Pathology of Lung Cancer

Etiology, Epidemiology, and Precursor Lesions

Saccomano studied uranium miners, Auerbach studied smokers, they concluded:

(1) Squamous metaplasia is a nonspecific response to injury of the bronchial epithelium and not all who developed squamous metaplasia progressed to carcinoma.
(2) There was an approximately 4-5 year lag period from the onset of marked atypia to the onset of invasive cancer.
(3) The 2 major types of cancer arising in this group were squamous cell carcinoma and small cell undifferentiated carcinoma.
(4) Cigarette smoking appeared to potentiate the carcinogenic effects of exposure to radiation.
(5) Increasingly severe atypia and carcinoma in situ were correlated with the number of cigarettes smoked
(6) Bronchial reserve cell hyperplasia and multifocal epithelial atypia were common in patients dying of lung cancer.

At this time there is no optimal therapy for CA of the lung. Elimination of environmental carcinogens is the current goal

Chemical carcinogens: asbestos, benzopyrene, arsenic, nickel carbonyl, beryllium sulfate, mustard gas, nitrosamine, choro-methyl ether, possibly herbicides and pesticides. MOST CLOSELY LINKEDÞ Pollutants (e.g. SMOKING)

Radiation x-ray, uranium, radon, polonium 210

Viral bronchioloalveolar cell carcinoma, in some instances, may be due to a virus.

Classification

Epidermoid (squamous cell)

Small cell (oat cell, intermediate cell, combined oat cell)

Adenocarcinoma (acinar, papillary, bronchioalveolar, solid CA with mucous formation)

Large cell (giant cell, "clear" cell)

Combined Epidermoid and Adenocarcinoma (adenosquamous)

Carcinoid

Bronchial gland (adenoid cystic, mucoepidermoid, others)

Primary mesenchymal tumors (lymphoma, fibrosarcoma, mesothelioma, others)

Carcinosarcoma

Metastastic cancer to the lung

Oncogenes and other genetic markers

Activation of proto-oncogenes and repression of tumor suppressor genes are likely the earliest steps in the evolution of lung cancer.

Activation of the K-ras oncogene is seen in non-small cell lung cancer (NSCLC), especially in tumors of current and former smokers.

Overexpression of the myc-oncogene occurs in 20-40% of small cell lung cancer. The allelic loss of tumor suppressor gene 3p is seen in nearly all small cell lung cancers (SCLC) and 20-50% of NSCLC.

Suppressor gene p53 mutations are more common in squamous carcinoma. Epidermal growth factor over- expression is especially associated with squamous carcinoma.

The emergence of aneuploidy correlates with advanced disease and worsened survival.

Mutations in K-ras and activation of Her2/neu are associated with a negative prognosis in NSCLC.

Alteration of adhesion molecules is likely important in the spread and metastasis of lung cancer. Downregulation of Epithelial adherins correlate with tumor invasion and metastasis. Upregulation of vascular adhesion molecules may increase attachment of tumor cells to endothelium. De-regulation of protease expression also correlates with invasive potentials.

Clinical Presentation, Natural History, and Diagnosis

4 most common types – Squamous cell, Small cell, Adenocarcinoma, and Large cell

6 typical pulmonary syndromes that patients with Lung CA present with:

(1) Endobroncial obstruction
(2) Peripheral nodule
(3) Unresolved pneumonia behind an endobronchial obstruction
(4) Central mass
(5) Pancoast’s tumor of the superior sulcus,an adenocarcinoma of a lung apex causing Pancoast syndrome.

Pancoast’s syndrome: pain and tingling of the arm over the area of distribution of the ulnar nerve, constriction of the pupil, and paralysis of the levator palpebrae superioris muscle, due to pressure on the brachial plexus by a malignant tumor (shown by x-ray) in the region of the superior pulmonary sulcus.

(6) Multicentric pulmonary nodules

Modalities for diagnosis: CXR, Sputum culture, bronchoscopy, needle biopsy, mediastinoscopy, thoracotomy.

Screening – probably finds some lungs cancers earlier but does not change overall life expectancy

Staging – limited value since all but small cell CA are resected unless there is evidence of distant or extensive metastastic disease. Small cell has a poorer prognosis if disseminated rather than limited but therapy is the same either way.

Squamous Cell Carcinoma

Incidence: common variant of lung CA. More frequent in men than women

Etiology: strong correlation between smoking and squamous cell CA

Location: Centrally located within major bronchi. ("bronchogenic" = tumors arising from the large central airways)

Histology: well differentiated, Keratinzation, Keratin pearls, and intracellular bridges. Typically abundant tumor necrosis

Natural History: begin at the surface epithelium of segmental bronchi and spreads to involve lobar bronchi.

Tend to be endobronchial and cause obstructive symptoms early (early detection and best prognosis, 55% 2 year survival)
most frequent cavitating tumor of the lung
frequently associated with hypercalcemia due to ectopic PTH secretion

Diagnosis: usually made from sputum cytology or endobronchial biopsy

Small Cell Carcinoma

Incidence: ~12% and is rapidly increasing

Etiology: high correlation with smoking and is the tumor most frequently seen in uranium miners

Location: centrally located near the hilum. Often early and extensive involvement of the mediastinum.

Histology: small lymphocytic-like cells with hyperchromatic nuclei with fine stippled chromatin. Current thought to arise form the basal cell layer.

Natural history: most rapidly growing and malignant form of primary lung cancer. Metastases are common at diagnosis. Þ Tumors tend to undermine the bronchial mucosa rather than obstruct the bronchus.

Small Cell CA is the most frequent tumor associated with hormone secretion and endocrine (paraneoplastic) syndromes

Diagosis: sputum cytology, bronchial brushings, or transbronchial biopsy.

Adenocarcinoma

Incidence: ~40% of all lung CA, women> men, most frequent form of lung CA seen in non-smokers

Etiology: majority associated with smoking (association less than squamous or small cell).

association with pulmonary scars.

Location: peripheral, often subpleural

Histology: highly variable. Characterized ultrastructurally by cellular microvilli and tubular lumina.

bronchiolalveolar cell type- an important variant that usually has mucin producing columnar cells that grow along the pre-existing septal architecture of the lung.

Natural history: because of it’s peripheral location it is often difficult to detect. Easiest tumor to resect but often metastastic at diagnosis and carries a poor prognosis (41% 2 year survival).

Diagnosis: because of location require fine needle aspiration or open biopsy for diagnosis

Large Cell Undifferentiated Carcinoma

Incidence: ~15%

Etiology: wastebasket diagnosis, less strongly associated with smoking as squamous and small cell

Location: usually peripheral

Histology: tumors consist of sheets of cells with occasional central necrosis. Pleomorphic cells with abundant mitotic figures and irregular chromatin distribution. Giant cell carcinoma has (you guessed it) giant cells.

Natural history: behave poorly (32%2 year survival rate)

Diagnosis: least amount of agreement by pathologists on the diagnosis of this tumor type.

Routes of Spread of Carcinoma of the Lung

Transpleural Intrathoracic Extension – Lung CA may transgress pleural boundaries producing intrathoracic complications.

Growth along the pleural surface, most common with adenocarcinoma can simulate mesothelioma.
Extension into the mediastinum can result in esophageal or recurrent laryngeal nerve involvement leading to dysphagia and hoarseness.
Compression of the SVC, seen with central tumors, results in a typical syndrome of UE congestion.
Carcinoma of the lung is the most common tumor to involve the heart often producing malignant pericardial effusions. Occasionally, tumors in the apex of the lung extend into the thoracic inlet involve the sympathetic chain, brachial plexus and subclavian vessels. Neoplasms in this location have been termed Pancoast tumors, and lead to Horner's syndrome and brachial palsies.

Extrathoracic Spread - Distant metastasis, a serious complication of carcinoma of the lung, occurs frequently. The most common metastatic sites are, respectively, liver, adrenal glands, brain, and bone. Carcinoma of the lung may metastasize by either pulmonary veins or lymphatics. Spread via the pulmonary lymphatics to regional nodes often results initially in hilar and mediastinal lymphadenopathy.

Therapy of Carcinoma of the Lung

Non Small Cell Tumors are treated with resection. Pancoast’s tumor may be resectable after radiation (5% cure rate)

Small Cell tumors are treated with Chemotherapy. Prophylactic CNS radiation is administered to most patients.

Tumors of the Pleura

Localized Fibrous Tumor of the Pleura – present in 4^th-6^th decades, no association with asbestos,. Well circumscribed masses attached to the visceral pleura by a pedicle. Composed of spindle cells with abundant collagen. Usually benign and cured by surgical resection.

Diffuse Malignant Mesothelioma – malignant mesothelioma arises from the pleural surface. Definate link to asbestos exposure. Grossly appears as a diffuse thickening of the parietal and visceral pleura. Often associated pleural effusion is present (hemorrhagic in 50% of cases).

Mesotheliomas are rich in hyaluronic acid. Pleural fluid hyaluronic acid level > 120 mg/mL suggests mesothelioma.

Bronchial Carcinoid Tumor

a tumor with low malignant potential which arises from Kulchitsky cells of the bronchial mucosa. Occasionally associated with Carcinoid syndrome although this is much less frequent than with carcinoid tumor of the intestine. Composed of nests and cords of cells in a richly vascularized stroma. Carcinoid tumors contain abundant intracytoplasmic neurosecretory granules. Usually cured by resection.