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Carcinoma Of The Lung

  1. Epidemiology
    Most types are linked to cigarette smoking, but the strongest association is with squamous cell carcinoma and small cell carcinoma The peak age is between 60 and 70 years, and most patients are between 50 and 80 years old.
  2. Classification:
    1. Non small cell lung carcinoma (70% -75%)
      1. Squamous cell carcinoma (25 -30%)
      2. Adenocarcinoma including bronchioalveolar carcinoma (30-35%)
      3. Large cell carcinoma (10-15%)
    2. Small cell lung carcinoma (20-25%)
    3. Combined patterns (5%-10%).
  1. Pathogenesis
  1. Mutations in the K-ras oncogene.Q
  2. Myc oncogene overexpression occurs in 10% to 40% of small cell carcinomas. Two important tumor-suppressor genes in lung cancer are the p53 and retinoblastoma (Rb) genes. Q
  3. Mutations in p53 are found in more than 80% of small cell carcinomas and 50% of non-small cell tumors. Q
  4. Rb mutations occur in over 80% of small cell carcinomas and 25% of non-small cell cancers. The protooncogene bcl-2, which encodes a protein that inhibits programmed cell death (apoptosis), is expressed in 25% of squamous cell carcinomas and 10% of adenocarcinomas. Q
  1. Pathology
  1. The most important issue in the histological subclassification of lung cancer is separating small cell carcinoma from the other types (non-small cell carcinoma), because small cell carcinoma responds to chemotherapy, whereas other histological types do not.
  1. Clinical Features
    Tumor stage remains the single most important predictor of prognosis. Q
  1. General Features Of Lung Cancer
    1. Local Effects:
      a. Lung cancer can produce cough, dyspnea, hemoptysis, chest pain, obstructive pneumonia, and pleural effusion.
      b. Growth of a lung cancer (usually squamous) in the apex of the lung (Pancoast tumor) may extend to involve the eighth cervical and first and second thoracic nerves. Q
      c. A Pancoast tumor also may paralyze cervical sympathetic nerves and cause Horner syndrome, characterized on the affected side by (1) depression of the eyeball (enophthalmos), (2) ptosis of the upper eyelid, (3) constriction of the pupil (miosis), and (4) absence of sweating (anhidrosis). Q
    2. Metastases: Carcinomas of the lung metastasize most frequently to regional lymph nodes, particularly the hilar and mediastinal nodes, but also to the brain, bone, and liver. The most frequent site of extranodal metastases is the adrenal gland. Q
    3. Paraneoplastic Syndromes:
      1. Disorders associated with lung cancer include acanthosis nigricans, dermatomyositis/polymyositis, clubbing of the fingers, and myasthenic syndromes, such as Eaton-Lambert syndrome and progressive multifocal encephalopathy.
      2. Endocrine syndromes, Cushing syndrome or inappropriate release of antidiuretic hormone (SIADH) by small cell carcinoma, and hypercalcemia (secretion of a parathormone-like substance by squamous cell carcinoma). 
  1. Pathology
  1. Most squamous cell carcinomas arise in the central portion of the lung.
  2. They tend to be firm, grey-white, 3- to 5-cm ulcerated lesions.
  3. The microscopic appearance of squamous cell carcinoma is highly variable. Well-differentiated squamous cell carcinomas display keratin which are small round nests of brightly eosinophilic aggregates of keratin surrounded by concentric layers of squamous cells.
  4. Tumor cells may be readily found in the sputum, in which case the diagnosis is made by exfoliative cytology.
  1. It tends to arise in the periphery and is often associated with pleural fibrosis and subpleural scars. Q 
  1. Adenocarcinomas of the lung most often appear as irregular masses 2 to 5 cm in diameter.
  2. On cut section, the tumor is grayish white and often glistening, depending on the amount of mucus production.
  3. Four major subtypes of adenocarcinoma, as defined by the World Health Organization (1) acinar, (2) papillary, (3) solid with mucus formation, and (4) bronchioloalveolar.
The most common histologic type of adenocarcinoma features the acinar pattern, which is distinguished by regular glands lined by cuboidal or columnar cells, Papillary adenocarcinomas exhibit a single cell layer on a core of fibrovascular connective tissue. Solid adenocarcinomas with mucus formation are poorly differentiated tumors, distinguishable from large cell carcinomas by demonstrating mucin with mucicarmine or periodic acid-Schiff (PAS) stains.
Bronchioloalveolar Carcinoma:
  1. It has not been definitively linked to smoking.
  2. Copious mucin in the sputum (bronchorrhea) is a distinctive sign of bronchioloalveolar carcinoma.
  3. On gross examination, bronchioloalveolar carcinoma may appear as a single peripheral nodule or coin lesion (>50% of cases), multiple nodules, or a diffuse infiltrate indistinguishable from lobar pneumonia Q
  4. Two-thirds of tumors are nonmucinous, the remaining third are mucinous tumors featuring goblet cell.
  5. In nonmucinous tumors cuboidal cells grow along the alveolar walls.
  6. Mucinous tumors are composed of columnar cells with abundant apical cytoplasm filled with mucus. Q
Small Cell Carcinoma
  1. Small cell carcinoma is a highly malignant epithelial tumor of the lung that exhibits neuroendocrine features.
  2. It is strongly associated with cigarette smoking. The male-to-female ratio is 2:1.
  3. The tumor grows and metastasizes rapidly.
  4. A variety of paraneoplastic syndromes are distinctive for small cell carcinoma, including diabetes insipidus, ectopic ACTH (corticotropin) syndrome, and the Eaton-Lambert syndrome. Q
  1. On cut section, it is soft and white but often shows extensive hemorrhage and necrosis. Q
  2. The tumor typically spreads along bronchi in a submucosal and circumferential fashion.
  3. Histologically, small cell carcinoma consists of sheets of small, round, oval or spindle-shaped cells with scant cytoplasm. Their nuclei are distinctive, featuring finely granular nuclear chromatin and absent or inconspicuous nucleoli. By electron microscopy, many of the cells contain secretory neuroendocrine granules. Q
  4. A high mitotic rate is characteristic.
Large Cell Carcinoma
  1. The cells are large and exhibit ample cytoplasm. The nuclei frequently show prominent nucleoli and vesicular chromatin.
Carcinoid Tumors
  1. Carcinoid tumors of the lung comprise two subtypes of neuroendocrine neoplasms and are thought to arise from the resident neuroendocrine cells.
  2. These neoplasms account for 2% of all primary lung cancers, show no sex predilection, and are not related to cigarette smoking.
  3. A small subset of cases is associated with an endocrinopathy, such as Cushing syndrome with ectopic ACTH production by tumor cells.
  4. Carcinoid syndrome occurs in 1% of cases.
  1. One third of carcinoid tumors are central, one-third are peripheral (subpleural), and one-third are in the midportion of the lung.
  2. Central carcinoid tumors tend to have a large endobronchial component, with a fleshy, smooth, polypoid mass protruding into the bronchial lumen.
  3. The tumors average 3.0 cm in diameter, but range from 0.5 to 10 cm.
Carcinoid Tumors: Q
  1. Characterized histologically by an organoid growth pattern and uniform cytologic features: eosinophilic, finely granular cytoplasm and nuclei with finely granular chromatin.
  2. A variety of neuroendocrine patterns may be seen, including trabecular growth, peripheral palisading, and rosettes.
Atypical Carcinoid Tumors:
  1. Differ from typical carcinoids by: Q
  1. increased mitoses, with 2 to 10 mitoses per10 hpt.
  2. tumor necrosis
  3. areas of increased cellularity and disorganization of the architecture; and
  4. nuclear pleomorphism, hyperchromatism and high nuclear:cytoplasmic ratio.
Clinical Features
  1. Half of patients are asymptomatic.
  2. The most common pulmonary manifestations include hemoptysis, post-obstructive pneumonitis, and dyspnea.
  3. Slight female predominance.
  4. Atypical carcinoid tumors tend to be more aggressive than typical ones.
  5. Patients with typical carcinoids have an excellent prognosis, with 90% 5-year survival after surgery, compared with 60% for atypical carcinoids.
Malignant Mesothelioma
Malignant mesothelioma is a neoplasm of mesothelial cells that is most common in the pleura.
The latency period between asbestos exposure and the appearance of malignant mesothelioma is usually to 40 years, with a range of 12 to 60 years.
Immunohistochemistry provides more-refined criteria for differentiating mesothelioma from adenocarcinoma. Adenocarcinomas often, but not always, express carcinoembryonic antigen, Leu-M1, B72.3, and BER-EP4. Mesotheliomas are negative for these markers. Both mesothelioma and adenocarcinoma are positive for cytokeratins. Calretinin, a recently developed marker, usually stains mesotheliomas, whereas adenocarcinoma is typically negative. Wilms tumor-1 (WT-1), thrombomodulin, and podoplanin are other markers typically expressed in mesotheliomas but not pulmonary adenocarcinomas.

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