1. Diseases of Respiratory System
Dr. Faten Ghazal
Prof. of Pathology, Ain Shams University
Lecture 5
Lung Tumours

2. By the end of this lecture you will be able to:
Recognize lung hamartoma & describe its pathological features.
Classify lung tumours
Explain this statement: Statistical evidence incriminates cigarette smoking as the cause of bronchogenic carcinoma.
Describe the pathologic features of the different types of bronchogenic carcinoma & recognize their precursors
Define & describe Pancoast tumour
Describe the methods of spread of lung carcinoma.
Identify paraneoplastic syndrome
Recognize carcinoid tumour & describe its pathologic features.

3. Tumours of the Lung
Lungs are frequently the site of metastases from cancers of extra thoracic organs, however primary lung cancer is currently the most frequently diagnosed major cancer in the world &the most common cause of mortality worldwide.
Ninety five percent (95%)of primary lung tumours arise from the bronchial epithelium (bronchogenic carcinoma) .The remaining 5% are a miscellaneous group including:
Bronchial carcinoid
Bronchial gland tumours ( e.g.. adenoid cystic & mucoepidermoid carcinoma), mesenchymal malignancies (e.g. fibrosarcoma, leiomyosarcoma)
Lymphoma
Benign lesions (e.g.hamartoma, squamous cell papilloma, benign connective tissue tumours).

4. Hamartoma

5. Hamartoma
They are tumour-like malformations formed of abnormal mixing of normal components of the organ.
Hamartomas of the lung are also called chondroid adenoma or chondroid hamartoma.
They are usually solitary, subpleural in position appearing as a coin –like well circumscribed opacity maximum 3-4 cm in diameter (in chest X-rays & CT).

6. Hamartoma
CT Chest

7. Hamartoma Gross: It is sharply delineated (well circumscribed).
The cut surface is lobulated & shows a glistening nodule of cartilage separated by ill defined clefts.
clefts
lobulation

8. Hamartoma
Microscopic : It consists of lobules mature cartilage mixed with fat , smooth muscle cells, blood vessels and clefts lined by respiratory-epithelium.
clefts lined by resp. epith.

9. Bronchogenic Carcinoma

10. Bronchogenic Carcinoma
Incidence: Bronchogenic carcinoma is the number 1 cause of cancer – related death in industrialized countries.
Sex: It has long held this position among males and has become the leading cause of cancer deaths in women as well, (due to increase of smoking among females!!) .The ratio has changed from 2:1 to 1.5:1.
Age: The peak incidence of lung cancers occurs between ages The range is from
At diagnosis: More than half %(50%) of patients have already distant metastases.
While one fourth (25%) of them have regional lymph nodal metastases.

11. Lung Carcinoma (SqCC & SCC)
Do you remember the hazards of smoking mentioned in the previous lectures (in respiratory system)?
Laryngeal polyp
Laryngeal Carcinoma
Intrinsic Bronchial Asthma
Chronic Bronchitis
Bronchiectasis
Pulmonary Infection
Centriacinar Emphysema
Lung Carcinoma (SqCC & SCC)

12. What is the aetiology or pathogenesis of bronchogenic carcinoma?

13. Aetiology and Pathogenesis of Bronchogenic carcinoma
Bronchogenic carcinoma, (similar to cancers at many other anatomic sites) arises by a stepwise accumulation of genetic abnormalities that result in transformation of benign bronchial epithelium into neoplastic tissue.

14. Aetiology and Pathogenesis of Bronchogenic carcinoma
The sequence of molecular (genetic) changes follows a predictable sequence that parallels the histologic progression toward cancer.
Early genetic changes in bronchial epithelium as inactivation of tumour suppressor gene
Late changes as mutation of T suppressor gene P53 & activation of K-RAS oncogene
Different Carcinogens:
SMOKING
Industrial hazards
Air pollution
Genetic factors
Scarring
Lung Cancer
Early histologic changes in bronchial epithelium as goblet cell hyperplasia, basal cell hyperplasia, squamous metaplasia
Late changes as dysplasia

15. Explain this statement: Statistical evidence incriminates cigarette smoking as the cause of bronchogenic carcinoma.

16. Aetiology and Pathogenesis of Bronchogenic Carcinoma
Statistically: 90%of lung cancer occurs in active smokers.
There is a linear correlation between the frequency of lung cancer and no. of packs/day & duration of cigarette smoking. The increased risk becomes 60 times greater among heavy smokers (2 packs /day for 20 years) compared with nonsmokers.
Although cessation of smoking decreases the risk of developing lung cancer overtime, it may never return to baseline. NEVER START SMOKING & if you are a smoker STOP SMOKING NOW.
Passive smoking (proximity to a cigarette smoker) increases the risk of developing lung cancer to twice that of non passive smoker. NEVER SIT BESIDE SMOKERS.
The smoking of pipes and cigars also increases the risk.

17. Aetiology and Pathogenesis of Bronchogenic Carcinoma
Other influences (risk factors = carcinogens ) may act in concert with smoking or may by themselves be responsible for lung cancers.
Industrial hazards:
All types of radiation.
Asbestos: Exposure to asbestos increases the risk of lung cancer 5 times in nonsmokers. By contrast heavy smokers exposed to asbestos have times greater risk of lung cancer than do nonsmokers not exposed to asbestos.
Workers exposed to dusts containing arsenic, chromium, uranium, vinyl chloride & mustard gas.
Genetic Susceptibility
Air Pollution
Scarring

18. Aetiology and Pathogenesis of Bronchogenic Carcinoma
Histologically: There is progressive alteration in bronchial epithelium of habitual cigarette smokers, starting by goblet cell metaplasia, basal cell hyperplasia, squamous metaplasia & dysplasia, then carcinoma in situ.
Goblet cell metaplasia

19. Aetiology and Pathogenesis of Bronchogenic Carcinoma

20. Aetiology and Pathogenesis of Bronchogenic Carcinoma
Invasive squamous cell carcinoma
Squamous metaplasia, dysplasia and invasive squamous cell carcinoma

21. Classify Lung Tumours

22. Histologic Classification of Bronchogenic Carcinoma
The 4 major histologic types of bronchogenic carcinoma are:
1. Squamous cell carcinoma, 2. adenocarcinoma, 3. large cell carcinoma, and 4. small cell carcinoma.
For therapeutic purposes bronchogenic carcinoma are classified into 2 broad groups:
Small cell lung cancer (SCLC)(20%-25%) and
Non small cell lung cancer (NSCLC) (70%-75%) including squamous cell carcinoma (25%-30%), adenocarcinoma (30%-35%), and large cell carcinoma (10%-15%).
Combined Patterns (5%-10%)
The key reason for this distinction is that virtually all SCLCs have metastasized by the time of diagnosis and hence are not amenable to curative surgery. They are best treated by chemotherapy with or without radiation. In contrast NSCLCs usually respond poorly to chemotherapy and better treated by surgery.

23. WHO Histological Classification of Lung Tumours
Squamous Cell Carcinoma
Small Cell Carcinoma
Combined Small Cell Carcinoma
Adenocarcinoma
Acinar, Papillary, Bronchioalveolar, solid mixed subtypes
Large Cell Carcinoma
Large Cell Neuroendocrine Carcinoma
Adenosquamous Carcinoma
Carcinoid Tumour
Typical, atypical
Carcinomas of Salivary gland Type
Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements
Unclassified Carcinoma

24. Describe the pathologic features of bronchogenic carcinoma.

25. Pathologic Features of Bronchogenic Carcinoma
Gross Picture for most of bronchogenic carcinoma
It appears as a firm mass having greyish white cut surface with areas of hemorrhage & necrosis. It may arise central or peripheral.

26. Pathologic Features of Bronchogenic Carcinoma
It begins as a small mucosal lesion.
It grows as intraluminal mass.
Then invades the bronchial wall.
Then invades the surrounding lung parenchyma.
It may extend to the pleura.
It may spread to the hilar lymph nodes.

27. 1.Squamous Cell Carcinoma
It is more common in men than women.
It is preceded often for years by squamous metaplasia , dysplasia then carcinoma in situ in the bronchial epithelium.
It tends to arise centrally in major bronchi (first order, second order, third order bronchi).
It grows intraluminally obstructing the bronchus leading to either atelectasis (absorption collapse), or infection with central cavitation & abscess formation.
It invades the lung parenchyma.
It may spread to the hilar lymph nodes but distant metastasis is late.

28. 1.Squamous Cell Carcinoma
Cavitary Lung Cancer

29. Microscopic Picture of Squamous cell carcinoma:
It ranges from well differentiated squamous cell carcinoma showing central keratin pearls and intercellular bridges to poorly differentiated squamous cell carcinoma. (Grading of the tumour is based on the cytological diff.& no. of mitotic figures).
Well diff sq c c
Mod diff sq c c
Poorly diff sq c c

30. 2.Adenocarcinoma
Peripheral mass
It comprises half of all lung carcinomas in females & a lower % of those in males.
It tends to arise peripherally but it may occur as a central lesion.
It may be associated with scarring, however recently scarring may be considered to occur secondary to the tumour (desmoplasia) rather than the cause.
It has the weakest association with smoking.
It grows slowly but tends to metastasize widely at an early stage.
spreads widely

31. Precursor of Adenocarcinoma
a focus of epithelial proliferation
Cuboidal cells with cytological atypia lining the alveoli
Atypical Adenomatous Hyperplasia (AAH) is recognized as well demarcated focus of epithelial proliferation composed of cuboidal cells showing various degrees of cytological atypia (nuclear hyperchromasia, pleomorphism & prominent nucleoli) but not to the extent seen in adenocarcinoma.

32. Atypical Adenomatous Hyperplasia
Precursor of Adenocarcinoma
a focus of epithelial proliferation
Atypical Adenomatous Hyperplasia
Copyright ©2001 BMJ Publishing Group Ltd.

33. A) & B) Atypical Adenomatous Hyperplasia
C) Bronchioalveolar Carcinoma D) Adenocarcinoma

34. Microscopic Picture of Adenocarcinoma
It assumes a variety of forms including acinar (glandular), papillary and solid.
The last variant (solid) requires demonstration of intracellular mucin production by special stains to establish its adenocarcinomatous lineage.

35. Invasive adenocarcinoma

36. Microscopic Picture of Adenocarcinoma
Glandular (acinar)
Papillary
Cribriform gland
Papillary

37. Papillary Pulmonary Adenocarcinoma

38. Bronchioloalveolar Carcinoma (BAC)
It is included as a subtype of adenocarcinoma with no stromal invasion.
It involves the peripheral parts of the lung either as a single nodule or as multiple diffuse nodules that may coalesce to produce pneumonia like consolidation ( may cause suffocation without any metastases).
Nonmucinous BAC
Mucinous BAC
The characteristic feature of BAC is its growth along the pre-existing structures with preservation of alveolar architecture.

39. Large vesicular nucleus (blue)& prominent nucleolus (dark blue)
3.Large Cell Carcinoma
It constitutes a group of neoplasm that lack cytological differentiation and probably represent squamous cell or glandular neoplasm that are undifferentiated to permit categorization.
The cells are large , highly anaplastic and have large vesicular nuclei and prominent nucleoli . Occasionally these tumours have multinucleated giant cells or may be composed of spindle cells.
Large cell carcinoma has a poor prognosis because its tendency to spread to distant sites early.
Abnormal mitosis

40. Round or fusiform cells & little cytoplasm Finely granular chromatin
4.Small Cell Carcinoma
It appears as a pale grey centrally located mass with extension into the lung parenchyma.
It involves the hilar & mediastinal lymph nodes early.
Microscopic: It is composed of tumour cells with a round, oval or fusiform shape with scanty cytoplasm and a finely granular chromatin. Mitotic figures are frequently seen.
Round or fusiform cells & little cytoplasm
dark small cells
Finely granular chromatin

41. 4.Small Cell Carcinoma

42. 4.Small Cell Carcinoma

43. 4.Small Cell Carcinoma
Nuclear molding of cells in cytological specimens due to close proximity of tumour cells that have scant cytoplasm

44. Spread of Bronchogenic Carcinoma

45. Local Spread of Lung Cancer
Pancoast Tumour
It is an apical lung carcinoma that tends to invade (1) brachial plexus leading to severe pain in the distribution of ulnar nerve or and (2) cervical sympathetic plexus to produce Horner syndrome (ipsilateral enophthalmos, ptosis, meiosis and anhydrosis).
It is associated with destruction of first & second ribs and sometimes thoracic vertebrae.

46. Spread of Bronchogenic Carcinoma
Lymphatic Spread of Bronchogenic Carcinoma
Invasion of successive chains of nodes around the carina, in the mediastinum, in the neck (cervical), in the clavicular region and in the axilla; may occur.
Involvement of the supraclavicular node (Virchow node) is characteristic and calls attention of occult primary tumour.
Blood Spread of Bronchogenic Carcinoma
Haematogenous spread is common usually due to invasion of pulmonary veins. The common sites are the adrenals (50%), liver (30%), bone & brain.

47. Clinical Course of Bronchogenic Carcinoma
Bronchogenic carcinoma is usually silent and insidious, however chronic cough & expectoration may call attention to still localized resectable tumour.
The symptoms may vary according to the site of the tumour and the tissue invaded.
Sympathetic G invasion: Horner Syndr & Br Px: pain
Recurrent Laryngeal nerve invasion: Hoarseness of voice
Local Spread of Lung Cancer
Oeosophageal invasion: Dysphagia & broncho- oesophageal fistula
Pleural invasion: pleural effusion empyema
Bronchial obstruction:
Atelectasis & lung infection as lung abscess, pneumonia & bronchiectasis
Superior vena caval invasion: head & neck venous congestion
Phrenic n. invasion Diaphragm Paralysis

48. Oesophagus= dysphagia or broncho-oesophageal fistula
Clinical Picture: In addition to cough & haemoptysis, the symptoms may vary according to the site of the tumour and the tissue invaded.
Lung: bronchial obstruction (complete obstruction= collapse) or incomplete obstruction= infection : abscess, pneumonia, bronchiectasis & bronchitis)
Pleural effusion
Nerves: a) recurrent laryngeal n = hoarseness of voice, b) phrenic nerve= paralysis of diaphragm, c) brachial plexus= ulnar nerve pain, d) sympathetic chain= Horner syndrome
Oesophagus= dysphagia or broncho-oesophageal fistula
Superior vena cava= head &neck congestion

49. Clinical Course of Bronchogenic Carcinoma
3%-10% of all lung cancer patients may develop paraneoplastic syndrome.
1. Hypercalcaemia due to release of parathyroid like hormone (*most commonly with squamous cell carcinoma).
2. Cushing syndrome due to release of adrenocorticotrophic hormone (*most commonly with Small Cell Carcinoma).
3. Hyponatremia and water retention due to inappropriate ADH secretion (*Small Cell Carcinoma).
4. Neuromuscular syndrome including mysthenic syndrome, peripheral neuropathy and polymyositis due to autoantibodies.
5. Hypocalcaemia due to calcitonin secretion.
6. Carcinoid syndrome due to serotonin & bradykinin
7. Gynaecomastia due to gonadotrophins
8. Clubbing of fingers and hypertrophic pulmonary osteoarthropathy
9. Hematologic manifestations as migratory thrombophlebitis, nonbacterial endocarditis, and disseminated intravascular coagulation. (*most commonly with adenocarcinoma)

50. Bronchial Carcinoid

51. Bronchial Carcinoid
Bronchial carcinoids are thought to arise from the neuroendocrine cells that are present in the bronchial mucosa Typical carcinoid arises centrally while atypical carcinoid (those carcinoid tumours with nuclear atypia) arises mostly peripherally.
Incidence: They represent about 5% of all lung tumours.
Age: They often appear at an early age (mean 40 years).

52. Bronchial Carcinoid
Gross Most bronchial carcinoids originate in mainstem bronchi and grow in one of 2 patterns:
An obstructing spherical intraluminal mass.
A mucosal plaque penetrating the bronchial wall to fan out into the peribronchial tissue the so called collar-button lesion.

53. salt & pepper chromatin nests &masses of round cells
Bronchial carcinoids are composed of nests, cords and masses of uniform round cells with regular round nuclei having salt and pepper chromatin, no mitosis and little pleomorphism.
nests &masses of round cells

54. An Area of Necrosis
Atypical carcinoid tumour: The nuclei are atypical: pleomorphic, hyperchromatic with increased number of mitotic figures (black arrows) and areas of necrosis with higher incidence of nodal and distant metastases.

55. Typical carcinoid, atypical carcinoid & small cell carcinoma can be considered to represent a continuum (range) of increasing histologic aggressiveness and malignant potential within the spectrum of pulmonary neuroendocrine neoplasms.

56. What are the precursors (premalignant lesions) for each of the malignant lung tumours: squamous cell carcinoma, adenocarcinoma & small cell carcinoma?

57. Complete the following statements by specifying the suitable type of tumour:
1.The most common lung carcinoma occurring in women is…..
2. Lung carcinomas most commonly arising peripherally are……………………….
3. Lung carcinomas most commonly arising centrally are……………………….
4. Lung carcinomas most commonly associated with smoking are ……………………
5. The precursor of squamous cell carcinoma is ……………
6. The precursor of adenocarcinoma is……………………
appear as a coin like shadow 3-4cm, well circumscribed & subpleural in position in chest x ray.
8. ……………….. is the most common lung carcinoma.

58. Complete the following statements by specifying the suitable type of tumour:
9. In ………………… there is no stromal invasion.
10. Most commonly, in ……………..distant metastases have already occurred so it is better to treat it by chemotherapy.
11. …………….may appear as a single or multiple pneumonic patches of consolidation
12. ………………….grows as either intraluminal mass or as a mucosal plaque that penetrate the bronchial wall and fan out (grow as a larger mass) giving the collar button appearance.
13. ……… are not associated or not related to smoking.
14. ………………… may be associated with hypercalcaemia.
15. …………………. may be associated with ectopic hormone production.

59. Complete the following statements by specifying the type of emphysema
………………… occurs in apparently healthy persons, in upper half , subpleural in position and is usually asymptomatic unless pneumothorax develops.
…………………occurs mainly in lower half & is associated with alpha 1 antitrypsin deficiency.
………………….occurs in residual lung after lobectomy.
……………….. may occur due to vigorous coughing in a child suffering of whooping cough.
…………………..occurs most commonly in smokers.
……………………is usually asymptomatic, discovered accidentally & is associated with scarring.
……………………occurs due to diminished elastic recoil in elderly persons.

60. By the end of this lecture you will be able to:
Recognize lung hamartoma & describe its pathological features.
Classify lung tumours
Explain this statement: Statistical evidence incriminates cigarette smoking as the cause of bronchogenic carcinoma.
Describe the pathologic features of the different types of bronchogenic carcinoma & recognize their precursors
Define & describe Pancoast tumour
Describe the methods of spread of lung carcinoma.
Identify paraneoplastic syndrome
Recognize carcinoid tumour & describe its pathologic features.