General Pathology 601 for Dental Students

PATHOLOGY OF TUMORS OF THE LUNG

Margaret M Grimes, MD Surgical Pathology Sanger Hall, 5th Floor (804) 828-9739 mmgrimes@vcu.edu

Objectives
Upon completion of this section of the lecture you will be able to:

1. Recognize the most common risk factors for lung cancer.
2. List 4 histologic types of lung cancer.
3. Briefly describe the pathogenesis and prognosis of lung cancer.
4. Discuss the growth patterns and clinical symptoms of carcinoid tumors.
5. Discuss the growth patterns of metastatic tumors.
6. Describe the histologic features of pulmonary hamartomas.

Important Terms in Lung Carcinomas
Small cell (Oat Cell) carcinoma
Adenocarcinoma
Bronchioloalveolar carcinoma
Large cell carcinoma
Squamous cell carcinoma
Pancoast's or Superior Sulcus Tumor
Paraneoplastic Syndromes
Ectopic Hormone Secretion

Carcinoma of the Lung (Bronchogenic Carcinoma)

Statistics
Carcinoma of the lung is the most common malignant visceral neoplasm worldwide. It is the most common cause of cancer deaths in American men, and recently surpassed carcinoma of the breast as the most common cause of cancer deaths in American women.

Risk Factors
Tobacco Smoke
Several lines of evidence strongly link tobacco use with the development of lung cancer:

• The majority (at least 80%) of lung cancers occur in cigarette smokers.
• The risk of developing lung cancer is 10-20 times greater in male cigarette smokers than in non-smokers.
• There is a direct correlation between the incidence of lung cancer and the prevalence of cigarette smoking in men and women.
• The risk of developing lung cancer correlates with the number of cigarettes smoked and the duration of the habit.
• Cessation of smoking reduces the risk of developing lung cancer.
• Cigarette smoke contains carcinogenic substances.
• Smokers have a much higher incidence of atypical cytologic changes in bronchial epithelium than do non-smokers. (The relationship of these changes to the development of neoplasia is debated).

Since not all cigarette smokers develop lung cancer, other factors, such as genetic predisposition, may play a role in the development of neoplasia. Lung carcinoma also occurs in non-smokers, but is much less common in this population. 

Radiation
The incidence of lung cancer increased in survivors of the atomic bomb blasts in Japan. Uranium miners have an increased risk of lung cancer compared with non-miners. Exposure to radon has been linked to lung cancer.

Fibrosis/Scarring in the Lung
Peripheral lung cancers are sometimes associated with areas of fibrous scar. In most cases of these "scar cancers," the fibrosis may result from, rather than precede the development of the neoplasia. Some lung cancers arise in the setting of diffuse interstitial fibrosis.

Histologic Types
Squamous Cell Carcinoma

• strong association with cigarette smoking
• histologically defined by keratinization or intercellular bridging
• majority occur centrally (i.e., associated with a bronchus)
• may attain large size
• may cavitate
• may be associated with hypercalcemia

• most common histologic type in non-smokers and women
• histologically defined by glandular differentiation or mucin production
• majority occur in periphery of lung
• peripheral tumors sometimes associated with fibrous "scar"
• may be difficult to distinguish from metastatic carcinoma

Subtype: Bronchioloalveolar Carcinoma

• tumor cells grow along pre-existing alveolar septa
• may present as a solitary mass, multiple nodules, or a diffuse process
• well-differentiated, diffuse form may be associated with abundant mucus production

• strong association with cigarette smoking
• "undifferentiated" tumor composed of small cells (i.e., high nuclear/cytoplasmic ratio, very little cytoplasm; sometimes referred to as "oat cell")
• most cases arise centrally
• high incidence of extrapulmonary spread at diagnosis
• histologic type most commonly associated with ectopic hormone production
• represents the most malignant end of the spectrum of neuroendocrine tumors of the lung

• includes any non-small cell carcinoma that does not display obvious squamous or glandular differentiation
• may be central or peripheral

• Tumor growing in a bronchus may cause bronchial irritation and mucosal erosion leading to cough and/or hemoptysis.
• Obstruction of a bronchus may result in post-obstructive pneumonia, abscess formation, atelectasis, or air trapping.
• Peripheral (subpleural) tumors may be clinically silent and detected incidentally on chest x-ray.

• Centrally located tumors may invade the mediastinum.
• Compression and/or invasion of the superior vena cava causes superior vena cava syndrome, (i.e., dusky cyanosis with distension of veins of the head, neck, and upper extremities)
• Invasion of the recurrent laryngeal nerve may lead to hoarseness.
• Peripherally located tumors may invade the pleura, causing pain.
• Apically-located tumors (Pancoast's or Superior Sulcus Tumor) may invade the brachial plexus, causing arm pain, and/or the cervical sympathetic plexus, causing Horner's syndrome, (i.e., ipsilateral enophthalmos, ptosis, meiosis and anhidrosis).

• Regional metastasis occurs to bronchopulmonary and mediastinal lymph nodes.
• Distant metastasis frequently occurs to extrathoracic lymph nodes, liver, bone, brain, and adrenal glands
• Symptoms related to metastatic disease may be the first manifestation of a lung carcinoma.

• Lambert-Eaton syndrome--symptoms resembling myasthenia gravis
• hypertrophic pulmonary osteoarthropathy--with periostitis, clubbing of digits, and sometimes arthritis
• myopathy

Recent work has demonstrated the presence of mutational changes in certain oncogenes in lung carcinomas. Carcinogenesis in the lung, as in other sites, probably involves activation of oncogenes and/or loss of tumor suppressor genes.

Prognosis
Prognosis in lung carcinoma depends on the clinical staging at the time of diagnosis, and to some extent on the histologic type.

Overall prognosis for lung carcinoma is poor, with five year survival rates of only 10-15%. This is because approximately 65% of patients with lung cancer present with Stage III disease. Patients with Stage I disease (small, localized, resectable tumor) may have 50% or better five-year survival rates.

Small cell carcinoma is associated with the worst prognosis of all the major histologic types because of the high frequency of metastatic spread at initial diagnosis. Squamous cell carcinomas tend to grow more slowly than other histologic types. In general, poorly differentiated tumors of any histologic type behave more aggressively than better differentiated tumors.

Carcinoid Tumors

Statistics
These neuroendocrine tumors comprise 1-5% of all lung tumors. The male:female incidence ratio is roughly equal. Most patients are under age 40, but this tumor may be seen in older individuals as well.

Growth Patterns and Clinical Symptoms
Central (Bronchial)
Carcinoid tumor typically grows as a polypoid mass projecting into the lumen of a bronchus. Usually the tumor also infiltrates into the peribronchial tissue. Because of the intralumenal growth, this tumor often produces cough and/or post-obstructive pneumonia, atelectasis or air trapping.

Peripheral
Some carcinoid tumors arise in peripheral lung parenchyma, associated with a small bronchiole. Because of the peripheral location, the tumor is usually clinically silent and only found incidentally on chest x-ray.

Histologic Features
These tumors have neuroendocrine features, with uniform cells arranged in organoid, ribbon or rosette patterns. Mitotic activity is low, and necrosis is absent. These tumors are usually very vascular. Ultrastructurally, tumor cells contain dense-core granules typical of neuroendocrine neoplasias. The tumor cells may be demonstrated to contain one or several peptides by immunohistochemistry.

Metastatic Growth
Most pulmonary carcinoid tumors do not metastasize; however, some of these tumors spread to regional lymph nodes, and a small percentage metastasize distantly, usually to the liver.

Prognosis
Carcinoid tumors are low-grade malignant neoplasms. The majority of these tumors are slow-growing and do not metastasize. Five year survival rate is approximately 90%.

Metastatic Tumors in the Lung

The lung is one of the most common locations to which carcinomas of other viscera will metastasize; thus, metastatic tumor in the lung occurs more frequently than primary carcinoma of the lung.

Solitary nodule
Occasionally, metastatic tumor may occur as a single mass in the lung. In these cases, clinical distinction from a primary lung cancer may be difficult. The tumor may involve a bronchus or the peirpheral parenchyma. Clinical symptoms will depend on the location. Primary sites from which solitary metastases not infrequently occur include kidney, colon and thyroid.

Lymphangitic spread
Rarely, metastatic tumor may diffusely infiltrate the pulmonary lymphatics, giving rise to an appearance of an interstitial pattern on chest x-ray, with or without a nodular pattern. The clinical symptoms also may mimic those of an interstitial disease process.

Histologic Features
The histology of metastatic carcinoma resembles that of the primary tumor. Since adenocarcinoma is the most common histologic type of primary cancer arising in the viscera, it is the most common histology found in metastatic cancer in the lung. There may be marked similarity to primary adenocarcinoma of the lung; thus, clinical history and knowledge of the x-ray appearance are important in interpretation.

There is a high incidence of pulmonary metastasis from sarcomas of soft tissue and bone. Metastatic sarcoma usually presents as multiple nodules.

Benign Neoplasms of the Lung

Benign tumors of the lung are relatively rare, compared to carcinoma of the lung. The most common of the benign tumors is the hamartoma. 

The term "hamartoma" refers to a tumor composed of a mixture of mature tissue types that are normally present in the organ in which it arises. Pulmonary hamartomas are usually composed of a mixture of cartilage, fibrous tissue and fat. The tumor usually presents as a solitary nodule on chest x-ray. Often it is present in the periphery of the lung, and is clinically silent. Less often, it may involve a bronchus. These tumors are usually surgically resected because of a clinical concern of carcinoma. Excision is curative.

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Updated September 5, 2007