Monoparesis in association with feline pulmonary carcinoma: A literature review with 3 new cases

Abstract

We describe 3 cases of cats that were presented with a sudden onset of monoparesis as a result of arterial thromboembolism without evidence of cardiovascular disease that were subsequently diagnosed with a primary pulmonary carcinoma. Arterial tumor thromboemboli due to pulmonary carcinoma should be considered as a differential diagnosis in cases of lameness or paresis in older cats. We theorize that large tumor emboli may obstruct peripheral arteries leading to acute monoparesis.

Primary pulmonary neoplasia is uncommonly diagnosed in cats, with a median age of 11 y at diagnosis (1,2). The most common histological diagnoses are adenocarcinoma (58.8%), anaplastic cell carcinoma (17.6%), and squamous cell carcinoma (11.8%) (1). Compared to dogs (3–5), the prognosis for cats with primary pulmonary carcinoma is poor. Cats with pulmonary carcinoma have a reported mean survival time of 115 d after surgical intervention (6); without treatment, the survival is also poor (1,2,7).

A common cause of paresis in middle-aged to older cats is arterial thromboembolism most often as a consequence of underlying hypertrophic cardiomyopathy (8–12). Less common causes of thromboembolic disease in cats include neoplasia (13), progestagen administration, general anesthesia (13–15), hyperthyroidism (16,17), and hypercortisolism (18–20).

Paresis as the primary complaint in cats with pulmonary neoplasia has been reported in the veterinary literature in a total of 9 cats. This syndrome has been specifically reported in 4 cases (13,21,22). Five more cases can be inferred from 3 larger retrospective series on arterial thromboembolism (12,14,23). Details of these cases are found in Table 1.

Table 1.

Clinical presentation, important parameters, and survival data for 10 cases with paresis as the primary complaint in cats with pulmonary neoplasia

Case	Age (y), gender	Affected limb	Presenting signs	Lung lobe affected	Blood features	Serum CK	Coagulation panel	Anticoagulant	Post-presentation survival (d)
1a	13, FS	Left fore	Weakness, respiratory distress, paresis, cold extremities	Left caudal	Thrombocytopenia, stress leucogram	12792 U/L, RI: 62–362 U/L	Mild elevation PTT	Clopidogrel	29
2b	11, FS	Right hind	Paresis, cold extremities	Accessory	Lymphopenia, platelet clumps	> 555800 U/L RI: 62–362 U/L	Unremarkable	Aspirin	26
3c	9, FS	Right fore	Paresis, cold extremities	Right middle	Anemia, lymphopenia	Unremarkable	Unremarkable	Dalteparin	15
4d	13, MC	Left hind, left fore	Paresis, cold extremities	All	Neutrophilia, lymphopenia, thrombocytosis	?	?	Dalteparin	11
5e	11, FS	Right hind	Paresis, cold extremities	All	Unremarkable	?	?	Heparin, aspirin	51
6f	14, MC	Right fore	Paresis, right carpal hyperextension	Left caudal	Hyperglobulinemia, monocytosis, anemia	4770 U/L RI: 55–382 U/L	Increased fibrin split products & fibrinogen		21
7f,8f	?	?	?	?	?	?	?	Aspirin	?
9g	?	Right hind	?	?	?	?	?	Coumadin, aspirin, streptokinase	8
10h	6, MC	Bilateral pelvic	Hind limb paralysis, cold extremities	Left & right caudal, left cranial	Thrombocytosis, leucopenia, neutropenia	?	?		0

? — Information not available or not specified per case. Cases 11 and 12 (12) had no information specified per case and are not in this table. Cardiac evaluation was performed in Cases 1 to 10 in which only case #9 showed mild cardiac changes. Thoracic imaging was performed in cases 1–4 and 6, other cases did not specify on diagnostic imaging of the thorax.

^aFirst new case described in this article,

^bsecond new case described in this article,

^cthird new case described in this article,

^d(21),

^e(22),

^f(13),

^g(23),

^h(4).

FS — female spayed, MC — male castrated, CK — creatine kinase.

Of 9 reported cases of paresis or paralysis as the presenting complaint in occult primary lung cancer in the cat, 5 had confirmed arterial tumor embolism on histopathology. We describe an additional 3 cases of pulmonary carcinoma in cats with paresis as the presenting complaint. All 3 new cases had a cardiac ultrasound and electrocardiogram performed and had no evidence of structural cardiac disease. Histopathology samples were reviewed by a pathologist (AV) and all new cases were diagnosed with primary pulmonary carcinoma (Table 1).

Case descriptions

Case 1

A 13-year-old, spayed female, domestic shorthaired (DSH) cat was presented to the primary veterinarian with a 2-day history of lethargy and weakness, followed by an acute onset of weight bearing left forelimb lameness, vocalization and open mouth breathing. Abnormalities on physical examination included a cold distal left forelimb with proprioceptive deficits and a reduced flexor reflex. Blood glucose (BG) samples were taken from both left and right cephalic veins, revealing a BG of 14.6 mmol/L in the right forelimb and 6.3 mmol/L in the left forelimb. The cat received hydromorphone (Sandoz, Boucherville, Quebec), 0.05 mg/kg body weight (BW), IM and was referred to our hospital for further evaluation.

Upon presentation, physical examination confirmed a weight-bearing lameness and mild pain on manipulation of the left fore-limb. No pulses were detected in the left forelimb on palpation or by Doppler-assisted extravasal blood pressure measurement. Neurological abnormalities in the left forelimb remained similar to evaluation by the primary veterinarian. Complete blood (cell) count (CBC), biochemistry profile, electrolytes, and blood gas analysis were performed, the results are shown in Table 1. A severe elevation of creatine kinase (CK) supported the suspected diagnosis of left brachial arterial thromboembolism (ATE), causing ischemic damage in the muscles of the affected forelimb.

The cat was hospitalized and supportive care provided. Fentanyl (Sandoz) continuous rate infusion (CRI), 2 to 6 μg/kg BW per hour, was administered for analgesia and clopidogrel (Plavix; Sanofi, Laval, Quebec), 18.75 mg PO, q24h, was also prescribed to prevent further clot formation in this suspected thromboembolic event.

Three-view thoracic radiographs performed the following day revealed the presence of a mass in the left caudal lung field (Figure 1). An ultrasound-guided fine-needle aspirate (FNA) of the mass was performed. Cytology showed sheets of epithelial cells, occasionally forming papillary structures with at least 3-fold anisocytosis and anisokaryosis. A diagnosis of carcinoma was made based upon these results.

Figure 1.

Thoracic radiographs — Case 1. A right lateral view reveals a distinct soft tissue mass (black dotted line) in the dorsal part of the thoracic cavity, just caudodorsal to the heart.

Clopidogrel therapy was discontinued to facilitate surgical intervention 7 d later. The cat was discharged on buprenorphine (Temgesic; Reckitt Benckiser, Slough, Berkshire, UK), 10 μg/kg BW, transmucosally, q8h. Eight days later, the cat was readmitted and the lameness had significantly improved. The following day the cat was anesthetized and a staging thoracic CT scan (Figure 2) was performed. Subsequently, a left lateral intercostal thoracotomy was performed for left caudal lung lobectomy. The lung lobe was submitted for histopathology. A thoracic drain and a pain diffusion catheter (MILA International, Erlanger, Kentucky, USA) were placed upon closure of the thorax. The cat recovered in the ICU and was treated supportively with intravenous fluid therapy, fentanyl (Sandoz) CRI, 1 to 4 μg/kg BW per hour, ketamine (Vetalar; Boehringer Ingelheim Vetmedica, St. Joseph, Misssouri, USA) CRI, 0.1 to 0.5 mg/kg BW per hour, bupivacaine (Sandoz), 1.5 mg/kg BW via the pain diffusion catheter q6h, and meloxicam (Metacam; Boehringer Ingelheim Vetmedica), 0.1 mg/kg BW, IV, q24h. The immediate post-operative period was unremarkable and the cat made significant improvement in both recovering from her thoracotomy as well as her lameness. The cat was discharged 2 d after surgery on tramadol (Sanofi-Aventis, Laval, Quebec), 15 mg PO, q8h for 5 d and clopidogrel (Sanofi), 18.75 mg PO, q24h for 7 d.

Figure 2.

CT images — Case 1. Contrast CT of the thorax reveals a cavitated soft tissue mass (white arrow) in the left dorsal part of the caudal lung lobe encroaching the main stem bronchus.

Fifteen days after surgery, the cat returned for re-evaluation and suture removal. She was anorexic, lethargic, and had reduced interaction with her owner at home. The owner had discontinued all oral medication prior to assessment. The cat showed pallor, mild tachycardia, and weight loss (300 g since discharge). The surgical site was healing without complication.

In an attempt to stimulate appetite, ranitidine (Zantac; GlaxoSmithKline, Missisauga, Ontario), 2 μg/kg BW, PO, q12h for 10 d and mirtazipine (Remeron; Sando), 0.47 mg PO once every 3 d for 3 to 4 treatments, were prescribed. The following day, the cat died at home following an episode of acute onset respiratory distress.

Case 2

An 11-year-old, spayed female, DSH cat was presented to the family veterinarian after a sudden onset of right hind limb paresis and coolness of the limb. Upon examination by the family veterinarian, pulses in the affected limb could not be palpated. Thoracic radiographs were unremarkable. On the suspicion of a unilateral saddle thrombus, the cat was given ketoprofen (Anafen; Merial Canada, Montreal, Quebec), 2 mg/kg BW, SQ, and heparin (Mayne Pharma, Kirkland, Quebec), 1800 IU, SQ. She was referred to an emergency clinic for overnight intravenous fluid therapy and heparin, 200 IU, SQ, q10h, treatment. The following morning, the cat was transferred to our hospital.

Physical examination revealed pain on palpation of the right pelvic limb, with rigid musculature and no femoral pulse on palpation or Doppler examination. A nail on the digit of the affected limb was cut short; however, bleeding did not occur. Arterial thromboembolism (ATE) was suspected and the patient was admitted to the ICU where intravenous low molecular weight heparin (Mayne Pharma), 20I U/kg BW per hour, and fentanyl (Sandoz), CRI, 2 to 6 μg/kg BW per hour, were initiated.

A CBC and serum biochemistry profile were performed (Table 1). Due to platelet clumps, an accurate thrombocyte count could not be performed. High CK supported the suspected diagnosis of ATE. Thoracic radiographs demonstrated a soft tissue opacity within the caudodorsal lung field but an FNA was not performed due to the location. Ultrasound of the affected limb identified blood flow in the proximal right hind limb. Over the following 3 d of hospitalization, the right hind leg became warmer, and a femoral pulse was palpable intermittently. Heparin therapy was tapered off, while clopidogrel therapy was initiated (18.75 mg PO, q24h). A fentanyl patch (Sandoz), 12.5 μg/h, was placed and intravenous administration of fentanyl was discontinued. Five days after initial presentation at the referring emergency clinic, a CT scan of the thorax and right pelvic limb were performed, revealing a soft tissue mass in the accessory lung lobe and a partial thrombus in the right internal iliac artery (Figures 3 and 4).

Figure 3.

CT images of the thorax in Case 2. Contrast CT of the thorax demonstrates a cavitated soft tissue mass (black arrow) obliterating the majority of the accessory lung lobe.

Figure 4.

CT image pelvic region. Case 2 Contrast CT images of the pelvic region demonstrate dilatation of the right iliac artery (white arrow) with a lack of contrast in the arterial lumen, suggestive of an intraluminal mass effect. The black arrow indicates the left iliac artery, which in the contrast phase of this CT study, shows complete filling of the arterial lumen with contrast. A — aorta, b — bladder.

Eighteen days after initial presentation to the referring emergency clinic, the cat was admitted to our hospital for excision of the accessory lung lobe via median sternotomy. A thoracic drain, esophagostomy tube, and a pain diffusion catheter were placed for postoperative management.

The cat recovered in ICU on intravenous fluid therapy, perioperative antibiotics [cefazolin sodium (Mayne Pharma)], 22 mg/kg BW, IV, q8h for 72 h, fentanyl (Sandoz) CRI, 1 to 4 μg/kg BW per hour, ketamine (Boehringer Ingelheim Vetmedica) CRI, 0.1 to 0.5 mg/kg BW per hour, bupivacaine (Sandoz), 1.5 mg/kg BW, via the pain diffusion catheter q6h and meloxicam (Boehringer Ingelheim Vetmedica), 0.1 mg/kg BW, IV, q24h. The thoracic drain was removed 24 h after surgery. On the second day, a fentanyl patch (Sandoz), 12.5 μg/h was placed, IV fentanyl was weaned and clopidogrel (Sanofi), 18.75 mg PO, q24h therapy was initiated. Three days after surgery, oral amoxicillin-clavulanate solution (Synulox; Pfizer Canada, Kirkland, Quebec), 13.75 mg/kg BW, PO, q12h, was administered. On the third day after surgery, the cat had two 1- to 2-minute episodes of dyspnea, marked by open mouth breathing and pale mucous membranes, after which she returned to normal.

The cat was discharged 7 d after surgery on clopidogrel, 18.75 mg PO, q24h, amoxicillin-clavulanate solution (Pfizer Canada), 13.75 mg/kg BW, PO, q12h, and with esophagostomy tube feeding instructions. She was euthanized the following day by the family veterinarian as the owner felt the cat was recovering poorly and had a poor quality of life.

Case 3

A 9-year-old, spayed female, DSH cat was presented to an emergency hospital with an acute onset of respiratory distress and severe right forelimb lameness. On presentation, the right forelimb was cold to the touch distal to the carpus. Pain on palpation of brachial plexus and humerus, as well as neurological deficits were noted in this limb. Radiographs of the affected limb were unremarkable, but thoracic radiographs revealed a right-sided pulmonary mass. The cat was treated with ketoprofen, butorphanol, dexamethasone, aspirin, and cephalexin (doses unknown). Respiratory difficulties resolved; however, inappetence remained and lameness only partially improved.

Ten days later, the cat was referred to our hospital. Physical examination revealed moderate dehydration and a moderate right forelimb lameness. Results of serum biochemistry profile and CBC are shown in Table 1. Thoracic radiographs demonstrated a soft tissue opacity in the right middle lung lobe (Figure 5). Ultrasound of the right hemithorax revealed consolidation and atelectasis of both the right middle and right cranial lung lobes. Three view thoracic radiographs showed a mass in the right middle lung lobe that was most consistent with neoplasia.

Figure 5.

Thoracic radiographs — Case 3. Ventrodorsal view of the thorax of case 3 showing a soft tissue opacity (white arrows), reaching cranial and dorsal to the cardiac silhouette.

A routine right lateral intercostal thoracotomy was performed. The majority of the right middle lung lobe was consolidated and pale, with abnormal tissue extending proximally into the hilus and adhered to the pericardium. Portions of the right cranial and caudal lobes had similar firm and pale areas. Intraoperative cytology through FNA of the right middle lung lobe rendered results suspicious for carcinoma with necrosis and mixed non-septic inflammation; a diagnosis later confirmed by histopathology. The cat was euthanized prior to recovery from anesthesia at the owner’s wish due to the poor prognosis.

Histopathology

Lung tissues were kept in 10% neutral buffered formalin for 24 to 48 h, sectioned, embedded in paraffin, and 5-μm thick sections were stained on glass slides with hematoxylin and eosin (using standard methods). A diagnosis of primary pulmonary adenocarcinoma was made in each of the 3 cases, which are described collectively below.

Within the lungs from each cat there were poorly circumscribed and unencapsulated masses, often multiple, comprised of squamous-to-columnar polygonal cells arranged in variable proportions of solid clusters, tubules, papillae, and occasionally cysts on large quantities of fibrous stroma; satellite nodules and destruction of adjacent normal tissue were common (Figures 6a and d). The cells comprising these masses have well-demarcated cell margins, moderate to large quantities of homogeneous or slightly foamy eosinophilic cytoplasm, round-to-oval centrally- or basally-oriented nuclei, occasional binucleation, between 3-fold and 5-fold anisokaryosis, finely granular-to-fibrillar and often peripheralized chromatin, individual large magenta nucleoli, and between 1 and 4 mitotic figures per 400× field. Within all tumors, there were regions of necrosis and cavitation with accumulated neutrophils, macrophages, and variably mineralized cell debris. Adjacent to all tumors, there was regionally extensive accumulation of foamy macrophages within bronchiolar and alveolar lumina, as well as frequent lymphoid follicles. At rare sites in all affected lungs, there were blood vessels that contained tumor cells that either filled the lumen as a sheet, grew along the endothelium, or infiltrated the tunica media (Figures 6b, c, e, and f)

Figure 6.

Histology images in hematoxylin and eosin (H&E) — Cases 1 to 3. A — Lung, Case 3, 200× magnification. A small artery (SM) in section, with cuboidal polygonal tumor cells (black arrows) forming a sheet that lines the vascular lumen and forms plexiform bridges (white arrow) across the lumen. The adjacent lung is replaced by small cysts and tubules lined by cuboidal polygonal cells on dense fibrous connective tissue. B — Lung, Case 3, 200× magnification. A small artery, with cuboidal polygonal tumor cells forming a sheet that lines the vascular lumen (black arrows). The adjacent lung is replaced by small cysts (C) lined by cuboidal polygonal cells on dense fibrous connective tissue (large arrows), with a lymphoid follicle (LF) on the lower edge. C — Lung, Case 2, 100× magnification. A small artery, with squamous-to-columnar polygonal tumor cells (arrows) lining a fibrin thrombus (F). D — Lung, Case 2, 200× magnification. Squamous-to-columnar polygonal cells forming tubules and papillae on dense fibrous cores, with a LF on the left edge. E — Lung, Case 1, 100× magnification. Cuboidal polygonal cells infiltrating a bronchus (B), expanding the bronchial submucosa, and narrowing the bronchial lumen (arrows). The tumor is forming occasional tubules (T) that are sometimes filled with eosinophilic finely granular debris (Star). F — Lung, Case 1, 200× magnification. A small artery (arrows), with cuboidal polygonal tumor cells (t) forming a sheet that lines the vascular lumen (L).

Discussion

The prognosis for cats with primary pulmonary neoplasia is poor (1,2) with a reported mean survival time (MST) of 115 d following diagnosis (6). In that study, 18 of 21 cats died from meta-static disease and 3 cats were lost to follow-up. Of the 21 cases reported, none were treated with chemotherapy. Combining surgical removal of gross disease with adjuvant chemotherapy may improve survival time (24).

Although rarely described, survival of cats with lameness or paresis as the main presenting sign for occult pulmonary carcinoma is universally poor. Van der Linde-Sipman and van den Ingh (25) reported a median survival time of 4.9 wk for 64 cats presenting with digital metastatic carcinomas, 87.5% of which were metastatic lesions from pulmonary carcinoma. A unique feature of pulmonary carcinoma in cats is the predilection for metastasis to the digits and over 40 cases of so-called pulmonary digit syndrome are reported (26–29). The 12 cats reported here with signs of arterial thromboembolism in occult pulmonary carcinoma had a MST of 18 d after primary presentation (12–14,21–23) (Table 1). It is unknown why the digits are susceptible metastatic sites of pulmonary carcinoma in cats. Hematogenous spread of tumor thrombi that lodge in the digits, with the ability of tumor thrombi to proliferate at these sites is a likely explanation (30–34). Paresis due to large thromboembolism to the arteries of the limbs in cats with pulmonary carcinoma could theoretically be considered a related syndrome, where larger tumor thrombi are released and instead of lodging in the digits, they lodge in the major arteries of the limbs.

There are several reports in humans with pulmonary carcinoma that describe metastasis to the digits. Reports have described both the involvement of the tip of a single finger (35,36) or metastasis to the phalanges (37,38). Libson et al (39) describe 105 cases of primary pulmonary neoplasia in humans that metastasized to the bones of the distal extremities, with a predisposition to the hand over the foot. Cohen (35) describes 133 human cases of subungual metastasis and found that 41% of subungual metastases originated from primary pulmonary neoplasia. Pulmonary neoplasia with metastasis to the muscle and soft tissues of the extremities has also been reported in cats and humans (1,26,40,41).

A report from 1978 (42) describes 4 human cases that had surgery for a primary pulmonary neoplasm that all developed arterial tumor embolism in the proximal extremities perioperatively, confirmed by histopathology. Unfortunately, none of the cats in this report had histopathological evaluation of the affected limbs. There are several reports of arterial tumor-thromboembolism in humans, during the perioperative period when undergoing treatment for pulmonary carcinoma (42,43). There is some similarity in routes of metastasis between cats and humans, as seen in the example of the digital metastasis in pulmonary carcinoma. Extrapolating the tumor embolic events in humans to cats, makes the possibility of pulmonary carcinoma metastasis causing arterial tumor-embolism a consideration.

Hypercoagulability as part of Virchows’s triad is another differential diagnosis for the development of thromboembolism in cancer-bearing animals and humans (44–49). In human medicine there is a major discrepancy between the incidence of venous thromboembolism (VTE), which is a well-described complication in human pulmonary cancer (44–46), and ATE, which is a rare event and is still under investigation (46–48). Kristensen et al (49) found that 50% of dogs with a malignant tumor showed hypercoagulability.

Hypercoagulability studies include assays for prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimers, fibrinogen, activated clotting time (ACT), clotting factors, and platelet count (8,14). A relatively new test that can be considered is thromboelastrography (TEG) (49,50). However, this test is not a standard “bedside” test, and its clinical relevance in cats is being investigated (51,52). Although it is likely that TEG would have been performed if these cases were seen at our hospital today, TEG was not available at the time of case accrual for the cases in this series.

Besides hypercoagulability, there are reports on other clotting disorders found in humans with pulmonary carcinoma. Thrombocytosis has been found to be a negative prognostic factor in human pulmonary neoplasia, but was not associated with the formation of thromboembolism (53).

The clinical outcome of our cases was poor, but seems typical for pulmonary carcinoma with a presenting complaint of paresis or lameness. A median survival time from initial presentation for all reported cases with survival information, including our 3 new cases is 18 d (n = 8; range 0 to 31 d).

In conclusion, we report limb monoparesis as an atypical presentation of a primary pulmonary carcinoma in 3 cats. Neoplasia should be considered in older cats presenting with clinical signs attributed to arterial thromboembolism. In this case series, lameness and paresis were caused by ischemic neuromyopathy due to suspected tumor embolism as a consequence of pulmonary neoplasia. The prognosis in these cases was poor, even with treatment. Surgical intervention may not be the treatment of choice. We theorize that whereas small pulmonary carcinoma emboli lodge in digits and muscle causing lung-digit syndrome metastasis or muscle-effacing metastases, larger tumor emboli may obstruct the larger peripheral arteries with acute and devastating effects. CVJ