Chapter 7TUMORS OF THE RESPIRATORY SYSTEM

7.1.1. Nasal and paranasal sinus tumors in dogs

The incidence of benign tumors (papillomas and adenomas) is much lower compared to malignant neoplasms. The literature reports, depending on the tumor type, similar figures and percentages, for nasal and paranasal carcinomas about 1 % [11]; other authors place adenocarcinoma in the first position, followed by squamous cell carcinoma and undifferentiated carcinoma, and olfactory gland carcinoma is mentioned by ZAKI and LIU (1974). Malignant forms, in the first place carcinomas (epithelial carcinoma; adenocarcinoma; squamous cell carcinoma; mucoepidermoid carcinoma and undifferentiated carcinoma) are more numerous, compared to sarcomas (chondrosarcoma and undifferentiated sarcoma) [17]. Of a total of 78 connective tissue tumors, MOULTON (1978) diagnosed: 28 fibrosarcomas, 18 chondrosarcomas, 13 osteosarcomas, 3 reticular cell sarcomas, 3 mastocytomas, 6 undifferentiated sarcomas, 3 angiosarcomas, and 1 leiomyoma.

Nasal and paranasal sinus tumors in dogs are associated with chronic irritations produced by the polluted environment, presenting as a first morphological change the metaplasia of the mucosal epithelium. An additional argument for this supposition is the advanced age at which neoplasms appear in this species, at a mean age of 9.7 years for epithelial neoplasms and 8.1 years for mesenchymal tissue neoplasms [101].

The mean age of dogs with nasal and paranasal sinus neoplasms is 9 years, with extremely wide variations, from 1 year to 16 years; however, adult or old subjects are frequently affected [75].

Dog breeds with long noses, medium and large size breeds, such as German Shepherd, Collie and Cocker Spaniel, are most frequently affected [30, 75]. Breed peculiarities and the length of the nose could be explained by the higher possibility of filtration of irritating substances, noxious pollutants, which induce changes, metaplasias and initiate the neoplastic phenomenon.

Sex in both dogs and cats influences the incidence of nasal and sinus tumors, males being more affected than females; a 45:25 ratio is estimated [64,101].

Clinical signs are not specific, and the following may appear: sneezing, epistaxis, mucopus, tumefactions or other manifestations that are found in rhinitis, sinusitis, osteomyelitis, foreign bodies, traumas, etc. Additional data in the making of diagnosis are provided by radiological examination and especially tomographic evaluation [75]. The cited authors mention the presence of metastases in regional lymph nodes in 41% of cases and sometimes at distance.

MOULTON (1990) states that benign tumors are much more rarely found, compared to malignant tumors. The author cites the observations of ZAKI and LIU (1974), who report olfactory gland adenocarcinomas, extremely rare neoplasms in dogs. The epidemiological data provided by GEORGE and FUHRER (1988) show a 1% incidence of nasal tumors, of all tumors in dogs. Malignant forms represent 80%, the tumors of epithelial origin being the most frequent (67%). PATNAIK (1989) established the following incidence of histological types, of a total of 285 sinonasal tumors: lymphomas 26.6%, fibrosarcomas 22%, hemangiosarcomas 16%, fibrous histiocytomas 11%, myosarcomas 11%, malignant nerve sheath tumors 7%. The rate of metastases was 17.6%, lower than in other dog neoplasms.

Nasal neoplasms, especially malignant ones, have infiltrative growth and tend to extend, possibly up to the sinuses. Concomitant osteolytic and deforming bone changes occur. On necropsy, the atrophy or even disappearance of the nasal conchae is found, as well as the thinning and deviation of the nasal septum. Complications also occur in the mucosa, under the form of extended necrosis, ulcerations with hemorrhagic purulent exudate [102,103].

Nasal and sinus carcinomas rarely produce distant metastases; locally, they have invasive growth, with serious bone lesions, reaching more rarely the orbit. Neoplastic cells have been identified in mandibular, retropharyngeal and lower cervical ganglia. Cases of metastases in the lungs, liver, exceptionally in the brain, adrenal gland, testicle, ischium and femur are reported (MORGAN et al., 1972) [66].

Nasal papilloma appears as a single or multiple exophytic tumor, more frequently unilateral, sometimes with a polypous aspect. The polyp is smooth, pedunculated, dense, sometimes with bleeding ulcers, of white, pink or red color. The incidence of papilloma in dogs and cats is moderate, being higher in horses. Occasionally, it recurs after removal.

In the etiology of this tumor, chronic inflammations of the nasal mucosa or/and allergic reactions may be incriminated [12,17].

Histopathologically, structure suggests a soft fibroma aspect, sometimes with islands of bone metaplasia, covered on the surface by cuboid or prismatic epithelium, with the frequent presence of inflammatory cells (Fig. 7.1.).

Fig. 7.1

Nasal papilloma, with focal slight keratinization.

Nasal adenoma is a rare benign tumor, being localized and well circumscribed, frequently small sized. Histologically, it is formed by exophytic surface epithelium and glandular structures, with collagenous stroma, which sometimes may be abundant [101].

Squamous cell carcinoma is relatively frequent in dogs, it appears as an irregular white formation, and in section, the connective tissue provides a lobular aspect. Secondary infections, necroses and hemorrhages confer a low consistency to both the tumor and the adjacent tissues.

Histological, structure is characterized by hyperkeratosis on the surface and the presence of keratotic globes in the depth, but in many cases keratinization is reduced, and the characteristics of increased malignancy are obvious. Tumor cells form islands of compact carcinoma or ramified bands. Cells are large, non-uniform, with the presence of intercellular bridges, abundant, red, finely granulated or foamy cytoplasm. Nuclei are heterogeneous, pale, with 1 or 2 nucleoli. In general, anaplasia and the high number of mitoses is remarked. The connective stroma separates groups and islands of neoplastic cells, sometimes being infiltrated with monocytes (Fig. 7.2. and 7.3.).

Fig. 7.2

Nasal squamos carcinoma, slight keratinization.

Fig. 7.3

Nasal epidermoid - squamos carcinoma, without keratinization.

Spindle cell carcinoma is considered by STUNZI and HUSER (1976) as a variant, a type of squamous cell carcinoma, since forms of transition of neoplastic cells to squamous or polyhedral cells have been noted. The tumor is more rarely found in animals. Macroscopically, the tumor appears as poorly delimited masses, of white-gray color, in general similar to squamous cell carcinoma. Fusiform cells are arranged in layers, nests or ramified bundles. In the center of the tumor, cells form spirals, and at the periphery they are perpendicular to the neoplasm margin. Cellular limits are little obvious and keratinization is usually absent. The stroma, which is not particularly abundant, delimits tumor islands and may be infiltrated with monocytes (Fig. 7.4.).

Fig. 7.4

Nasal spindle- cell carcinoma.

Transitional or intermediate carcinoma is formed by cuboid cells, arranged in layers, similarly to transitional epithelium and respiratory epithelium neoplasm, and in humans to nasal epithelium tumor. It is classified as a non-keratinized squamous cell tumor. Characteristic of this neoplasm is the arrangement of cuboid cells in thick layers, nuclei being round, without border cells, with an obvious basal membrane. Fine connective vascular septa are noted in the structure of carcinoma, which delimit neoplastic cell groups. Microcysts can be sometimes found in the epithelial mass. Squamous metaplasia is absent, and necrotic microfoci appear occasionally [35,101] (Fig. 7.5. and 7.6.).

Fig. 7.5

Nasal transitional carcinoma.

Fig. 7.6

Nasal transitional carcinoma.

Adenocarcinoma is formed by acini and canaliculi of serous and mucous glands. The histological aspect is an acinar or papillary neoplasm, with mucus retention, sometimes taking the aspect of mucinous carcinoma.

Papillary adenocarcinoma is the most frequent, in which cylindrical epithelium is arranged on a basal membrane that lies on connective filaments. Massive connective tissue proliferation is rare (Fig. 7.7.).

Fig. 7.7

Nasal adenocarcinoma.

Mixed carcinomas are composed of miscellaneous cells, some of which with compact arrangement, others in bundles or acini or even squamous metaplasias.

Adenoid cystic carcinoma is more rarely diagnosed, having a multilobular aspect, and it may be derived from the salivary gland tissue in the soft palate, rather than from the nasal epithelial structure [35].

Anaplastic or undifferentiated carcinoma has been diagnosed in both the nasal cavities and the paranasal sinuses of dogs. Microscopic structure is characterized by large islands of round or polygonal cells, without the possibility of establishing their origin. Sometimes, by special methodologies, carcinoma types such as olfactory neuroblastomas, amelanotic melanomas, lymphoreticular tumors and poorly differentiated mastocytomas may be distinguished.

The poorly differentiated cells are arranged in thick compact cords or bundles of cells with minimal glandular appearance, separated by fine septa of connective tissue. No glandular structures appear in these neoplastic forms. Some tumor cells resemble reticular sarcoma cells or histiocytic lymphosarcoma. Mitotic forms are numerous, and squamous metaplasias may be found extremely sporadically in the structures of the undifferentiated carcinoma (Fig. 7.8.).

Fig. 7.8

Nasal anaplastic carcinoma.

Neuroendocrine carcinoma, a highly malignant tumor consisting of small-to-medium-sized cells arranged in sheets or packets and with phenotypic characteristics of neuroendocrine cells. These tumors are extremely rare; report of their occurrence in dogs. The sheets, nests or cords of cells are separated by mostly delicate fibrovascular stroma to give an endocrinelike packeting. Differential diagnosis is made from olfactory neuroblastomas [123].

Megavoltage radiation therapy of nasal and paranasal tumors was used by THÉON et al. (1993), in 58 dogs with carcinomas and 19 subjects with sarcomas. The authors obtained a 1-year survival time in 60.3% of cases and a 2-year survival time in 25% of cases. In cases without recurrences, 1-year survival was 38.2% and 2-year survival 17.6%.

Surgical treatment, sometimes quite laborious, provides good results in the case of benign forms. By performing surgical excision alone in 37 dogs with nasal tumors, MORRISON et al. (1989) did not obtain significant results in increasing survival time. In the case of malignant tumors, the surgical act is supplemented by cobalt therapy, the results of which are satisfactory, according to MC ENTEE et al. (1991). The authors obtained a survival time between 2.5 months and 46 months, with a mean of 20.7 months.

7.1.2. Nasal and paranasal sinus tumors in cats

The incidence of nasal and paranasal tumors in cats is much lower compared to the incidence in dogs. Thus, the data mentioned by MOULTON (1978), in a study performed on 100 000 cats, show a 2.8% incidence rate of malignant tumors. The same author mentions that of 571 nasal tumors in cats, only 5 had a nasal location, and of these, 4 were carcinomas. In another study performed on 31 nasal neoplasms, the following were diagnosed: 22 squamous cell carcinomas, most of them located on the external side of the nostrils; 4 adenocarcinomas, of which one was mucinous carcinoma; 2 carcinomas of undetermined type and 3 sarcomas. Incidence is estimated at 90% of all nasal tumors in cats, being of malignant nature [67].

Adult or old cats have a higher incidence of nasal neoplasms [30]. Clinical signs consist of nervous and respiratory manifestations, sometimes with epistaxis and facial bone deformity [95].

The treatment of nasal neoplasms includes surgery, followed by additional therapy, especially that total excision is difficult to perform. The results obtained by THEON et al. (1994) in 16 cats with nasal and paranasal neoplasms recommend the use of radiotherapy. Thus, 14 cats were treated by radiation alone, and 2 cats were treated by radiation following incomplete surgery. Survival, after treatment, was between 1 and 36 months. The survival rate at 1 year was 44.3%, and at 2 years 16.6%. The authors emphasize the good tolerance to radiation in cats, especially compared to dogs. PEASTON et al. (1993) treated 19 squamous cell carcinomas using aluminium phthalocyanine tetrasulfonate as a photosensitizer; the result obtained in 10 tumors after one treatment and in more than 2 tumors was a complete response after 1 or 2 additional treatments, and in 5 tumors, a partial response. Therapy was well tolerated by all cats.

Olfactory neuroblastoma in cats is a rare neoplasm. Its histogenetic origin is controversial, hence the various designations of these tumors, such as: olfactory esthesioneuroblastoma; esthesioneurocytoma; esthesioneuroepithelioma; olfactory neuroepithelioma; intranasal neuroblastoma [13]. A malignant tumor composed primarily of neuroblasts that originate from the olfactory membrane.

Spontaneous cases of olfactory neuroblastoma have been reported in dogs, horses and young cows [5, 53]. It has been experimentally induced in rats, hamsters and Cynomolgus monkeys. The growth of these nasal tumors may be complicated by the invasion of paranasal sinuses, orbits and nasal bones, accidentally and intracranially. Frequently, metastases are found in the regional lymph nodes, lungs and bones.

Histologically, the structure of the neoplasm is difficult to differentiate from other nasal tumors with small, round cells, such as anaplastic carcinoma, poorly differentiated carcinoma, malignant lymphoma, melanoma and poorly differentiated rhabdomyosarcoma. Histologically, olfactory neuroblastoma may have a stratified cell arrangement or a lobular aspect, under the form of nests or cords of cells separated by fibrovascular stroma. Cells are frequently arranged in palisades around the vessels. Cells have a uniform appearance; they are poorly differentiated, with round or oval nuclei and scarce cytoplasm. The arrangement in rosettes or pseudorosettes is extremely sporadical, but there are also cases in which these aspects may be present in a high number. Occasionally, cells are apparently bipolar and have a positive reaction to silver impregnation [19]. The presence of rosettes is a useful, but not absolute, diagnostic aid for neuroblastomas, and is mostly applicable to the cat. Ultrastructural demonstration of neural processes containing microtubules is the most specific criterion. Immunohistochemical identification of neuron-specific enolase, S-100 protein, and possibly other neural and glial markers adds to the weight of the evidence [123].

7.1.3. Nasal and paranasal sinus tumors in horses

Nasal and paranasal tumors in horses have a medium frequency, incidence increasing with age. The tumors diagnosed in horses are: carcinomas of the covering and glandular epithelium; squamous cell carcinomas; myxomas; chondromas and osteomas; melanomas; sarcomas and osteosarcomas [31, 43, 67].

Regarding the histogenesis of nasal tumors in horses, NOACK (1956) [67] suggests three possibilities: 1.chronic inflammations of the nasal mucosa, with metaplasia; 2.tumors of the oral mucosa that invade the sinuses. Concerning this hypothesis, the author himself makes some remarks, such as the fact that the primary tumors of the oral epithelium are intensely keratinized, unlike those of the horse maxillary sinus. Sinus tumors may be present, although there are no lesions in the oral cavity and, finally, gingival tumors also occur in other species, e.g. in dogs, but only exceptionally do they invade maxillary sinuses; 3.maxillary sinus tumors in horses may originate from tooth germ residues, but it is known that adamantinoma occurs in young horses, while maxillary sinus tumors appear in old subjects, and adamantinoma usually involves the mandible, not the maxillary.

Nasal mucosal polyps have a high incidence; this tumor is reported to appear on a chronic inflammation background. No age, breed or sex preference has been found.

Histologically, they have a dense structure, with abundant fibrous connective tissue, without a spiral arrangement, sometimes with bone tissue islands, and on the surface, cuboid or prismatic epithelium, the structure being frequently infiltrated with inflammatory cells.

The therapeutic approach consists of surgical removal, either through the nasal cavity or by trepanation.

Nasal and paranasal sinus fibrosarcoma is a neoplasm found in adult and old horses [60], while in young subjects, congenital nasal tumors occur in particular, but they are extremely rare [1, 58]. Congenital nasal tumors have been diagnosed under the form of spindle cell fibrosarcomas [45]. The cited authors diagnosed a congenital ethmoid carcinoma and a paranasal sinus osteoma in a newborn foal. In 2 young horses, they reported a fibrosarcoma of the nasal and maxillary sinuses, and in other subjects, a spindle cell sarcoma. Electron microscopy showed irregular fusiform cells, with irregularly shaped elongated nuclei that contained prominent, frequently multiple nucleoli. The endoplasmic reticulum was prominent, frequently vesiculated and dilated; the presence of rough endoplasmic reticulum was mentioned, as well as of polyribosomes, the Golgi complex and occasionally, mitochondria. Numerous mitotic forms were present.

In general, the tumor is not frequently diagnosed and it seems to be a variant of squamous cell carcinoma. Neoplastic cells are arranged in layers, in nests or ramified bundles, at the tumor periphery they are arranged in palisades, and in the center they form spirals.

The fibroblastic tumors of the skin and the anterior cavities in the horse are suspected of viral etiology [9].

Nasal cavity and paranasal sinus adenocarcinomas are rare, especially congenital ones.

In old subjects, adenocarcinomas are reported in the frontal sinus, extending to the cribriform plate, the cranial cavity and the orbit. Purulent discharge, hemorrhage and exophthalmos are clinically found [43, 84]. A congenital ethmoid carcinoma in a foal was described by ACLAND et al. (1984).

Squamous cell carcinoma has been diagnosed in both the nasal cavities and the paranasal sinuses, with a relatively high frequency, compared to other neoplasms [57, 66]. Of a total of 141 horses with squamous cell carcinomas, SCHUH (1986) showed the following locations: tongue mucosa, 3 cases; gums, 1 case; oral mucosa, 1 case; soft palate, 1 case; pharynx, 1 case; pharynx and epiglottis, 1 case; maxillary sinus, 1 case; and nasal septum, 1 case. The macroscopic characteristics proved, in some cases, the presence of keratin pearls, and at other times, poor keratinization, with the presence of intercellular connections.

Histologically, neoplastic cells are grouped in islands or ramified cords, with necrotic foci and/or keratotic pearls. Intercellular bridges and the presence of mitoses can be seen. Due to the occasional presence of mucus drops, this tumor has been compared to human mucoepidermoid carcinoma [101].

Progressive ethmoid hematoma is only mentioned in horses. The tumor usually has a unilateral, occasionally bilateral, development. Age may vary between 3 and 18 years, without any sex influence [49]. Macroscopically, prominent formations appear, 1–2 cm in diameter, surrounded by smaller, red or brownish tumors, bordered by a capsule. Neoplasms frequently ulcerate and bleed. The more frequent location is in the posterior third, sometimes with pharyngeal extension.

Histologically, old and recent hemorrhages appear, with fibrous stroma, with numerous microphages that have phagocytosed hemosiderin, with the presence of giant cells grouped in nests. Necrotic foci appear in the bone tissue.

Progressive ethmoid hematomas have raised controversies, whether they are true neoplasms or not. The lesion has been considered as the result of a chronic infection or repeated hemorrhage, while the pleomorphic aspect suggests its tumor al nature.

Surgical treatment, by total removal, is followed in more than 30% of cases by recurrences or/and the appearance of the tumor on the other side, which would be an additional argument for its neoplastic nature [49].

7.1.4. Nasal and paranasal sinus tumors in cattle

The incidence of nasal and paranasal tumors in cattle is low, only reaching 0.1% of all respiratory tract neoplasms [88, 93]. By exfoliative cytology, in 18 cattle suspected of ethmoid carcinoma that subsequently underwent necropsy examination, MURRALIMANOHAR and SUNDARARAY (1991) diagnosed 16 neoplasms: 7 adenocarcinomas, 6 squamous cell carcinomas, and 3 undifferentiated carcinomas.

The osteoma of the nasal cavity and/or paranasal sinuses has been described in cattle as a sporadic tumor, whose etiology can be discussed in terms of a metaplasia of chronically inflamed connective tissues. The neoplastic nature of bone and cartilaginous tissues of the nasal cavities in cattle is placed under question by COTCHIN (1967) [105].

RUMBAUCH et al. (1978) reported a calcified tumor in the nasal cavities and paranasal sinuses of a 4-year-old Holstein bull. Histologically, the tumor tissue was formed by fusiform cells, similar to fibroblasts, which made up a fibrous bone matrix. The microscopic image showed a benign process or at most, low malignancy. The diagnosis was of atypical osteoma.

Sporadic nasal and paranasal sinus tumors have been diagnosed in cattle as: adenocarcinomas; squamous cell carcinomas and undifferentiated carcinomas.

In 1984, BABA and ROTARU described ethmoid tumors in 2 Holstein cows aged 7 and 8 years, respectively, which presented dyspnea and suffocation signs. On necropsy, the nasal cavities and the paranasal sinuses, bilaterally and unilaterally, respectively, presented large tumor formations that filled the cavities and compressed the nasal conchae and septum. Histologically, adenocarcinoma was established in one subject, and in the other, myxosarcoma with islands of bone metaplasia.

In small ruminants, sheep and goats, sporadic neoplasms, similar to those found in cattle, have been reported. STEEN et al. (1985) described in a 10.5-year-old female goat a tumor developed at the base of the nasal cavities, penetrating in the retrobulbar area and the cranial cavity, and compressing the left cerebral hemisphere. Macroscopically, soft, gray tumor masses appeared, with necrotic and hemorrhagic foci. Microscopically, the authors described two types of tumors with invasive growth. A structure was formed by fusiform cells, with palisade arrangement and rosette disposition and "fishbone" images, the diagnosis of malignant schwannoma being established. Within the same formations, epithelial proliferations were present, with poorly differentiated cells and vascular connective stroma, with papilliferous aspect, the carcinoma diagnosis being made.

7.3.1. Papillary adenoma

A benign tumor consisting of mucus-secreting glandular structures with a predominant papillary pattern. The literature considers this tumor to be extremely rare in domestic animals. Adenoma has been diagnosed in cattle and dogs. The majority of the affected subjects are adult, without any breed or sex predisposition.

The tumor may be located in one or both lungs, it can have a unicentric or multicentric onset. Its origin is bronchial, under the form of papillary excrescences on the mucosal surface. The tumor may develop both at the surface of the epithelium and on the bronchial mucosal glands.

Histologically, bronchial papillary adenoma has fine, central, sligthly vascularized connective tissue, covered with one or more layers of columnar or cuboid epithelial cells. These cells secrete mucin. Bronchial papillary adenoma does not manifest invasive characteristics and malignant transformation has not been evidenced.

Pulmonary papillary adenomas have a globoid aspect, a yellow to gray color, a diameter that varies from several millimeters to 4–5 cm, and are encapsulated. Histologically, the presence of cuboid to columnar cells is noted, which are pale and foamy. Cells have an orderly arrangement, papilliferous growth and secrete abundant mucin; they may form cysts lined by flat epithelium (Fig. 7.14).

Fig. 7.14

Lung adenoma.

7.3.2. Bronchioloalveolar adenoma

Usually, a solitary nodule located peripherally in the pulmonary parenchyma and consisting of cuboidal or low-columnar cells arranged in a regular alveolar or perhaps papillary pattern. The use of the designation bronchioloalveolar implies a presumed origin from bronchiolar Clara cells and/or alveolar type II epithelial cells. The neoplastic cells are cuboidal to columnar, and sometimes clear cytoplasmic vacuoles are present; the epithelial cells are uniform and lack significant atypia, and mitotic figures are rare or absent. Separation of benign and malignant bronchioloalveolar tumors is not absolute. Differentiation between a bronchioloalveolar adenoma and papillary adenoma can also be difficult. When an adenoma is present within the pulmonary parenchyma, a papillary adenoma is distinguished from a bronchioloalveolar adenoma by the presence of a nodular growth that replaces normal pulmonary parenchyma and has a coarsely irregular papillary pattern formed by cuboidal to columnar, often mucus-secreting cells. Identification of a bronchioloalveolar adenoma can also be confirmed by positive immunostaining for Clara cell antigen (CC-10) or surfactant apoprotein [123].

7.3.3. Epidermoid or squamous cell carcinoma

Squamous cell carcinoma originates almost always from the bronchial epithelium, being located more frequently in the pulmonary hilum.

Histologically, it is characterized by compact masses of large, stratified cells, with different degrees of flattening and keratinization. Intercellular desmosomes and/or keratinizations can be identified, which facilitates diagnosis. Necrotic foci sometimes appear in the neoplastic cell islands, and around the neoplastic islands, fibrous stroma may develop. Metastases occur in bronchial lymph nodes, but they can also develop at distance [100,104] (Fig. 7.10, 7.12).

Fig. 7.10

Lung epidermoid - squamous carcinoma.

Fig. 7.12

Lung anaplastic carcinoma, lymphocyte - like type.

7.3.4. Adenocarcinoma

Adenocarcinoma is characterized by a structure similar to a gland, with the specific peculiarities of a neoplasm. The histological origin of this neoplasm can be bronchial epithelium, in the bronchial or bronchiolar glands [66] (Fig. 7.21).

Fig. 7.21

Bronchial gland adenocarcinoma.

The growth of adenocarcinoma is infiltrative, which makes it appear as pneumonia. These pulmonary neoplasms are frequent, they metastasize easily in the lymph nodes, the pleura or parenchymatous organs.

Microscopically, adenocarcinoma may develop as papillary, acinar, solid or mixed adenocarcinoma and bronchioloalveolar adenocarcinoma.

Papillary and acinar adenocarcinomas are the most frequent type of primary lung tumor found in domestic animals; usually highly destructive and invasive; formation of satellite nodules by intra-airspace spread is common, as is more widespread dissemination through lymphatics; metastases to other organs are not common. Frequently, it is not possible to determine the site of origin.

Histologically, malignant cells are usually columnar and have large, ovoid basal nuclei; occasionally, vacuoles with mucous content and abundant secretion appear in the cytoplasm; frequently, large tumors have regional variations in the size, height, and nuclear and cytoplasmic appearance of the cells. Necroses, cholesterol and/or calcareous salt deposits and inflammatory reaction are present; cartilaginous or even bone metaplasias are sometimes found [100,123] (Fig. 7.15).

Fig. 7.15

Lung papillary adenocarcinoma.

Bronchioloalveolar carcinoma occurs mostly in dogs, occasionally in horses. The main distinguishing structural feature of the bronchioloalveolar carcinoma is its regular alveolar pattern and general preservation of pulmonary architecture, although the alveolar structures frequently contain sloughed cells. There might be a delicate papillary or tubulopapillary pattern superimposed on the alveolar appearance. The cells are cuboidal to low columnar, and lie on a fibrous septum.

Clara cells are positive for Clara-cell antigen (CC-10), and alveolar type II cells are more strongly positive for surfactant apoprotein A. Histologically, architecture maintains tumor cell lines from both the alveoli and the terminal bronchioles. Moderate cellular pleomorphism is found, with rare binucleated or multinucleated cells.

Differentiation of bronchioloalveolar carcinomas from adenomas can be difficult in the absence of stromal and/or lymphatic invasion; also, differentiation between bronchioloalveolar carcinomas and papillary adenocarcinomas can be a problem [6,123] (Fig. 7.16).

Fig. 7.16

Bronchioloalveolar adenocarcinoma.

7.3.5. Ovine pulmonary carcinomatosis

Ovine pulmonary carcinomatosis or carcinoma, a neoplasm known under the older designation of ovine pulmonary adenomatosis, is a bronchoalveolar tumor, its viral etiology being demonstrated by numerous investigations and experiments. The disease is considered as a transmissible pulmonary tumor [117], which is also demonstrated by the possibility of reproduction by cells from pulmonary exudate, as well as from the neoplastic focus.

Ovine pulmonary carcinoma is produced by a retrovirus, type B and/or D, and experiments have proved that the lymphoid interstitial pneumonia lentivirus significantly shortens the incubation period. In fact, this lentivirus is almost constantly isolated, concomitantly with the retrovirus, from ovine pulmonary carcinoma. The lentivirus replicates in alveolar macrophages, and macrophages regulate the remodeling and repair of the connective tissue from pulmonary lesions, by the production of soluble mediators. Macrophages can also promote, by similar mechanisms, the proliferation of type II alveolar cells, increasing in this way the potential of target-cells for the ovine pulmonary carcinoma retrovirus [28, 88, 92]. Interdependence between the pathogenicity of the two viruses may be supposed.

Ovine pulmonary carcinoma, produced by a retrovirus in the presence of the ovine lentivirus of lymphoid interstitial pneumonia, is of special interest for human pathology, since the association of HIV retroviruses and lymphoid interstitial pneumonia is known [28]. The neoplasm has been reproduced in goats, by intratracheal inoculation with partially purified virus [112], goats developing both macroscopic and microscopic lesions characteristic of ovine pulmonary carcinoma.

Macroscopically, small, well-delimited, white-gray, dense nodules appear subpleurally, which gradually become confluent, reaching 1–3 cm in diameter, and form large nodules or include large portions of the lung, having a diffuse growth. The extended lesion becomes dense, cartilaginous, and may coexist with verminous pneumonia or chronic lymphoid interstitial pneumonia (Maedi). Differential diagnosis is performed microscopically. Metastases [2, 7, 74] have been found in the lymph nodes of the respiratory tract, more rarely in muscles or parenchymatous organs.

Clinically, signs appear late, when neoplastic lesions affect extensive areas of the pulmonary mass. Natural disease occurs in 1–4-year-old sheep. Non-specific signs appear, such as tachypnea, dyspnea, especially following exercise, occasionally cough, weight loss and mucous discharge, which is eliminated in high amounts in forced head position. Signs are similar to those of pneumonia, but subjects do not manifest fever.

Histologically, characteristic of pulmonary carcinoma is the proliferation in foci of cuboid or columnar cells in alveolar septa, with epithelialization aspects and under the form of papillary projections in the alveolar lumen, frequently with palisade proliferation images (Fig. 7.16., 7.17–7.20). In advanced forms, epithelial proliferation is accompanied by fibrosis or even a sarcomatous aspect of the mesenchyma. Epithelial proliferations extend to the bronchioles. Columnar or cuboid cells lie against a supporting stromal connective tissue, with the occasional presence of multinucleated cells [87]. The presence of intranuclear inclusions has been reported in pulmonary histiocytes or even in proliferated epithelium [92]. In the lumen of bronchioles and in alveoli, columnar epithelial cells are found, with secretory cytoplasmic granules and glycogen, which suggests their origin in the secretory epithelial (Clara) cells, from the bronchioles [35]. Electron microscopically, type II neoplastic cells present microvilli, lamellar formations and desmosomes [29,117].

Fig. 7.17

Ovine pulmonary carcinoma.

Fig. 7.18

Ovine pulmonary carcinoma.

Fig. 7.19

Ovine pulmonary carcinoma.

Fig. 7.20

Ovine pulmonary carcinoma.

The lesions of ovine pulmonary carcinoma are very similar to those of human bronchoalveolar carcinoma, which has a 3% incidence of all pulmonary neoplasms, and are not associated with smoking.

7.3.6. Anaplastic carcinoma

Anaplastic carcinoma is characterized by poor differentiation and marked anaplasia, and depending on the shape and size of the cells that compose it, the following types may be distinguished: large cell, small cell, round cell, fusiform cell, and polygonal cell anaplastic carcinoma. This subclassification is used for humans, in whom incidence and variability are high.

Small cell anaplastic carcinoma is characterized by dispersed, isolated cells, with an extremely fine, discrete stroma, delimiting cell groups under the form of lobes. Optical microscopy shows cellular uniformity, but electron microscopically, diversity is wide. RONALD et al. (1987) remark the ultrastructural, cellular diversity of cell components, as well as architectural diversity, which suggest the possibility of differentiation towards epidermoid or glandular aspects. The authors support the unicist theory of bronchopulmonary carcinoma based on small cell carcinoma. Tumors with a predominance of small, dense, fusiform cells are sometimes referred to as oat cell carcinoma. Subsequently, by transitional forms, large cell carcinoma appears that may generate through a double differentiation neuroendocrine carcinoma and glandular carcinoma. The authors underscore the capacity of these carcinomas to elaborate hormone peptides. The invasive character of the neoplasm manifests by the presence of tumor cells in the lymphatic, blood capillaries and in alveoli. Metastasizing in regional lymph nodes is a rule (Fig. 7.12). The few reports of small cell tumors have been in dogs, and cows. Most tumors diagnosed as small cell carcinomas have not been subjected to the detailed ultrastructural and immunohistochemical investigations necessary to establish either their epithelial origin (cytokeratin markers) or their phenotypic characteristics [123].

Large lymphocyte-like cell anaplastic carcinoma is extremely rare. Histologically, the tumor structure is characterized by islands formed by lymphocyte-like cells, with small, round, dense nuclei, and scarce, annular cytoplasm. The stroma is fine, and necroses and inflammatory areas may sometimes occur. Large cell anaplastic carcinoma is frequently diagnosed in humans. This neoplasm may contain pleomorphic, multinucleated giant cells. Tumor cells are poorly differentiated, they frequently form cords, and mitotic activity is less reduced than in small cell anaplastic carcinomas (Fig. 7.13).

Fig. 7.13

Lung squamous cell carcinoma with anaplastic areas.

Large cell carcinoma, a malignant epithelial tumor consisting of large, anaplastic cells with large nuclei, prominent nucleoli, abundant cytoplasm, and usually well-defined cell borders without identifying features of squamous cell carcinomas, adenocarcinomas, or small cell carcinomas. The tumors consist of large, rounded-to-polyhedral cells occupying and effacing alveolar parenchyma. The cells have ample eosinophilic, sometimes foamy cytoplasm and large, round, oval, or distorted nuclei. Accurately identified cases of large carcinoma, of giant cell or any other type, are therefore extremely rare. There is no current justification for separate listing of giant cell or clear cell types [123].

Small spindle cell anaplastic carcinoma can be considered, according to STUNZI et al. (1974) as a form or a stage in the development of epidermoid carcinoma.

Small polygonal cell anaplastic carcinoma is similar to lymphocyte-like cell carcinoma, only cells have a more abundant cytoplasm and an irregular shape.

Anaplastic carcinomas with either small cells or giant cells have been diagnosed in dogs [72]. The authors mention the malignancy grade, with marked pleomorphism, with metastases in the regional lymph nodes and in the central nervous system. Anaplastic carcinomas have been diagnosed in horses, sometimes as single carcinomas [32] or as adenocarcinomas and anaplastic bronchogenic carcinomas [91].

7.3.7. Adenosquamous carcinoma

Adenosquamous carcinoma is characterized by the presence of both structures within the same neoplasm. In general, one structure is dominant, and diagnosis will be attributed to that form, but the presence of the other structure will also be mentioned. This adenosquamous neoplasm or combined tumor is rarely reported by the literature, being mentioned in dogs and cats [100] (Fig. 7.19.). Adenosquamous carcinomas tend to be highly aggressive malignancies.

7.3.8. Neuroendocrine tumor

A tumor believed to be derived from the dispersed neuroendocrine system and consisting of polyhedral large cells with fine granular eosinophilic or clear cytoplasm, and a rounded nucleus. Neuroendocrine tumors have been diagnosed in dogs as large, pale, firm nodules located in the neighborhood of a main bronchus, with metastases in bronchial lymph nodes and more rarely the brain [100].

Histologically, the cells form either cords a few cells wide or packets separated by delicate, well-vascularized stroma. The cytoplasm of the cells is slightly granular, and special stains reveal argentophilic and/or argyrophilic granules. Ultrastructurally, the cells contain small, dense-core "neurosecretory" granules in their cytoplasm. More accurate diagnosis is based on immunohistochemical demonstration of functional markers such as calcitonin gene-related peptide, neuron-specific enolase, chromogranin A, and synaptophysin.

Diagnosis must be based on the sum of morphologic and immunohistochemical features. The term carcinoid should be avoided until the situation in animals is clarified [123].

7.3.9. Granular cell tumor

Granular cell tumor is rarely diagnosed in animals, as well as in humans. In 1926, ABRIKOSSOFF described it for the first time in man.

The strictly pulmonary location seems to be found only in horses [4], species in which granular cell tumor has been most frequently diagnosed [62]. In dogs, lingual [120] and cutaneous [111] locations have been reported.

Macroscopically, multiple well delimited, nodules are found, with a 0.5–8 cm diameter, firm consistency, of a white, slightly yellowish color in section, situated in the proximity of the bronchi. Sometimes, nodules contain mucous cysts. Tumor formations cause the narrowing, even obliteration of the bronchi, and they are more frequently located in the right lung, exceptionally in the left lung [76, 46].

Regarding clinical symptomatology, there are few data reported by the literature. In an 8-year-old mare, INOUE et al. (1987) found rales and severe dyspnea, and radiological examination showed multiple formations, some of them reaching 25 cm in diameter. ALEXANDER et al. (1965) found hypertrophic osteoarthropathy in a stallion with granular cell myoblastoma.

Histologically, the tumor is formed by large, uniform, ovoid or polyhedral cells, arranged in compact areas, apparently dissociated by clear spaces or by fine collagen bands. The cell cytoplasm is abundant, with fine acidophilic and PAS-positive granulations [48].

Electron microscopy shows chromatin in moderate amounts, an irregular nuclear membrane, pleomorphic cytoplasmic granules with variable arrangements. Myelin figures occasionally appear in the cytoplasm.

The origin of these granular cells has raised numerous debates and hypotheses: ABRIKOSSOFF (1926) considers them to be derived from smooth muscle cells. The mesenchymal origin is supported, from fibroblasts, histiocytes or Schwann cells [35]; immunohistochemistry has demonstrated the presence of protein S-100, neuron-specific enolase antibodies, and vimentin, which suggests the neuronal origin [46, 48].

Bronchial gland tumors, originating from the bronchial mucosal glands, have been diagnosed in dogs and cats. The tumor has the character of mucous metaplasia, sometimes with keratinization images. In cats, tumor proliferations originating from the serous glands have been observed. These neoplasms frequently induce metastases in the regional lymph nodes.

Macroscopically, the bronchial mucosa, especially the pulmonary hilum, presents prominent, relatively well-delimited, soft, pink-red nodular formations, with local infiltration.

Microscopically, metaplastic changes are found, with flattened and less or more keratinized epithelium. The tumor base contains connective tissue that infiltrates between cartilage rings.

Pulmonary sarcomas are generally rare. GIESEL (1980) diagnosed pulmonary sarcomas in dogs. Histologically, the author identified: lipo- and angioblastic sarcoma; chondro- and osteoblastic sarcoma; polymorphic cell sarcoma. Metastases were found in the regional lymph nodes, kidneys, pancreas, diaphragm, breast and encephalon (Fig. 7.22–7.24).

Fig. 7.22

Lung osteosarcoma.

Fig. 7.23

Lung productive osteoblastic osteosarcoma.

Fig. 7.24

Lung chondrosarcoma.

Carcinosarcomas have been diagnosed in adult Holstein cattle [47]. Macroscopically, they appear as circumscribed nodular masses, with pleural invasion and metastases in the lymph nodes of the respiratory tract. The cited authors microscopically identified two neoplastic cell populations, mesenchymal and epithelial cells. Epithelial cells were arranged in nests, tubules and formations similar to normal pulmonary bronchioles. Mesenchymal cells were fusiform, with oval nuclei and eosinophilic fibrillar cytoplasm, along with large round cells with multiple nuclei, eosinophilic granular or blast cell-like cytoplasm, with large hyperchromatic nuclei and amphophilic cytoplasm.

Following the studies performed, the authors subclassified pulmonary blastomas, defining sarcomatoid carcinoma or carcinosarcoma, supporting by the absence of epithelial markers and cytokeratin in all mesenchymal cells.

Pulmonary carcinosarcomas are also known in humans, in adult men.

Secondary tumors. The lung is the site of numerous neoplasms that metastasize, especially mammary carcinomas in dogs and cats, uterine adenocarcinomas in cattle and melanomas in horses. Another group of malignant tumors that metastasize in the lung is represented by endocrine gland carcinomas and skin carcinomas. Likewise, sarcomas, with their high variability, frequently metastasize in the lung.

Sometimes diagnosis is difficult, in order to establish the origin and especially the primary form of the tumor.

Usually, metastasis is microscopically similar to the primary tumor, but there are cases in which differences are significant. Microscopic examination of various tumor areas, as well as the presence of tumor cells in the arterioles, may help diagnosis.

Formaldehyde as a potential inducer of nasal mucosal tumors

Experimental studies have demonstrated that formaldehyde induces nasal mucosal hyper- and metaplasias in rats, changes that persist long after the cessation of formaldehyde exposure.

The experiments performed by FERON et al. (1988) in rats established that hyper- and metaplastic changes induced by formaldehyde exposure in the nasal respiratory epithelium of rats did not always disappear after a long non-exposure time. In contrast, a number of rats that were exposed to 20ppm formaldehyde developed nasal tumors that were attributed to formaldehyde. This was demonstrated by the highest incidence of nasal tumors in rats exposed to 20ppm formaldehyde over a 13 week period. These rats developed squamous cell carcinoma. The appearance of polyploid adenomas has been reported in other experiments with formaldehydes. In conclusion, the nasal respiratory epithelium severely damaged by formaldehyde vapors no longer regenerates and in some cases develops tumors.

Rhesus monkeys exposed to formaldehyde in various concentrations, over a shorter or longer duration, have demonstrated changes in nasal mucosal epithelium, from moderate degeneration to squamous metaplasia [63]. These changes have been found in the epithelium of the nasal mucosa, tracheal mucosa, and large bronchi. Minimal histological changes have been detected in subjects exposed for a short time; changes worsen with the increase in the exposure duration, both in terms of intensity and surface of the mucosa. Thus, the proliferation rate of nasal mucosal epithelium is 18-fold higher in subjects exposed to formaldehyde for 6 weeks. The lower airways, the trachea, bronchi and sinuses are less affected. The authors mention the differences that appear depending on the species, regarding the most affected segments of the nasal mucosa. Thus, in rats, the lateral mucosa of the nasal conchae and the lateral walls of the nasal cavity are affected, while in monkeys, the middle conchal mucosa is more affected. Obvious lesions also occur in the anterior nasal mucosa. The explanation consists in interspecies differences regarding the direction of the airstream that enters the nasal cavity.

Animal experiments may represent predictions for the assessment of risk in respiratory cancer in humans exposed to formaldehyde. Epidemiological studies have attempted to answer the question whether there is a cancer risk for humans exposed to formaldehyde. Some observations estimate a risk by 10–14% higher for subjects exposed to formaldehyde [81].

Other carcinogens of the respiratory tract have also been experimentally tested. The direct carcinogenic action of beta-propiolactone, methylmethane sulfonate and dimethylcarbamyl chloride has been experimentally evaluated in the nasal mucosa of the rat [96]. The carcinogenic potential of these substances has revealed the action on nasal mucosal DNA. The ideal experimental model for the oncogenic capacity of some substances is the rat nasal mucosa, conclusion reached by HOCHWALT et al. (1988).

STONER et al. (1986) have studied the possibility of inducing pulmonary adenomas, using benzotrichloride, in order to verify the epidemiological data suggesting the carcinogenic effect of this chemical agent. Following intraperitoneal injection of benzotrichloride in rats, the authors conclude that the product only induces statistically significant lung tumors. So, benzotrichloride exposure involves a carcinogenic risk for humans.

Fig. 7.9

Bronchial carcinoma.

Fig. 7.11

Lung anaplastic carcinoma. ^*)