Veterinary Pathology OnlineFirst, published on April 16, 2015 as doi:10.1177/0300985815579997

Original Article

Cartilaginous Tumors of the Larynx and Trachea in the Dog: Literature Review and 10 Additional Cases (1995–2014)

Veterinary Pathology 1-8 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0300985815579997 vet.sagepub.com

G. A. Ramı´rez1, J. Altimira1, and M. Vilafranca1

Abstract Cartilaginous tumors of the larynx and trachea are uncommon in the dog. The authors describe 10 cases diagnosed between 1995 and 2014 and review 16 cases in the literature. Seven of our cases were tracheal and 3 were laryngeal. Two of the laryngeal tumors were chondromas, which have not been previously reported in this site. The third laryngeal tumor was a myxochondroma. Of the 7 tracheal tumors, 6 arose from the ventral tracheal wall, including 2 that were extraluminal. Tracheal tumor types included chondrosarcoma (n ¼ 3), chondroma (n ¼ 2), and osteochondroma (n ¼ 2). All of the laryngeal tumors and 5 of 7 of the tracheal tumors occurred in adult dogs (aged 5–11 years). The 2 tracheal osteochondromas were in young dogs (3–4 months) and were intrathoracic, while the remaining tracheal tumors were cervical. Surgical excision had a good outcome in most cases. Combining our 10 cases with the 16 previously reported cases showed that 6 (27%) of the affected dogs were Arctic breeds (Alaskan Malamute or Siberian Husky) suggesting a predisposition in this type of dog. Keywords cartilage, dog, larynx, neoplasia, review, trachea, tumor

Primary neoplastic disease of the larynx is rare in domestic animals.29,31 The most common types of primary laryngeal tumors are squamous cell carcinoma, oncocytoma, and rhabdomyoma.7,10,26,31 Mast cell tumor,7,15,31 melanoma,22,31 undifferentiated carcinoma,7 leiomyoma,20 rhabdomyosarcoma,17 lipoma,29 plasmacytoma,16 granular cell tumor,28 and osteosarcoma5 have also been reported. Primary tracheal neoplasia is even more uncommon. Adenocarcinoma,7 undifferentiated carcinoma,18 plasmacytoma,9 leiomyoma,3 fibrosarcoma,21 mast cell tumor,7,15 rhabdomyosarcoma,34 and osteosarcoma5 have been reported. Neoplastic disease of the cartilaginous component of the larynx and trachea are rare and described only in single-case reports or brief communications including a few cases. A total of 16 cases have been described in the dog in the veterinary literature in English language, among 13 publications.* Veterinary pathology textbooks describe them only briefly.8,32 Myxochondroma and chondrosarcoma are the only cartilaginous neoplasms described in the larynx. Chondroma, osteochondroma, and chondrosarcoma have been reported in trachea. The present article describes the clinical and pathologic features of 10 additional cases and compares them to those previously reported.

*References 1, 2, 6, 7, 11, 13, 14, 19, 23, 24, 29, 30, 33.

Material and Methods Our records were reviewed for dogs with a diagnosis of primary tracheal or laryngeal neoplasia. The search produced a series of 10 dogs with cartilaginous neoplasms diagnosed between 1995 and 2014. All cases had been fixed in 10% neutral buffered formalin, processed routinely, and embedded in paraffin wax. We confirmed histologic diagnoses by reexamination of archived specimens. Paraffin blocks were sectioned at 3 mm and stained with hematoxylin and eosin and with Alcian blue (pH 2.5 for acid mucopolysaccharides) for routine histopathologic study. When available, signalment, history, clinical signs, radiographic findings, response to treatment, and follow-up information were obtained through e-mail and telephone interviews with the referring clinicians. A review of the peer-reviewed scientific literature was performed in the Medline database (National Library of Medicine, PubMed) and Google Scholar database up to September 2014 using different associations of the following keywords: 1

Laboratorio de Diagno´stico Histopatolo´gico Histovet, Avda Paı¨sos Catalans, Sant Quirze del Valle`s, Barcelona, Spain Corresponding Author: Gustavo A. Ramı´rez, Laboratorio de Diagno´stico Histopatolo´gico Histovet, Avda Paı¨sos Catalans, 12D, 08192 Sant Quirze del Valle`s, Barcelona, Spain. Email: [email protected]

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Table 1. Signalment, Tumor Type, Clinical Features, Treatment, and Follow-up for 10 Dogs With Tracheal or Laryngeal Tumors. No. Location

Breed

Age Sex Type

1

Larynx

5y M

2 3

Larynx Larynx

4

Cervical trachea Cervical trachea

Miniature Poodle Mixed Alaskan Malamute Boxer

5

6 7 8 9

10

9y M 13 y M 11 y M

Greyhound 10 y M

Thoracic trachea Thoracic trachea Cervical trachea Cervical trachea

Boxer

Cervical trachea

English Bulldog

Mixed Siberian Husky Doberman

Clinical Signs

Chondroma

Inability to bark, cough, thickening of vocal folds Myxochondroma Cough, dysphagia, hoarseness Chondroma Hoarseness, cough, dyspnea, dysphagia, collapse Chondroma Asymptomatic Chondroma

4 M mo 3 F mo 10 y F

Hoarse respiration, exercise intolerance, cough, dyspnea, cyanosis, collapse Osteochondroma Persistent cough, stridor, respiratory distress, cyanosis Osteochondroma Dyspnea, respiratory distress, cyanosis, collapse Chondrosarcoma Asymptomatic

9y M

Chondrosarcoma Occasional respiratory distress

6y M

Chondrosarcoma Persistent cough, stridor, dyspnea

Treatment and Follow-up Excised, no follow-up Excised, no recurrence Excised, lived 6 mo (dnr) Excised, lived 2 mo (dnr) Biopsy, not treated; death 4 mo after diagnosis (dnr) Euthanasia, not treated Euthanasia, not treated Excised, lived 36 mo (dnr) Excised, recurrence in 3 mo; lived 8 mo following second surgery (necropsy not performed) Excised, no recurrence

Abbreviations: dnr, death not related to neoplasm; F, female; M, male.

cartilage, cartilaginous, neoplasia, tumor, trachea, tracheal, larynx, laryngeal, chondroma, osteochondroma, chondrosarcoma, dog, canine. The search was focused on the clinical, macroscopic, and histologic characteristics.

Results Clinical Features Ten cases of cartilaginous tumors were included in the study and are summarized in table 1. Three of 10 cases in our series had laryngeal tumors. All were benign and had been diagnosed as chondromas. After reexamination, case No. 2 was reclassified as myxochondroma based on histologic features. The ages of the 3 dogs were 5, 9, and 13 years. All 3 were males. The most frequent clinical sign was persistent cough. Other signs included hoarseness, inability to bark associated with thickening of vocal folds, and variable grades of dysphagia. Case No. 3 was the largest lesion in the series (1.5 cm in diameter) and caused dyspnea, respiratory distress, and occasional collapse. The lesions were confined caudally to epiglottis and were covered by mucosa. Complete blood count and biochemical analyses were normal in the 2 cases in which they were performed. Radiographs were obtained only for case No. 3, which showed a single, wellcircumscribed nodule arising from the ventral larynx. There was no perilaryngeal tissue involvement. Surgical resection of all 3 lesions was performed with an uneventful recovery for case Nos. 2 and 3; follow-up information was not available for case No. 1. Seven of 10 cases were tracheal tumors and presented either as extraluminal growths infiltrating cervical soft

tissues (n ¼ 2) or as intraluminal masses (n ¼ 5). The extraluminal growths included 1 chondroma and 1 chondrosarcoma. Intraluminal tumors included 1 chondroma, 2 osteochondromas, and 2 chondrosarcomas. Both osteochondromas occurred in young dogs (3 and 4 months of age). The mean age of the remaining patients with tracheal tumors was 9.2 years. Five of 7 dogs were male. The most common clinical signs were dyspnea, cough, respiratory distress, and cyanosis. Occasionally, syncope was reported. The 2 patients with extraluminal masses were asymptomatic and were presented for a palpable growth in the neck. Intraluminal growths were not visible or palpable externally. Six of 7 lesions arose from the ventral wall of the trachea. The complete blood count and serum biochemical parameters were within the reference intervals for the 4 cases in which they were performed. Radiographs were obtained in 3 patients (case Nos. 6, 7, 9). A distinct intratracheal mass containing mineralized foci and occupying two-thirds of the tracheal lumen in the carina characterized the lesions in case Nos. 6 and 7. Case No. 9 was an ill-defined extraluminal mass of cartilaginous appearance without evident mineralization. Tracheoscopy was done in 1 dog (case No. 10) and revealed multiple small polypoid growths protruding from the tracheal mucosa into the lumen. Surgical resection was performed in 4 cases. Three patients had an uneventful recovery. One chondrosarcoma (case No. 9) recurred 3 months later and required 2 surgical procedures to eradicate the disease. Two patients (case Nos. 6 and 7; both young dogs with intrathoracic osteochondromas) had no treatment and were euthanized because of poor prognosis. Metastases were not reported in any case.

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Gross Pathology and Histopathologic Findings Laryngeal Chondroma: Case Nos. 1 and 3. Grossly, lesions were firm to hard, blue-white to milk-white nodules (1 to 1.5 cm in diameter) with evenly contoured borders and covered by a thin fibrous capsule. Microscopic examination of these masses revealed a thin capsule of dense collagen overlying multiple irregular lobules of alcian blue–positive, normalappearing hyaline cartilaginous tissue (Fig. 1). Case No. 3 had a fibrous stroma with small areas of loose organization. Cells in these lobules were uniform in size and shape and had small hyperchromatic nuclei. Anisokaryosis was minimal. No mitoses were seen. Laryngeal Myxochondroma: Case No. 2. This was a roughly spherical mass 1 cm in diameter. Histologically, the lesion was characterized by a noncircumscribed, lobulated, variably cellular proliferation of fusiform to stellate cells with no atypia in a fibromyxoid background with areas showing distinct stromal basophilia and a chondroid appearance (Figs. 2, 3). Scattered foci of mineralization were within the matrix. Cartilaginous matrix was alcian blue positive. No mitoses were noted. Tracheal Chondroma: Case Nos. 4 and 5. Case No. 4 was a firm, well-demarcated oval mass (3  2  2 cm) attached to the trachea. The small biopsies submitted for histopathologic examination consisted of fragments of hyaline cartilage composed of small, well-differentiated chondrocytes with no atypia. No mitoses were seen. Case No. 5 was a firm and slightly lobulated well-demarcated mass (1.5  1.7 cm). It was histologically composed of plump cartilage cells (Fig. 4) immersed within an alcian blue–positive cartilaginous matrix that was separated into lobules by indistinct fibrous connective tissue septa with no ossification or evidence of marrow cavity development. Tracheal Osteochondroma: Case Nos. 6 and 7. These tumors were spherical masses measuring 1 cm in diameter that extended into the tracheal lumen from the ventral aspect of a tracheal ring and were attached by a wide base. Cut section of the masses revealed a bony central portion surrounded by a discontinuous outer zone of cartilage (Fig. 5). Microscopic examination showed that the tumors were located subjacent to the tracheal epithelium and consisted of a cap or outer zone of alcian blue–positive hyaline cartilage contiguous with the adjacent tracheal ring, with endochondral ossification forming the central bony tissue containing variable amounts of marrow elements (Figs. 6, 7). Cells in the cartilaginous component were small, with inconspicuous cytoplasm and small dark nuclei. No mitoses were noted. Tracheal Chondrosarcoma: Case Nos. 8–10. Case Nos. 8 and 9 were firm to hard masses (2 and 4 cm in diameter, respectively) with a convoluted surface and indistinct borders. They were attached to the ventral wall of the trachea by a wide stalk. Growth was extraluminal for case No. 8 and intraluminal for case No. 9.

On cut section, the tumors were composed of variably sized multiple nodules or lobules of translucent to grayish-white or shinygray appearance with small areas of gelatinous consistency. Microscopically, they were characterized by areas of interconnected lobules of alcian blue–positive hyaline cartilage divided by dense fibrous connective tissue with ill-defined foci of basophilic myxomatous matrix (Fig. 8). In these areas, lacunae usually contained single chondrocytes, but groups of 1–4 chondrocytes per lacuna were occasionally present. The cells were round to stellate and variable in size. Nuclei were round, variably sized, and often hyperchromatic, with a single nucleolus and coarse chromatin (Fig. 9). Mitotic index was low (0–2 mitoses/ 400) in these areas. Other zones in the tumors were highly cellular and composed of round, plump, spindle, or stellate cells with large cytoplasmic processes and hyperchromatic large nuclei with marked anisokaryosis and frequent mitoses (2–4 mitoses/400; Fig. 10). Nuclear pleomorphism and bi- or multinucleated giant cells were also noted. Small random foci of coagulation necrosis were also present. Small foci of mineralization were present in case No. 8. No evidence of vascular invasion was observed in the histologic sections. Case No. 10 consisted of multiple irregularly shaped, firm polypoid formations (0.2–1 cm) growing into the tracheal lumen. They were composed of soft to moderately firm tissue with small foci of white cartilage. Histologically, areas of moderately cellular sarcomatous tissue composed of spindle to stellate cells with moderate anisokaryosis alternated with areas of basophilic and alcian blue–positive cartilaginous tissue composed of round or stellate cells with small hyperchromatic nuclei with low atypia (Figs. 11, 12). Mitotic figures were rarely detected (0–1 mitosis/400).

Discussion The types of tracheal and laryngeal cartilaginous tumors identified in our series were similar to those reported previously (Table 2). In addition, 2 laryngeal chondromas were identified in our case series. Considering the 16 cases reported in the literature and the 10 cases described herein, there have been 26 primary cartilaginous tumors of the larynx and trachea reported in the dog.y Tracheal tumors appear to be more common than laryngeal tumors (20 vs 6), and benign forms are more frequently found than malignant forms (19 vs 7; Tables 1, 2). Tracheal osteochondroma is the most frequent cartilaginous neoplasm reported, representing 42.3% of all tumors described, followed by tracheal chondrosarcoma (19.2%), tracheal chondroma (15.4%), laryngeal chondroma (7.7%), laryngeal myxochondroma (7.7%), and laryngeal chondrosarcoma (7.7%). The ages of affected animals in our series were very similar to those previously reported in the literature.6,7 Osteochondromas occur in younger dogs (10 weeks to 11 months), and all other types of tumor occur in adult dogs. Clear sexual predisposition is not y

References 1, 2, 6, 7, 11, 13, 14, 19, 23, 24, 29, 30, 33.

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Figures 1–7. Figure 1. Chondroma, larynx, dog, case No. 1. Variably sized ill-defined lobules of cartilaginous tissue limited by a thin fibrous capsule. Hematoxylin and eosin (HE). Inset: Matrix is alcian blue positive. Figures 2, 3. Myxochondroma, larynx, dog, case No. 2. Figure 2. A myxoid lobulated mass is under the laryngeal epithelium. HE. Figure 3. Higher magnification showing fusiform to stellate cells in a basophilic myxoid background. HE. Figure 4. Chondroma, trachea, dog, case No. 5. Solid mass composed of well-differentiated plump chondrocytes covered by normal respiratory mucosa. HE. Figures 5–7. Osteochondroma, trachea, dog, case No. 6. Figure 5. Cartilage-capped bony mass with a wide-based attachment to the ventral cartilage ring. Incised formalin-fixed specimen. Figure 6. The mass is composed of ossified tissue with marrow elements covered by hyaline cartilage. The preexisting tracheal ring is below. HE. Figure 7. Higher magnification showing the central endochondral ossification. HE. Downloaded from vet.sagepub.com at UNIV OF LETHBRIDGE on September 8, 2015

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Figures 8–12. Figures 8–10. High-grade chondrosarcoma, trachea, dog, case No. 9. Figure 8. Low magnification showing atypical cartilage with basophilic myxomatous matrix. Hematoxylin and eosin (HE). Figure 9. Higher magnification showing atypical chondrocytes with occasional mitoses (arrowhead). HE. Figure 10. Highly cellular sarcomatous tissue with scattered cartilaginous differentiation. HE. Figures 11, 12. Low-grade chondrosarcoma, trachea, dog, case No. 10. Figure 11. Polypoid formations covered by tracheal mucosa. HE. Figure 12. Higher magnification showing spindle or stellate cells with low nuclear atypia and foci of well-formed cartilage. HE.

observed for tracheal tumors (12 males, 7 females), whereas for laryngeal ones, males outnumbered females by 5 to 1. This value appears to be similar to the sexual predisposition for laryngeal cancer described in human beings, where it is 5 times as common in males as females.7,25 More frequent breeds affected are Alaskan Malamute, Doberman, and Boxer dogs. Of the 26 affected dogs, 7 (27%) were Arctic breeds (Alaskan Malamute or Siberian Husky), suggesting a predisposition in this type of dog. No cause has been identified for cartilaginous tumors. The higher incidence in aged people has led to speculation that their development may be related to the ossification of the laryngeal cartilages, which begins most commonly in older individuals. Metaplasia secondary to chronic inflammation and chondroplastic predisposition of connective tissue cells arising from branchial tissue have been also postulated.25

Clinical signs in patients described herein were typical of airway obstruction and similar to those previously reported, including loss or changes in vocalization (barking), coughing, noisy respiration, progressive dyspnea, stridor, cyanosis, and collapse in some cases.z Pulmonary hyperinflation, an expected sequel to airway obstruction, was documented in only 1 patient.19 There is little information in the literature on the radiographic appearance of canine laryngeal tumors.7 Either this information was not included, or it was stated that radiographs were not made because the tumor was visible upon gross examination of the larynx through the glottis. Most tracheal tumors appear radiographically as a solitary distinct mass. Mineralization is unlikely except for osteochondromas.2,6,7,19,23 Note that it is not possible

z

References 1, 2, 6, 11, 13, 14, 19, 23, 24, 29, 30, 33,

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Table 2. Tracheal and Laryngeal Cartilaginous Tumours Previously Reported in the Dog (n ¼ 16). Type

Location

Breed

Chondroma6

Cervical trachea Cervical trachea Larynx

Mixed

2y

F

Palpable, slightly movable, neck mass

Excised, successful outcome

Collie

10 y

F

Dyspnea, stridor

Excised, no follow-up

Labrador Retriever Alaskan Malamute Labrador Retriever Old English Sheepdog German Shepherd Alaskan Malamute Siberian Husky

5y

Chondroma7 Myxochondroma29

Osteochondroma14 Thoracic trachea Osteochondroma19 Thoracic trachea Osteochondroma33 Thoracic trachea Osteochondroma7 Thoracic trachea Osteochondroma11 Cervical trachea Osteochondroma6 Cervical trachea Osteochondroma23 Cervical trachea Osteochondroma30 Cervical trachea Osteochondroma2 Cervical trachea Chondrosarcoma13 Larynx Chondrosarcoma24 Larynx Chondrosarcoma1 Chondrosarcoma7

Thoracic trachea Cervical trachea

Age

Alaskan Malamute Dobermann Alaskan Malamute Boxer Doberman Pinscher German Shepherd Doberman

Sex Clinical signs

NF Dyspnea, voice change, exercise intolerance, cyanosis 11 mo F Respiratory distress

Treatment and Follow-up

Excised, no follow-up Excised, successful outcome

6 mo

F

3 mo

M

Dyspnea, coughing, exercise intolerance, Excised, no recurrence cyanosis Wheezing Excised, successful outcome

6 mo

M

Dyspnea, stridor

6 mo

N/A Dyspnea, collapse

Excised, no follow-up Excision unsuccessful

11 mo

M

Fainting, wheeze

Excised, successful outcome

10 wk

F

Exercise intolerance, dyspnea

Excised, successful outcome

4 mo

M

Difficulty breathing, dyspnea

Excised, successful outcome

7 mo

M

N/A

Excised, successful outcome

10 y

M

Stridor, exercise intolerance

8y

M

Stridor, dysphonia

Excised, metastases in 15 wk, euthanized Excised, successful outcome

6y

M

Respiratory distress

Excised, free of disease

1y

CM Dyspnea, stridor

Excised, metastases in 9 mo

Abbreviations: CM ¼ castrated male; F ¼ female; M ¼ male; N/A ¼ not available; NF ¼ neutered female.

to differentiate between inflammatory processes and benign or malignant neoplasms radiographically. Cysts or abscesses can show similar radiographic features.7 Therefore, when abnormal densities are detected radiographically within the larynx or trachea, additional measures (eg, laryngoscopy, endoscopic biopsy) are required to obtain a definitive diagnosis. Needle biopsy or cytology by fine-needle aspiration can reveal large plump cells with single and, occasionally, double nuclei suggestive of cartilaginous origin,6,8 but it is not possible to definitively differentiate malignant or benign character. Excisional biopsy provides the most rapid and accurate means of final diagnosis6–8,29,32 and relieves the clinical signs for intraluminal tumors. A cartilage tumor is considered to be malignant when the following features are found, even in small scattered fields: many cells with plump nuclei, more than an occasional cell with 2 nuclei, and especially giant chondrocytes with single or multiple nuclei and clumps of chromatin.25,32 Other cellular features of malignancy, including prominent nucleoli and irregularly shaped nuclei, also support a diagnosis of chondrosarcoma.32 The absence of mitotic figures does not rule out malignancy, since cell division in chondrosarcomas may be amitotic.25 It has been

suggested that even a single mitotic figure strongly supports a diagnosis of malignancy in these tumors.32 Laryngeal and tracheal chondromas in the dog appear to be identical to those in the skeletal system. Chondromas lack nuclear atypia, mitotic figures, necrosis, and invasive character.6,7 The differentiation between chondroma and welldifferentiated chondrosarcoma can be very difficult and is often a matter of personal interpretation. A diagnosis of chondroma should never create a false sense of security for the pathologist or surgeon, not only because chondroma-like areas can be present in the biopsy of a chondrosarcoma but because the clinical behavior of chondroma is often indistinguishable from a lowgrade chondrosarcoma. Osteochondromas are cartilaginous nodules with central endochondral ossification as a distinctive feature. They are the most commonly reported tumor in the trachea and only in young dogs (

Cartilaginous Tumors of the Larynx and Trachea in the Dog: Literature Review and 10 Additional Cases (1995-2014).

Cartilaginous tumors of the larynx and trachea are uncommon in the dog. The authors describe 10 cases diagnosed between 1995 and 2014 and review 16 ca...
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