Three types of precursor epithelial lesions are recognized:

Squamous dysplasia and Atypical adenomatous Diffuse idiopathic pulmonary

carcinoma in situ can lead to: hyperplasia can lead to: neuroendocrine cell
hyperplasia can lead to:
• Squamous cell • Adenocarcinoma • Neuroendocrine
carcinoma tumors

• It should be noted that the term "precursor" does not imply that progression to invasion will occur
in all cases.

TYPES OF BRONCHOGENIC CANCER:

1. Squamous cell carcinoma (25%-35%)

I. Non-Small Cell Lung 2. Adenocarcinoma, including

Types:

Carcinoma (NSCC) (70%-75%) bronchioloalveolar carcinoma (30%-35%)

II. Small cell lung carcinoma 3. Large cell carcinoma (10%-15%)

(SCC) (20%-25%).

Squamous cell carcinoma (SCC)

• Second most common bronchogenic carcinoma
• Strong association with smoking (25 times risk)
• Before Males >Females, now incidence in females is rising because of smoking.
• It has a poor prognosis
• This type of cancer is preceded by:
squamous
years of progressive mucosal changes carcinoma invasive
metaplasi dysplasia
of respiratory epithelium in situ SCC
a

• SCC arise in the central airways (centrally located).

• So they appear as a hilar mass, frequently cavitate
• Tumor cells secrete a parathyroid hormone (PTH)- like peptide leading to hypercalcemia.
• Histologically, these tumors are graded according to degree of squamous differentiation and
tumors ranges from:
(A ) (B) (C)

well-differentiated squamous cell carcinoma moderately differentiated SqCC poorly differentiated SqCC
 Adenocarcinomas
• Adenocarcinomas is now the most frequent histologic subtype of bronchogenic
carcinoma ( before the squamous cell carcinoma was the first)

• More common in patients under the age of 40, women and non-smokers (They do not
have a clear link to smoking history)

• Peripheral adenocarcinomas are sometimes associated with pulmonary scars (from a

previous pulmonary inflammation/infection) and therefore are also referred to as scar
carcinomas. (adenocarcinoma is peripherally located not related to smoking but its related to
scars and that’s why it call scar carcinoma)

• Tend to metastasize widely at early stage

• They are classically peripheral tumors arising from the peripheral airways and alveoli.

• The hallmark of adenocarcinomas is the tendency to form glands that may or may not
produce mucin.

• Rarely cavitate

• Associated with hypertrophic pulmonary osteoarthropathy “Clubbing of the fingers”(look

at pic4)

• 20% of adenocarcinoma of the lung are associated with mutations of epidermal growth
factor receptor (EGFR) and respond to its anti therapy

pic1 pic2 Pic3 : TTF1 pic4

 Adenocarcinoma Precursor Lesions

Minimally invasive Adenocarcinoma in situ Atypical adenomatous

adenocarcinoma of lung (AIS)* hyperplasia
(MIA)

• Lesion ≤3 cm • lesion less than 3 cm • small lesion (≤5 mm)

• describes small solitary • composed entirely of • characterized by
adenocarcinomas with dysplastic cells growing dysplastic
either pure lepidic growth along preexisting pneumocytes lining
or predominant lepidic alveolar septa alveolar walls that are
growth with ≤5 mm of • Lepidic growth pattern mildly fibrotic
stromal invasion. • no feature of necrosis or
invasion

*AIS

• Formerly called bronchioloalveolar carcinoma but now it’s referred to as adenocarcinoma

in situ according to the new classification of lung cancers

• What is AIS ? malignant cells grow along alveolar septa

• ** ” tumor cells which may be nonluminous, mucinous or mixed grow on a monolayer along the
alveolar septa which serve as scaffold this has been termed as a lepidic growth pattern, an
allusion to the resemblance of neoplastic cells to bufferflies sitting on a fence” Robbins
 Large Cell Carcinoma*

• Frequency: 10 %

• strongly associated with smoking

• usually located peripherally.

• This group of carcinomas is undifferentiated.

• They are made up of large and anaplastic cells.

• They may exhibit neuroendocrine or glandular differentiation markers when studied

by immunohistochemistry or electron microscopy.

• Poor prognosis.

* “Large cell carcinomas are undifferentiated malignant epithelial tumors that lack the
cytologic features of small cell carcinoma and have no glandular or squamous differentiation. The
cells typically have large nuclei, prominent nucleoli, and a moderate amount of cytoplasm. Large
cell carcinomas probably represent squamous cell or adenocarcinomas that are so undifferentiated
that they can no longer be recognized by means of light microscopy. On ultrastructural
examination, however, minimal glandular or squamous differentiation is common.” robbins
SMALL CELL CARCINOMAS
SCLC are a type neuroendocrine tumors arising from neuroendocrine cells
+ more common in men.

Highly malignant and aggressive tumor, poor prognosis, rarely

resectable.

Strongly associated with cigarette smoking. 95% of patients are

smokers

Centrally located perihilar mass with early metastases (Early

involvement of the hilar and mediastinal nodes)

- Chemotherapy responsive
- least likely form to be cured by surgery; usually already
metastatic at diagnosis
Able to secrete a host of polypeptide hormones like ACTH,
antidiuretic hormone (ADH), calcitonin, gastrin-releasing peptide
and chromogranin.

It may be associated with paraneoplastic syndrome, Cushing’s, and Eaton-

Lambert syndrome

Eaton-Lambert syndrome

• An autoimmune disease

• The immune system attacks the connection

between nerve and muscle (the
neuromuscular junction) and interferes with
the ability of nerve cells to send signals to
muscle cells lead to muscle weakness
Microscopically composed of small, dark, round to oval, lymphocyte-like
cells with little cytoplasm.

Electron microscopy: dense-core neurosecretory granules.

Bronchogenic carcinoma sites:

• Squamous cell CA
Central
tumors • Small cell CA

• Adenocarcinoma
• - bronchial derived
Peripheral • - bronchioloalveolar ca
tumors
• Large cell carcinoma
Molecular genetics in lung cancer:
A. Most common oncogenes*: KRAS, MYC family, HER-2/neu, BCL-2, EGFR
(epidermal growth factor receptor found in 20% of pulmonary adenocarcinomas, if certain
mutation is positive, will respond to anti-tyrosine kinase therapy**)
*A mutated form of a gene involved in normal cell growth, may cause the growth of cancer cells.
**Is targeted therapy that interferes with specific cell signaling pathways allowing target-specific
therapy for selected malignancies. Tyrosine kinases are an important target because they play an
important role in the modulation of growth factor signaling.
If the KRAS gene is not present then ALC I targeted treatment can be used. Anti PDLI is used for
Squamous Carcinoma.
Most common suppressor* genes: p53 (most common), RB1, p16
*When this gene mutates to cause a loss or reduction in its function, the cell can progress to
cancer.

Clinical features of bronchogenic carcinoma:

o Can be silent *early stage, no symptoms or insidious lesions.
o Cough *when the tumor gets larger -Most common symptom (75% of cases)-
o Weight loss (40% of cases)
o Chest pain (30% of cases)
o Hemoptysis (25%–30% of cases) *especially when cavitation starts.
o Dyspnea *when it’s enlarged and obstructing the lung.
o Hoarseness *because of invasion of hilum –recurrent laryngeal nerve paralysis-, chest pain
*especially when it reaches pleura, pericardial or pleural effusion.
o Symptoms due to invasion and metastatic spread.
May also be manifest by the following:
Superior vena cava syndrome: invasion leads to obstruction of venous drainage
which leads to dilation of veins in the upper part of the chest and neck resulting in
swelling and cyanosis of the face, neck, and arms.

Pancoast tumor (superior sulcus tumor): Apical neoplasms may invade the
brachial sympathetic plexus to cause severe pain, numbness and weakness in the
distribution of the ulnar nerve.
Pancoast tumor is often accompanied by destruction of the first and second ribs and
thoracic vertebrae. It often coexists with Horner syndrome

Horner syndrome: invasion of the cervical thoracic sympathetic nerves and it leads to
ipsilateral enophthalmos (displacement of the eyeball within the orbit –eyes goes inside-)., miosis, ptosis, and
facial anhidrosis. (Anhidrosis is the inability to sweat normally –leads to dryness in facial areas-)

The combination of these clinical findings is known as Pancoast syndrome.

Complications of bronchogenic carcinoma:
• Bronchiectasis
• Obstructive pneumonia
• Pleural effusion, bloody
• Hoarseness from recurrent laryngeal nerve paralysis
• Paraneoplastic syndrome

Paraneoplastic syndrome:
 Are extrapulmonary, remote effects of the tumor.
 3% to 10% of lung cancers develop paraneoplastic syndromes.

Squamous cell Adenocarcinomas can Small cell carcinomas

carcinomas may secrete lead to hematologic ACTH (leading to
parathyroid hormone-like manifestations (repeated Cushing's syndrome)
peptide leading to coagulations, thrombosis ADH (water retention
hypercalcemia. in different parts of the and hyponatremia)
body) and Digital clubbing
due to reactive periosteal
changes

Clinical features
and complications
of bronchogenic
carcinoma
Spread of bronchogenic carcinoma:
1. Lymphatic spread.
 Successive chains of nodes (scalene nodes).
 Involvement of the supraclavicular node (Virchow’s node).
2. Extend into the pericardial or pleural spaces. Infiltrate the superior vena cava.
3.A tumor may extend directly into the esophagus, producing obstruction, sometimes
complicated by a fistula.
[Link] nerve invasion usually causes diaphragmatic paralysis
[Link] invade the brachial or cervical sympathetic plexus (Horner’s Syndrome). Or
Pancoast syndrome
[Link] metastasis to liver (30-50%), adrenals (>50%), brain (20%) and bone
(20%).

* If we check X-Ray and there’s a mass in the lung. And the abdominal scan shows
bilateral adrenal gland enlargement. Then it is bronchogenic carcinoma with
metastasis to adrenals.

Prognosis: (poor in general, especially if there’s metastasis)

• Histological types and the stage of lung cancer determine the outcome
• Survival is better for early stage disease, except for small cell carcinoma (very early
metastases)
• Non–small cell cancers fare better than small cell carcinoma
• Overall combined 5-year survival rate is ~15%
 CARCINOID TUMOR
• Carcinoid tumors of the lung are neuroendocrine neoplasms
• These neoplasms account for 2% of all primary lung cancers,
• It shows no sex predilection, and are not related to cigarette smoking or other
environmental factors.
• Usually seen in adults
• Can be central or peripheral in location.
• Tumor cells produce serotonin and bradykinin leading to carcinoid syndrome
• Can occur in patients with Multiple Endocrine Neoplasia (MEN-I)
• Low grade malignancy, Often resectable and curable.
• Spreads by direct extension into adjacent tissue

MORPHOLOGY OF TYPICAL CARCINOID TUOMORS

Composed of uniform cuboidal cells that have regular round nuclei with few mitoses
and little or no anaplasia.

Electron microscopy: dense-core neurosecretory granules

 MESOTHELIOMA
• Malignant tumor of mesothelial cells lining the pleura
• Highly malignant neoplasm
• Most patients (70%) have a history of exposure to asbestos
• Smoking is not related to mesothelioma
• The age of patients with mesothelioma is 60 years.
• Pleural mesotheliomas tend to spread locally within
the chest cavity, invading and compressing major structures.
• Metastases can occur to the lung parenchyma and mediastinal lymph nodes, liver,
bones, peritoneum etc.
• Treatment is largely ineffective and prognosis is poor
• Few patients survive longer than 18 months after diagnosis

CARCINOMA METASTATIC TO THE LUNG

• Pulmonary metastases are more common than Primary Lung Tumors

• Metastatic tumors in the lung are typically multiple and circumscribed. When
large nodules are seen in the lungs radiologically, they are called cannon ball
metastases

• The common primary sites are the breast, stomach, pancreas, kidney and colon.
SUMMARY:
MCQ’S:

• 1- Which of the following is the most aggressive bronchogenic carcinoma ?

• a) Small cell carcinoma
• b) Adenocarcinoma
• c) Squamous cell carcinoma
• 2- Which of the following is develop in the site of pulmonary inflammation ?
• a) Small cell carcinoma
• b) Adenocarcinoma (scar carcinoma)
• c) Bronchoalveolar adenocarcinoma
• 3- Which of the following is primary neoplastic lesion of pleura?
• a) Adenocarcinoma
• b) Squamous cell carcinoma
• c) Mesothelioma
• 4- Which of the following is more common in women and nonsmokers?
• a) Squamous cell carcinoma
• b) Carcinoid
• c) Adenocarcinoma
• 5- Which of the following is clearly linked to smoking?
• a) Adenocarcinoma
• b) Squamous cell carcinoma
• c) Large cell carcinoma
•

Answers: 1- A 2- B 3- C 4- C 5- B
CASES:

• 1- A 67 year old non smoker female presents with worsening dyspnea for the past 6 weeks.
She has noticed 13 kg weight loss and occasional excessive sweating. On examination, she is
in mild respiratory distress. Her RR is 22 and her BP is 134\76. The physician has also noticed
ptosis on her left eye and miosis . chest X-ray shows peripheral mass in her right upper lobe
of the right lung . what the most probable diagnosis :
• a) Large cell carcinoma
• b) Small cell carcinoma
• c) Adenocarcinoma
• d) Squamous cell carcinoma
• 2- A 53-year-old male smoker presents to the emergency department with exertional dyspnea
that has progressed to dyspnea at rest and a cough for 1 month. Two weeks ago, he started
having headaches and noticed swelling of his face. He noticed some urination disorders.
Laboratory tests has shows excessive concentration of ADH (antidiuretic hormone ).A chest
radiograph demonstrates a suspicious nodule in the right hilar region. Which of the following
types of lung cancer is most commonly associated with the signs and symptoms this patient is
experiencing?
• a) Adenocarcinoma of the lung
• b) Small cell lung cancer (SCLC)
• c) Large cell carcinoma
• d) Squamous cell lung cancer .

Answers: 1)c 2)b

 CASES:
• 3- 49-year-old man has sudden onset of severe lower abdominal pain with hematuria. He passes a ureteral
calculus. Laboratory studies show that the calculus is composed of calcium oxalate. He is found to have a serum
calcium concentration of 10.2 mg/dL, serum phosphorus level of 2.9 mg/dL, and serum albumin level of 4.6 g/dL.
A chest radiograph shows a 7-cm hilar mass in the right lung. Chest CT scan shows prominent central necrosis in
this mass. Which of the following neoplasms is most likely to be associated with these findings?
• a) Metastatic colonic adenocarcinoma
• b) Small cell anaplastic carcinoma
• c) Bronchioloalveolar carcinoma
• d) Squamous cell carcinoma
• 4- A 57-year-old woman comes to her physician because she has had a cough and pleuritic chest pain for the past 3
weeks. On physical examination, she is afebrile. Some crackles are audible over the left lower lung on
auscultation. A chest radiograph shows an ill-defined area of opacification in the left lower lobe. After 1 month of
antibiotic therapy, her condition has not improved, and the lesion is still visible radiographically. CT-guided needle
biopsy of the left lower lobe of the lung is performed, and the specimen has the histologic appearance of neoplastic
growth along pre existing alveolar septa without invasion . Which of the following neoplasms is most likely to be
present in this patient?
• A) Adenocarcinoma
• b) Bronchioloalveolar carcinoma
• c) Hamartoma
• d) Squamous cell carcinoma
• 5- A 40-year-old woman has never smoked and works as a file clerk at a university that designates all work areas
as “nonsmoking.” She goes to the physician for a routine health maintenance examination. On physical
examination, there are no remarkable findings. A routine chest radiograph shows a 3-cm, sharply demarcated mass
in the left upper lobe of the lung. Fine-needle aspiration of the mass is attempted, but the pathologist performing
the procedure remarks, “This is like trying to biopsy a ping-pong ball.” No tissue is obtained. Thoracotomy with
wedge resection is performed. On sectioning, the mass has a firm, glistening, bluish white cut surface. A culture of
the mass yields no growth. Which of the following terms best describes this mass?
• a) Hamartoma
• b) Adenocarcinoma
• c) Large-cell carcinoma
• d) Squamous cell carcinoma

Answers: 3) D 4) B 5) A
 ‫‪Males:‬‬
‫‪Females:‬‬
‫بثينة آل ماجد ‪-Leader :‬‬ ‫محمد باحاذق‪-Leader :‬‬
‫‪ -‬فاطمة بالشرف‬ ‫فهد عبدهللا الفايز‬
‫‪ -‬روان الحربي‬ ‫سيف المشاري‬
‫‪ -‬رهف الشمري‬ ‫محمد األصقه‬
‫‪ -‬رناد الفرم‬ ‫خالد المطيري‬
‫‪ -‬هديل عورتاني‬ ‫داود اسماعيل‬
‫‪ -‬منيره المسعد‬ ‫خالد محمد العقيلي‬
‫‪ -‬الجوهرة الشنيفي‬ ‫احمد وليد الراشد‬
‫‪ -‬رزان الزهراني‬ ‫فهد النهابي‬
‫‪ -‬روان مشعل‬ ‫عبدهللا السرجاني‬
‫‪ -‬نوف العتيبي‬ ‫رشيد سليمان البالع‬
‫‪ -‬ابتسام المطيري‬ ‫معاذ ابراهيم الحمود‬
‫‪ -‬غرام جليدان‬ ‫فايز غياث الدرسوني‬
‫‪ -‬بلقيس الراجحي‬ ‫عبدالحكيم إبراهيم العنّيق‬
‫‪ -‬نورة القاضي‬ ‫خالد محمد العقيلي‬
‫‪ -‬آالء الصويغ‬ ‫عبدهللا سليمان احمد بالعبيد‬
‫‪ -‬ريم القحطاني‬ ‫أنس عبدهللا السيف‬
‫‪ -‬شوق القحطاني‬ ‫سعد محمد الفوزان‬
‫عبدالعزيز بن خالد السرحاني‬
‫عبد اإلله الحسين‬
‫عبدالجبار اليماني‬
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*references:
-Robbins Basic Pathology

Pathology
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