Tumors of the Respiratory Tract

12
Tumors of the Respiratory Tract


Dennis W. Wilson


University of California, Davis, USA


NASAL CAVITY AND PARANASAL SINUS TUMORS OF THE DOG


Classification


The many different types of tissue in the walls of the nasal cavity and paranasal sinuses give rise to a wide variety of tumors (Box 12.1). Most of the mesenchymal tumors in this region do not differ histologically from their counterparts in other locations but are significant because of their frequency in this site and the need for consideration in differential diagnosis. Epithelial tumors of the nasal cavity are generally thought to arise from the nasal epithelium. Normal nasal epithelium exhibits divergent differentiation based on anatomic location within the nasal cavity. The most rostral nasal epithelium is stratified squamous nonkeratinizing. The respiratory epithelium lining the majority of the central nasal cavity is separated from the squamous portion by a region containing highly pseudostratified tall columnar secretory epithelium that lacks ciliated cells. This latter region is described as transitional epithelium. Although the patterns that characterize nasal epithelial neoplasms reflect similarities to the morphology of the normal epithelium, their occurrence does not necessarily imply origin from these sites. As in much of the respiratory lining, there is considerable plasticity in the differentiation of non‐neoplastic epithelium in reaction to stimuli. Other than tumors evidently arising from olfactory epithelium, it is likely that patterns of nasal tumors represent the diversity of cell types making up normal respiratory epithelium.


Prevalence


Only approximations can be provided for prevalence data because of variations in populations sampled, sample bias, inconsistencies in diagnosis, or a combination of these factors. Figures for overall prevalence of sinonasal tumors vary according to whether frequency is based on total population of dogs, on medical admissions in a large hospital, or on total canine tumors. The only estimate for a population‐based incidence reports a rate of 2.5 sinonasal tumors per 100,000 dogs.1 Data from surveys of hospital admissions have been used to calculate rates of 81 per 100,000 dogs at risk2 or 38 per 100,000 medical admissions.3


Occupational associations of wood dust, glues, and adhesives with nasal carcinomas in humans suggests the potential for chemical carcinogenesis in animal tumors.4 Detailed studies on the pathogenesis of formaldehyde‐induced nasal squamous cell carcinoma in rats5 have not been extended to other species. It has been suggested that environmental factors increase the risk of nasal tumors in dogs,3 but a separate study6 reported no significant difference in frequency between urban and rural dogs. The possible influence of environmental factors therefore remains debatable.


Tumor location


Data in published reports vary according to the thoroughness of evaluation and how early in the disease process the lesions were evaluated. The largest pooled data set contained 504 canine carcinomas, of which 88% originated in the nasal cavity, 6% in the sinuses and 6% were multicentric.3 Most tumors arise in the caudal regions of the nasal cavity.


Tumor type


Pooled data from major veterinary hospitals revealed that of 239 recorded tumors, 82% were malignant and 18% were benign.2 The percentage of benign tumors in this series was higher than is normally experienced and probably reflected the fact that a miscellaneous group of non‐epithelial tumors constituted the majority (74%) of the benign lesions listed, some of which might not have been strictly of sinonasal origin. Despite the malignant categorization, most nasal tumors in dogs do not have detectable metastases at the time of diagnosis. Reports that have focused exclusively on malignant tumors indicate that 60% of the tumors were carcinomas and 40% were of mesenchymal or other origin.7 The frequency of carcinomas in moderately large series reported in connection with treatment trials has generally been in the region of 75% but here selection bias plays a role.8


Adenocarcinomas predominate among the carcinomas, followed by transitional carcinomas (nonkeratinizing squamous cell carcinomas) and squamous cell carcinomas. The relative frequencies of the various types of carcinoma recorded in one series was adenocarcinoma 53%, nonkeratinizing squamous cell carcinoma (transitional carcinoma) 32%, and keratinizing squamous cell carcinoma 15%.9 For comparison, the relative frequency in another series was adenocarcinoma 33%, transitional carcinoma 26%, squamous cell carcinoma 26%, and undifferentiated carcinoma 15%.8 Chondrosarcoma is clearly the most frequent sarcoma.10 Osteosarcoma, fibrosarcoma or lymphoma are next most frequent, depending on the population sampled and the type of sampling.


Age, breed, and sex


Age

The greatest risk for canine sinonasal tumors occurs approximately between 10 and 15 years of age.2,3 The mean age of affected dogs has ranged from 8.7 to 10.7 years,2,8 but nasal tumors have been observed in dogs less than 6 months to greater than 16 years of age. Chondrosarcomas occur at a slightly younger age, with a mean of 7–8.7 years depending on the series reported.9 There is some evidence that neuroendocrine carcinomas and olfactory neuroblastomas occur at a later age than other types of tumor, but this needs to be confirmed because of the small numbers reported.7


Breed

Certain breeds of dog are unquestionably at greater risk for sinonasal tumors. Whether the observed difference among various breeds can lead to the conclusion that long‐skulled (dolichocephalic) breeds are more at risk than those breeds with medium (mesaticephalic) or short skulls (brachycephalic) is controversial. The largest available set of pooled data reveals that breeds with significantly increased risk of nasal carcinoma are, in decreasing order, Airedale terrier, basset hound, old English sheepdog, Scottish terrier, collie, Shetland sheepdog, and German shorthair pointer.3 All of these breeds but the collie and Shetland sheepdog are mesaticephalic. Brachycephalic breeds, however, are at decreased risk, with the exception of the Boston terrier.


Sex

Whether male dogs are at higher risk for sinonasal tumors than females is debatable and if there is a difference it appears to be small. Pooled hospital data comprising the largest reported series of carcinomas gave a male‐to‐female ratio of 1.3 to 1.3 The male‐to‐female ratio varied considerably among breeds, and was reversed in a number of them. The implication of the varied male‐to‐female ratios among pure breeds is uncertain because of the small numbers involved. The next largest series reported were all from one center and included epithelial and other types of tumors.7 An overall male predominance was found, but there were exceptions for different types of tumor. The male‐to‐female ratio was greatest for olfactory neuroblastoma (4.0:1) and least for adenocarcinoma (1.2:1). The significance of this is unknown. Pooled data from large series of sinonasal tumors therefore show a slightly greater risk in males. The numbers of cases in small series are insufficient to reveal this consistently. There also appear to be exceptions according to the breed of dog and tumor type.


Clinical characteristics


Clinical signs are referable to a slowly and insidiously expanding space‐occupying mass in the sinonasal region with attendant invasion and destruction of adjacent structures, and associated loss of function. The most common sign is unilateral or bilateral nasal discharge, which is commonly mucopurulent and may be bloodstained. Other signs include sneezing, dyspnea, and ocular discharge. Advanced cases tend to cause facial deformity and exophthalmos. Occasionally, presenting signs are predominantly neurologic, with little or no clinical evidence of nasal disease. One or more of seizures, behavioral changes, circling, visual deficits, and ataxia are the most common neurologic signs in such cases and are associated with preferential invasion of the tumor through the cribriform plate into the cranial vault and brain.


The presenting signs, whether relating to upper respiratory tract, neurologic abnormalities, or both, are not specific for sinonasal neoplasia. Differential diagnoses of upper respiratory signs should include rhinitis, especially chronic bacterial and fungal infections, foreign body impaction, osteomyelitis and periodontal abscess. The development of a paraneoplastic syndrome is not expected but there are reports of associated polycythemia or hypercalcemia.11,12


Radiography and computed tomography can often provide a high probability of diagnosis of sinonasal tumors. Computed tomography provides more detailed information and is especially useful in early stages. Definitive diagnosis depends on histopathologic examination of an adequate sample of the primary nasal lesion. Examination of cells obtained by nasal swabs or flushes is not a reliable diagnostic method, however when used in combination with imaging studies a diagnosis of neoplasia is usually possible. Many carcinomas and sarcomas appear as round cell neoplasms via cytology and in dogs are incorrectly diagnosed as lymphomas. Although surgical biopsy specimens provide the most representative samples of the lesion, most initial clinical approaches use core needle biopsies. To ensure that the core biopsy accurately samples the primary lesion, the biopsy instrument should be directed to the appropriate site by radiography or computed tomography; at least three to four samples should be taken. The key to an accurate diagnosis is aggressive sampling that yields multiple tissue cores. If the surgeon samples the neoplasm adequately the pathologist usually has little difficulty in establishing a diagnosis. Because of the common association with rhinitis, and frequency of tumors in the caudal portions of the nasal cavity and inadequate sampling techniques, false‐negative biopsies lacking tumor may occur.


Growth and metastasis


Malignant sinonasal tumors typically grow slowly and most do not have detectable metastases at the time of initial diagnosis. They cause their effects mainly by space occupation and local destruction and invasion. More extensive destruction and invasion is usual with carcinomas, neuroendocrine carcinomas, and olfactory neuroblastomas (esthesioneuroblastomas) than with sarcomas.7 Neuroendocrine carcinomas and olfactory neuroblastomas are particularly prone to invade the cribriform plate, cranial cavity, and brain.


Metastasis of malignant sinonasal tumors is uncommon and usually late. An overall metastasis rate of 41% in 120 necropsies of advanced cases has been reported, however, the majority of the cases in which metastasis was considered to have occurred were actually local extension into the cranial cavity and brain. If metastasis to regional lymph nodes or lung is taken as the index of metastasis, then only 16% of 68 carcinomas had metastases in regional nodes and 12% had metastases in the lung.7 Sarcomas are much less likely to metastasize to discontinuous sites. Only 3 of 37 (8%) sarcomas had pulmonary metastases and one had nodal metastasis. A higher overall percentage of metastases occurs in dogs with recurrence following radiotherapy.8


Treatment and prognosis


For epithelial and usual nonlymphoid mesenchymal tumors, the only treatment regimen that has proved to be of benefit is radiotherapy, with or without surgical debulking. There is consensus that lymphomas should be treated differently from sarcomas or carcinomas and therefore need to be distinguished. Some oncologists will treat sarcomas and carcinomas similarly and others use different treatment protocols; regardless, pathologists should try to identify if the neoplasm is a sarcoma or carcinoma. Lymphomas are a special case and are dealt with elsewhere. With specific reference to the influence of pathologic diagnosis, it is important to note that there are conflicting reports about the prognostic value of tumor staging and histologic typing. The only treatment regimen that has proved to be of benefit is radiotherapy, with or without surgical debulking. A comparison of survival times in dogs with nasal adenocarcinoma found that neither chemotherapy protocol nor surgical procedure influenced survival time, while dogs given radiotherapy had significantly increased survival time.13 Recent findings demonstrate that a large proportion of nasal carcinomas express tyrosine kinase receptors. Vascular endothelial growth factor receptor (VEGFR was expressed in 85% of cases and was not specific to any histologic subtype. Platelet‐derived growth factor receptor (PDGFRα and PDGFRβ) expression was less frequent (71 and 40% respectively) with neither PDGFR subtype evident in adenocarcinomas. These findings suggest a potential role for tyrosine kinase inhibitors in adjunct therapy.43


Although TMN‐based staging has limited usefulness, broader use of CT criteria demonstrates differences in survival times based on extent of tissue invasion. Stage I neoplasms are unilateral and do not invade the septum. Stage II have one and stage III two or more manifestations of aggressive behavior, including septal invasion, bilateral involvement, bone destruction, extension to the hard palate, involvement of the orbit, or evident facial swelling. Stage IV tumors show extension to the brain14 (Figure 12.1A–D). Dogs with stage II tumors had longer survival times than those with stage III and both stages had longer survival when treated with radiation ± surgery, while stage IV patients had no increased survival despite radiation treatment. Combining CT staging with histologic diagnosis improved predictability in one study where there was no difference between survival times for carcinomas or sarcomas but anaplastic, squamous cell, and undifferentiated carcinomas had a significantly shorter median recurrence‐free survival.15

CT scan examples of staging of nasal tumors from 4 dogs: unilateral mass without invasion of septum (a) and with invasion of maxillary bone (b), destruction of septum (c), and invasion of cribriform plate (4).
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Figure 12.1 Examples of CT staging of nasal tumors from four dogs. (A) Stage 1: Unilateral mass, right side without invasion of septum or adjacent bone. (B) Stage 2: Only one aggressive feature: unilateral mass, right side with invasion of maxillary bone. (C) Stage 3: Two or more features of invasion: destruction of septum, maxillary bone and extension to retro‐orbital soft tissues. (D) Stage 4: Invasion of cribriform plate in addition to septal and turbinate lysis. Note remnant cribriform plate on left (arrow).


Gross morphology


Papillomas of the nasal or sinus cavities can be solitary or multiple. They are small verrucous or papillary projections from the mucous membrane. These lesions are most often inflammatory hyperplasias with true tumors rare findings in species other than sheep and goats, where retroviral‐induced tumors begin as papillary growths. Carcinomas and sarcomas are generally irregular, bulky masses by the time they are diagnosed. Initially they tend to be unilateral and conform to the cavities in which they grow, but at necropsy considerable invasion and destruction of adjacent structures is usually observed (Figure 12.2). Secondary infection, necrosis, and/or hemorrhage are common. Carcinomatous tissue is usually soft, friable, or fleshy, and pink to off‐white with dark red mottling. Occasionally, carcinomas will be firm when extensive scirrhous response has developed.

Photo of canine nasal adenocarcinoma displaying ill-defined mass replacing turbinates in the caudal nasal cavity with invasion of the cribriform plate and extension into the cranial vault for stage IV lesion.

Figure 12.2 Canine nasal adenocarcinoma: An ill‐defined mass replaces turbinates in the caudal nasal cavity. Invasion of the cribriform plate and extension into the cranial vault makes this a stage IV lesion.


Sarcomas have a gross appearance similar to counterparts in other regions of the body. Because the tumors grow into a cavity, they develop edema and other vascular complications due to obstructed venous and lymphatic outflow. Therefore the majority tend to be soft and edematous regardless of whether they are carcinomas or sarcomas. Gross appearance is therefore not a reliable discriminator between carcinomas and sarcomas in most instances.


Histological features


Non‐epithelial tumors are similar to their counterparts at other sites, and are described in relevant chapters. Typical patterns of epithelial tumors are shown in Figure 12.3.

6 Micrographs (a–f) of histologic patterns of nasal carcinomas illustrating adenocarcinoma, transitional carcinoma, adenoid cystic, squamous cell carcinoma, spindle cell carcinoma, and undifferentiated.

Figure 12.3 Histologic patterns of nasal carcinomas. (A) Adenocarcinoma: Papillary growths of tall columnar to pseudostratified secretory cells line a modest fibrovascular stroma. (B) Transitional carcinoma: Chords of stratified secretory cells are arranged on a fibrovascular stroma. Although glandular formations are rare, there is a palisading appearance and occasional microcysts may be present. (C) Adenoid cystic: Chords of neoplastic secretory cells are separated by amphophilic lakes of secretory product. (D) Squamous cell carcinoma: Chords of dysplastic cells with abundant eosinophilic cytoplasm undergo central keratinization. (E) Spindle cell carcinoma: Neoplastic epithelial cells form solid masses composed of elongate intersecting cells with plump nuclei and indistinct cytoplasm. IHC may be necessary to differentiate from fibrosarcoma. (F) Undifferentiated: Small poorly differentiated and irregularly arranged cells form nests in a schirrhous fibrovascular stroma.


Papilloma

The surface epithelium of the papilloma is predominantly of well‐differentiated squamous type with an intact basement membrane unless secondary ulceration has occurred. Sometimes other cell types, such as mucous cells, can be interspersed among the squamous epithelium, or, less commonly, the epithelium resembles normal pseudostratified respiratory epithelium. Nasal papillomas are uncommon. Differential diagnosis from nasal polyps is important and will be addressed under that heading later in this chapter. While adenomas within the nasal mucosa occur in rats exposed to carcinogens,16 there are no anecdotal or published reports of their occurrence in domestic animals. The lateral nasal gland of the dog is relatively large; it can be seen grossly and when included in nasal biopsies it can be confused with an adenoma.


Adenocarcinoma

Adenocarcinomas (Figure 12.3A) are characterized by the presence of glandular structures which usually contain secretory products. The most common glandular patterns are papillary, tubulopapillary, and acinar. Mixed patterns are fairly frequent. Low‐grade adenocarcinomas have glandular spaces or papillary fronds lined by cuboidal to columnar cells in a single layer or perhaps with pseudostratified appearance. The cells have uniform round or oval nuclei and inconspicuous nucleoli. Cytologic atypia is minimal and mitoses are uncommon. High‐grade adenocarcinomas have irregular glandular spaces and more solid sheets of cells. Cellular pleomorphism, nuclear atypia, and a high mitotic count are present. Mucus is the most common type of secretion in adenocarcinomas, but serous material predominates in some tumors. Retention of secretion can lead to a cystic appearance.


Transitional carcinoma

The name transitional carcinoma was originally applied because the stratified arrangement of nonkeratinizing cuboidal cells resembles the transitional epithelium in the urinary tract (Figure 12.3B). The recognition of a distinctive zone of transitional epithelium lying between the rostral squamous epithelium of the nose and the more caudal respiratory epithelium17 confirms the appropriateness of the term for the corresponding type of nasal tumor.


Transitional carcinomas typically consist of thick stratified layers of cells. Large tumors have complex infolding or pleating of epithelial layers which are separated by delicate fibrovascular septa. The cells in large tumors are mostly cuboidal to polyhedral in shape. These tumors may have a characteristic palisading arrangement of columnar cells that is most apparent perpendicular to the basement membrane. The cells have a small to moderate amount of pale cytoplasm, medium‐sized nuclei with stippled chromatin, and one or two prominent nucleoli and indistinct cell boundaries. A well‐defined basement membrane is present beneath the stratified layers of neoplastic cells. Microcysts are sometimes present within the epithelial layers of transitional carcinomas. They are often associated with necrosis and “drop‐out” of cells. When these microcysts are prominent and contain precipitated protein or cell debris, they superficially resemble glandular acini and can lead to the mistaken diagnosis of adenocarcinoma. Mitotic figures, cellular atypia and desmoplasia are usually not noteworthy features of transitional carcinomas.


Mixed phenotypic expression is fairly common in nasal carcinomas, especially if multiple sections are examined. Transitional carcinomas, therefore, sometimes have scattered foci of squamous differentiation and/or focal adenocarcinomatous pattern but the great preponderance of transitional components warrants a diagnosis of transitional carcinoma rather than squamous cell or adenosquamous carcinoma.


For accuracy of classification, but without current evidence of prognostic significance, differentiation needs to be made between transitional carcinomas in which the basal layer of cells is columnar and tumors that are more appropriately designated nonkeratinizing squamous cell carcinomas. Although the separation is not absolute, in the nonkeratinizing squamous cell carcinomas there is progression within the epithelial layers from the basal columnar cells to more central keratinocytes with ample acidophilic cytoplasm and sometimes detectable intercellular bridges. Such progression is not a feature of transitional carcinomas.


Adenoid cystic carcinoma

This is a rare nasal tumor. The tumor typically consists of small, uniform cords, and/or solid nests (Figure 12.3C). The tumor cells tend to be surrounded by basophilic mucoid or hyaline material, and cystic spaces filled with the same material occur within cellular aggregate. The effect is to produce a characteristic cribriform pattern. The basaloid cells have hyperchromatic nuclei and a small amount of indistinct basophilic cytoplasm. Mitoses are rare. Myoepithelial‐like cells are also present in stromal regions. The amount of mucoid material, and therefore the prominence of the cribriform pattern, varies from tumor to tumor and from one lobule to another within a single tumor.


Adenoid cystic carcinomas are believed to originate from submucosal glands or minor salivary glands.


Squamous cell carcinoma

Squamous cell carcinomas of the sinonasal region have the same range of histological features as those arising elsewhere in the body, although they tend to be poorly keratinized (Figure 12.2D). The characteristic tumor cells have abundant eosinophilic cytoplasm and large pale nuclei with one or more distinct nucleoli. Some degree of differentiation is usually detectable from basal to central regions and, in well‐differentiated carcinomas there can be close resemblance to the normal sequence of squamous differentiation. Intercellular bridges and keratinization are easy to discern in well‐differentiated squamous cell carcinomas but might be difficult to resolve in poorly differentiated ones. Immunostaining with antibodies to cytokeratin 5/6 characteristic of squamous epithelium is a diagnostic aid in poorly differentiated cases. The degree of cellular and nuclear atypia, and the frequency of mitotic figures, increase with the degree of malignancy. Invading tumor cells are usually associated with a florid desmoplastic response.


Adenosquamous carcinoma

These are malignant tumors with intermixing of both adenocarcinomatous and malignant squamous cell components. Adenosquamous carcinomas with abundant mucin‐secreting tumor cells are also referred to as mucoepidermoid carcinomas.


Both glandular and squamous components in an adenosquamous carcinoma have the expected cytologic features of malignancy, regardless of their respective proportions. The term adenocarcinoma with squamous metaplasia should only be used for an adenocarcinoma in which there are minor portions with regular squamous differentiation. Adenosquamous carcinoma tends to be among the more highly invasive nasal carcinomas.


Spindle cell carcinoma

The spindle cell carcinoma is an unusual variant of squamous cell carcinoma described in humans that is nonkeratinizing and in which the majority of the tumor is composed of spindle‐shaped cells similar to those of a spindle cell sarcoma (Figure 12.3E). Careful search of several sections is often needed to reveal transition from recognizable squamous cell carcinoma. Spindle cell carcinomas can also resemble transitional carcinomas, in which some columnar cells appear slightly spindle‐shaped, but in the spindle cell carcinoma there is a monomorphic accumulation of spindle‐shaped (sarcoma‐like) cells. Positive immunohistochemical (IHC) staining for cytokeratins and a negative reaction for vimentin in tumor cells is the most certain way of differentiating between spindle cell squamous carcinoma and a sarcoma of fibroblastic or other origin. Care also has to be taken to distinguish spindle cell carcinoma cells from spindle‐shaped fibroblasts of an exaggerated desmoplastic response. In the desmoplastic response, a separate population of inciting neoplastic cells and desmoplastic cells should be evident and, in difficult cases, IHC distinction between carcinomatous and desmoplastic cells should be possible.


Undifferentiated (anaplastic) carcinoma

These tumors are characterized by sheets or highly packed clusters of round to polyhedral cells with no discernible features of the more differentiated adenocarcinomas (Figure 12.3.F). Some degree of cellular atypia and pleomorphism are usually present, as are fairly frequent mitoses. These features help to distinguish undifferentiated carcinomas from poorly differentiated transitional carcinomas, although the boundary between the two tumors is not well defined. Classification of nasal tumors by histologic features alone can be challenging. One study estimates that 60% of tumors are diagnosed as generic carcinomas.43 The absence of easily definable carcinomatous characteristics in undifferentiated carcinomas also makes for difficult separation from tumors such as olfactory neuroblastomas, neuroendocrine carcinomas, amelanotic malignant melanomas, lymphoid tumors, poorly differentiated mast cell tumors, and undifferentiated sarcomas. This situation requires the use of IHC markers for phenotypic characteristics, as described under the specific tumors. The distinction between undifferentiated carcinomas, olfactory neuroblastomas, and neuroendocrine carcinomas is not sharp, however, because of the overlap of ultrastructural and IHC features. Current therapies emphasizing radiation for most tumor types suggest staging for prognosis and the distinction from chemically treated lymphoid tumors are the principal clinically relevant findings from biopsy.


Neuroendocrine carcinoma (carcinoid)

The term neuroendocrine carcinoma is preferred to carcinoid. Neuroendocrine carcinomas of the nasal cavity are unusual in domesticated animals but have been reported in the dog18 and horse.19 They are characterized by sheets, nests, or cords of small‐ to medium‐sized cells separated by delicate fibrovascular stroma to give an “endocrine‐type packeting” (Figure 12.4A). The stroma is more dense in some regions. The tumor cells are round to polyhedral with rounded, centrally placed nuclei and distinct granular eosinophilic cytoplasm. Nuclei can be small and dense or have coarsely clumped chromatin or be slightly vesiculate with a prominent nucleolus. Peripheral palisading of tumor cells and formation of rosettes similar to neuroblastomas has been described, as has variable distribution of mitotic figures, and necrosis and mineralization in the centers of large tumor masses.

2 Micrographs of canine neuroendocrine tumor illustrating polygonal cells in discrete nests by thin fibrovascular stroma (left) and IHC probe for synaptophysin in discrete cytoplasmic granules (right).

Figure 12.4 Canine neuroendocrine tumor. (A) Polygonal cells arranged in discrete nests by thin fibrovascular stroma recapitulate neuroendocrine patterns found in other tissues. (B) IHC probe for synaptophysin demonstrates discrete generalized cytoplasmic granules. Similar staining for chromogranin A can also be demonstrated.


Differential diagnosis from other highly cellular tumors of the region can be difficult. It is particularly difficult to distinguish poorly developed neuroendocrine carcinomas from olfactory neuroblastomas. Neuroendocrine tumors contain dense cored neurosecretory granules20 and while neuroblastomas can also have granules, they also have cell processes containing microtubules. Neurosecretory granules are resistant to autolysis and if present will be identifiable even in tissues not preserved optimally for TEM. With IHC there is considerable overlap but neuroendocrine carcinomas stain more regularly for cytokeratins, chromogranin A, and synaptophysin (Figure 12.4B).


Olfactory neuroblastoma (esthesioneuroblastoma)

This tumor is rarely recognized in veterinary species. Their histologic similarity to neuroendocrine tumors and nonspecificity in domestic animals of IHC markers used to diagnose human tumors makes definitive diagnosis dependent on electron microscopic features. S100 staining of sustentacular cells surrounding packets of nonstaining neural‐derived cells as used in humans20 is not effective in canine tissues. Microtubule‐associated protein 2 (MAP‐2) is a more specific marker of neurons and is reported to be positive in 21 of 22 canine and feline nasal neuroblastomas, but these cases were not confirmed by electron microscopy.21 Both neuroblastomas and neuroendocrine tumors may contain neurosecretory granules containing chromogranin or synaptophysin.20 In practice, nasal neuroblastomas are exceedingly rare and very few ultrastructurally confirmed cases have been reported. Additional caution in interpreting neuroendocrine markers is warranted as chromogranin A and synaptophysin probes will also stain neuroblastomas as well as some tumors with adenocarcinoma patterns.22


Ultrastructural evidence supporting a diagnosis of neuroblastoma requires cell processes containing microtubular neurofilaments. The overlap in immunohistology and location of both neuroendocrine tumors and neuroblastoma in the caudal nasal cavity combined with the rarity of these tumors make prediction of clinical behavior difficult. There are no published clinical outcome reports for domestic animals. Case reports and practical experience suggest both can be locally aggressive tumors.


NASAL CAVITY AND PARANASAL SINUS TUMORS IN OTHER SPECIES


Cat


The incidence of nasal tumors in cats relative to dogs differs significantly from survey to survey. Although one comparative survey found a lower incidence in cats,1 comparison of frequencies from hospital and necropsy records suggests that cats have a slightly higher incidence than dogs. The prevalence of feline sinonasal tumors in a clinic population has been reported to be 23 tumors per 10,000 cats. Sinonasal tumors are reported to be 8.4% of all feline tumors. These figures are probably higher due to the inclusion of squamous cell carcinomas, many of which presumably originated from the nasal planum rather than within the sinonasal region proper.2 Even when squamous cell carcinomas of the nasal planum are eliminated, the hospital‐based incidence of intranasal tumors in cats can be calculated to be 11 per 10,000 admissions compared with 4 per 10,000 canine admissions in other surveys.3


As in dogs, the risk for sinonasal tumors increases with age. The mean age of affected cats is around 10 years. Squamous cell carcinomas of the nasal planum tend to occur at a later age (mean 12.1 years) than tumors within the sinonasal region (mean 8.7 years). Neutered cats of both sexes, especially males, have increased risk.2 Clinical signs, diagnostic work‐up and treatment are similar to those described for dogs.


The relative frequencies of tumor types differ between the cat and dog. In cats, as many as half the recorded tumors are squamous cell tumors of the nasal planum. Within the nasal cavity, adenocarcinomas are the most frequent carcinoma. In contrast to the dog, transitional carcinomas have not been recorded for the cat. Lymphoma usually predominates among the non‐epithelial tumors in the cat and chondrosarcomas are uncommon.


Squamous cell carcinoma of the nasal planum in cats is multifactorial, with UV radiation a strong cofactor. Molecular and IHC evidence associates approximately half of feline nasal planum squamous cell tumors with feline papillomavirus.23 Oncogenic human papillomaviruses degrade retinoblastoma protein with subsequent overexpression of another tumor suppressor gene, p16. Positive nuclear immunostaining for p16 is used as a marker for human papillomavirus‐associated squamous cell tumors. Feline papillomavirus 2 DNA is present in a significant number of squamous cell carcinomas and is also associated with overexpression of p16.24 In a retrospective study of 51 cats with nasal squamous cell carcinoma, 32 stained positively for p16 protein (Figure 12.5A,B) and 19 did not. The cats with p16‐positive squamous cell carcinomas survived longer (mean 643 days) than cats with p16‐negative (217 days). The authors suggested that p16‐positive squamous cell carcinomas may have a less aggressive clinical behavior and this could prove useful to predict survival and possibly help select treatment protocols.23

4 Micrographs of squamous cell carcinoma illustrating feline nasal planum (a), protein antibodies (b), epidermis in the nucleus (arrowed; c), and cell clusters in the epidermis (d).

Figure 12.5 Feline nasal planum squamous cell carcinoma. (A) Feline nasal planum squamous cell carcinoma. Neoplastic cells exhibit intense nuclear and cytoplasmic immunostaining to antibodies against the p16CDKN2A protein. Note the presence of nests of neoplastic cells infiltrating from the overlying epidermis into the dermis. (B) Minimal immunostaining against p16CDKN2A protein antibodies is visible within the neoplastic cells. Bond Refine Detection staining kit with haematoxylin counterstain. (C) Epidermis surrounding a feline nasal planum squamous cell carcinoma. The epidermal cells within the follicle are swollen and some have a clear halo surrounding the nucleus (arrows). Immunostaining is restricted to cells showing cytopathic evidence of papillomaviral infection with no immunostaining visible within histologically normal cells. (D) The majority of the neoplastic cells do not show immunostaining to anti‐p16CDKN2A antibodies. However, focal immunostaining is visible within clusters of cells within the surrounding epidermis.


(Source: Munday et al., 2013.23 Reproduced with permission of SAGE Publications.)


Horse


The most common proliferative nasal lesion in the horse is not considered a true neoplasm. “Progressive” ethmoid hematoma is a clinically challenging syndrome that presents as enlarging hemorrhagic lesions that obstruct nasal passages. Despite its seeming non‐neoplastic nature, there is only a one‐third remission rate.25 These lesions traditionally have been considered to arise in the ethmoturbinates. A review of cases examined by CT concluded that the majority did arise from the ethmoturbinate region but some cases were considered to arise from the caudal maxillary sinus. The polyps typically arise unilaterally from the ethmoid region and can be large enough to reach the nostril or choanae and may expand to present as bilateral lesions. Except for surface hemorrhage or ulceration and secondary infection, the polyps have a smooth surface. The cut section appears hemorrhagic or mottled pale, brown, and hemorrhagic (Figure 12.6A). Histologically, the polyps are highly vascular and have a distinctive appearance resulting from repeated hemorrhage, hemoglobin breakdown, and organization by fibrous tissue (Figure 12.6B). There is extensive hemosiderin deposition, lipofuscin accumulation and prominent ferruginous and calcareous encrustations of collagen fibers and vessel walls. Giant cells and hemosiderin‐laden macrophages are common. Vascular walls in the lesions may be mineralized and arterioles with thickened media are sometimes evident.

Left: Photo of equine ethmoid hematoma displaying nasal septum in coronal section. Right: Micrograph of ethmoid hematoma illustrating red blood cells of phagocytosis and pigment breakdown.

Figure 12.6 Equine ethmoid hematoma. (A) Characteristic hemorrhagic friable variegated mass distorts the nasal septum in this horizontal section. (B) Histology of ethmoid hematoma shows red blood cells in varying stages of phagocytosis and pigment breakdown by plump macrophages. A variety of interlacing spindle cells represent progressive fibroblastic and endothelial cell organization.


True neoplasms of the nasal region are uncommon in the horse. One series examined 15 neoplasms identified by CT with histologic classification: 1 nasal adenocarcinoma, 2 undifferentiated carcinomas, 7 mesenchymal tumors, and 5 neuroendocrine carcinomas.26 A comprehensive review of literature suggests the most common sinonasal neoplasms in the horse are squamous cell carcinomas of the maxillary sinus.27 A survey of records from the UC Davis Veterinary Medical Teaching hospital found 12 epithelial malignancies with 4 squamous cell carcinomas, 2 adenocarcinomas, and 5 neuroendocrine carcinomas. Neuroendocrine tumors appear to be a specific syndrome of the equine nasal cavity.19 They often present with exopthalmus with extensive bone destruction on CT. Histologically, they are highly vascularized tumors of cells with regular spherical nuclei and finely granular cytoplasm that are arranged in chords or packets in close apposition to small vessels (Figure 12.7A). With IHC they are variable positive for chromogranin A and regularly positive for synaptophysin (Figure 12.7B).

2 Micrographs of equine neuroendocrine tumors illustrating equine nasal neuroendocrine tumors packeted by fibrovascular septae (left) and synaptophysin IHC having granular cytoplasmic staining (right).

Figure 12.7 Equine neuroendocrine tumors. (A) Similar to the dog, equine nasal neuroendocrine tumors are packeted by fibrovascular septae. (B) Synaptophysin IHC demonstrates fine granular cytoplasmic staining.


One case report of an aggressive tumor with ultrastructural features of neuroblastoma in a horse has been published.28 Distinction between neuroendocrine tumors and neuroblastoma in the horse has similar caveats to that presented for the dog. Most equine nasal tumors are identified late in their progression and present with extensive local invasion regardless of histologic type.


Sheep and goats


Enzootic intranasal tumors of sheep and goats occur widely throughout the world, except for the United Kingdom and Australia.29 These tumors are caused by species specific retroviruses (ovine ENTV‐1 or caprine ENTV‐2) related to the jaagsiekte sheep retrovirus (JSRV) that causes ovine pulmonary tumors.30 The viral envelope protein appears to drive tumorigenesis but the mechanism of tissue trophism remains uncertain.


Clinically affected sheep and goats have profuse seromucinous nasal exudate, dyspnea, stertorous breathing, and coughing. Persistent nasal secretions are the most evident features in herd situations.29 Open‐mouthed breathing, exophthalmos, and facial deformity are possible complications. Incidence in affected flocks varies from 0.1 to 15%. Grossly, the tumors are unilateral or bilateral, polypoid to confluent masses centered on the ethmoid region (Figure 12.8). Their origin from ethmoid mucosa is sometimes still evident. Tumor tissue ranges from whitish to pink to dark red and from firm to friable. A granular or papillary surface covered by mucus often covers polypoid masses. Advanced tumors cause local bone destruction, invade frontal or maxillary sinuses, and can invade gingiva and orbit. Occasionally, tumor tissue can protrude through the anterior nares or into the nasopharynx. Non‐neoplastic nasal polyps adjacent to neoplastic tissue are reported for goats.4

Photo of enzootic tumor of goats displaying extensive replacement of the nasal cavity by a lobulated mass, with polypoid to confluent masses centered on the ethmoid region.

Figure 12.8 Enzootic tumor of goats: Extensive replacement of the nasal cavity by a lobulated mass. Despite extensive involvement, the appearance is of compressive rather than invasive growth.


Histologically, the tumors are considered low‐grade adenocarcinomas. The papillary subtype is common in sheep (Figure 12.9A,B), although mucinous, tubular, and acinar patterns are also seen. The tumors in goats are interpreted to be well‐differentiated (low‐grade) carcinomas, also with papillary, tubular, or acinar patterns. The tumors in sheep and goats do not appear to differ significantly in histologic type.29 Although tumor cells are well differentiated and form regular polarized glandular structures, the progressive infiltrative and destructive growth are support the diagnosis of well‐differentiated adenocarcinoma. Metastases to regional lymph nodes or systemically are not reported.

2 Micrographs of enzootic tumor of goats and sheep illustrating exophytic papillary growth from surface epithelium overlying nasal turbinate (top) and prominent goblet cell formation and mucus secretion (bottom).

Figure 12.9 Histology of enzootic tumor of goats and sheep. (A) Overview demonstrates an exophytic papillary growth extending from surface epithelium overlying a nasal turbinate. (B) Neoplastic epithelium is simple columnar and well differentiated with prominent goblet cell formation and mucus secretion.


NASAL AND NASOPHARYNGEAL POLYPS


These polyps are non‐neoplastic, usually pedunculated growths arising from the mucosal surface of the nasal cavity or nasopharynx (Figure 12.10A). Polyps occur infrequently. They are seen most often in the cat and horse. In the cat, they can also arise from the lining of the auditory canal or middle ear and obstruct the canal. The cause and pathogenesis of polyps is unknown. They are associated with hyperplasia of the mucous membrane and some degree of chronic inflammation of the underlying connective tissues but the causal relationship between these two features is uncertain. After attaining a certain size, they can become self‐perpetuating because of impairment of venous and lymphatic drainage in the stalk and development of edematous stroma.

Photo and micrograph of feline nasal polyp with well‐delimited sessile mass (arrowed) extending from the pharyngeal mucosa and bland collagenous structure lined by pharyngeal epithelium, respectively.

Figure 12.10 Feline nasal polyp. (A) A slightly irregular but smooth surfaced well‐delimited sessile mass (arrow) extends from the underlying pharyngeal mucosa. (B) Histology of nasal polyp demonstrates a largely bland collagenous structure lined by pharyngeal epithelium. Occasional lymphoid follicles may be present.


Differentiation of polyps from polypoid tumors, particularly fibromas, papillomas, or hemangiomas, is usually fairly clear because a polyp lacks any regions with consistent and characteristic features of neoplasia (see earlier descriptions) and most of the lesion is formed by chronically inflamed, edematous stroma. Venous and lymphatic dilation is unusual other than when there are regions of granulation or scarring. These latter regions are usually found underlying mucosal ulceration. One differential to be considered in the dog is angioleiomyoma.31 Differentiation between polyps and tumors can sometimes be very difficult and requires either careful search of numerous sections or, in the case of biopsy material, examination of recurrent lesions.


Grossly, polyps are moist, glistening and spherical, ovoid or elongated (Figure 12.10A). They are often pedunculated. The growths are firm or rubbery and commonly have a slimy, smooth or roughened surface which may be ulcerated. They are off‐white, pink, or red. Polyps are sometimes multiple (polyposis). Polyps can attain a size sufficient to produce respiratory difficulty. They can also cause complications by becoming secondarily infected. Removal of a polyp can be followed by recurrence, especially if excision was incomplete.


Nasopharyngeal and middle ear polyps in cats


These polyps typically occur in cats less than a year old and lead to progressive increase in clinical signs associated with nasopharyngeal obstruction. The polyps can originate from mucous membrane of the nasopharynx, auditory canal, or tympanic bulla. Polyps arising in the auditory canal frequently extend back up into the middle ear or down into the nasopharynx. Histologically, polyps consist of edematous fibrous tissue covered by regular respiratory epithelium or stratified squamous epithelium (Figure 12.10B). Some degree of subepithelial accumulation of chronic inflammatory cells is present. Cause of the feline polyps is unknown. More detailed clinicopathologic features of the condition have been published.32


TUMORS OF THE LARYNX AND TRACHEA


Neoplasms of the larynx and trachea are very rare and most published reports are of single cases. Information is therefore fragmentary. Any tissue in or adjacent to the walls of these structures can give rise to tumors so a variety of epithelial and mesenchymal tumors have been found.


Larynx


The most comprehensive report of veterinary laryngeal neoplasms reviews canine and feline laryngeal tumors.33 Laryngeal tumors were 0.02% of all biopsy and necropsy specimens in dogs and 0.14% in the cat. The higher frequency in the cat was mainly due to the preponderance of lymphoma. Ages of affected animals ranged from 2 to 12 years for dogs and 2 to 17 for cats. Males outnumbered females by more than 2 to 1 in both dogs and cats. No one tumor type predominated in the dog since 11 different types of tumor were recorded. In contrast, the majority of tumors in the cat (8 of 11) were lymphomas. Although no laryngeal squamous cell carcinomas were described, they do occur34 and appear to arise from laryngeal epithelium.


Chondromas or osteochondromas occasionally originate from laryngeal cartilages, particularly in horses.35 The osteochondromas are usually cartilaginous nodules with central endochondral ossification. They may be primary or secondary to laryngeal trauma.


The histologic appearance of most laryngeal tumors resembles that of the same tumor types found elsewhere. Two unusual but specific laryngeal tumors deserving of discussion here are canine laryngeal rhabdomyomas, previously considered to be oncoctyomas, and laryngeal squamous cell carcinomas.


Laryngeal rhabdomyoma of the dog


Laryngeal rhabdomyomas are solitary nodules that originate in the submucosal tissues of the larynx and protrude into the laryngeal lumen, thus causing dyspnea and stertorous respiration. Grossly, these tumors are pink, fleshy masses with occasional areas of hemorrhage (Figure 12.11A). Histologically, they are lobular accumulations of variously sized and shaped cells with abundant finely granular or foamy cytoplasm. While the “strap” cells of rhabdomyosarcomas are unusual, multinucleate cells are often present as a small proportion of the population (Figure 12.11B). Careful search may reveal cross‐striations in cells with elongated eosinophilic cytoplasm, preferably in sections stained with phosphotungstic acid–hematoxylin. Ultrastructural features include numerous mitochondria and bundles of myofibrils with electron‐dense Z‐lines typical of striated muscle cells. With IHC these tumors are positive for myoglobin and desmin36 (Figure 12.11C). These tumors are histologically benign and metastases are not reported.

Photo of laryngeal rhabdomyoma in canine, displaying mottled ulcerated mass (a) and 3 micrographs (b–d) of laryngeal mass with polygonal cells, IHC staining for sarcomeric actin, and myoglobin, respectively.

Figure 12.11 Canine laryngeal rhabdomyoma. (A) An irregular mottled mass with ulcerated surface extends into the laryngeal lumen. (B) Laryngeal mass composed of polygonal cells with abundant eosinophilic cytoplasm. Nuclei are round, mild to moderately pleomorphic, and have prominent nucleoli. Multinucleate polygonal cells are infrequent but more common than rare striated “strap” cells. (C) IHC staining for sarcomeric actin and (D) myoglobin.


Laryngeal squamous cell carcinoma


Squamous cell carcinoma of the larynx is the sixth most common human cancer and has strong etiologic association with smoking.37 Human papillomavirus has also recently been identified in a significant proportion of human laryngeal cancers with a stronger association with squamous cell tumors.38 In contrast, squamous cell carcinomas do occur in the dog and cat but they are rare. Involvement of the larynx by lymphosarcoma is much more common in the cat than primary squamous cell carcinoma.39 Arborizing cords of variably differentiated squamous cells extend from the laryngeal mucosa to fill the submucosa and invade between laryngeal cartilages (Figure 12.12). A potential role for papillomavirus in small animal laryngeal tumors has not been investigated.

2 Micrographs of laryngeal squamous cell carcinoma illustrating cords of neoplastic cell extending from dysplastic laryngeal epithelium (left) and dysplastic laryngeal epithelium cords extending to nests (right).

Figure 12.12 Laryngeal squamous cell carcinoma. (A) Chords of neoplastic cells extend from dysplastic laryngeal epithelium to form a poorly delimited mass overlying the laryngeal cartilage and obliterating the vocal cords. (B) Dysplastic laryngeal epithelium overlies invasive cords of neoplastic epithelium extending to nests that have undergone early keratinization.


Trachea


There are even fewer reports of tracheal tumors than laryngeal tumors. A variety of epithelial and non‐epithelial tumors are possible but examples occur very rarely.40 Reports of canine cases include: leiomyomas41 and chondrosarcoma.40 Chondromas and chondrosarcomas are reported in the cervical trachea and appear to have a predilection to occur in Alaskan malamutes or Siberian huskies. Cases of laryngeal chondroma have also been reported.44 Adenocarcinomas are occasionally found in the tracheal of cats. Tracheal osteochondromas in young dogs represent a slightly more definitive syndrome.42 These cartilagenous tumors likely represent dysplasia of cartilage ring formation. A definitive connection to tracheal rings may or may not be evident (Figure 12.13A). Some of these apparently benign growths may have central endochondral ossification with marrow space formation Figure 12.13B. Surgical removal is generally curative. An association with multiple cartilagenous lesions has been suggested.42

2 Micrographs of tracheal osteochondroma illustrating mass of trabecular bone with cartilaginous cap underlying the tracheal epithelium (left) and cartilaginous cap with endochondral ossification (right).

Figure 12.13 Tracheal osteochondroma. (A) Overview demonstrates a well‐differentiated mass of trabecular bone with a cartilaginous cap underlying the tracheal epithelium. (B) The cartilaginous cap is well differentiated and has little endochondral ossification. Mature trabecular bone contains sparsely cellular marrow spaces.


References



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TUMORS OF THE LUNG


Epithelial tumors


Classification: origin of pulmonary tumors


Neoplasms can arise from every component of the lung. Tumors of clinically significant incidence, however, mostly arise from epithelium of the conducting airways or alveolar parenchyma. Various approaches to classification of lung tumors in both humans and animals have used site of origin (bronchogenic, bronchial gland or bronchioloalveolar) histologic pattern (adenoid, squamous, large cell, small cell) or combinations thereof. Unfortunately, there is significant overlap in the histologic pattern of tumors from various sites of origin within the lung. Further complications arise because the site of origin is often obscured by aggressive tumor growth by the time tumors are examined and by transdifferentiation from one phenotype to another at various stages in the neoplastic process. Phenotype is, therefore, not a completely reliable indication of histogenesis.


Tumors derived from the large airway epithelium are more often located near the hilus of the lung, whereas tumors of parenchymal origin tend to be peripheral. Tumors of large airway origin predominate in humans and are associated with inhalation of carcinogens, particularly cigarette smoke, whereas tumors of the bronchioloalveolar region are more common in the dog where they can be multicentric. Epithelial‐derived lung tumors can arise from a variety of progenitor cells, including basal and secretory cells in large airways and nonciliated secretory (Club) cells and type II pneumocytes in the terminal bronchiolar unit. Traditionally, lung tumors of humans were considered either bronchogenic or bronchioloalveolar in origin, with squamous cell and small cell (neuroendocrine) carcinomas thought to arise predominantly from large airways and adenocarcinomas derived from distal airways.


Although increased incidences of tumors from both locations are associated with cigarette smoking, tumors of the distal lung are more common in nonsmokers. More recent theories of histogenesis combine the long‐accepted plasticity of airway epithelial cell differentiation with new concepts of stem cell contribution to carcinogenesis and suggest that tumors of differing histologic patterns, including small cell carcinomas, may all be derived from common precursors with initiating genetic lesions driving alternative differentiation. Similar to the consensus in veterinary pathology, lung tumors in humans are now classified by their histologic patterns without reference to possible cell of origin1 (Box 12.2). Broad classifications in human pathology include:



  • adenocarcinoma
  • squamous cell carcinoma
  • small cell carcinoma
  • carcinoid
  • non‐small cell carcinoma
  • non‐small cell carcinoma with squamous cell and adenocarcinoma patterns.
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Mar 30, 2020 | Posted by in INTERNAL MEDICINE | Comments Off on Tumors of the Respiratory Tract

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