Classification of Lung Carcinomas in the Dog and Cat

Vet. Pathol. 18: 513-528 (1981) Classification of Lung Carcinomas in the Dog and Cat J. E. MOULTON, C. VON TSCHARNER and R. SCHNEIDER Department o...
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Vet. Pathol. 18: 513-528 (1981)

Classification of Lung Carcinomas in the Dog and Cat J. E. MOULTON, C.

VON

TSCHARNER and R. SCHNEIDER

Department of Pathology, School of Veterinary Medicine, University of California, Davis, Calif.; lnstitut fur Tierpathologie, Universitat Bern, Bern. Switzerland; Department of Epidemiology and Preventive Medicine, University of California, Davis, Calif.

Abstract. A total of 218 lung carcinomas from dogs and cats were examined histologically. The tumors were classified into adenocarcinoma, squamous-cell carcinoma, bronchial gland carcinoma, and alveolar-cell carcinoma. We believe that adenocarcinoma should be subdivided into differentiated and undifferentiated types because the two are distinct histologically and vary in frequency in the cat and dog. It is also important to recognize bronchial gland carcinoma, a distinct histological type, and to subdivide alveolar-cell carcinoma into three separate types: anaplastic small-cell and large-cell types, and adenomatosis type.

There have been many reports [2,4,7,8, 12, 13,20,21,23-25,28,29,31,3639,42,44,46,48, 50, 51, 571 on lung carcinoma in the dog and cat, some citing references as far back as 1872. The continued interest in these tumors is because of the great increase in lung carcinoma in man during the last several decades, with the strong possibility that this increase is related to atmospheric pollutants, especially cigarette smoking. The dog and cat breathe the same polluted air as man, are exposed to the same irradiation, and eat similar food often containing the same additives [37, 511. Unlike food animals which are sent to slaughter before they reach the “cancer age,” dogs and cats are allowed to live a full lifespan, thus are more at risk for developing neoplasms. All of these factors make the dog and cat interesting models for comparative studies of lung carcinoma. Most reports [4,6, 13, 33, 35, 38,41,49, 53, 571 point out the infrequency of lung carcinomas in the dog and cat, in contrast with the high incidence in man. In Europe and North America, for example, the occurrence of lung carcinoma is approximately 0.5% of dogs and cats that die from all causes and are examined at necropsy. In a survey 191 of neoplasms of all types affecting dogs in two counties in California, lung carcinomas were found in 4.17 dogs per 100,000. A report [40] from the Dominican Republic shows an 11% incidence of lung carcinomas among all neoplasms in dogs and cats. Lung carcinomas in dogs and cats have increased at least two-fold during the last 20 years, but most investigators [ 14, 20, 32, 37, 521 believe this increase is related to 513

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the greater age reached by dogs and cats today because of present-day vaccination of young animals against common infectious diseases [49]. Also, the greater number of necropsies done today affects the incidence data. One worker [57] believes this increase is real and attributes it to various pollutants in the environment. A study in Russia [27] indicated that city dogs had a significantly higher incidence of lung carcinomas than country dogs, and this was attributed to air pollution. With the rise in lung carcinomas in man there has been a disproportionate increase in squamous-cell (epidermoid) and anaplastic small-cell carcinomas, but no significant increase in other carcinoma types. There has been no such disproportionate increase in these carcinomas in animals. Even with the experimental exposure of dogs to carcinogenic substances such as cigarette smoke or radioisotopes [ 1,5, 1719,451, there has been no increase in these types of tumors, though there has been an overall increase in number of tumors. Lung carcinomas occur in dogs at an average age of 1 1 years and in cats at an average age of 12 years [4, 8, 381. Alveolar anaplastic small-cell carcinoma, a rare form of lung tumor, may occur at a younger age in dogs [52]. Most reviews [38, 521 indicate no breed prevalence for lung carcinomas in dogs and cats. One, however, reported a higher incidence of these tumors in Boxer dogs [4], and a report from Russia [47] indicates that the Boxer and East European sheep dogs represent almost half of the dogs with lung carcinoma. No sex predilection has been found. Almost half of the animals with lung carcinomas are killed after a relatively short clinical course of approximately two months. The usual clinical signs [3,4, 11, 37,39,43,52,59] are cough, dyspnea, rales, cardiac insufficiency, pericardial effusion, and occasionally, hypertrophic osteoarthropathy. The sites of metastasis from lung carcinomas are poorly recorded because the animals usually are killed before metastasis develops fully. The reported sites of metastasis are the regional (usually bronchial) lymph nodes, spleen, heart, pericardium, pleura, kidney, skeleton, and skeletal muscles [4, 10, 15, 16,26,36,48,5 1,581. Metastasis to the adrenal gland and brain, which is common in man [24], is rarely reported in animals [ 12, 15,581. In man and animals, lung carcinomas appear in three sites: in the hilus of the lung, in multifocal and often peripheral sites, and in an entire lobe or lobes in one or both lungs [20,24,48]. The hilus is the most common site in man, whereas multifocal, peripheral sites are most common in animals, particularly in the dog. The diaphragmatic lobes are involved more often than other lobes, and the right lung is affected more often than the left [24,38], possibly because it is larger. Our principle objective is to present a simple classification for lung carcinomas in the dog and cat. The classification adopted by the World Health Organization (551 and others that have appeared in the literature [4,7,33,37,38,44] often are based on criteria that cannot be substantiated histologically.

Materials and Methods In this study, 218 lung carcinomas were examined histologically: 102 from dogs and 39 from cats in the University of California Animal Neoplasm Registry, collected from Alameda

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and Contra Costa counties of California from 1963 to 1978; and 69 from dogs and eight from cats from the Department of Pathology, School of Veterinary Medicine, University of California at Davis, from 1950 to 1979. All tumors occurred naturally and were taken at necropsy. We could not evaluate the completeness of necropsies done by practicing veterinarians who supplied the neoplasms in the Registry series, but complete necropsies were done on all the animals in the University series. The original histological diagnoses in the Registry were done by six different medical pathologists in private practice, with every tenth neoplasm checked by the author. The neoplasms from the University were examined by one or more of 30 veterinary pathologists in the department. For light microscopic studies, tissues were fmed in 10%phosphate-buffered neutral formalin, embedded in paraffin, and sectioned at 4 to 6 pm. For morphological evaluation, sections were stained with Harris’ hematoxylin and eosin (HE). Periodic acid-Schiff (PAS) or Alcian blue (pH 2.5) was used for mucin (mucopolysaccharide) localization.

Results The lung carcinomas from dogs and cats in the Registry and University series have been subdivided on the basis of histological type and number. Table I shows the great prevalence of adenocarcinomas (both differentiated and undifferentiated), which comprised 132 of 171 of all the dog carcinomas and 34 of 47 of the cat carcinomas in the two groups. The other types of carcinoma were far less common: squamous-cell carcinoma, 1 1 in the dog and two in the cat; bronchial-gland carcinomas, two in the dog and six in the cat; and alveolar-cell carcinoma, 26 in the dog and five in the cat. Adenocarcinoma

Differentiated rype: These neoplasms had regular, well-formed glands, often bronchiolar or acinar in appearance. The glandular structures characteristically had Table I. Classification and numbers of 218 lung carcinomas in the dog and cat Numbers examined Type carcinoma

Adenocarcinoma: Differentiated Undifferentiated Squamous-cell carcinoma Bronchial-gland carcinoma Alveolar carcinoma: Anaplastic small-cell Anaplastic large-cell “Adenomatosis”

UCD series

ANR series

Dog (69)

Cat (8)

Dog (102)

Cat (39)

35 20

3 4

39 38

I1 16 2 6

2

0 0

3 3 2

1

4

0 0

12 2

4

7 0

0 3 1

UCD refers to neoplasms from the Department of Pathology, School of Veterinary Medicine, University of California at Davis, and ANR refers to the Animal Neoplasm Registry at the same institution.

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ingrowths of papillae supported by connective tissue stalks and covered by columnar or cuboidal epithelium (fig. I). The papillae appeared as simple invaginations or were arranged as complex interwoven congeries (fig. 2). Some small acinar formations had small papillae composed entirely of epithelial cells. The epithelium that lined the gland lumina or covered the papillae was usually columnar and arranged in a single layer with basally located nuclei (fig. 3), but sometimes was multilayered and two to three cell layers thick. It was not uncommon to see variations of columnar and cuboidal cells in the same neoplasm. Occasionally, the columnar cells had carrot-like shapes, with the apices of the cells protruding into the gland lumina and the nuclei at the base. In a few tumors, the glands were lined by single layers of columnar cells that were arranged regularly and sometimes had cilia. Cytoplasmic vacuoles in epithelial cells were positive for mucin with PAS or Alcian blue stains. Mucin appeared as small blebs on the surface of epithelial cells or collected in the gland lumina. Metaplasia of cuboidal or columnar cells to squamous cells with intercellular bridges was found in a few carcinomas. Keratinization never was seen. Fibrosis of connective tissue stroma in these carcinomas was uncommon, and when present, usually involved the interalveolar areas or the cores of the papillae. Diffuse fibrosis was rare. Invasion of tumor cells was uncommon in this form of adenocarcinoma. Infiltrates of neoplastic cells were found in the alveolar lumina in many carcinomas, but invasion of the stroma associated with fibrosis was seen in only seven tumors. Invasion of pulmonary lymphatics was found in 15 tumors. Metaplasia of the connective tissue stroma into cartilage or bone was seen in seven neoplasms. Pneumonia, often with suppuration, was found in about three-fourths of the lungs involved with tumors. Necrosis of tumor tissue, often with cholesterol cleft formation and calcification, also was common. Undqferentiated type: The histological characteristic of this form of adenocarcinoma was the presence of irregular, poorly formed glands of various sizes and shapes (fig. 4). Papillary growth was similar to that of the differentiated adenocarcinoma, but the papillae were irregular. Small acinar structures with micropapillae were common (fig. 5 ) . Epithelial cell strata lining the gland-like structures were more common in this than in differentiated carcinoma. The epithelial cells were cuboidal rather than columnar, and lacked nuclear polarity. Detachment of neoplastic cells into gland lumina was common, and some lumina were nearly filled with these cells (fig. 6). The typical carcinoma cells were irregular in size and shape and had large, open-faced nuclei, prominent nucleoli, and frequent mitotic figures. Stromal fibrosis, often diffuse, was far more common than in the differentiated tumor and always was accompanied by carcinoma invasion (fig. 7, 8). Invasion into local lymphatics was present in all but three of these carcinomas. Squamous metaplasia of glandular epithelium was found in nine neoplasms, and metaplasia of the stroma to cartilage and bone was seen in two neoplasms in dogs.

Fig. I: Adenocarcinoma, differentiated. Irregular gland formations with papillary ingrowths. HE. Fig. 2 Adenocarcinoma, differentiated. Complex papillary growth. HE. Fig. 3 Adenocarcinoma, differentiated. Papillae covered by single layer of columnar cells with basal nuclei. These cells cover fibrovascular stroma. HE. Fig. 4 Adenocarcinoma, undifferentiated. Irregular, papillary gland formation. Papillae covered with cuboidal and columnar epithelium. HE.

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Fig. 5: Adenocarcinoma. undifferentiated. Small acinar structures with irregular papillary growths. HE. Fig. 6 Adenocarcinoma, undifferentiated. Large irregular glands with irregular papillae and detachment of tumor cells into gland lumina. Glands lined by single or multiple layers of epithelium. HE. Fig. 7: Adenocarcinoma, undifferentiated. Invasion of carcinoma into alveoli. Some cells columnar. most cells cuboidal or pleomorphic. HE. Fig. 8: Adenocarcinoma, undifferentiated. Invasion of carcinoma cells and stromal fibrosis. HE. %

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Fig. 9: Epidermoid (squamous)carcinoma. Infiltrating tumor cells fill some alveoli. HE.

Necrosis of tumor tissue and secondary pneumonia were more common than in the differentiated tumor. Squatnous-cell carcinoma (epidermoid carcinoma)

There were thirteen squamous-cell carcinomas (table I). Three of these had histological evidence of origin from the major bronchi. The origin was unknown in the others. The dominant squamous-cell appearance and absence of glandular pattern were the important features of this neoplasm. There was always doubt as to whether the carcinoma had arisen from the surface epithelium of the airways, from the bronchial glands, or from squamous metaplasia of adenocarcinoma. This carcinoma was composed of solid, often branching cords or masses of cells irregular in shape and size. These cells had intercellular bridges. The cells often filled the alveolar lumina (fig. 9). Keratinization of squamous cells was found in only one carcinoma, in a dog. Some of the squamous cells were large and polygonal, and others were flattened and stratified. Occasionally, solid cords of squamous cells showed central necrosis and resembled glands. Epidermoid carcinoma was highly invasive and always had stromal fibrosis. Tumor cells were found in local lymphatics in all carcinomas. Bronchial gland carcinoma

Clear evidence of origin of this carcinoma from bronchial glands was necessary before this diagnosis was made. There was always suspicion that the tumors represented metastasis of other carcinomas in peribronchial lymphatics.

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Fig. 1 0 Bronchial gland carcinoma. Low magnification of bronchus with carcinoma arising from bronchial glands (between surface epithelium and cartilage plates). Lining epithelium of bronchus hyperplastic in one area. detached in other areas. HE. Fig. 11: Bronchial gland carcinoma. Peribronchial cartilage plates surrounded by infiltrative glandular and squamous neoplastic cells. Stromal fibrosis. HE. Fig. 12: Anaplastic small-cell carcinoma. Small, uniform, dark cells fill alveoli. HE. Fig. 1 3 Anaplastic small-cell carcinoma. Higher magnification of tumor in fig. 12. Uniform dark cell type with scant cytoplasm. Cells resemble lymphocytes. HE.

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This neoplasm had a distinct histological pattern of: adenocarcinoma arising from the bronchial glands in the wall of a bronchus and extending into peribronchial tissue (fig. 10); squamous metaplasia of carcinoma cells in more peripheral sites; and hyperplastic thickening of bronchial epithelium overlying the neoplastic tissue. It was common to see a mixture of adeno- and squamous carcinomas in a junctional area between bronchial cartilagenous plates (fig. 1 1). Invasion of glandular or squamous cells accompanied by stromal fibrosis was seen in all of these tumors. Lymphatic infiltration of tumor cells was a consistent finding. Alveolar carcinoma

Anaplastic small-cell type: The most consistent histological feature of the anaplastic small-cell carcinoma was the presence of small, hyperchromatic, blast-like cells that filled the pulmonary alveoli but rarely distorted the alveolar framework (fig. 12, 13). Masses of tumor cells sometimes obscured the alveolar walls. The neoplastic cells were uniform in size, and spherical, ovoid, or spindle-shaped at" cells). They had dark basophilic nuclei, many mitotic figures, and barely perceptible cytoplasm. Some of the spherical epithelial cells looked like lymphocytes. Stromal reaction usually was absent, though sometimes there was a slight fibrotic change in the interalveolar septa. The lymphatics contained tumor cells in two carcinomas. Anaplastic large-cell type: This carcinoma appeared as differentiated, rosette-cell type, or as an undifferentiated type. In the rosette-cell type (seven cases in the dog and cat), the neoplastic cells were larger than in the small-cell carcinoma, and they often looked like transitional epithelium. The most consistent feature was the presence of many cell groups or rosettes within the alveoli (fig. 14, a, 6). Some of the cells had lighter nuclei than in small-cell carcinoma, and the cytoplasm was obvious but not abundant. Some of the cells had a palisade arrangement. Invasion of the stroma or lymphatics never was seen. In the undifferentiated form of large-cell carcinoma (1 1 cases in the dog and cat), the cells lacked rosette formation and appeared in solid sheets that obscured the alveolar architecture (fig. 15). Some of the solid cell masses formed gland-like clefts. The tumor cells were similar to those in the rosette type, being fairly large and of transitional cell type, with abundant cytoplasm. No stromal fibrosis was seen. The neoplastic cells were found in lymphatics in all of the neoplasms. Adenomatosis type: The adenomatosis form of alveolar tumor was more differentiated than the other types. The tumor cells appeared to be budding from the alveolar walls (or terminal bronchioles) (fig. 16), and sometimes paved the alveolar walls or partly filled the lumina. The alveolar architecture rarely was distorted. The neoplastic cells were small, cuboidal, or sometimes columnar, with spheroidal or ovoid nuclei, and mitotic figures were uncommon. Invasion of stroma by tumor cells was absent.

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14 a

14 b

15

16

Fig. 14, a, 6: Anaplastic large-cell carcinoma. Low (a) and high ( 6 ) magnifications of neoplasm showing intact alveolar structure and tumor cells that form rosettes. HE. Fig. 1 5 Anaplastic large-cell carcinoma. Clusters of tumor cells fill alveoli. Resembles endocrine tumor. HE. Fig. 1 6 Alveolar carcinoma, “adenomatosis” type. Intact alveoli with tumor cells budding from alveolar surface. HE.

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Discussion The chief obstacle in comparing data on lung tumors in dogs and cats is the lack of a simple classification. This has made it difficult to compare data from different laboratories and has made it almost impossible to teach the subject clearly. The most useful classification to date is that of the World Health Organization [55], but even this is unnecessarily complicated. This and most other classifications [4,7,22,33,37,38,45,56] have been adapted largely from man and are based on information we often do not have in animals. Classifications based entirely on topographical nomenclature, i.e., bronchial, bronchiolar, or bronchiolo-alveolar carcinomas [4,21,22,37], should not be used in the veterinary field because the carcinomas usually are too far advanced at the time of examination to determine site of origin. Also, too much reliance on cell type, i.e., columnar, cuboidal, or anaplastic, or on the pattern of gland formation as an indication of origin, is risky because the carcinomas often have variations in cell morphology. Most carcinomas in the dog and cat are peripheral in location and often multifocal, rather than hilar as in man, and this also complicates classification. In animals, we have no alternative to classifying lung carcinomas on the basis of the prevailing histological pattern [53]. With these tumors, as with others, we always have a problem as to whether the piece of tissue submitted is representative of the whole mass. Also, most of the specimens are from necropsies done by veterinary practitioners and these often are incomplete, so we cannot rely very much on gross description. The frequent occurrence of adenocarcinoma in the dog and cat in this study, 77% and 72% respectively, corresponds with the reported frequency of approximately 80% [4,7,9,37,49,54,55,62]. The infrequency of squamous-cell carcinoma in the dog and cat, 6% and 4% respectively, is in sharp contrast to its high frequency in man, where squamous-cell carcinoma is the dominant type. It is tempting to speculate that the frequencies of carcinoma types in man might resemble those in animals if cigarette smoking were not a factor. Bronchial gland carcinoma, considered rare by some, was surprisingly common, especially in cats (13% of total tumors in this species). This neoplasm often is misdiagnosed as adenocarcinoma, bronchial carcinoma, or squamous-cell carcinoma. Precancerous changes are common in the larger airways of man, especially prior to the formation of squamous-cell carcinoma. Changes such as cellular atypia, irregular hyperplasia, and metaplasia of columnar cells to squamous cells are encountered. These changes rarely are reported in animals because animals are not examined regularly with a bronchoscope, and by the time the diagnosis is made the carcinoma is far advanced. It is also likely that precancerous changes in man occur in relation to carcinogens, e.g., smoke. A few adenomas of the lung have been reported in the dog and cat [8,20,36,56]. Some of these may have been called well-differentiated adenocarcinomas by other

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pathologists. Just as with precancerous change, we have no idea whether adenoma precedes carcinoma in dogs and cats. Epithelial cell types in adenocarcinomas range from tall, regularly spaced columnar cells to pleomorphic cuboidal cells. Terms such as “cylindrical cell,” “columnar cell,’’ or “cuboidal cell,” used to designate different classifications [33], should be avoided, for it is common to have different cell types in the same tumor. Metaplasia of columnar or cuboidal cells to squamous cells sometimes is found. Mucin secretions are common in adenocarcinoma. Occasionally, there is a striking amount of mucin, but such tumors need not be separated as “mucinous carcinomas.” It is important to distinguish between the differentiated and undifferentiated adenocarcinomas, especially in the cat, which has a very high incidence of the undifferentiated type [50]. The undifferentiated carcinoma is far more invasive and has a greater tendency to metastasize than the differentiated type. The criteria we use in separating differentiated from undifferentiated adenocarcinomas are as follows: 1. The differentiated tumors have well-formed glandular structures, lack of epithelial stratification, uniform cell size, absence of mitotic figures, minimal stromal fibrosis, and single-layered columnar epithelium with uniform basal nuclei. Sometimes the cells have cilia or mucin droplets. 2. The undifferentiated carcinomas have few recognizable components to indicate origin, and have irregularly arranged stratified epithelium with lack of nuclear polarity, detachment of cells, irregular cell size, frequent mitotic figures, prevalent fibrous stroma, and extensive invasion of the stroma, lymphatics, or blood vessels. Both types of carcinoma show growth within the alveoli. Most pathologists agree [4,7,33,37,55,62] that squamous-cell carcinoma (epidermoid carcinoma) is a distinct type. It represents about 15% of the carcinomas in dogs and cats [50],and has been described in detail [52]. Its histological origin is sometimes in dispute. Most of these neoplasms arise from the lining epithelium of the bronchi, but some may arise from squamous metaplasia of glandular epithelium. Metaplasia of cuboidal or columnar epithelial cells to squamous cells in an adenocarcinoma does not justify use of terms like “combined carcinoma,” “composite carcinoma,” or “adenoacanthoma.” These terms should be used only if adenocarcinoma and epidermoid carcinoma exist together in the same lung but are unrelated histologically [4,37,55]. Bronchial gland carcinoma was seen in many cats in this study (table I). It is now a recognized carcinoma type [24,25,36,55,57,61,621. We share the view [24,25] that more lung carcinomas arise from the bronchial glands than is appreciated. The difficulty in making this diagnosis is tracing the origin of the carcinoma to the bronchial glands, since metastasis of carcinoma cells in peribronchial lymphatics resembles this tumor [4]. It is helpful to recognize that the bronchial lining epithelium over the neoplasm may undergo hyperplasia, and that squamous metaplasia often occurs in this neoplasm. Anaplastic carcinomas of alveolar structure arise from alveolar epithelial cells in

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the dog and cat [30,33,37,42,52,55,62]. These neoplasms have been subdivided extensively according to cytological type, e.g., “oat” cell, polymorphic cell, giant cell, lymphocyte-type cell, and spindle cell. It is useful, at least for the present, to divide this neoplasm into small-cell and large-cell types and omit all other terminology. The small-cell type (anaplastic small-cell carcinoma) usually is a distinct type, but the large-cell type (anaplastic large-cell carcinoma) is a less clearly separable neoplasm and often is misdiagnosed as bronchiolo-alveolar carcinoma. The large-cell type was relatively common in dogs in our series (table I). We had the most difficulty with a form of alveolar tumor that histologically resembles pulmonary adenomatosis (jaagsiekte) [34] of sheep. This tumor has been reported in the cat [60]. It is seen less often than the other alveolar tumors. It usually is diagnosed as bronchiolo-alveolar carcinoma. It is well to remember that epithelialization of the alveoli, alveolar ducts, or terminal bronchioles occurs in certain chronic inflammatory reactions of the lung and may be confused with this neoplasm. “Carcinoid” is used by a few veterinary pathologists [5] to describe a pulmonary neoplasm that has small nests of endocrine-type cells. Since few of these tumors have been described and the origin is in doubt, this classification was omitted from this series.

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Request reprints from J. E. Moulton. Department of Pathology, School of Veterinary Medicine, University of California, Davis, CA 95616 (USA).

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