CHAPTER SEVEN: TYPES OF LUNG CANCER

7.0 THE IMPORTANCE OF CLASSIFICATION

Treatment for lung cancer is dependent upon the stage and type of cancer. Thus, the patient interested in understanding the type of care he will receive, must first understand the stage and type of tumor he has.

7 Lung cancer is divided into two basic types, non-small cell and small cell. This classification [provides a standardized system useful in estimating prognosis, selecting treatment and reporting data.

About 80% of lung cancers are non-small cell. Non-small cell lung cancer (NSCLC) combines three types of lung cancer: squamous cell, adenocarcinoma, and large cell carcinoma. These are classified together because their treatment and prognosis are generally similar:

The remaining common histologic varieties of lung cancer- adenocarcinoma, squamous cell carcinoma, large cell carcinoma- behave as a group in a biologically similar fashion and respond similarly to therapeutic intervention. These tumors account for approximately 85% of all lung cancers. Aisner, (1).

7.11 Squamous Cell Carcinoma

Squamous cell refers to a type of cell. These line the large bronchi and squamous cell tumors are generally centrally located. Approximately 90% of squamous cell carcinomas arise in subsegmental or larger bronchi and grow centrally toward the main bronchus and, infiltrate the underlying bronchial cartilage, lymph nodes, and adjacent lung parenchyma. In time, this progression may lead to the formation of large nodular masses.

Because squamous cell tumors are centrally located, they are sometimes seen on chest x-rays and through other diagnostic tests. Sputum cytology is a device to analyze sputum from a deep cough. Squamous cell tumors can frequently be detected through this test. The cytology can frequently identify early stage cancers and if sputum cytology were used more widely, many lives would be saved.

 

7.12 Percentage of Squamous Cell Carcinomas is Decreasing With Smokers Breathing Low Tar Cigarettes More Deeply Leading to Peripheral Tumors

While squamous cell remains the most prevalent form of lung cancer, its incidence is decreasing. One study found the percentage of squamous tumors in men decreased from 51.8% to 42.7%. Aisner (1) at 251. With filtered cigarettes becoming more prevalent, smokers are inhaling more deeply leading to the development of more peripheral adenocarcinomas rather than the central squamous cell carcinomas.

7.13 Adenocarcinoma

Adenocarcinoma is the second type of non-small cell lung cancer. It represents about 40% of all cancers and has become the most common lung cancer among women. It generally starts near the outer edges of the lungs, and its increasing incidence is connected with the tendency of smokers to breath the lower-tar cigarettes more deeply.

7.141 Adenocarcinoma, Asbestosis and Silicosis

While smoking remains the largest cause of adenocarcinoma, some scientists have seen an association with lung scars, and the term scar carcinomas has been used with adenocarcinoma. Where a foreign particle deposits in the lung, and collagen forms to encapsulate the particle, some call this scar formation. For a detailed discussion of silica-related scar formation, See Castranova (2). Asbestosis, silicosis, residuals of tuberculosis along with other scar formations have been linked to adenocarcinoma. Thus, an individual with asbestosis and adenocarcinoma, would likely have a legal claim. See Chapter 22. Some have questioned how closely adenocarcinoma should be associated with the various types of fibrosis or scaring in the lung:

For many years, adenocarcinoma was believed to develop on the basis of scar of (a) any kind. Although we do not deny the existence of scar cancer in the lung,... We have proposed the concept that central or subpleural scars in most peripheral adenocarcinomas were formed not before, but after, the development of carcinoma, and showed the mode of development of such a scar or a fibrotic focus.

7.141 Bronchioalveolar Carcinoma

Bronchioalveolar carcinoma is a type of adenocarcinoma which originates in the alveoli. Bronchioalveolar cancer is hard to detect since a clear nodule may not be seen on tests, and it can initially be confused with tuberculosis or other lung disease.

Women are being increasingly diagnosed with this disease. Showing that different subtypes can respond differently to treatment, this type of tumor is particularly responsive to the new drug, Iressa. See FDA. Gov. carcinomas originate in the smaller or peripheral airways, even at the microscopic level of the alveoli.

7.15 Large Cell Cancer

Large cell cancer constitutes about 15% of all cancers and the term large cell refers to large, masses of tissue usually displaying signs of necrosis (cell death). "Undifferentiated large cell carcinoma are defined by the WHO as "a malignant epithelial tumor with large nuclei, prominent nucleoli, abundant cytoplasm and usually well defined cell borders, without the characteristic features of squamous cell, small cell or adenocarcinomas." (9)

Large cell can sometimes be confused with a poorly differentiated adenocarcinoma or squamous cell carcinoma. However, since the treatment for adenocarcinoma, squamous cell, and large cell are generally grouped together, a physician might not be overly concerned with distinguishing cell type within the group. A subtype of large cell carcinoma is giant cell.

7.16 Differences within the Non-small Cell Category

7.161 Greater Expression of MMP

Adenocarcinoma has a greater tendency to metastasize, compared with squamous cell. Most organs have a protective barrier called the extracellular matrix. During cancer, certain proteins called metalloproteinases or MMP help enable the tumor to penetrate these barriers. "Matrix metalloproteinases (MMPs) are a class of structurally related enzymes that function in the degradation of extracellular matrix proteins that constitute the pericellular connective tissue and play an important role in both normal and pathological tissue remodeling. Increased MMP activity is detected in a wide range of cancers and seems correlated to their invasive and metastatic potential. MMPs thus seem an attractive target for both diagnostic and therapeutic purposes." Dennis (3).

" Matrix metalloproteinases are a family of enzymes that break down extracellular matrix proteins in normal physiological processes such as embryogenesis, tissue growth, and wound healing. The family includes collagenases, gelatinases, stromelysins and metalloelastase. Observational and experimental data from studies of human malignancy indicate that these proteinases are induced by the tumour in order to reconstruct adjacent normal tissue to allow neovascularisation, tumour growth and spread. Tumours have been shown to overexpress certain matrix metalloproteinases relative to normal tissue and recent studies have shown an association between high levels of expression and poor prognosis." Brown, (4).

One study found that adenocarcinomas produced greater quantities of these MMPís than squamous cell tumors possibly accounting for the greater tendency of adenocarcinomas to metastasize. "Compared with squamous cell carcinoma (SqCC), adenocarcinoma (AdC) more frequently overexpressed MMP-1, -11, -13, -14, and TIMP-2, and TIMP-1 and/or TIMP-2 overexpression." Thomas, (5). Thus, we can theorize that an additional amount of MMP inhibitors, would be needed to accomplish the same result with adenocarcinomas as with squamous cell tumors.

7.162 Longer Survival with Squamous Cell

One study found, "For the 71 stage II patients with a squamous histology, a 5-year survival rate of 44% was noted as opposed to 14% for patients with a large cell or adenocarcinoma." (1) Given that dramatic difference in survival, one could argue that it could be erroneous to group squamous cell and adenocarcinoma patients in the same clinical trial. Using this assumption about 5 year survival, if the same drug were given to two groups of patients, one squamous and adeno, results could be interpreted to show triple the effectiveness (as measured by 5 year mortality) in the first group. Additionally, since adenocarcinomas usually produce a greater number of MMPís, we can theorize that higher doses of MMP inhibitors may be necessary to accomplish the same result as with squamous cell.

Thus, there are dangers in grouping these three types of cancer together, both for treatment and research. Future research may examine how the tumors act differently, allowing physicians to make more accurate judgments, and refine treatment based upon type.

7.2 CELL DIFFERENTIATION

Physicians also classify lung cancer by its cell differentiation. Normal tissue is differentiated while cancerous tissue is haphazard, disorganized if you will:

When a cell grows and develops normally, it becomes more specialized to perform a particular function in life. This process is called differentiation and it results in irreversible changes in the cell's characteristics. Differentiated cells are mature cells that perform a particular function. For example, a lung cell looks and works like other lung cells. As a cell becomes more differentiated, it becomes more restricted in what it can do.... As malignant, or cancerous cell grow and divide, they become less and less differentiated. Eventually, they can nor longer perform the functions of the tissue where they originated.... The term differentiation is also used to describe how the cells of a tumor appear in comparison to normal cells. For example, tumors that are classified as "well differentiated" still contain cells that resemble normal cells of the original tissue. Alcase,(6).

Tumors are classified this way:

! Well differentiated, (a cell at its earliest stage of carcinogenesis)

! Moderately differentiated (more progression in the change to cancer cells)

! Poorly differentiated (a cell seen as clearly cancerous)

Within those categories, there may be subcategories, such as well to-moderately differentiated, or moderately to poor differentiated. Generally, the level of differentiation is a positive factor in survival with the more differentiated the cancer cell, the less chance of metastasis. One study found the DNA content of poorly differentiated adenocarcinoma significantly greater than that of well-differentiated adenocarcinoma. Carney, (7). Thus one can assume that the loss of differentiation is associated with increasing DNA mutations in the cell. However, stage rather than differentiation remains the primary factor in determining treatment.

7.22 Related Hormonal Syndromes

Small cell carcinoma can cause a number of hormonal syndromes. "The tumor cells may produce ectopic adrenocorticotropic hormone (ACTH), resulting in Cushing's syndrome, another paraneoplastic hormone syndrome that commonly occurs is the syndrome of inappropriate anti-diuretic hormone (SIADH). This is caused by secretion of ADH from the tumor.

7.3 SMALL CELL STAGING

Small cell cancer is another type of lung cancer. Because it behaves differently than non-small cell, it has its only staging system. Small cell cancer moves quickly though initially it is usually susceptible to chemotherapy, with complete response (no evidence of cancer on x-ray) not unusual. Sadly the tumors frequently return, and preventing that phenomenon is a central goal for research.

Clinical trials generally do not mix small cell and non-small cell patients. Small cell is staged as limited or extensive, unlike non-small cell which has a four part staging system, with subcategories.

Limited stage carcinomas account for 30% of all cases. Limited stage means the small cell cancer is confined to one of the regional lymph nodes. Regional lymph nodes means lymph nodes in the area where the tumor originates. 70% of small cell carcinomas are extensive meaning at the time of diagnosis, the cancer has spread to other organs, or at least beyond the regional lymph nodes. Because extensive disease is common, patients are evaluated with head CT scan, bone scan, liver scan and bone marrow biopsy to see if any metastasis is present.

7.31 Small Cell Location and Appearance

Over 90% of small cell tumors are found in a central location and they typically grow around major bronchi.. The tumor typically extends also to lymph nodes and may invade vascular tissue which explains why many patients have metastasises at the time of diagnosis.

7.32 Role of Surgery in Small Cell Lung Cancer

With non-small lung cancer, surgery is the preferred option and is invariably used for early stage lung cancers, except when the patient has other significant health problems which create risks for surgery. However, a medical article discusses surgery for small cell lung cancer patients:

In the 1950's, surgical resection was still considered the preferred treatment of SCLC (small cell lung cancer) However, in a study conducted by the British Medical Research Council in the 1960's, patients were randomly assigned to receive surgery alone or radiotherapy alone; in patients with limited disease, the median survival was 199 days for those receiving surgical treatment versus 300 days for those receiving radiotherapy. One the basis of this study and the discovery of systemic chemotherapeutic agents with activity, surgical treatment for SCLC has been abandoned, and chemotherapy has been used for both limited and extensive disease. Midthun, (8).

Some observations:

1. Scientists determine the validity of certain treatment forms through epidemiological studies. The word epidemiological comes from epidemic and epidemiological studies investigate the patterns of disease, sometimes comparing the impact of disease between two group receiving different types of treatment.

2. Books like this are intended to provide a general overview, and you need to listen to your physician's advice regarding specific types of treatment, since statements in books and articles can be misinterpreted by patients unaware of subtle difference, for example, differences between non-small cell and small cell. Likewise, your physician should be familiar with recent studies and developments.

3. The National Cancer Institute agrees that surgery has limited utility in small cell lung cancer, but would not agree that surgery has been abandoned. See Chapter Four. One has to be careful of making quick conclusions based upon one or two studies, and you need to measure a study conclusions against our overall medical knowledge in an area. Perhaps a better way of assessing surgery and small cell cancer is to say that many small cell cancers have already had significant spread at the time of diagnosis. Where there has been such spread, that is movement to lymph nodes or other organs, surgical resection cannot accomplish the goal of completely removing the tumor. However, if we can be persuaded that the entire cancer can be removed, surgery might be appropriate.

7.34 Comparison among the Different Types

The book Lung Cancer categorizes the different forms of cancer as follows: In lung cancer, we know that the histological type (type of cell) is one of the most important factors, and that SCLC is most malignant of all; squamous cell carcinoma, adenocarcinoma and large cell are intermediate in terms of malignancy; while carcinoid tumor, adenoid cystic carcinoma and mucoepidermoid carcinoma (all relatively rare) are low grade malignancies.

Carney, (7).

REFERENCES

1. Aisner, Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996). 2. Castranova Silica and Silica-Related Diseases (CRC Publications 1997) 3. Dennis, Matrix Metalloproteinases Inhibitors: Present Achievements and Future Prospect, Invest New Drugs 1997;15(3):175-85.

4. Brown, Matrix Metalloproteinases Inhibitors in the treatment of cancer, Med Oncol 1997 Mar;14(1):1-10.

5. Thomas, Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer, J Pathol, 2000 02, 190: 2, 150-6.

6. Alcase, The Lung Cancer Manual 2.4 (1998).

7. Carney, Lung Cancer (Little Brown 1995).

8. Midthun, Chemotherapy for Advanced Lung Cancer Postgraduate Medicine, vol. 101, no. 3, March 1997.

9. Virtual Hospital, Lung Cancer,www.vh.org.

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