Choanal lymphosarcoma in a 7-year-old golden retriever: Diagnosis and treatment

Abstract

A 7-year-old, spayed female, golden retriever with a 1-year history of progressive stertor and reverse sneezing was referred for further diagnostics. Endoscopy and computed tomography of the head revealed a bilobed mass in the choanae. Cytologic and histopathologic examinations of the mass were consistent with lymphosarcoma. Treatment consisted of chemotherapy.

A 7.5-year-old, spayed female, golden retriever was referred for a 1-year history of progressive stertor and intermittent reverse sneezing. Referral pharyngeal and laryngeal examinations, observations with a rhinoscope, and radiographs of the thorax (lateral and dorsoventral) and skull (lateral and dorsoventral openmouth) under general anesthesia were unremarkable. Results from a biochemical panel and routine complete blood (cell) count (CBC) were within normal limits. Trials of dexamethasone and various antibiotics by a referring veterinarian had resulted in transient reductions in clinical signs, but no long-term improvement had been achieved.

On physical examination, stertorous breathing was noted and the dog licked its nose repeatedly. There was no evidence of sinus pain, facial deformity, nasal discharge, or cough upon palpation of the trachea. Both eyes retropulsed normally and there was good airflow through both nares. On palpation, the sizes of all lymph nodes were within normal limits. Differential diagnoses for stertor and reverse sneezing in mesaticephalic dogs include neoplasia, foreign body, granuloma, abscess, or enlarged lymphoid tissue within or external to the pharynx.

The pharynx, larynx, ears, and nasal passages were thoroughly examined with the dog under general anesthesia 7 wk later. Both tonsils were mildly enlarged and erythematous, as were the vocal folds. Laryngeal function was normal. Endoscopy revealed a smooth, pale, bilobed mass in the choanal region (Figure 1); the mass was biopsied by using endoscopic pinch forceps. The biopsy specimens were fixed in 10% neutral-buffered formalin and submitted for histopathologic examination, which revealed diffuse infiltration of glandular tissue by neoplastic lymphocytes. The lymphocyte population was uniform, consisting of small round cells with scant cytoplasm and few mitotic figures, consistent with a diagnosis of lymphocytic lymphosarcoma of the choanae.

Figure 1.

Rostral endoscopic view of bilobed choanal mass. The soft palate is visible in the lower right quadrant. (Olympus VET-XP10 Veterinary Fibroscope; Melville, New York, USA)

A helical computed-tomography (CT) scan of the head was performed to assess the size and invasiveness of the tumor. Figure 2 depicts a transverse view at the level of the angular processes of the mandible. The mass appeared to be bilobed and occupy the choanal space, bordered by the basisphenoid bone dorsally, the soft palate ventrally, and the caudal margins of the pterygoid bones laterally, just cranial to the stylohyoid bones. The soft palate appeared to be ventrally displaced by the mass. The mass was hypodense relative to bone, isodense to muscle, and slightly hyperdense to brain.

Figure 2.

Transverse computed tomographic scan at the level of the angular processes of the mandible. A 3-cm × 2-cm bilobed mass occupies the space bordered by the base of the skull dorsally and the soft palate ventrally. Scanner (Picker PQ-series crx200 helical CT scanner; Picker International, Highland Heights, Ohio, USA) settings, KVP 130, MA 100; 5 mm slice.

Staging of the tumor involved cytologic examination of local lymph nodes, thoracic radiographs, and abdominal ultrasonographs. Examination of fine needle aspirates of an enlarged left submandibular lymph node (which was not present on the initial physical examination) and of the left prescapular lymph node indicated reactive lymphoid hyperplasia. Thoracic radiographs (left and right lateral, and ventrodorsal views) appeared to be normal. The abdominal ultrasonographs were unremarkable, except for a subjectively small liver with changes consistent with mild fibrosis, including a coarse appearance and ill-defined hyperechoic areas. Results from a repeat CBC and biochemical panel were also within normal limits. According to the World Health Organization’s (WHO) clinical staging system for lymphosarcoma, the tumor was classified as Stage I (involvement limited to a single node or lymphoid tissue in a single organ), substage ‘a’ (without systemic signs).

Radiation therapy was considered due to the apparent localized nature of the tumor, but it was not pursued. A modified version of the University of Wisconsin-Madison (U-WM) protocol for canine lymphosarcoma was instituted 3 d later (Table 1). The modified protocol consists of induction and maintenance phases, and continues to week 104 as long as complete remission is maintained, at which time all therapy ceases. Several changes to the chemotherapy protocol were made, as required, to rescue and maintain remission, and minimize adverse effects. The U-WM chemotherapy protocol is included for comparison (Table 2). Due to the potential costs of monitoring treatment response by CT, endoscopy, or both, efficacy was evaluated on the presence or absence of clinical signs, such as stertor or reverse sneezing, on physical examination, and as reported by the owner at each visit.

Table 1.

Schematic of chemotherapy drugs administered for the treatment of canine lymphosarcoma in a 7-year-old golden retriever from weeks 1 to 37

	Week
Drug	1	2	3	5	7	8	9	10	12	14	16	17	20	22	23	25	26	27	28	31	33	35	37
L-asparaginasea 400 IU/kg BW, IM	•
Vincristineb 0.7 mg/m2, IV	•		•		•		•		•			•		•		•		•
Cyclophosphamidec 200 mg/m2, IV		•				•
Doxorubicind 30 mg/m2, IV				•				•							•							•
Chlorambucile 1.4 mg/m2, PO										•			•				•			•
Methotrexatef 0.5 mg/kg BW, IV											•
Lomustineg 70 mg/m2, PO																			•				•
Actinomycin-Dh 0.7 mg/m2, IV																					•
Prednisonei	Starting at week 1: 0.75 mg/kg BW, q12h, × 14 d, then 0.75 mg/kg BW am and 0.35 mg/kg 0.75 mg/kg BW, q24h, × 7 d, then 0.75 mg/kg BW, q48h × 7 d, then 0.75 mg/kg BW, q48h × 7 d

^aElspar; Merck, Sharpe, & Dohme, West Point, Pennsylvania, USA

^bOncovin; Eli Lilly, Indianapolis, Indiana, USA

^cCytoxan; Mead Johnson Oncology, Evansville, Indiana, USA

^dAdriamycin; Parmacia-Upjohn, Kalamazoo, Michigan, USA

^eLeukeran; GlaxoSmithKline, Research Triangle Park, North Carolina, USA

^fMethotrexate; Lederle, Wayne, New Jersey, USA

^gCeeNU; Bristol-Myers Squibb, New York, New York, USA

^hCosmogen; Merck, Sharpe, & Dohme

ⁱApo-Prednisone; Apotex, Toronto, Ontario

Table 2.

University of Wisconsin-Madison chemotherapy protocol for canine lymphosarcoma (9)

	Week
Drug	1	2	3	4	6	7	8	9	11	13	15	17	19	21	23	25
L-asparaginasea 400 IU/kg, BW, IM	•
Vincristineb 0.7 mg/m2, IV	•		•		•		•		•		•		•		•
Cyclophosphamidec 200 mg/m2, IV		•				•
Doxorubicind 30 mg/m2, IV				•				•								•
Chlorambucile 1.4 mg/m2, PO										•				•
Methotrexatef 0.5 mg/kg BW, IV												•
Prednisoneg	2.0 mg/kg BW, PO, q24h × 7 d, then 1.5 mg/kg, BW, PO, q24h × 7 d, then 1.0 mg/kg BW, PO, q24h × 7 d, then 0.5 mg/kg BW, PO, q24h × 7 d, then stop.
Repeat weeks 11 to 25 at 3-week intervals for 1 cycle, then at 4-week intervals substituting methotrexate for all doxorubicin. Stop all therapy at week 104 if free from disease.

^aElspar; Merck, Sharpe, & Dohme, West Point, Pennsylvania, USA

^bOncovin; Eli Lilly, Indianapolis, Indiana, USA

^cCytoxan; Mead Johnson Oncology, Evansville, Indiana, USA

^dAdriamycin; Parmacia-Upjohn, Kalamazoo, Michigan, USA

^eLeukeran; GlaxoSmithKline, Research Triangle Park, North Carolina, USA

^fMethotrexate; Lederle, Wayne, New Jersey, USA

^gApo-Prednisone; Apotex, Toronto, Ontario

Due to the potential cardiotoxic effects of doxorubicin, echocardiography was performed prior to the 1st administration of this chemotherapeutic agent. The echocardiogram was unremarkable, except for a high-normal to mildly elevated aortic outflow velocity, measuring 2.0 m/s, which was indicative of a subclinical subaortic stenosis. However, contractility and chamber sizes were normal and there was no evidence of aortic insufficiency or anatomic changes along the aortic outflow tract. An electrocardiogram (ECG) was normal, except for isolated atrial premature contractions (APC) (< 1/min), which were not considered clinically significant.

Side-effects exhibited throughout the course of therapy were mild and included polydipsia, polyphagia, and mild lethargy and gastrointestinal upset during the first few weeks of chemotherapy and 1 wk after the administration of lomustine at week 27. Treatment was delayed twice at weeks 4 and 19. Administration of doxorubicin was delayed at week 4 due to a marginal neutrophil count (4.26 × 10⁹ cells/L; reference range 2.80 to 10.56 × 10⁹ cells/L) on the CBC. Chemotherapy was again delayed at week 19 due to inappetance, vomiting, and diarrhea of 3 days’ duration, with neutrophilia (17.05 × 10⁹ cells/L). An abdominal ultrasonograph was normal, except for a fluid-filled colon, with no evidence of foreign body obstruction or infiltrative disease. The vomiting and diarrhea resolved uneventfully and chemotherapy was resumed.

A significant reduction in clinical signs was observed by week 3, and stertor and reverse sneezing were absent until week 11, when a relapse of clinical signs was reported by the owner. Therapy was continued as scheduled, but by week 15, intermittent reverse sneezing and stertor were still being reported; therefore, methotrexate was administered in place of vincristine as a rescue agent (Table 1), resulting in attenuation of clinical signs. The protocol was continued until week 21, when stertor and reverse sneezing were again reported, so it was recommended that once weekly treatments be reinstituted. The frequency of clinical signs in the following weeks decreased significantly and eventually all clinical signs abated. A resurgence of clinical signs occurred once again at week 30, resulting in rescue therapy with actinomycin-D. Clinical signs persisted until therapy with doxorubicin was reinstated at week 34, after which all sneezing and stertor disappeared. At the time of writing (week 37), all clinical signs remain absent.

Lymphosarcoma accounts for approximately 5% to 7% of all canine neoplasms and 80% to 90% of all hematopoeitic tumors in dogs (1). Although dogs of any age may be affected, the median age of diagnosis is 5 to 9 y (1). There is a breed-related predisposition, with certain breeds, such as the golden retriever, boxer, basset hound, rottweiler, cocker spaniel, St. Bernard, Scottish terrier, Airedale terrier, and English bulldog, being at higher risk (2). In one study, golden retrievers comprised 13% of 75 dogs with lymphosarcoma (3).

The most common anatomic presentations in the dog are multicentric (80% to 85%), followed by alimentary (~ 7%), cutaneous (~ 6%), mediastinal (~ 3%), and miscellaneous extranodal sites (< 5%), of which the central nervous system, bone, heart, and eye are most commonly reported (4). Extranodal lymphosarcomas arise from malignant transformation of a single lymphocyte within a tissue, and although they may be categorized initially as Stage I, it is believed that most eventually progress to systemic disease (Stage III and higher) (2,5). Although lymphosarcoma has been reported in the nasal cavity and sinuses of the dog (6), nasopharyngeal lymphosarcoma is extremely rare (2) and there are no reports of choanal lymphosarcoma in this species.

Untreated, most dogs with lymphosarcoma survive 4 to 8 wk (2). Remission rates with the U-WM protocol are high (80% to 90%), with a mean survival time of 1 y and with 25% of dogs surviving 2 y or more (7). Although there is conflicting evidence regarding pretreatment prognostic factors for canine lymphosarcoma, it is generally agreed that the presence of systemic signs (WHO substage b), T-cell phenotype, high-grade malignancy, and involvement of the mediastinal lymph node, skin, central nervous system, alimentary system, or kidney is associated with a poorer outcome (1,4,7,8). Other proposed negative prognostic indicators include bone marrow involvement (Stage V), hypercalcemia, body weight > 18 kg, expression of P-glycoprotein associated with multidrug resistance (MDR), and increased argyrophilic nucleolar organizing regions (Ag-NORs) associated with cell proliferation (1,4,5,7,8).

The most common histologic classification systems for canine lymphosarcoma that categorize tumors as low-, intermediate-, or high-grade malignancies are the National Cancer Institute Working Formulation (NCIWF) and the updated Kiel Classification System (1,7). Both systems classify tumors based on mitotic index, cell size, and cell shape, whereas only the Kiel system describes immunophenotype (B-, T-, null-cell) (1,7). Low-grade lymphosarcomas, composed of small cells with a low mitotic rate, are associated with a long survival but low cure-rate. High grade lymphosarcomas occur in 80% of cases and are composed of larger cells with a higher mitotic rate; they tend to progress rapidly but are more likely to respond to chemotherapy and, in humans, are potentially curable (1,7). The differences in biologic behavior and prognosis between nodal and extranodal lymphosarcomas are well recognized (7); however, the classification systems fail to include extranodal lymphosarcomas as a separate category, and detailed characterization of extranodal lymphosarcomas in dogs is lacking, making prognostication of such tumors difficult.

The need for maintenance therapy is controversial. The relative survival times of dogs treated with the standard U-WM protocol involving induction and maintenance phases compared with those treated with dose-intensive protocols with no maintenance have been debated. There is evidence that dogs receiving shorter, less expensive protocols have comparable remission rates and survival times and are more likely to achieve 2nd remissions than are dogs receiving long-term maintenance therapy (7). However, many shorter protocols involve higher doses of cyclophosphamide (250 mg/m² versus 200 mg/m²) or doxorubicin (37.5 mg/m² versus 30 mg/m²), or both; consequently, there is an increased frequency of toxicity and death (9). Since the goal of chemotherapy in companion animals is to maintain a good quality of life while prolonging survival, an increase in toxicity may be considered unacceptable.

Although many dogs achieve extended remissions, complete cures are rare with populations of cells that are resistant to chemotherapeutic agents eventually emerging. The use of combination therapy and dose intensification are theorized to minimize the development of drug resistance (7). The dose of drugs used in chemotherapy is limited in veterinary patients due a lack of support systems, including bone marrow transplantation. Although tumor cells may possess inherent resistance to chemotherapy, certain agents, such as vincristine, may promote the emergence of cells expressing the P-glycoprotein efflux pump that results in MDR (3), with crossresistance to many other agents, including doxorubicin (10). Resistance also occurs in canine lymphosarcoma with alterations in the p53 gene that regulates apoptosis and with up-regulation of glutatione-S-transferase involved in free-radical scavenging (5,10). Future therapeutic modalities, such as recombinant immunotoxins, new chemotherapeutic agents, and monoclonal antibodies conjugated to radioisotopes, may be required to further extend survival times in canine patients (5).

This case represents an unusual presentation of canine lymphosarcoma and indicates that lymphosarcoma should be considered in cases of chronic progressive stertor and reverse sneezing, particularly in nonbrachycephalic breeds. CJV