Although primary pulmonary neoplasms are rare findings in dogs and cats, the reported incidence may be increasing.1-6 This potential rise may reflect multiple factors, including increased exposure to environmental carcinogens, the availability of more sensitive diagnostic tools, a greater number of necropsies being performed, and improved animal healthcare services resulting in the increased longevity of companion animals.1,2,4,7
Pneumonectomy remains the cornerstone of therapy for primary lung tumors, but novel adjunctive therapies (e.g. combination chemotherapy) are being developed and evaluated for improving local disease control. In addition to advances in detecting and treating primary lung tumor growth, new systemic therapies have been investigated for prolonging the disease-free interval, as well as palliating secondary bony metastasis.9-11
The goal of this article is to describe the common histologic variants, clinical signs, biologic behavior, and newest options for early diagnosis and effective treatment of primary lung tumors in dogs and cats.
PREDILECTION AND INCIDENCE
Primary lung tumors occur most commonly in larger, older animals, with a mean age of 10 or 11 and 12 years in dogs and cats, respectively.2,4,5,8,12-14,16 Although no definitive breed or sex predilection has been identified, boxers represented 37% of all lung tumor patients in one study,12 and in a feline investigation, older females were more often affected than males.10,14
Similar to people in which chemical carcinogenesis plays a prominent role in the genesis of primary lung tumors, a causal link is suspected to exist between smoking households and primary lung tumors in dogs, especially in mesocephalic and brachycephalic breeds.17 Moreover, dogs living in urban environments more commonly have lung tumors than do dogs in rural settings.4 This apparent environmental effect could reflect the greater pollutants within an urban environment or may simply be due to the greater population density of animals receiving routine veterinary care.
In dogs, the right caudal lung lobe is the most common anatomical location of primary pulmonary neoplasia.5,6,8,10,13,16,18 This observed anatomical preference is thought to be a result of greater lung tissue mass, thereby increasing the likelihood for spontaneous mutations within the right caudal lung fields.12 In cats, the caudal lobes are also more commonly affected, but they tend to have an equal occurrence in the right and left lung fields.14
Carcinomas are the most frequently diagnosed lung tumors, but consensus for the most common histologic subtype is lacking. This lack of agreement is partially attributed to researchers using differing classification schemes, precluding direct comparisons between historical and recent studies.
In veterinary medicine, the simplest classification scheme is by general cellular morphology, which includes adenocarcinoma, squamous cell carcinoma, and anaplastic carcinoma.6,19 Primary lung carcinomas can also be organized by topographical location, inclusive of bronchial, bronchoalveolar, or alveolar carcinoma.6,10 Confusingly, some studies categorize bronchoalveolar carcinoma into a separate cellular morphologic subtype altogether.5,8,14 Although organizing primary lung tumors by topographical location is useful in people, veterinary pathologists do not recommend this classification scheme in companion animals because of the advanced stage of the disease at the time of diagnosis, which makes determining the exact topographical origin of lung tumors extremely difficult.10,19 Instead, in veterinary studies, pulmonary carcinomas are generally divided into four subgroups—adenocarcinoma, squamous cell carcinoma, bronchial gland carcinoma, and alveolar cell carcinoma.4,10
Adenocarcinoma, regardless of tissue cell origin, is the most common histologic type in dogs and cats.2,4,10,12-14,16,19 In two studies, adenocarcinoma made up 74% to 77% of all primary lung tumors histologically examined.4,10 Other reports suggest adenocarcinoma is more common in people and cats and bronchoalveolar carcinoma is more common in dogs.5 Squamous cell carcinoma, which is the most common pulmonary neoplasm in people, is less common in companion animals, representing 6% and 4% of all of canine and feline lung tumors, respectively. Anaplastic carcinoma is the rarest morphologic subtype in dogs and cats,10 but it is still more common than primary mesenchymal lung tumors, which are extremely rare in dogs and cats.4,10,20
In a case report of four dogs with mesenchymal or mixed-cell-origin lung tumors, the age range was 4 to 15 years, with spayed females and castrated males in equal proportion.20 All tumors were in the right lung fields—two were hamartomas, one was a pulmonary chondroblastic osteosarcoma, and one was a biphasic pulmonary blastoma. Only the patient with the chondroblastic osteosarcoma had pulmonary metastasis visible on thoracic radiography. Both patients with hamartomas were alive at least one year post pneumonectomy.20 Other reports of canine sarcomas include an osteosarcoma, a chondrosarcoma, and a Spirocerca lupi-associated fibrosarcoma, with two of the three patients presenting with hypertrophic osteopathy.21-23
Pulmonary lymphomatoid granulomatosis is an extremely rare, diffuse disease of the canine lung that has a yet undetermined cause and may be immune-mediated or preneoplastic in origin.24-26 Fine-needle aspiration provides poor diagnostic yield with this disease process, and definitive diagnosis must be based on histologic examination. However, because of the historically rapid response to chemotherapy, empirical treatment may be used to aid in diagnosis.24 Of the primary neoplastic diseases of the lungs, pulmonary lymphomatoid granulomatosis carries the best prognosis.24,25
Despite certain growth and distribution patterns associated with primary lung tumors in companion animals, it remains impossible to definitively classify such tumors based purely on topographic anatomy, mostly because, as mentioned earlier, canine and feline neoplasms are often too advanced at diagnosis to identify their anatomical site of origin.5,12 This limitation has been underscored in several veterinary studies in which no correlation was found between a tumor's location and its histologic subtype. Thus, once a pulmonary mass has been identified on initial thoracic imaging, histologic or cytologic evaluation of the suspect lesion is absolutely necessary for definitive diagnosis.8,16,19
The clinical signs of primary lung tumors depend on many factors such as tumor invasiveness, the extent of lung tissue involvement, the presence of metastatic disease, and the occurrence of paraneoplastic syndromes.
The most common sign in dogs is a nonproductive cough, occurring in 52% to 58% of dogs with a primary lung tumor.2,4,8,12 Other respiratory signs may include tachypnea, wheezing, exercise intolerance, and hemoptysis. Nonspecific signs in dogs are common and include lethargy, weight loss, and anorexia.2,4 Dyspnea may occur if a large portion of the lung is involved or if pneumothorax, pleural effusion, or concurrent disease (congestive heart failure or tracheal collapse) is present.1,8 Severe lameness and pain may also be a presenting complaint if hypertrophic osteopathy or bone metastasis has occurred.1,2,4,12 Despite many patients presenting with overt clinical signs associated with primary lung tumors, up to 30% of all dogs will have no signs of disease at the time of diagnosis.2,4,12
Clinical signs seen in cats with primary pulmonary neoplasia are extremely variable, but dyspnea, weight loss, lethargy, anorexia, weakness, and vomiting are frequently reported.16,27 In one study of 35 cats with primary lung tumors, about 25% of cats presented with lameness, likely resulting from digital skeletal metastasis associated with primary pulmonary carcinoma. Respiratory signs were noted in only one-third of the cats, and coughing was rarely reported.1 In contrast, another feline study found that all 86 cats had at least one clinical sign directly or indirectly related to their primary lung tumor, and 53 of the cats (61.6%) had signs of respiratory difficulty.16 In general, cats with primary lung tumors present with a wide range of clinical findings, and the absence of overt pulmonary signs should not preclude a primary lung tumor as a differential diagnosis.
Primary pulmonary neoplasms are usually an incidental finding in animals presented for general health checks or evaluation of nonspecific signs. Thoracic radiography is often the initial step in evaluating patients with respiratory disease, but radiographic patterns are not specific for a single disease process so further diagnostic tests are necessary.
The appearance of primary lung tumors varies from a solitary mass (Figure 1) to involvement of an entire lung lobe or multiple lobes (Figure 2), indicating metastatic disease or multicentric pulmonary tumors. Radiographic assessment may be confounded by atelectasis secondary to pneumothorax or pleural effusion. Pleural effusion may result from regional lymph node metastasis, extension of the tumor into the pleura, or concurrent disease such as congestive heart failure or other nonneoplastic processes such as hypertrophic cardiomyopathy, feline infectious peritonitis, and chylothorax.1,14 But keep in mind that pleural effusion devoid of neoplastic cells on cytologic examination does not necessarily rule out primary pulmonary neoplasia.14,19,28
In most patients without pleural effusion or severe concurrent thoracic disease, survey thoracic radiographs are considered a high-yield diagnostic test, often revealing a pulmonary mass when present.16 Differential diagnoses for pulmonary masses include primary lung tumors (77% in one study), granulomas, cysts, abscesses, infarcts, diaphragmatic hernias, and metastatic neoplasia.4,29
In addition to needle size, the technique used for sampling is important, as fenestration (sampling without the use of negative pressure) has proved to be more effective than aspiration (using a syringe to create negative pressure). Although sample volume is decreased with fenestration, cellularity is improved because of less hemodilution.35
The limitations of fine-needle aspiration cytology include poor cell recovery, poor exfoliation of certain cell types (i.e. mesenchymal cells), failure to obtain a representative sample, and the inability to provide architectural information (i.e. vascular lesions or fibrosis).30 Other methods of obtaining cytology samples such as transtracheal wash and bronchoalveolar lavage offer poor diagnostic yield with primary pulmonary tumors when compared with fine-needle aspiration.4,16,30,36-38
The correlation between tracheobronchial lymph node involvement and shorter remission times stresses the importance of computed tomography (CT) in the diagnostic work-up of dogs with primary lung tumors.2,3,7 In a study of 14 dogs with primary lung tumors, researchers evaluated the accuracy of CT vs. thoracic radiography in determining tracheobronchial lymph node involvement. CT had greater sensitivity and an increased predictive value for detecting tracheobronchial lymph node metastasis. The overall accuracy of CT in detecting lymph node metastasis was 93% compared with 57% for thoracic radiographs. False negative diagnoses made with thoracic radiographs may be attributable to the fact that the lymph nodes were still small (< 15 mm) or may have been obscured by surrounding structures, including the primary tumor itself.7
METASTASIS AND STAGING
The presence of metastasis greatly affects prognosis, and appropriate clinical staging involves thoroughly investigating the common sites of pulmonary tumor dissemination. Pulmonary carcinomas tend to invade locally and spread through the lymphatic system to additional lung sites, hilar lymph nodes, and other thoracic tissues.2,3,5,12,15,16 Multiple tumor masses within the lung may indicate intrapulmonary metastasis or multicentric primary lung tumors.6 In addition to neighboring lung tissue, additional sites of metastasis include other lymph nodes, abdominal viscera, and the kidneys.12 Less common sites include the uvea, brain, and adrenal gland.40
In dogs, the rate of metastasis correlates well with the histologic type of tumor. The reported rate of metastasis is 50% for adenocarcinoma, with the most common sites of metastases being the tracheobronchial lymph nodes or other sites within the thoracic cavity.2,3,12,15 The metastatic rate is 90% for the more aggressive squamous cell carcinomas and anaplastic carcinomas.12
Because cats tend to have a higher incidence of poorly differentiated adenocarcinomas,10,16 it is not surprising that cats with primary lung tumors usually do not survive as long as dogs do. In a study of 21 cats treated with surgical resection, only histologic differentiation of the primary lung tumor had a significant correlation with survival time.27 Twelve cats with moderately differentiated tumors (57.1%) had a median survival time of 698 days, while nine cats with poorly differentiated tumors (42.9%) had a median survival time of 75 days. Although the study had inadequate power for statistical analysis of lymph node status, it did appear, as in dogs, that draining lymph node involvement may correlate with survival time, as 12 cats without enlarged tracheobronchial lymph nodes survived for a median of 412 days, whereas four cats with enlarged lymph nodes survived only a median of 73 days.27
In addition to histologic differentiation and lymph node enlargement, digital metastasis in cats with primary lung tumors is a poor prognostic finding. Cats with digital metastases have an average survival of 4.9 weeks (median 4 weeks) compared with a survival of 29.5 weeks (mean 12.5 weeks) in cats with primary digital squamous cell carcinoma.42
Paraneoplastic syndromes in cats occur even less frequently. In a study of 86 cats with primary lung tumors, none of the patients experienced paraneoplastic syndromes.16 Although lameness may be a common presenting sign (25% in one study), it is usually indicative of bone metastases rather than hypertrophic osteopathy.1 Single case reports of paraneoplastic syndromes have been suggested in cats, including marked leukocytosis in a cat with squamous cell carcinoma, hypercalcemia with bronchogenic adenocarcinoma, and thrombocytosis with bronchoalveolar carcinoma.45-47
The treatment of choice for solitary primary pulmonary tumors in dogs and cats is wide surgical resection—either a complete lung lobectomy or a partial lobectomy if the tumor is in the periphery.27,48 However, in cats more often than dogs, even if a single pulmonary nodule is seen radiographically, it is not uncommon to find multiple small lesions at surgery, suggesting the importance of advanced diagnostic imaging (CT or magnetic resonance imaging) before surgery.1
Given the advent of fiberoptic technologies and the training of surgical residents in noninvasive techniques, thoracoscopic lung lobectomy is becoming a more common surgical approach for managing lung tumors in companion animals. When compared with thoracotomy in people, the results of thoracoscopy are less tissue trauma, decreased morbidity, shorter hospitalization, and earlier return to normal activity.49 Adequate exposure of the thoracic cavity and access to the hilar lymph nodes may still require conventional thoracotomy, so thoracoscopic procedures are best suited for removing small, peripherally located masses.48
For conventional thoracotomy, a lateral intercostal surgical approach allows access to the primary bronchi for lobectomy of the side involved but prevents adequate examination of the opposite hemithorax. During thoracotomy, examine and palpate all accessible lung lobes and tracheobronchial lymph nodes for metastasis or multifocal primary masses. If the tracheobronchial lymph nodes appear enlarged, they should at least be biopsied and preferentially be extirpated.
After the primary tumor and associated draining lymph nodes are removed, adjunctive chemotherapy may be warranted based on host factors (clinical stage) and tumor characteristics (histologic findings). Despite the availability of new chemotherapeutic drugs, few well-designed prospective studies have investigated the efficacy of one or multiple agents for treating primary pulmonary neoplasms in dogs and cats.
Vinorelbine, a semisynthetic derivative of vinca alkaloids, has recently been described for treating various neoplasms, including primary lung tumors, in dogs.50 Vinorelbine is widely distributed in all tissues except for the brain, with concentrations in the lungs reaching 13.8-fold higher than other vinca alkaloids.51 In one study, two of seven dogs with macroscopic bronchoalveolar carcinoma achieved a partial remission after vinorelbine treatment. Furthermore, in dogs with microscopic bronchoalveolar carcinoma (incompletely excised primary or lymph node metastases), vinorelbine's anticancer activity was suggested by the relatively durable survival times of 113, 196, and 730+ days in three dogs treated with surgery and systemic vinorelbine.50 Further investigations are warranted to determine the effectiveness of adjunctive vinorelbine for treating bronchoalveolar carcinomas as well as other pulmonary neoplasms in dogs.
In a study of 15 dogs with primary lung tumors treated by lobectomy, five dogs with advanced recurrent pulmonary carcinoma received one of three chemotherapy protocols: 1) cyclophosphamide, vincristine, and methotrexate, 2) vindesine alone, or 3) vindesine and cisplatin.8 Two dogs treated with vindesine and cisplatin showed partial responses, with greater than 50% reduction in radiographic lesions. Anorexia was the only side effect of the cyclophosphamide, vincristine, and methotrexate protocol, while reversible neurotoxicity was the only side effect of vindesine alone. In the dogs treated with vindesine and cisplatin, mild leukopenia and gastrointestinal upset were seen in both dogs, while only one dog experienced reversible peripheral neurotoxicity consisting of rear limb weakness and decreased patellar reflexes.8 The anecdotal favorable response observed in the two dogs treated with cisplatin and vindesine, along with this protocol's acceptable toxicity profile, warrants further studies examining this combination of chemotherapeutic agents for treating primary lung cancer, especially adenocarcinomas.8
THE FUTURE IN TREATMENT
Although complete surgical removal of primary lung tumors before metastasis offers the best hope for a cure, several promising treatment modalities are on the horizon.
Intensity-modulated radiation therapy
An alternative to conventional lung lobectomy in companion animals is the use of intensity-modulated radiation therapy (IMRT). This treatment modality allows the delivery of curative-intent megavoltage radiation to the neoplastic lesion. Excessive delivery of radiation to normal tissues is minimized by collimating multiple treatment beams in the radiation field to conform three-dimensionally to the geometry of the cancerous mass.52
In a case study, the effectiveness of IMRT for treating a primary bronchoalveolar carcinoma in a dog was assessed by using positron emission tomography combined with CT. After treatment with IMRT, the dog survived 22 months, only to be euthanized for clinical signs considered unrelated to the primary lung tumor or treatment with IMRT. This anecdotal case report demonstrates favorable clinical outcomes with combination IMRT and positron emission tomography and CT for the treatment and response-assessment of a primary lung tumor in a dog.52
Another promising alternative to surgical removal of primary lung tumors is radiofrequency ablation (RFA). A heating electrode is directly inserted into the tumor percutaneously under the guidance of CT, and alternating electrical currents are passed through the electrode into the neoplastic mass with the intent of inducing tumor cell necrosis.
In a study using animal models, transmissible venereal tumor fragments were injected into the lungs of five dogs, and the patients were subsequently subjected to site-directed RFA. After treatment, the dogs were euthanized, and lung lesions were histologically evaluated. All tumor lesions demonstrated complete thermal coagulative necrosis with no evidence of viable tumor cells. The damage to normal lung parenchyma involved only a narrow zone of hemorrhagic necrosis surrounding each ablated lesion.
The efficacy of RFA on primary pulmonary masses suggests that animals with metastatic pulmonary nodules may also benefit from this treatment modality. Such a supposition is supported by one study in which electrode placement in the epicenter of the cluster of nodules was adequate for complete nodule ablation.53
The localized delivery of chemotherapeutic agents or cytokines to the thoracic cavity or lung parenchyma may allow for enhanced anticancer effects within the immediate tumor microenvironment.
Intracavitary chemotherapy. The clinical effectiveness of intracavitary cisplatin administration (50 mg/m2) has been investigated in six dogs with malignant cavitary effusions.54 In three dogs with pleural mesothelioma, complete resolution of cancerous effusions was achieved after a maximum of two treatments. These favorable anecdotal findings warrant further exploration of intracavitary chemotherapeutic strategies for managing the clinical consequences associated with primary or metastatic lung tumors.
A more recent study evaluated the effectiveness of intracavitary mitoxantrone or carboplatin for treating thoracic or abdominal carcinomatosis, sarcomatosis, or mesothelioma in patients with and without malignant effusions. In dogs treated with intracavitary chemotherapy, the median survival time was 332 days, compared with only 25 days in untreated dogs.55 These findings derived from a small population of cancer-bearing dogs also suggest that intracavitary chemotherapy exerts some beneficial anticancer effects.
Inhaled chemotherapy. Although intracavitary chemotherapy may increase the concentration of drug within the pleural space and at the visceral surface of the lung, the attainment of higher drug concentrations within the pulmonary parenchyma is better achieved through inhalation therapy. In a recent study, either doxorubicin or paclitaxel was delivered by aerosolization to 28 dogs with either primary or metastatic pulmonary neoplasia.56 Tumor regression occurred in 25% of dogs treated, with one patient demonstrating partial regression of metastatic hilar lymphadenopathy. Although typical toxicities of systemic doxorubicin chemotherapy (myelosuppression, nausea, and vomiting) were not seen, acute local pulmonary effects (intermittent, nonproductive cough) were noted in about half the dogs.
An important finding in this study was that dogs receiving inhalation doxorubicin on the same day as systemic doxorubicin did not experience any increase in systemic toxicosis, suggesting that inhaled doxorubicin exerted its effects locally.56 Thus, combining two different routes of chemotherapy administration may exert superior anticancer effects without added toxicity.56,57
Inhaled cytokines. Similar to the delivery of inhaled chemotherapy, the aerosol delivery of liposome-encapsulated IL-2 produced clinical responses in dogs with osteosarcoma metastases, with two of four patients achieving complete remission of their metastatic disease.57 Disappointingly, two dogs with primary lung tumors did not respond as well, with one achieving stable disease and the other experiencing progressive disease. Nonetheless, this study demonstrates that antitumor immune responses may be augmented through the delivery of aerosolized cytokines.57
Primary lung tumors are uncommon in dogs and rare in cats. Most patients will not present with overt clinical signs of respiratory distress, but more commonly primary lung tumors will be incidental findings or will be the cause of nonspecific signs of illness, including weight loss and lethargy. Several predictive factors including tumor histologic subtype, size, and lymph node involvement have been demonstrated to aid in patient prognostication. Conventional therapeutic recommendations should include surgical resection of the primary tumor and draining lymph nodes, followed by adjuvant chemotherapy. In the near future, specialized local therapies such as IMRT and RFA may provide alternatives to surgery, and aerosolized chemotherapy may be used in conjunction with systemic drug administration to enhance overall anticancer effects. The net effect of these newer therapeutic options would be to provide longer disease-free intervals and survival times in dogs and cats with primary lung tumors.
Kerry C. Rissetto, DVM*
Pamela W. Lucas, DVM
Timothy M. Fan, DVM, PhD, DACVIM (small animal internal medicine, oncology)
Department of Veterinary Clinical Medicine
College of Veterinary Medicine
University of Illinois
Urbana, IL 61802-4714
*Current address: Department of Veterinary, Medicine and Surgery, College of Veterinary Medicine, University of Missouri-Columbia, Columbia, MO 65211
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