DR. SHIMOSATO: Thank you very much for inviting me to this third State of the Science meeting. I belong to a medical school in Tokyo now, but I retired from the National Cancer Center in Tokyo, where I was 33 years for lung cancer, particularly adenocarcinomas of the lung.

My talk is the prognostic markers of mostly pathologic prognostic markers, not the biological. I have to start with the cell type of adenocarcinoma of the lung.

You see we divided the adenocarcinoma in lung into four subtypes, which were described in detail in the Diagnostic Surgical Pathology edited by Steinberg. The first is the bronchial surface epithelial type, with little or no mucous formation. The second is goblet cell type. Third, bronchial gland cell type. Fourth, the Clara cell type II alveolar epithelial cell type, which means the lung isn't producing -- the mixed cell type, or indeterminate cell type.

The small adenocarcinoma of the lung consists often of the single cell type, but if the tumor grow because of the delayed presentation, the histology becomes complex.

The Clara cell type, alveolar epithelial, is the most common lung cancer among Japanese. It occupies 70-80% of the adenocarcinoma of the lung. And this is the only cell type associated with preneoplastic lesions such as atypical hyperplasia. We don't know any neoplastic lesions in the first three subtypes of adenocarcinoma.

I am one of the participants for the WHO classification of lung cancer. This is a new WHO classification of the adenocarcinoma, which was devised in 1999. In this subclassification the bronchoalveolar carcinoma is defined as a noninvasive tumor. If we see an invasive portion of the tumor, it is classified as a mixed subtype. So this is a quite different definition from the previous WHO classification.

During the discussion, I strongly insisted on the subtyping of the focally invasive bronchoalveolar carcinoma in 10% or less invasive areas. But this proposal was rejected, because there was no supporting data at that time. But we felt that the focally invasive bronchoalveolar carcinoma with less than 10% invasive areas showed very, very good prognosis, almost 100% cure by surgery. We can discuss this in detail a little more, later.

This is a slide reported in the American Journal of Surgical Pathology in 1994. What is surgically curable adenocarcinoma of the lung. We studied 56 cases of the stage 1A, 2centimeter or less in diameter with no dissection, with no adjuvant therapy, no double primary tumor, and no tumor unrelated within five years of surgery. These 56 cases were found in 1,815 cases of adenocarcinoma of the lung dissected during the 25 years of period since 1962.

This is the conclusion. Surgical cure of bronchoalveolar carcinoma of the lung at stage I, and 2 cm or less in diameter, with or without central or subpolar area of alveolar collapse, but localization, low mitotic index, less than 5-10 mitotic figures, and no blood vessel invasion.

And in these 56 cases, 46 cases, which means the 46 cases were associated with either atypical adenomatous hyperplasia, or very well differentiated bronchoalveolar carcinoma tumors, which is about 82%. By the way, adenomatous atypical hyperplasia, as the previous speaker mentioned, all of them were heavy smokers, but we frequently see it among non-smokers.

And in 1995, one of my co-workers, Dr. Noguchi reported this in the journal Cancer. He divided 236 cases of stage 1 adenocarcinoma of the lung into six subtypes. One is a localized bronchoalveolar carcinoma without foci collapse or fibrosis; (b) is with foci collapse or alveolar structures, but without fibrosis. This corresponds roughly to the bronchoalveolar carcinoma of the WHO new classifications with is no invasive tumors.

And (c) is the bronchoalveolar carcinoma with foci of active fibroblastic proliferation, indicating what you call scar. We denied the scar cancer concept though.
And (d) is a ploidy adenocarcinoma, (e) is a tubular adenocarcinoma, (f) papillary carcinoma with compressive and destructive growth. These are not common tubules. The most common are, as I mentioned, a, b, and c.

The results of the prognostic evaluation. The type A and B, which consists of 28 cases, survive 5 years without recurrence. Type C, which also includes the micro or focally invasive bronchoalveolar carcinoma shows a five year survival of about 75%. Type D, much worse prognosis. I mentioned the stage 1 cases, but this is less than 2 cm in diameter.

And as I mentioned, my proposal to include a subtype of the focal invasive bronchoalveolar carcinoma, less than 10% invasive areas, which was rejected at the division group, because of the lack of the data. But fortunately, two publications appeared recently, both of them from the National Cancer Center in Tokyo, and National Cancer Center East in Tokyo. Dr. Suzuki is one of the co-authors. Dr. Yoshida is present here.

Title: "The Prognostic Significance of the Size of the Center Fibrosis in Adenocarcinoma of the Lung." This is the result. These are cases of the stage PT1A. If the center fibrosis is less than 5 millimeter in diameter, the patient having such a tumor survived 100%, 5 years. The overall survival was 75%. And tumors with the central fibrosis of larger than 5 millimeters showed a 75% 5-year survival.

The second paper was published by Dr. Yokoti from the same institution, National Cancer Center East in Japan. And the title was, "Favorable and Unfavorable Morphological Prognostic in the Lung in Adenocarcinomas Less than Three Centimeter in Diameter." Dr. Yokoti expanded Dr. Suzuki's study to 200 cases of the PT1A adenocarcinoma of the lung. His conclusion is the tumor with the bronchoalveolar tumor with the preserved elastic fiber or center fibrosis of less than 5 millimeter in diameter, or areas of bronchoalveolar patterns, over 75% survived 100% 5 years.

The unfavorable prognosis factors was vascular invasion, and papillary growth pattern over 25% of the tumor area.

I show the morphological prognosis factors of the small adenocarcinoma of the lung. These prognostic factors can be applied to an adenocarcinoma less than 1 centimeter in diameter.

Now I'll show you quickly a very interesting case which was reported three years ago in the journal. And CT showed the 2.3 centimeter tumor, which was an adenocarcinoma of the lung. Besides this tumor, there were multiple atypical adenomatous hyperplasia. I should say multiple ground glass lesions on CT.

The left upper lobectomy was performed. And the two adenocarcinoma foci, T1 and T2. And at least 161 atypical adenomatous hyperplasia, which includes A1 to A6.

And in this case, a genetic study was performed in the two adenocarcinoma of the lung, and A1 to A6, atypical adenomatous hyperplasia. The L shows microsatellite LOH, and the other shows microsatellite instability.

From this result we can say that the atypical adenomatous hyperplasia is a clonal neoplastic lesion. And each of these 161 are atypical adenomatous hyperplasia are the independent lesions, not metastatic from main adenocarcinoma of the lung. By the way, this patient was a 77 year old lady, and after a left upper lobectomy, she was followed up by CT for five years, and we do not see any increase in size and density in what we call ground glass lesions here.

But in October 1997, two years after the left upper lobectomy, two new lesions appeared. This is one of the two lesions, which showed increase in size and density. We believe these two lesions are adenocarcinoma. But because of the age of the patient, and previous left upper lobectomy, she had to be placed under observation. We don't know whether these two new lesions have developed from the atypical adenomatous hyperplasia or not. But we have many cases which suggest the development of adenocarcinoma through the stage of atypical adenomatous hyperplasia. Thank you very much.

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