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Morphological Aspects of Experimental Actinic and Arsenic Carcinomas in the Skin of Rats W. C. Hueper, M.D. (F'rom the I4"arner Institute /or Therapeutic Research, New Yor/<, N. Y.) (Received for publication April 25, t942) Epidermal neoplasms of the human skin vary greatly in their degree of differentiation and in the type of special organic morphology which they reproduce. However, this diversity in structure is apparently unrelated to the physical or chemical nature of the causative carcinogcnic agent. Thus, epidermoid carcinomas as well as basal cell cancers are elicited by the action of arsenicals and sonar radiation containing ultraviolet rays. Similar conditions seem to apply to animals. Putschar and Holtz (8) observed in the skin of rats exposed to ultraviolet rays not only these 2 types of blastomas, but also trichoepitheliomas and spindle cell sarcomatoid carcinomas resembling those found not infrequently in the skin of mice subjected to paintings with tar. These observations show that the skin of rats possesses blastomatous potentialities which are equal to those of the human skin in spite of the fact that these tissues differ normally in their anatomical structure to a considerable degree. The following study on the morphological aspects of experimental actinic and arsenic carcinomas in the skin of rats is presented to emphasize the structural diversity of the various epithelial tumors produced by these carcinogenic agents and to add at the same time several new types of epidermal neoplasms hitherto not described in irradiated rats. ACTINIC CARCINOMAS MATERIAL The observations to be reported were made in a series of 20 rats which had been exposed, for a period of up to to morlths, to the radiation emitted from the mercury vapor burner of a Hanovia S u p e r s Alpine Lamp yielding 1,5oo milliwatts per square centimeter at a distance of 75 cm. Details concerning the experimental procedures which led in these animals to the development of cancers of the skin, as well as brief notes regarding the types of tumors produced, have been given in a previous paper (3). HISTOLOGICAl. I)ATA EPIDERMAL HYPERPLASTIC REACTIONS The primary effect of an exposure to ultraviolet rays is a thickening of the cornified lamellated layer and an increase in the number of cellular layers from the normal I or 2 to 5 or 6. Simultaneously, there occurs a progressive differentiation of the epidermal cells in the more superficial layers. They change from relatively small oval or round cells to large polygonal cells which, near the cornified lamella, contain eleidin granules. The cells of the basal layer not infrequently assume a low cuboidal shape and become arranged in regular palisade formation. The basal layer is covered in some areas by one or several layers of somewhat larger round cells. While these changes represent the most frequent epidermal reaction, there occur regions in which a diffuse and irregular proliferation of basal and round cells takes place without anv appreciable thickening of the cornified layer and any differentiation into squamous cells (Fig. i). Some of these atypical epidermal areas are covered by a layer of debris and leucocytes. They vary considerably in thickness and may include areas composed of spindle cells and squamous cells (Fig. 2). Following or accompanying these manifestations of epiderma[ proliferation, differentiation, and disorganization, small well circumscribed buds of round and oval cells project into the subepidermal vascular cot> nective tissue. These processes may preserve during further growth their oval, round, or spindle cell character, or they may develop in their central portions occasional small epithelial pearls surrounded by a few flattened squamous calls, or they may undergo progressive differentiation in these parts with the formation of large masses of polygonal cells and numerous pearls. The course last mentioned is the most frequent one, and is often associated with the development of solid epithelial papillary projections covered by a thick cornified layer and extending beyond the surface of the skin. The increased keratinization of the epidermis results 55I Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. 552 Cancer Research Fro. 1.--The epidermis shows proliferation of round cells, which extend in garland formations into the deeper tissue. Mag. X I55. Fta. 2.--Beneath a thick cornified layer lies a thickened epidermis, consisting of areas of densely packed spindle epithelial cells and squamous cell parakeratotic loci. Mag. X *55. Fro. 3.--Underneath a hyperplastic epidermis large accumulations of sebaceous glands are found. Mag. X 75. Fic. 4.--Squamous cell carcinoma with cornification. Mag. X 75- Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. Hueper Actinic and Arsenic Carcinomas in Skin not infrequently in a clogging of the orifices of the hair follicles which subsequently become distended thereby and filled with keratinized material and fragments of degenerated hair. The sebaceous glands occasionally undergo notable proliferation, and then form dense adenomatoid clusters (Fig. 3). These hyperplastic epidermal reactions form the basis for the subsequent development of various types of malignant tumors, whose morphological features are sometimes influenced to an appreciable degree by the benign or malignant proliferative processes affecting concomitantly the underlying mesenchymatous tissues. EPIDERMAL I%~TEoPLASTIC R~ACTtONS (a) The most common type of actinic carcinoma in the skin of rats subjected to ultraviolet radiation is the squamous cell carcinoma with cornification (Fig. 4). It is identical in all morphological respects to that seen in the human skin. (b) The squamous cell carcinoma without cornification is considerably less often encountered under the experimental conditions stated (Fig. 5)(c) The third type of epidermal neoplasm not infrequently met with in the skin of irradiated rats is a round cell carcinoma consisting of densely and irregularly packed, relatively large, not always well defined, round cells, which grow in large plump processes and sheets in which a n-targinal gern-tinal layer is not discernible (Fig. 6). (d) In son.te instances the cells of such an iml-t-tature neoplasm have an oval or spindle shape, either in scattered areas or throughout the bulk of the tumor. These spindle cell carcinomas differ, however, from the ordinary basal cell carcinoma of the human skin in that their ceils are larger, they have a more abundant amount of cytoplasm, and the cellular outlines are sometimes more distinct than those seen in the spindle cell type of basal cell cancer of human origin. Morphologically they resemble more closely the spindle cell carcinomas found in the human uterine cervix (Fig. 7)- Inasmuch as spindle cell sarcomas are not rare in the cutaneous tissue of irradiated rats (Fig. 8) and occur in coexistence with epidermal neoplasms, it is occasionally di~cult to distinguish between these 2 types of tumors, especially when they collide in the subcutaneous tissue. The use of silvered preparations for the demonstration of reticulum and the preparation of sections stained with phosphotungstic acid-hematoxylin for the demonstration of fibroglia and myoglia is of aid in the differential diagnosis of these tumors (2). (e) Carcinomas of the basal cell type, consisting of relatively small, round, oval, or spindle cells with ill defined outlines and hypochromatic nuclei grow- 553 ing either in large, well demarcated islands (Fig. 9) or composed of hyperchromatic cells forming slender, garland-like, reticulated structures in a loose, partly mucinous stroma (cylindromatous type) (Fig. ~o) occur rarely. (f) Somewhat more frequent are combinations of basal cell cancer and squamous cell carcinoma (keratinizing basal cell carcinoma, Fig. I i). The ratio of the 2 types of structures varies greatly with the individual tumors. (g) A very rare variety, which was seen only once in the present series, is represented by an adamantinomatoid type of carcinoma. This is composed of smaller or larger nests of well outlined cells of spindle shape surrounded by columnar elements resembling enameloblasts. In some of these alveoli pinkish stained pearls are present, which are embedded in a reticular, cellular matrix. The intervening stroma is very loosc and vascular (Fig. i2). (h) A pseudoglandular type of carcinoma occurs infrequently. It originates from a solid type of epithelial growth consisting of medium sized, polygonal, or cuboidal elements which undergo degenerative and lyric changes in the central portion of the strands and islands, leaving the peripheral cell layers intact. This process results in the formation of tubular or alveolar structures lined by somewhat irregularly arranged epithelial cells (Fig. I3), such as are seen in pseudoglandular carcinomas of the bladder in dogs treated with ~-naphthylamine (3)This tumor displays a definite similarity to anglosarcomas occurring in the subcutaneous tissue of irradiated rats and bordering on or involving the epidermis. It is important that in the case of anglosarcomas the overlying or adjacent epidermis displays merely hyperplastic changes without any appreciable atypical manifestations (Fig. *4)(i) The blastomatogenic effect exerted by ultraviolet rays on both the epidermal and vascular elements of the skin is exemplified, moreover, by the occurrence of squamous cell carcinomas possessing a loose, edematous, stroma which contains numerous dilated and congested blood vessels (Fig. I5). Such tumors have been termed angio-epitheliomas when occurring in the human bladder or in the skin of mice painted with tar. (j) A demonstration of the carcinogenic effect of ultraviolet rays upon epithelial structures situated in the subepidermal tissues is presented by the occasional occurrence of carcinomas reproducing in a defective form the structure of the sebaceous glands (sebaceous carcinomas, Fig. i6). These tumors consist of large, well circumscribed alveoli filled with distinctly outlined epithelial cells possessing a foamy cytoplasm. Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. 554 Cancer Research 5:1 1 a *. FIG. 5.--Squamous cell carcinoma without cornification. Mag. X I55. Fro. 6.--Round cell carcinoma with densely packed indistinctly outlined round and oval cells. Mag. X 155. Fro. 7,--Epidermal carcinoma consisting of oval and spindle shaped cells. Mag. X I55. Fro. 8.--Spindle cell sarcoma surrounding an epidermal cell nest with central necrosis. Mag. X 75. Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. Hueper--Actinic and Arsenic Carcinomas in Skin 555 Fro. 9.--Small, ill defined round cells with superficial necrosis advancing toward the auricular cartilage. Mag. X I55. Fro. i0.--Small round and spindle cells growing in reticular formation with a scanty loose stroma. Mag. X I55. Fro. i i.--Densely packed hyperchromatic round and spindle cells with numerous epithelial pearls. Mag. X I55. Fro. i2.--Irrcgularly arranged cords of epithelial cells lined by low cuboidal cells which surround a reticulate cellular mass. The stroma is scanty and very vascular. Mag. X I55. Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. 556 Cancer Research Ftc. i3.--Tubular and alveolar cavities lined by irregularly arranged cuboidal cells representing pseudoglandular carcinoma. Mag. X 155. FIG. I4.--Ill defined cells of irregular shape and size lining small and large cavities filled with erythrocytes and forming in part the cellular framework of these structures. Mag. )~ I55. Fio. I5.--Atypical squamous cell carcinoma with an extraordinary development of vascular stroma. Mag. X 75FIo. 16.--Densely packed long, oval, and spindle epithelial cells with a foamy cytoplasm arranged in relatively well defined alveoli showing a certain resemblance to sebaceous glandular structures. Mag. X 155. Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. Hueper--Actinic and Arsenic Carcinomas in Skin (k) A relatively rare type of actinic carcinoma is represented by anaplastic carcinomas. They are characterized by a kind of dissolution of the epidermis into highly atypical cells which vary greatly in size, shape, staining properties, and distinctness of outline. They invade the subcutaneous connective tissue diffusely in small groups or as solid sheets (Fig. I7). Their diagnosis sometimes offers great difficulties, as they have to be distinguished from equally atypical, polymorphous cell sarcomas occurring in the subcutaneous tissue of irradiated rats (Fig. t8) and in direct contact with the often hyperplastic and hyperkeratotic epidermis. This usually shows an intact basal layer. (t) The relatively thin epidermis of the rat, which permits a ready penetration of the ultraviolet rays into the subepidermal connective tissue, is responsible not only for the frequent occurrence of sarcomas in these tissues but also for that of carcinosarcomatous collision tumors. They are usually squamous cell carcinomas with an atypical, spindle cell sarcomatous stroma (Fig. I9). ARSENIC CARCINOMAS In spite of the fact that the epithelium lining the clogged and distended hair follicles was usually hyperplastic and hyperkeratotic, there was not a single instance of trichoepithelioma found in the ultraviolet light series. This is remarkable, as these tumors are relatively common in the skin of mice subjected to applications of tar, which penetrates into the lumen of the follicles and thus establishes direct contact with their epithelial lining. It is of significance for this reason that a tumor showing trichoepitheliomatous structure was observed in i out of ~o congenitally hairless rats which had received with their drinking water increasing amounts of arsenious acid in the form of Fowler's solution (Fig. 2o). Hairless rats were employed in this experiment because the absence of hair impairs the ready excretion of arsenic by the skin and its appendages and thus favors the retention of this carcinogenic agent, especially in the epithelial lining of the cystically distended hair follicles. Hairless rats normally develop papillary warts in their hyperkeratotic skin, which possibly might possess an increased tendency toward a malignant degeneration under the stimulus of an exogenous carcinogenic agent. The tumor was found in the last rat surviving for 2i monthsl It was located beneath the epidermis in the subcutaneous tissue and represented a more or less well defined nodule measuring about ~ cm. in diameter. It was the only tumor observed in this series as well as in a series of haired and identically treated control rats which were litter mates of the hairless 557 rats. Six of these haired rats survived for more than 23 months without showing any skin lesions. DISCUSSION The evidence presented is satisfactory proof that under proper stimulation (ultraviolet rays, arsenic) the epidermis of the rat is capable of producing as great a variety of carcinomas as that seen in the human skin. The carcinomas obtained in the skin of rats following an exposure to ultraviolet rays are even more complex than those occurring in man, as they are not infrequently associated with hyperplastic or sarcomatous proliferations of the mesenchymatous elements of the cutis, complications rare in tumors of the human skin. The great variety of epithelial tumors and their frequent combination or coexistence with mesenchymatous neoplasms observed in these animals is attributable to some extent to the fact that the skin of the rat is much thinner and less cornified than the human skin, so that the ultraviolet rays can penetrate deeper into the subepidermal tissue and elicit blastomatous responses both from the appendages of the skin and from thc mesenchymatous tissues. However, the occurrence of tumors differing widely in structure, yet located side by side in the skin of the exposed animals, indicates that the diversity depends not entirely upon the action of the carcinogenic agent as determined and modified in its degree and depth by the thickness of the keratin and cellular layer and by the density and distribution of pigmentation and hairs. The type of photochemical changes elicited in the skin seems to play a major role in this respect. These, in turn, seem to depend upon endogenous factors of metabolic nature and are responsible for the kind of pathological "internal environment" produced in the irradiated tissue, thereby providing a certain steering mechanism in the carcinogenic process. The validity of this concept receives some support from the fact that repeated attempts to elicit carcinomas of the skin in rabbits by prolonged exposure to ultraviolet rays have failed consistently, in spite of the production of such tumors with the aid of another actinic agent, roentgen rays. Inasmuch as the anatomical structure of the skin of the rabbit does not differ essentially from that of the rat it has been argued that intrinsic factors related to the herbivorous metabolism of the rabbit, and particularly to its lipoidal aspects, are responsible for this resistance of the skin. Baumann and his associates ( i ) attempted, therefore, to overcome this metabolic influence by feeding cholesterol to rabbits during the course of irradiation treatment. However, their results were negative. The writer's own experiments, conducted for a similar Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. 558 Cancer Research : i: fig. 1 7 f i r 18 Fro. 17.--Diffuse and highly anaplastic proliferation of the basal cell layer into the subcpidermal tissue. Mag. X I55,, Fro. iS.--Polymorphous cell sarcoma underncath a hyperkeratotic and hyperplastic epidermis. Mag. )K I55. Fro. Ig.--Nests of cornified squamous cell carcinoma imbedded in a polymorphous cellular sarcoma. Mag. )K 75Fw.. 2o.--Dcnsely packed nests of small cuboidal and oval cells surrounding frequently hyaline lamellated loci which contain occasional abortive hair formations. Mag. X i55. Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. Hueper--Actinic and Arsenic Carcinomas in Sl(in purpose several years ago with 17 white coated and blue eyed rabbits (crosses between Chinchilla and N e w Zealand Red rabbits), were equally unsuccessful. The skin of the back in 8 of these rabbits was shaved with an electric razor daily and was then exposed for increasing periods of time to ultraviolet rays. Moreover, the rabbits were given Fowler's solution by mouth in order to provide an additional specific carcinogenic stimulus and to enhance at the same time the photochemical action of the rays by the production of a chemical photosensitivity. A control series of 9 rabbits:received actinic treatment only. D u r i n g the experimental period, which lasted up to I2 months, all rabbits developed a chronic dermatitis with multiple and sometimes deep ulcerations, keratoses, pigmentary shifts, disturbances in the growth of hair, scaling, chronic congestion, etc. T h e epidermis of the back and o f the ears showed hyperplastic, hyperkeratotic, and atrophic changes. These alterations were not infrequently associated with numerous small ulcerations and with a ballooning of the basal cells. T h e basal cell layer of the skin of the ears often exhibited a diffuse proliferative budding of these cells, but in only one instance was there a displacement of discrete basal cell nests into the deeper tissue. T h e definite proliferation of the auricular cartilaginous tissue occasionally noted provided additional evidence concerning the deep penetration of the rays. These cutaneous changes were most decided in the rabbits of the arsenic series. Thus, endogenous metabolic factors seem to control the type and degree of proliferative epithelial response to ultraviolet rays, and in some species apparently exert a sort of protective action which, however, may not be absolute, as shown by similar observations m a d e in connection with tar carcinogenesis. Although arsenical epidermal cancer in m a n has appeared in the form of cancroid, mixed basal and squamous cell carcinoma, basal cell cancer, and Bowen's dyskeratosis, the few experimental arsenic carcinomas produced in mice or rabbits have all been squamous cell carcinomas (4, 9). T h e trichoepithelioma found in the skin of a congenitally hairless rat treated with Fowler's solution represents, therefore, a new morphological type of epidermal cancerous response to this agent. The frequent failure experienced in attempts to cause cancer of the skin in animals (mice, rats, rabbits) by the oral, parenteral, or cutaneous administration of various arsenicals may be related to the fact that arsenic cancer has a relatively long latent period, usually surpassing that of the 559 average life span of the species used in such experiments. This contention is supported by the observation that animals with a much longer life span (horses, sheep, deer) have developed an environmental type of arsenic carcinoma of the skin or of the nasal mucous membranes (5-7)CONCLUSIONS The evidence presented is proof that the epidermis of the rat is capable of producing under proper stimulation (ultraviolet rays, arsenic) as great a variety of carcinomas as that seen in the h u m a n skin. T h e carcinomas obtained in the skin of the rat following an exposure to ultraviolet rays are even more complex than those occurring in man, as they are not infrequently associated with hyperplastic or sarcomatous proliferations of the mesenchymatous elements of the cutis. The average life span of the rat is apparently shorter in general than the latent period of experimental arsenic carcinoma. REFERENCES I. BAUMANN, C. A., RUS(;H, H. P., KLINE~ B. E., and JACOBI, H. P. Does Cholesterol Stimulate Tumor Development? Am. J. Cancer, 38:76-8o. ~94o. 2. GRADY, H. G., BLt:M, H. F., and KIRBY-SMITH, J. S. Pathology of Tumors of tile External Ear in Mice Induced by Ultraviolet Radiation. J. Nat. Cancer Inst., 2:269-276. 1941. 3" HUEPER, W. C. Cutaneous Ncoplastic Responses Elicited by Ultraviolet Rays in Hairless Rats and in Their Haired Litter 'Mates. Cancer Research, I:4o2-4o6. I94~. Occupational Tumors and Allied 1)iseascs. P. 896. Springfield, II1.: Charles C. Thomas. I942. 4- LEITCI~, A. The Expcrilnental Inquiry into the Causes of Cancer. Brit. M. J., 2:1- 7. 1923. 5. NIEBEkLE, K. fJber endemischen Krebs im Siebbein yon Schafen. Ztschr. f. Krebsforsch., 49:I37-14I. 1939. 6. PaR~s,J. A. Pharmacology. Third edition. P. 123. London: W. Philipps. 1822. 7. PRFLL,H. Die Sch~idigung der Tierwelt durch die Fernwirkungen yon Industrieabgasen. Arch. f. Gcwerbepath., 7: 656-67o. 1937. 8. PUTSCHAR,W., and HoL'rz, F. Erzeugung yon ttautkrebsen bei Ratten durch langdauernde Ultraviolettbestrahlung. Ztschr. f. Krebsforsch., 3,3:2t9-26o. 193o. Erzeugung yon Sarkomen und sarkom~ihnlichen Geschwfilsten durch langdauernde Uhraviolettbestrahlung. Libro de Oro en hotnenaje al Prof. Dr. Angel H. Roffo. 1935. 9. Raposo, L. S. Le cancer 5 l'arsenic. Cornpt. rend. Soc. de biol., 98:86. 1928. Sur le rgle de l'arsenic dans le canc&isation par le goudron. Compt. rend. Soc. de biol., 98:997. I928. Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research. Morphological Aspects of Experimental Actinic and Arsenic Carcinomas in the Skin of Rats W. C. Hueper Cancer Res 1942;2:551-559. Updated version E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/2/8/551.citation Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1942 American Association for Cancer Research.