CHAPTER 9: DIAGNOSTIC TOOLS

The majority of patients are diagnosed with advanced tumors which are difficult to treat. There have been a number of tests developed or refined during the last ten years which significantly increase our ability to spot even small lung tumors, accurately diagnose existing ones, and identify recurrences of people already diagnosed.

Despite the tremendous gains, no test for early diagnosis is recommended by major organizations like the American Cancer Society or National Cancer Institute, and it appears no test for followup has been adopted either. Outside of some University hospitals, generally we are not utilizing all the tools available. While some HMO’s may be happy that expensive tests are not routinely utilized, many patients should be asking why not. Despite its inaccuracy, the chest x-ray continues to be the main-stay of lung cancer diagnosis.

The most widely used diagnostic tool is the chest x-ray. It is economical and easy to use; the typical x-ray takes as little as ten minutes and costs less than $100. However, it is not a reliable method of diagnosing lung cancer and many smaller tumors whose early detection could be critical to the patient's survival are missed with the chest x-ray.

9.11. Chest X-Ray Interpretation Problems

Radiologists are called upon to make critical assessments based upon what are frequently almost imperceptible shadows. The chest contains tissues of different consistency, with air next to thick soft tissue and bone. Adequately producing an image which provides clear definition of all structures in the chest requires meticulous technique and attention to detail. The machine (film processor) used to develop the film should be working properly though up to 50% of x-ray film processors may have some deficiency." (1)http://www.chest.x

9.12 Chest X-Ray Misses Over 75% of Treatable Stage 1 Tumors

An important 1999 study discussed deficiencies in the chest x-ray, contrasting it with the accuracy of the CT or Cat Scan. In this study 1,000 smokers with no symptoms of disease were evaluated with CT Scan and chest x-ray. 27 of the participants were found to have lung tumors which were detected by CT Scan. However, only 7 of the 27 tumors were detected by chest x-ray! Many corporations trumpet less than 1 in 100 defects for various products and the HLA test for detecting paternity is more than 99.7% accurate. The chest x-ray in contrast was shown here to be less than 30% accurate in the patients who would benefit most by early diagnosis. Not surprisingly but quite sadly, many patients with advanced lung cancer reveal that they had a prior x-ray which failed to detect the tumor.

Stage 1 or beginning stage cancers are the most treatable. The results of the chest x-ray in this study for small, stage 1 tumors was even worse. With the Ct Scan, 23 of the 27 tumors were detected at stage 1. However, the chest-ray revealed only 4 of the 23 small, stage 1 tumors. Thus "stage 1 tumors were detected six times more frequently on low-dose CT than on radiography." Note, that this study was done in a clinical context at a well-known hospital. The x-ray machines were presumably working correctly and the slides interpreted by capable radiologists. Even in this context, the chest-ray performed poorly.

The study dealt with smokers with at least 10 pack year histories (pack years are computed by multiplying the number of years smoked by the number of packs smoked per day), who had no symptoms of cancer. Most of the persons detected turned out to have highly treatable cancers. Chest x-rays do detect some tumors, but primarily those at advanced stages which are more difficult to treat. It is a test of limited use, better than nothing, but not even 40 or 50% reliable in detecting small tumors.

Given the unreliability of the x-ray, we hope that physicians will begin using CT Scans to test those at high risk. Certainly, where an x-ray is ambiguous or displays some abnormalities, the prudent physician should order an x-ray. Misread chest x-rays are a chief source of medical malpractice claims. The prudent physician will check his equipment and have all slides read by a qualified radiologist. While that can reduce the possibility of error, it cannot eliminate the inherent limitations of the test.

Sputum cytology is a microscopic analysis of cells from the lung. After the patient takes a deep cough the liquid or sputum is analyzed by a pathologist and a report prepared. Using sputum cytology, a man named Saccamanno in a landmark study was able to detect the progression of lung cancer in a smoker. This test has the following benefits and limitations:

1. The test is effective at diagnosing central squamous cell carcinomas, even at microscopic levels, imperceptible on a chest-ray and perhaps a CT Scan. Thus, it has utility is detecting certain tumors at an early stage when the disease can be cured.

2. Non-small cell lung cancer includes squamous cell cancer and adenocarcinoma. Squamous cell cancer is generally located in the larger central airways , while adenocarcinomas tend towards the smaller, peripheral airways of the lung. The nature of the test is to retrieve liquid in the lungs, and the patient is more likely to cough up liquid from the larger more central parts of the bronchial tree, than the parts of the smaller airways that produce adenocarcinoma. Thus, the test is effective at diagnosing squamous cell cancers, but less effective at detecting adenocarcinomas. While squamous cell remains the most common form of cancer, with low tar cigarette smokers inhaling more deeply, the number of adenocarcinomas in the peripheral airways is almost equal.

3. The European Cancer Institutes states, "Sputum cytological analysis is greater for squamous (93%) or small cell (89%) histotypes than for adenocarcinoma (25%) and large cell carcinoma (54%). (2)

Thus, sputum cytology is a good tool for detecting some lung tumors, but not others. Used with Ct Scan, the two become a reliable method of detecting lung cancer in its early stages. The test is inexpensive, running in the $100.00 range.

9.21 Recent Advances in Detection of Lung Cancer with Sputum Cytology

Sputum cytology is an economical, non-invasive way of detecting lung cancer in its earliest and most treatable stage, with its primary drawback difficulty in detecting adenocarcinomas. However, a recent study indicated progress in refining sputum cytology to improve detection of adenocarcinoma:

Lam and colleagues developed a computer-assisted and automated image analysis method that detects aneuploidy and nuclear abnormalities in sputum samples. Between 5000 and 10,000 cells are stained with a Feulgen thionine DNA cellular stain, analyzed with a digital camera, and then screened using computer-assisted algorithms. In a series presented at the presidential symposium, Lam reported results showing that this screening technique was 70% sensitive for stage 0/1 lesions and 80% for adenocarcinomas, with a specificity of 90%. Lynch, 9^th World Conference on Lung Cancer, (2000) citing, Lam (3).

Others are testing sputum cytology to detect P-53 mutations. If the test can be developed, we would have an inexpensive and reliable method of detecting lung cancer in its earliest and most curable stages.

Computerized tomography or CT uses a beam that rotates around the body to produce a series of pictures taken from different angles. See www. Colorado Health Net, org./cancerlung.symptoms.html. This information is then processed by computer to produce a cross-section of a specific area. CT can reveal the existence of a tumor, and specifics about its location and size. Today, CT is the best non-surgical method of detecting lung cancer and revealing its size and status.

9.31 Accuracy of the CT Scan in Diagnosing Lung Cancer, even Small

Nodules

The Early Lung Cancer Detection survey found a high rate of

reliability in detecting tumors:

compared with chest radiography, low-dose CT greatly increases the likelihood of detection of small non-calcified nodules and, thus, of lung cancer at an earlier and more curable stage. On low-dose CT, non-calcified nodules were detected three times as commonly as on chest radiography, malignant tumours four times as commonly, and stage I tumours six times as commonly. Moreover, the malignant tumours detected on low-dose CT were substantially smaller than those detected on chest radiography, even within stage I (table 3); 15 (56%) of the CT-detected tumours (13 [57%] of those in stage I) were of size 10 mm or less compared with only two of those detected on chest radiography. 26 (96%) of the 27 CT-detected lung cancers were resectable, a striking improvement over the Mayo Lung Project results, in which only 30 (51%) of the 59 tumours detected on baseline chest radiography were resectable.¹⁹ The mobile CT screening study by Sone and colleagues²⁰ also showed that low-dose CT greatly increased the likelihood of detection of malignant disease; ten times as many were detected on CT as on radiography. Hentschke, (4).

9.32 Should X-Rays Continue to Be Used Where We Have a Far More Reliable Test

The tremendous accuracy of the Ct Scan, combined with the inaccuracy of the x-ray raises serious questions about whether x-rays should continue to be used as a tool for diagnosing lung cancer. Yes, the x-rays are cheaper, but should we continue to use a tool 25% as accurate in diagnosing small tumors simply to save money. Indeed, x-rays can provide a false sense of security.

9.33 CT Scan to Detect the Nature and Extent of Disease.

Physicians go beyond using Ct as a device to detect cancer to using it to determine the extent of disease. CT is used to provide a picture of whether a tumor has infiltrated lymph nodes or other organs, and one study found the CT to be 80% effective in determining whether there was cancer in lymph nodes:

9.34 Test Specificity and Accuracy

Let us review these terms which are frequently used with medical tests. A false negative occurs where the patient has a disease or characteristic and the test fails to detect that. Thus, the test is falsely or incorrectly negative; it should have been positive. Another word for false negative is accuracy. That is, what percentage of persons with a given disease are detected. If the CT is 80% accurate in detecting lymph node metastasises, its accuracy or false negative rate is 80%.

Specificity is the number of false positives. That is, how many tests are incorrectly read as positive. For example, a person with inflamed nodes could have a CT Scan read as positive for spread of the cancer to the node.

If Ct Scan is the most reliable non-invasive test, bronchoscopy is the most reliable minimally invasive test. While bronchoscopy should be viewed as a surgical procedure, its risks are generally minimal. The Virtual Hospital is an excellent site which describes bronchoscopy:

"Bronchoscopy is the examination of the airways under direct visualization. Bronchoscopy began with the use of a candle and a rod with a polished metal disk to visualize the osopharaynx. It has evolved into a wide variety of precision optical instruments capable of visualizing the endobronchial tree to the 5th or 6th generation....

bronchoscopy is used to obtain peripheral lung samples in the presence of lung parenchymal disease such as peripheral coin lesion(s), hilar adenopathy, or diffuse or focal parenchymal infiltrates. Finally, bronchoscopy is useful in staging lung cancer, evaluating the airways in patients with normal radiographic findings and positive sputum cytology, and evaluating the airways after thoracic trauma, or if there is a suspected airway foreign body." Virtual Hospital, (6).

9.41. How the Patient Feels During a Bronchoscopy

Here is what the patient will experience:

"The surgeon makes a small incision in the skin on the chest with a scalpel. The biopsy needle is inserted into the lung. You may feel a sharp, temporary pain when the biopsy needle touches the lung. A small amount of lung tissue is removed. Biopsy needle and syringe are removed. Adhesive bandage is applied to the biopsy site. Tissue is sent to the laboratory for analysis."Healthgate (13)

9.42 Reliability of the Bronchoscopy

Reliability seems to depend upon the location of the tumor.

"Tumors may be present in three ways in the lung, as central endoscopically visible lesions, as submucosal or extrinsic lesions, and as peripheral lung lesions. The diagnostic yield and bronchscospic approach to diagnose these lesions varies among these three presentations. In endobronchial visible lesions, bronchoscopy will correctly diagnose the lesion in 94% of the cases if at least 5 samples of the lesion are obtained....

By contrast, direct forceps biopsy correctly diagnoses only 27% of patients with extrinsic airway compression or with submucosal or peribronchial disease. The low yield is most likely due to the fact that the forceps biopsy does not sample tissue deep enough. Much better diagnostic results are obtained in this situation by using transbronchial needle aspiration. In this technique, a 1 cm. needle attached to a catheter is placed through the mucosa using the bronchoscopy....

"The diagnostic yield for peripheral lung lesions varies widely from 30- 90% using transbronchial biopsies. In this technique, the forceps are passed through the airways distal to the directly visualized sites using fluoroscopy." Virtual Hospital,(6).

Sadly, some people have gone undiagnosed after a physician failed to detect a tumor during a bronchoscopy. The above highlights that the following:

1) Bronchoscopy is not a conclusive test. Where symptoms of lung cancer continue, and a definitive diagnosis of another disease is not made, additional diagnostic tests must be done. Where a patient seems to fit the profile of a lung cancer patient- significant smoking history, loss of weight, fatigue, chest pain, cough, and has other symptoms of the disease, a repeat bronchoscopy, needle biopsy, or even a thoracatomy (surgical biopsy) may be called for with a negative bronchoscopy. Timely diagnosis of lung cancer is critical.

2) Success in detecting the tumor will depend upon the tumor’s location and to some extent, the skill of the physician performing the procedure.

3) An adequate sampling is critical. Reports should clearly indicate how many samples have been taken so the extent of reliance on the bronchoscopy can be determined by other physicians.

PET or Positron Emission Tomography is a useful tool for diagnosing lung cancer and ascertaining the extent of disease.

9.51 How Does Pet Work

Here is one description of the PET process:

"Glycolysis is increased in tumor tissues. [A glucose analogue is] used in positron emission tomography (PET) to trace glucose metabolism.

All 82 patients with lung cancer had increased FDG uptake in the lungs, whereas only 12 of 25 patients with nonmalignant diseases had increased FDG uptake. Sixteen lung cancer patients with mediastinal metastasises had increased FDG uptake in the mediastinum, of whom three had no lymphadenopathy on computed tomography of the chest. Sixteen lung cancer patients without mediastinal nodal involvement had no FDG uptake in the mediastinum. Seven of these patients had lymphadenopathy on computed tomography. FDG-PET imaging is 100% accurate in predicting mediastinal involvement in patients with lung cancer. It is 100% sensitive and 52% specific in predicting the malignant nature of a chest radiographic abnormality." Sazon,(7).

Recent medical literature has trumpeted PET:

"the use of positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) has become a valuable tool in the detection of a variety of tumors including lung cancer..... FDG-PET had a sensitivity, specificity and accuracy of 98.0%, 78.6% and 93.8%, respectively, in detecting malignant pulmonary nodules. In N staging, sensitivity, specificity and accuracy were 66.7%, 81.3% and 76.0%, respectively. In M staging, the accuracy was 100%.... In our observations, whole-body 18FDG-PET images improved diagnostic accuracy in the evaluation of lung lesions and the staging of lung cancer. (8).

Its sensitivity is excellent, and it can detect many small tumors. The difficulty is that some normal areas may show as hotspots causing concerns, and occasionally unneeded surgery. Pet may be useful as a early detection tools for those at risk, such as heavy smokers. The high rate of false positives leads us to question its use as a screening device for the population at large. A new test, combined Pet/Ct, combines the benefits of both sets, creating a diagnostic tool that is both sensitive (detects most tumors) and specific (does not creates false positives).

9.56 Combined Pet and Ct Scan

The new device combines a PET Scan with a Ct Scan, providing a reading from both devices for the radiologist and a single seating for the patient. Items which could be misdiagnosed as cancer are eliminated, while the combined tests reduces the possibility that serious lesions are missed:

Integrated PET-CT provided additional information in 20 of 49 patients (41 percent), beyond that provided by conventional visual correlation of PET and CT. Integrated PET-CT had better diagnostic accuracy than the other imaging methods. Tumor staging was significantly more accurate with integrated PET-CT than with CT alone (P=0.001), PET alone (P<0.001), or visual correlation of PET and CT.

Some insurers may balk at the increased cost, and the tool may only be available at modern research facilities. However, its greater accuracy means it provides information unavailable in other modalities so insurance should be required to pay the cost.

9.61 Flow Cytometry

Cancer cells may be analyzed to assess their structure and DNA. Flow cytometry measures how many pairs of chromosomes the cell’s DNA contains. See American Cancer Society, (11). If a cells has a normal number of chromosomes, it is diploid. If the cells have severely disrupted DNA, it is said to be aneuploid.

9.62 S-plase Faction, SPF

SPF measures the percentage of diseased cells in the synthesis phase of cell division. If the number is high, a great percentage of cells are in the S-phase and dividing rapidly, indicating the tumor is growing quickly. American Cancer Society, (11). A low SPF indicates a slow-growing tumor.

Both flow cytometry and SPF show promise in providing an early indication of disease, though neither are routinely recommended for screening purposes.

9.63 P-53 Analysis

P-53 is an important tumor suppressor gene and we discuss its function in a separate chapter. A few words here. P-53 testing is being investigated as a means to identify early tumors, and changes in tumors already identified.

1. www.chest.x-ray.com 2. The European Cancer Institute 3. Lam et. al, Lung Cancer Control Strategy in the New Millennium. Lung Cancer. 2000;29(Suppl 2):145. 4. Hentschke, Early Lung Cancer Action Project: Baseline Screening, Lancet, 1999, 354, 99-105. 5.chestx-ray.com/StaginglungCa/Lung Cancer. 6. Virtual Hospital, Lung Tumors: A Multidisciplinary Database, Bronchoscopy, www.vh.org.Providers/Textbooks/LungTumors/Diagnosis/Bronchoscopy/bronchosopy.htm. 7. Sazon, Fluorodeoxyglucose-positron emission tomography in the detection and staging of Lung Cancer, Am J Respir Crit Care Med 1996 Jan;153(1):417-21.

8. Evaluation of Whole Body Positron Emission Tomography Imagin in the Clinical Diagnosis of Lung Cancer, Kokyuki Gakkai Zasshi 2000 Sep;38(9):676-81. 9. Dunagan, Staging by positron emission tomography predicts survival in patients with Non-Small Cell Lung Cancer,Chest 2001 Feb;119(2):333-9.

10. N. Engl J Med 2000 Jul 27;343(4):254-61.

11. American Cancer Society, Informed Decisions 136 (1997)

12. Lardinois, Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med. 2003 Jun 19;348(25):2500-7.

13. www.Healthgate.com