MALIGNANT EPITHELIAL TUMORS

OF THE LUNG

JOY MRIDHA,JUNIOR RESIDENT ACADEMIC.

GUIDE-Prof(Dr.)TRILOCHAN SINGHRIMS,RANCHI

INTRODUCTION The lungs are ingeniously constructed to carry

out their cardinal function, the exchange of gases between inspired air and blood.

Right lung› Three lobes; superior, middle and inferior› Oblique and horizontal fissure

Left Lung› Two lobes; superior and inferior also Lingula

and Cardiac notch, oblique fissure

THE LUNGS AND THE AIRWAY

AIRWAYS Numerous mucous secreting

goblet cells and submucosal glands are dispersed through the walls of trachea and bronchi but not in the bronchioles.

Bronchioles lack of cartilages.

Bronchioles have neurosecretory granules that secrets serotonin,calcitonin,and bombesin.

Acinus- respiratory bronchiole

alveolar duct alveolar sac alveoli. 3-5 terminal bronchiole is referred to as the pulmonary lobule.

LINING EPITHELIUM-

Except the vocal cord the entire respiratory tree is lined by pseudo-stratified tall columnar cilliated epthelium.

The vocal cord is lined by stratified squamous epithelial cell.

MICROSCOPIC STRUCTURE OF ALVEOLAR WALL-

Alveolar epithelium- type I pneumocytes type II pneumocytes. Alveolar macrophages. Basement membrane. Anastomosing capillaries. Interstitial tissue-elastic tissue collagen fibroblast like interstitial cell smooth muscle cell mast cell lymphocyte and monocyte(rare)Pores of Kohn-passage of bacteria and exhudate between adjacent alveoli.

TUMORS OF LUNG-A variety of benign and malignant tumors are arising from lung.

1.carcinoma- 90%-95%.2.Bronchilal carcinoid-5%.3.Mesenchymal tumor and others-2-

5%.

LUNG CARCINOMA- Lung cancer is currently the most frequently

diagnosed major cancer in the world(estimated 1.6 million new cases in 2008) and the most common cause of cancer mortality worldwide(1,380,000 deaths in 2008).

Since the early 1990s, lung cancer incidence and mortality rates have been decreasing in men, due to the decreased smoking rates over the past 35 years.

Cancer of the lung occurs most often between ages 40 and 70 years, with a peak incidence in the 50s or 60s.

AETIOPATHOGENESIS About 80% of lung cancers occur in active smokers or those

who stopped recently. There is a nearly linear correlation between the frequency

of lung cancer and pack-years of cigarette smoking. The increased risk becomes 60 times greater among

habitual heavy smokers (two packs a day for 20 years) compared with nonsmokers.

11% heavy smoker develop lung carcinoma. Women have a higher susceptibility to carcinogens in tobacco

than men. Although cessation of smoking decreases the risk for lung

cancer over time, it may never return to baseline levels. Passive smoking (proximity to cigarette smokers) increases the

risk for lung cancer development to approximately twice that of nonsmokers.

The smoking of pipes and cigars also increases the risk, but only modestly.

EFFECTS OF SMOKING-

Procarcinogen

carcinogen

Activation of polymorphic p-450

monoxygenase enzyme system

Genetic variation in

genes involved in DNA repair

BASAL CELL HYPERPLASI

A

METAPLASIA DYSPLASIA

Carcinoma –in-situ

Invasive carcinoma

ENVIRONMENTAL AND OCCUPATIONAL FACTOR -

DISEASE PATTERN THROUGH THE DECADES-

RELATION OF CIGARETTE CONSUMPTION AND DEATH RATE-

2015 WHO Classification of Lung Tumors1. Adenocarcinoma Lepidic adenocarcinoma Acinar adenocarcinoma Papillary adenocarcinoma Micropapillary adenocarcinoma Solid adenocarcinoma Invasive mucinous adenocarcinoma Mixed invasive mucinous and nonmucinous adenocarcinoma Colloid adenocarcinoma Fetal adenocarcinoma Enteric adenocarcinomae Minimally invasive adenocarcinoma Nonmucinous Mucinous Preinvasive lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ. Nonmucinous Mucinous Cont…

Cont.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 Large cell carcinoma Adenosquamous carcinoma Sarcomatoid carcinomas Pleomorphic carcinoma Spindle cell carcinoma Giant cell carcinoma Carcinosarcoma Pulmonary blastoma Cont….

Cont.. Other and Unclassified carcinomas Lymphoepithelioma-like carcinoma NUT carcinoma

Salivary gland-type tumors Mucoepidermoid carcinoma Adenoid cystic carcinoma Epithelial-myoepithelial carcinoma Pleomorphic adenoma Papillomas Squamous cell papilloma Exophytic Inverted Glandular papilloma Mixed squamous and glandular papilloma Adenomas Sclerosing pneumocytoma Alveolar adenoma Papillary adenoma Mucinous cystadenoma Mucous gland adenoma .

The relative proportion of major catgories-

ADENOCARCINOMA- 38% SQUAMOUS CELL CARCINOMA- 20% SMALL CELL CARCINOMA- 14% LARGE CELL CARCINOMA- 3% OTHERS- 25%.

COMPARISON BETWEEN WESTERN COUNTRIES AND INDIA

GENETIC MUTATION IN LUNG CARCINOMA

Squamous cell carcinoma- Highly associated with tobacco smoke. Deletion of tumor suppressor gene. Highest frequency of TP-53 mutation. P-16 loss is seen in 65% of tumors. EGFR-1 gene amplification. Grading of squamous cell carcinoma into well, moderately, and

poorly differentiated types will depend on the degree of squamous differentiation within the tumor, such as the presence of intercellular bridges and keratinization.

Well-differentiated tumors are characterized by sheets of cells that adopt a pavement-like architecture and contain ample eosinophilic cytoplasm, round to oval nuclei, and prominent nucleoli.

A central, comedo-type pattern of necrosis is typically seen in the higher grade lesions .

Cont.. Most common carcioma in smoker. Most common type in India . Produces PTH,PTH-rp causes hypercalcemia. Centrally distributed. Prone to develop central necrosis and cavitation. It is associated with best prognosis. PANCOAST TUMOR is a type of squamous cell

carcinoma.TYPES - Keratinizing squamous cell carcinoma Nonkeratinizing squamous cell carcinoma Basaloid squamous cell carcinoma Preinvasive lesion Squamous cell carcinoma in situ

SEQUENTIAL PATHOGENESIS OF SCC-

 

Well-differentiated squamous cell carcinoma showing keratinization

LOWER MAGNIFICATION

HIGHER MAGNIFICATION

KERATIN PEARL

Well- to moderately well-differentiated squamous carcinoma

Poorly differentiated squamous carcinoma with central comedo-like areas of necrosis.

BASALOID CARCINOMABasaloid carcinoma is a variant of bronchogenic carcinoma characterized by a proliferation of islands of relatively large, hyperchromatic tumor cells showing prominent peripheral palisading of nuclei .• more aggressive clinical behavior than conventional

squamous cell carcinoma.• Cellular atypia and mitotic figures are common.

Basaloid carcinoma showing solid islands of tumor cells with peripheral palisading of nuclei.

Pancoast tumor(superior sulcus tumor)

Results from the local extension of the tumor growing in the apex of the lung.

Involvement of C8,T1,T2 nerve. Shoulder pain radiates to the ulnar distribution

of the arm. Radiologic destruction of 1st and 2nd rib. Often Horner’s syndrome and pancoast tumor

co-exist. Histologicaly it is a type of squamous cell

carcinoma. Peripheral radiotherapy followed by En-bloc

resection followed by post-opeartive RT/intraoperative brachytherapy is given.

DIFFERENTIATION FROM SMAL CELL CARCINOMA

Poorly differentiated SCC should not be confused with small cell carcinoma.

SCC lacks –individual cell necrosis crush artifact nuclear molding.SCC positive for p63 by IHC,small cells are not.

ADENOCARCINOMA - PREINVASIVE LESION Atypical Alveolar Hyperplasia(AAH) Adenocarcinoma –in-situ/Bronchioloalveolar carcinoma(BAC) typeI/ Mucinous typeII/ Non Mucinous

Atypical Alveolar Hyperplasia(AAH)

Bronchioloalveolar carcinoma(BAC)

Small, <5 mm >5 mm polymorphous monomorphous Mildly atypical mildly atypical often unsuspected, may be found in grossly normal lung.

Radiographic and gross lesion is presnt.

BRONCHIOLOALVEOLAR CARCINOMA

• Present as ground glass opacities on chest x-ray.

• Dysplastic cell growing along the pre-existing alveolar septae-LEPIDIC GROWTH pattern.

• More often in woman and non-smokers.• Types-mucinous –intra alveolar mucin.• non mucinous-peg shaped

columnar cell, HOBNAIL configuration.• Lepidic-an allusion to the neoplastic

cells resembling butterflies sitting on a fence.

MUCINOUS VARIANT OF BAC.

NON MUCINOUS VARIANT OF BAC.

ADENOCARCINOMA- Most common histological type

worldwide. Most common in non smokers ,young

adults ,and females. Located peripherally, slow growing. Propensity to metastasize in opposite

lung. Metastasize more frequently in CNS. Most of the cells contain mucin. Noguchi classification is used for adeno

carcinoma.

Cont.

Majority expresses TTF-1. 15% Case are EGFR mutation. EMA(Epithelial membrane

antigen),cytokeratin-7 positive. Napsin positve. CEA , CD 15, MOC 31 –genetic markers

are also positive. ERLOTINIB-(Anti EGFR)-effective in stage

III/IV Adenocarcinoma. CRIZOTINIB-(EML4-ALK translocation)

effective in mucinous and clear cell variant.

. Well differentiated adenocarcinoma with TTF -1 POSITIVITY

Moderately differentiated adenocarcinoma.

Mucinous (So-Called Colloid) Carcinoma- Mucinous carcinoma represents a more recently described

variant of adenocarcinoma. The accumulation of abundant pools of mucin destroying the

normal lung parenchyma. Another distinctive and diagnostic feature of these tumors is the

presence of small clusters of, or singly scattered, mucinous tumor cells lying within the pools of mucin.

Capacity for distant metastasis is very much high . Aggressive behavior.

Mucinous (“colloid”) carcinoma.

Papillary Carcinoma- Conventional adenocarcinoma, with or without

a prominent lepidic pattern. The tumors are characterized by numerous

papillary infoldings with thin fibro-connective tissue stalks that completely fill and distort the air spaces.

Psammoma bodies may also be present. A “micropapillary” variant of pulmonary

adenocarcinoma has also been described characterized by small, abortive micropapillary structures.

Such tumors are associated with a highly aggressive behavior and increased incidence of metastasis.

Papillary carcinoma of the lung.

SMALL CELL CARCINOMA

Highly malignant tumor. Strong relationship to cigaratte smoking. Only 1 % occur in non smoker. Major bronchi and periphery of the lung are involved. Most aggressive tumor. Metastasizing widely and virtually always to be fatal. Microscopy-relatively small cells with scant cytoplasm. ill defined cell border. finely granular nuclear chromatin. (salt and pepper chromatin) the cells are round oval spindle shaped. Azzopardi effect-basophilic staining of the vascular wall due to

encrustation by DNA from the necrotic tumor. Dense core neurosecretory granules seen in electron microscopy. Anti-apoptotic BCL-2 in 90% of the tumor. Chromogranin,synaptophysin,CD57 POSITIVE. 5 year survival rate- 5%.

Poorly differentiated neuroendocrine carcinoma of the lung, small cell type

Small cell carcinoma with spindle cell features

Poorly differentiated neuroendocrine carcinoma of lung, mixed small cell–large cell type.

Large Cell Neuroendocrine Carcinoma

The cellular proliferation may be focally arranged in ribbons or cords admixed with rosette like structures, giving the lesion a neuroendocrine appearance. “Basaloid” appearance due to peripheral palisading of nuclei. A high degree of overlap can be observed between these tumors and moderately differentiated neuroendocrine carcinoma (atypical carcinoid). Diagnosis of exclusion. 5 year survival rate- 30%.

Large cell neuroendocrine carcinoma.

CARCINOID TUMOR 1%-5% of all lung tumor. Low grade tumor. Younger than 40 years of age. No gender preferrence. 20%-40% non smokers are involved. Types- typical- <2 mitotic figure/10 HPF. atypical- 2-10 mitotic figure/10 HPF. Gross-fingerlike/spherical polypoidal masses project into the

lumen of bronchus, covered by mucous membrane. Rarely exceeds 3-4 cm in diameter. Collar button lesion- when penetrated the peri-bronchial tissue. Peripherally located tumor are solid and nodular. Cells are separated by delicate fibro-vascular stroma . Cells have regular uniform round nuclei and moderate amount of

cytoplasm. IHC-Serotonin,NSE(Neuron Specific

Enolase),bombesin,calcitonin. Classic carcinoid syndrome- diarrhea ,flushing, cyanosis. 5 year survival rate for typical and atypical carcinoid -95% and

75%.

Carcinoid growing as a spherical mass (arrow) protruding into the lumen of the bronchus

The tumor cells have small, rounded, uniform nuclei and moderate amounts of cytoplasm.

Salivary gland type tumor-

Unusual family of primary neoplasm of the lung.

The tumor are most likely originate from the sub-mucosal glands of the bronchi.

May be arise from the pulmonary parenchyma.

Types- Mucoepidermoid carcinoma Adenoid cystic carcinoma Epithelial-myoepithelial carcinoma Pleomorphic adenoma.

Mucoepidermoid carcinoma Most common salivary gland type neoplasm of the

lung. Epidermoid differentiation with intracelluar and

extracelluar mucin. Low grade lacks of hemorrhage,necrosis,nuclear atypia,and

mitotic figure. PAS and mucicarmine positive.

Mucoepidermoid carcinoma

Adenoid cystic carcinoma

There are three types- cribriform ,solid and tubular.

Peri-neural invasion present. Luminal spaces often filled with mucous material. Fibrous band. Scant eosinophilic cytoplasm.

Cribriform type of adenoid cystic carcinoma

Epithelial myoepithelial carcinoma- Cells have abundant clear cytoplasm. Displacement of nuclei towards the

periphery. Pleomorphism, nuclear atypia, mitotic figure are

absent. Co-expression of actin and keratin. Focal positivity for vimentin and S-100.

clear Myo-epithelial outer cell layer in the glands.

Clinical features of lung cancer-

PARANEOPLASTIC SYNDROMES ASSOCIATED TO LUNG CARCINOMA

Small cell carcinoma- ADH Hyponatremia ACTH Cushing syndrome Calcitonin Hypocalcemia ANF,Gastrin releasing peptide,vasopressinSquamous cell carcinoma- PTH,PTH-rp Hypercalcemia. Prostaglandin-E,cytokines.

LAMBERT EATON MYASTHENIC SYNDROME

Peripheral neuropathy(purely sensory)-due to auto-antibodies against neuronal calcium channel.

Acanthosis nigricanus. Leukemoid reaction. Trousseau syndrome

(DVT+THROMBOEMBOLISM) Hypertrophic pulmonary

osteoarthropathy.

Metastasis of lung carcinoma

Pleural surface cavity pericardium. Bronchial, tracheal, mediastinal lymph nodes. Nodal involvement>50%. Lymphatic and hematogenous spread occurs. Squamous cell carcinoma metastasize the

thoracic cavity lately. Adrenals are involved more than 50% cases. Liver is involved 30%-50% case. Brain is involved 20% cases. Bone is involved in 20% cases.

CHEST X-RAY

CHEST X-RAY- LUNG CARCINOMA

CT SCAN showing lung carcinoma-

FNAC OF Squamous cell carcinoma of lung-

Varying degree of keratinization.

Polygonal cell. Amphophilic

cytoplasm. Dark pyknotic

nuclei. Dirty background

of necrosis.

FNAC finding of Adenocarcinoma Fine foamy vacuolated cytoplasm. Vesicular nuclei. Prominent nucleoli. Acinar pattern.

FNAC finding of carcinoid-

Polygonal cells with rounded nuclei and spindle cells with elongated nuclei.

Nucleoli are not prominent.

Nuclear molding.

Crush artifact.

FNAC- finding Large cell neuroendocrine carcinoma

Cohesive group of cells with round to polygonal nuclei. Cells have prominent nucleoli. Vesicular nuclear chromatin.

FNAC finding in small cell carcinoma of lung-

Cells with small amount of cytoplasm.

Nuclear molding.Fine granular

chromatin.Apoptotic debris.Cellular necrosis.

IHC markers of different types of lung carcinoma-

Treatment of lung carcinoma- Stage IA,IB,IIA,IIB SURGICAL RESECTION. Adjuvant chemotherapy is gien to stage II. Stage IIIA with minimal N2 involvement-

neoadjuvant CT followed by surgical resection with complete medistinal lymph node dissection.

Post-operative radiotherapy for patients found to have N2 disease.

SCLC-CISPLATIN+ ETOPOSIDE. NSCLC-

CISPLATIN+VINORELBINE(+/-)BEVACIZUMAB. CARCINOID-STREPTOZOCIN+ 5-FU.