46 Pathology 6: Lung Cancer

Question 1

Lung carcinoma

Answer 1

• Lung carcinoma is a disease of the adult population, usually affecting individuals in the 5th and 6th decades of life. Lung carcinoma is the leading cause of cancer death in the United States in both men and women. In terms of new patients it ranks second to prostate cancer in men and second to breast cancer in women. More people die of lung cancer than prostate, colon, and breast cancers combined.
• Although there are many types of lung tumors, four types of neoplasms: squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell carcinoma account for 95% of all lung tumors (Table 1). The first three are often combined under the name “non-small cell carcinoma”, based on cell morphology

Question 2

Gross pathology

Answer 2

• Those carcinomas that arise close to the mediastinum on chest x-rays (“central lesions”) derive from the mucosa of the tracheobronchial tree of the main, segmental or subsegmental bronchi. Quite often they arise in areas of squamous metaplasia of bronchial mucosa. These carcinomas are usually squamous cell carcinoma or small cell carcinoma. Because these carcinomas obstruct the lumen of the tracheobronchial tree, they may be associated with distal atelectasis and mucoid impaction when secretions accumulate behind an endobronchial obstruction. These secretions can be colonized by microorganisms resulting in a distal pneumonia. As some central lesions expand in size, the neoplastic cells at the center of the mass lose their blood supply and undergo necrosis. This often results in cavitation and the expectoration of sputum containing neoplastic cells (Thus the need for cytologic evaluation of sputum from patients with central tumors). Central carcinomas may also spread to hilar and mediastinal lymph nodes and chest radiographs showing enlarged lymph nodes at these sites may be the first hint of a primary lung carcinoma

Question 3

Gross pathology

Answer 3

• In the distal pulmonary parenchyma the alveolar epithelium usually does not undergo squamous metaplasia. Instead an atypical proliferation of alveolar pneumocytes occurs along intact alveolar septa. Presumably these atypical cells proliferate until sufficient genetic damage has occurred when they progress to an infiltrating tumor, perforating the basement membrane and invading the interstitial collagen and peribronchiolar connective tissue.
• These carcinomas are frequently described as “peripheral lesions” in that they originate in close proximity to the visceral pleura. Most of these carcinomas are adenocarcinomas. These lesions frequently present late in their evolution because they fail to produce symptoms and signs, as do the more central endobronchial neoplasms. These peripheral lung cancers may invade the chest wall, resulting in localized chest pain as the first manifestation of an underlying pulmonary tumor.
• Lung carcinomas may spread locally within the thoracic cavity. When lung carcinomas gain access to the lymphatics, they typically spread, beginning with involvement of the peribronchial and hilar lymph nodes, followed by involvement of the mediastinal nodes, and then subsequently the supraclavicular nodes and visceral organs. Distal metastases occur in over 50% of cases usually to the liver, brain, bone, and adrenal glands

Question 4

Carcinoma staging and its relation to prognosis

Answer 4

• Pathologic staging of malignant epithelial neoplasms of the lung includes evaluation of the primary tumor, evaluation of local lymph node metastases, and evaluation of distant metastases (Table 2). Primary tumors are staged from T0 (no evidence of tumor) to T4 (extensive tumor) on the basis of size, involvement of visceral pleura and main stem bronchi, invasion of chest wall and mediastinal organs. Involvement of local lymph nodes is staged from N0 (no metastases) to N3 on the basis of location of the positive nodes (ipsilateral peribronchial, ipsilateral mediastinal, or contralateral lymph nodes). Evaluation of distant metastasis is staged as M0 (no metastasis), or M1 (distant metastasis present). The three parameters are then combined together to establish pathologic stage of the disease (range from I to IV). This stage shows strong inverse correlation with prognosis (5-year survival). It is used for selecting a treatment strategy in any given case

Question 5

Pre-neoplastic lesions

Answer 5

• As with other epithelial malignancies, lung cancers are believed to arise through a series of progressive histopathologic changes (pre-neoplastic lesions) in the bronchial or alveolar epithelium.
• For squamous cell carcinoma, the changes include (from the earliest to the most advanced): bronchial epithelial hyperplasia, squamous metaplasia (transformation of pseudostratified respiratory epithelium of the normal bronchi into squamous epithelium), dysplasia of increasing severity, and carcinoma in situ. Squamous metaplasia of the respiratory epithelium is caused by exposure to carcinogens, by tobacco smoke, by vitamin-A deficiency, etc. These lesions are preinvasive and reversible, which means that they may not necessarily progress into invasive carcinoma and may regress (e.g. if an individual quits smoking)

Question 6

Pre-neoplastic lesions

Answer 6

• Atypical adenomatous hyperplasia is considered pre-invasive lesion for peripheral adenocarcinoma. It is composed of an alveolar epithelial cell proliferation with minimal cytologic atypia or stromal response. If such proliferation creates a distinct grossly recognizable nodule it is called bronchioloalveolar cell adenoma.
• Diffuse idiopathic neuroendocrine cell hyperplasia is viewed as possible preinvasive lesion for small cell and large cell neuroendocrine carcinoma, however its role has not been proven. It consists of a diffuse but patchy increase in the number of neuroendocrine (Kulchitsky) cells in the bronchioles. This process is associated with smoking, but is also seen in different physiologic and pathologic conditions

Question 7

Adenocarcinoma

Answer 7

• Adenocarcinoma is the most frequently diagnosed lung. Its incidence has increased in recent years for uncertain reasons. Adenocarcinoma is the most common carcinoma in non-smokers and women and is also the most likely lung carcinoma to develop in younger individuals. Over 75% of lung adenocarcinomas are peripheral lesions, presenting as asymptomatic “coin” lesions. The remainder are bronchogenic tumors and these patients present in a similar fashion to squamous cell carcinoma.
• Histologically, adenocarcinomas may show a variety of growth patterns. First the neoplastic cells may be arranged in a necklace-like configuration (“neoplastic glands”) around a central clear space, which often contains mucin. Other adenocarcinomas may have a papillary configuration where cells line fibrovascular cores, and still others may have a solid growth pattern. When it is difficult to identify a glandular pattern of growth, mucin stains may be helpful in demonstrating glandular differentiation. These stains demonstrate intra- and extracellular mucin in approximately 75% of cases

Question 8

Bronchioloalveolar adenocarcinoma

Answer 8

• A specific variety of adenocarcinoma called adenocarcinoma with broncholoalveolar pattern (formerly known as bronchioloalveolar adenocarcinoma) has unique clinical, pathologic, and radiographic features that warrant specific discussion. It is an adenocarcinoma in which the neoplastic cells recapitulate Clara cells, goblet cells, or Type I and II pneumocytes. It is frequently seen in non-smokers and in young patients. In addition to its capacity to spread through the lymphatic system, this adenocarcinoma is unique in its ability to spread aerogenously, with plugs of neoplastic cells seeding other portions of the lung parenchyma as they are carried up the mucociliary escalator of the tracheobronchial tree and deposited at sites distant from their site of origin.
• Histologically, the neoplastic columnar cells grow along intact alveolar septa. The cells may have two distinct cytologic appearances. First, serous cells resemble Clara cells and alveolar pneumocytes. Second, the mucinous variety is characterized by neoplastic goblet cells, which produce abundant intracellular and extracellular mucin. When this mucin accumulates in the lung, it is often expectorated and patients may present with the production of copious amounts of mucinous sputum (bronchorrhea)

Question 9

Squamous cell carcinoma

Answer 9

• Squamous cell carcinoma has historically accounted for 30% - 40% of lung carcinomas, although most recently it has been replaced by adenocarcinoma as the most common pulmonary carcinoma. Squamous cell carcinomas usually arise in the proximal tracheobronchial tree (main, segmental, and subsegmental bronchi) although approximately 20% of squamous cell carcinomas arise in the periphery of the lung. As mentioned earlier, squamous cell carcinomas are usually preceded by intraepithelial squamous metaplasia and dysplasia prior to the development of an infiltrating carcinoma. They may be associated with parenchymal scars or bronchiectatic cavities, and they are the most common lung carcinomas associated with cavitation and obstructive pneumonia.
• Histologically, the neoplastic squamous cells grow in large irregular sheets and lobules. The cells have pleomorphic nuclei with abundant optically dense eosinophilic cytoplasm. Between neoplastic cells one can often identify intercellular bridges or desmosomes, which result in a zipper-like intercellular space. Neoplastic squamous cells also form squamous pearls. Squamous pearls derive from the neoplastic cells assuming an elongate shape and wrapping or spiraling around one another in a pattern similar to a cross section of an onion. In the central portion of these arrangements is often a large acellular keratin plug.
• Squamous cell carcinomas are locally invasive tumors that may invade the mediastinum, esophagus, chest wall, or apex of the lung. They are often associated with a dramatic host inflammatory response and a distal bronchopneumonia

Question 10

Large cell carcinoma

Answer 10

• This diagnosis includes two different types of tumors. First type, large cell anaplastic carcinoma, represent undefferentiated squamous carcinoma and undefferentiated adenocarcinoma that do not express their histologic features, described above. They may be centrally or peripherally located. Histologically they composed of large pleomorphic cells with vesicular nuclei and prominent nucleoli arranged in solid sheets. Some of them have histologically unusual features (multinucleated giant cells, clear cells, spindle cells).
• Second type, large cell neuroendocrine carcinoma, is located predominantly peripherally. Histologically it is composed of relatively uniform medium-size cells that grow in clusters (so called “organoid” pattern). The main distinguishing feature of these tumors is neuroendocrine differentiation – expression of different neuroendocrine peptides (chromogranin, synaptophysin, etc) that may be identified by immunohistochemical methods. Neuroendocrine granules (cytoplasmic dense core granules) may be found on ultrastructural examination (electron microscopy).

Question 11

Small cell neuroendocrine carcinoma

Answer 11

• Small cell neuroendocrine carcinomas comprise 15-25% of lung carcinomas. These carcinomas are characterized by neuroendocrine differentiation in the malignant cells. This implies that the neoplastic cells often contain neurosecretory granules with hormone-like substances, similar to large cell neuroendocrine carcinoma, that when secreted can cause paraneoplastic syndromes.
• These carcinomas often present as large central neoplasms involving the main or segmental bronchi with extensive hilar and mediastinal node involvement. Interestingly, the bronchial mucosa overlying these tumors may appear unremarkable and it is believed that these neoplasms derive from cells at the basal layer of the epithelium. Extensive infiltration of the angiolymphatic spaces is characteristic, and explains the frequent involvement of mediastinal lymph nodes.
• Histologically the cells of the small cell carcinoma grow in sheets. Often this is associated with areas of necrosis. The neoplastic cells are small, 1.5 to 3 times the size of lymphocytes, and they have oval nuclei with very dense diffuse chromatin, scant cytoplasm, inconspicuous nuclei and high mitotic activity. These carcinomas are associated with extensive lymphatic permeation and this is reflected in their common presentation with extensive metastatic disease often involving the liver, adrenal gland, central nervous system, and bone

Question 12

Pathologic diagnosis of lung cancer

Answer 12

• Accurate histologic diagnosis of lung tumors is very important since there are many different types of treatments for many different types of cancers. Histologic diagnosis may be obtained with sputum cytology, bronchoscopy, transthoracic needle aspiration, video-assisted thoracoscopy, or thoracotomy. Selecting the most appropriate test usually requires consultation with a pulmonologist, interventional radiologist, and thoracic surgeon.
• Sputum cytology is an evaluation of cells present in patients’ sputum. It is a noninvasive test that may be useful in patients who present with centrally located tumors (i.e., squamous call carcinoma or small cell carcinoma) and in those who present with hemoptysis. The test detects the majority of central tumors but less than 50 percent of peripheral tumors; therefore, further testing must follow a negative result

Question 13

Pathologic diagnosis of lung cancer

Answer 13

• Flexible bronchoscopy often is the test of choice in patients with central tumors, with a sensitivity of 90 percent in these patients. Direct forceps biopsy of bronchoscopically visible lesions is the technique used most frequently, but bronchial brushing can also be diagnostic

Question 14

Pathologic diagnosis of lung cancer

Answer 14

• In patients with peripheral lung tumors transthoracic needle aspiration is a preferred technique. In this procedure a needle is inserted into a tumor through the chest wall and pleural space, and the tumor cells are aspirated into a syringe. The cells are smeared on a slide, stained, and examined under a microscope by the pathologist. A diagnosis can often be rendered in a few minutes. It is typically done by a radiologist under guidance by ultrasound or computed tomography (CT scan)

Question 15

Pathologic diagnosis of lung cancer

Answer 15

• Video-assisted thoracoscopy (VATS) is a method that may be used to sample small peripheral tumors (less than 2 cm in diameter), pleural tumors, or pleural effusions. A VATS uses a scope (called a thorascope) passed through a small incision in the chest to remove a sample of lung tissue.
• An open biopsy uses surgery to make an incision between the ribs and remove a sample of lung tissue. An open biopsy is usually done when the other methods of lung biopsy have not been successful, cannot be used, or when a larger piece of lung tissue is needed for a diagnosis