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WASHIN(;TON II N I V N R 9 I T Y SCHOOL OF MEDICINE ST. LOUIS. MISSOURI 68110 May 16, 1974 DEPARTMENT OF PATHOLOGY DIVISION OF SURGICAL PATHOLOGY BARNES HOSPITAL PLAZA Freddy Homburger, M.D. Director, Bio-Research Consultants, Inc. 9 Commercial Avenue Cambridge, Massachusetts 02141. Dear Dr. Homburger: I have now reviewed the slides which'you so kindly sent me for review concerning your study on effects of cigarette smoke in the upper respiratory tract. My comments are as follows: Fig. 2: I agree with the word "thickened" but the adjective "markedly" might be changed to "moderate". There are areas that show considerable hyperkeratosis which were not photographed. Fig. 3: I agree with the descriptions of this figure. Fig. 5: I do not see "pseudoepitheliomatous hyperplasia" as we use the term in human pathology. I agree that there is hyperkeratosis. The predominant striking feature which is nicely illustrated in the photomicrograph is the basilar cell hyperplasia or basilar cell hyperactivity. The numerous mitotic figures referred to in the legend indicate active cellular pro- liferation. Fig. 6: Again this is not the way I use the term "pseudo- epitheliomatous hyperplasia". I agree that this shows hyperkera- tosis with atypia of at least a moderate degree. There are atypical cells quite close to the cells keratinized on the surface. These atypical changes are seen on both cords and ex- tend for some distance below the true cords. There are dis- turbances of the maturation sequence but the very superficial layers are still keratinizing in a reasonably orderly fashion. r EXHIBIT NO f ~~~ ~~ 0 42 " " % -9 7"

., Dr. F. Homburger -2- May 16, 1974 Fig.. 7: These sections show the most severe hyperkeratosis of any seen so far. The epithelium is drawn into acanthotic folds. The bases of these folds extend into the mucosa creating the appearance of isolated epithelial masses in the submucosa. There is considei'able atypia, particularly in the basilar region. Fig. 9: I think part of the difficulty here is that this section has been cut tangentially. Apparently what we are looking at are t)ie anastomosing acanthotic folds. I do not believe the changes in this larynx are in any way different from the preceding one in Figure 7. I do not regard this as cancer. Fig. 10: Line 3, should be "pleomorphism" rather than "pheomorphism". I think the evaluation of this lesion is essentially correct. This would be difficult to distinguish from a super- ficially invasive epidermoid carcinoma. There is extension.of the epithelial changes into the ducts of submucosal glands. The cytologic features are quite compatible with malignancy. The surface cells are still undergoing maturation. However, there is sufficient cytologic abnormalities in the deeper cell nests to regard this lesion as a small focus of cancer. Fig. 11: The changes in this lesion approximate those seen in the previous animal. I would not be as confident of a malig- nant diagnosis in this case as most of the changes are not as clear-cut as in the previous animal. I am not sure how to in- terpret the area suggestive of lymphatic invasion. Perhaps ad- ditional sections would resolve my difficulty. The nest of cells is adjacent or within a dilated channel but it really is very close to the surface eFithelium. Fig. 12: I am not clear as to the nature of this epithelial proliferation. I suspect it is the result of a tangential section and not a papilloma. Additional levels would resolve this problem. There are, however, very atypical epithelial changes with ex- tension into the ducts of submucosal glands. There is considerable acanthosis and cellular atypia. L.r TR f f f`i 0422798

Dr. F. Homburger -3- May 16, 1974 Fig. 13: Again I have the problem of the plane of section and again I doubt whether this is a true papilloma. Figs. 14, 15, 16 and 17: No comment. Fig. 19: I would prefer basal cell hyperplasia to describe this change. Iswould describe the inflammatory response as slight. Fig. 20: I think this is a very interesting neoplasm of glandular origin. It has double layering of cells as one would see in a tumor of salivary gland origin. There are also foci of so-called intermediate cells with a tendency toward squamous metaplasia. Could this tumor possibly be related to mucoepider- moid tumors of humans? Stains for epithelial mucin might be positive. Some areas in the stroma appear myxomatous and Alcian blue PAS stain might demonstrate the presence of acidic muco- polysaccharides. Fig. 21: Very little of this tumor is present in the slide, but I think this one could pass for a papilloma. It appears to me to be distinctly different than the tumor seen in the previous animal. Fig. 23: This is an obvious malignant tumor in the region of the nasopharynx. I can find no connection with the overlying epithelium in this section. I am not sufficiently familiar with tumors in the hamsters to classify it properly. I find it curious that there is a glandular structure in exactly the same location on the opposite side. Could this neoplasm have originated in such a gland? Is that gland on the other side the equivalent of the human parotid gland? Might not the malignant tumor be of salivary gland origin? Fig. 24: Multiple pulmonary metastases are present as depicted in Fig. 23 and appear to be related to the previous described tumor. In summary I would say that there are severe epithelial abnormalities seen in the animals exposed to cigarette smoke_._ Maiiy of the changes such as hyperkeratosis, epithelial hyper- plasia, cytologic abnormalities, and disturbances of'iaeaturatfkffi L..r T i h f i N 04,2799

Dr. F. Homburger -4- May 16, 1974 I sequence are those seen in association with invasive cancer ~.. _... __. . _ .. .. .... in humans. There is one animal (Fig. 10) that has a small cancer .superficially iiivading the submucosa. Many of the others have severe atypia. I am not able to properly evaluate the tumor in the region of the nasopharynx but I would suggest that a salivary gland origin-be considered for this tumor. Thank you very much for the opportunity to review this material. I believe it to be very interesting and has great importance in elucidating the effects.of the tobacco smoke in the upper respiratory tract. Sinr rely yours, / // „A , Walter C. Bauer, M.D. Professor of Surgical Pathology and Pathology WCB : eg P.S. The slides are being returned to you today via air mail, certified, under separate cover) CTR ININ 042800