Presumptive seeding metastasis of pericardial mesothelioma following repeated pericardiocentesis in a dog

Abstract

A dog with a history of recurrent pericardial effusion that required repeated pericardiocentesis was presented to the surgical service at the Ontario Veterinary College Health Sciences Centre for thoracoscopic pericardiectomy. Physical examination revealed a subcutaneous mass in the right lateral thorax. Cytology of the subcutaneous mass and histopathology of the pericardium were consistent with mesothelioma. This article details the first reported case of pericardial mesothelioma with suspected extra-thoracic metastasis following pericardiocentesis in a dog.

Pericardial effusion is a well-described clinical abnormality with differential diagnoses including but not limited to idiopathic pericardial effusion (IPE), hemangiosarcoma, chemodectoma, or diffuse neoplastic disease such as lymphoma or mesothelioma (1,2). Mesothelioma is a rare neoplastic disease that occurs in small animals, arising from the mesenchymal cells lining coelomic cavities and accounts for < 0.2% of tumors in dogs (3,4). The surfaces that are most often affected include the pericardium, pleura, and peritoneum, although there have been reports of mesothelioma in the scrotum and tunica vaginalis (3,4). This disease is characterized by a diffuse invasion of the coelomic cavities and rarely presents with a distinct mass (1,5,6).

Given the difficulty in obtaining a diagnosis, cases of mesothelioma are typically diagnosed late in the course of the disease (1). Diagnostic workup generally includes cardiac ultrasonography, thoracic radiography, pericardial fluid cytology, and microbial culture. Results for these tests in both idiopathic pericardial effusion (IPE) and mesothelioma are commonly negative (7,8) and, therefore, dogs presenting with pericardial effusions are often diagnosed with IPE (1,7). A postulated difference between mesothelioma and IPE is the speed of clinical course, with mesothelioma having a faster recurrence of pericardial effusion, whereas IPE is more slowly progressive (7). After recurrent pericardial effusions and subsequent therapeutic pericardiocentesis, affected dogs often undergo a palliative pericardiectomy. At this stage, a diagnosis of mesothelioma may be made following histopathological examination of pericardial and pleural tissue samples (7–9). Histopathology of biopsied tissues is considered necessary to achieve a diagnosis of mesothelioma, as it can be challenging on cytology to differentiate between the similar appearance of hyperplastic and neoplastic mesothelial cells (1,3,10). Histopathological diagnosis requires, at a minimum, a microscopic accumulation, or “piling” of mesothelial cells and invasion of the underlying collagenous connective tissue (11). It is unclear whether mesothelioma develops secondary to chronic inflammation associated with IPE or is challenging to diagnose without tissue biopsy (7). Regardless, in cases with negative initial diagnostics and a presumptive diagnosis of IPE or mesothelioma the risk of seeding metastasis following repeated pericardiocentesis events is rarely considered.

Definitive treatment for mesothelioma has not been defined in the dog due to the low incidence of disease (12). Pericardiectomy via open or minimally invasive techniques is the current standard of care to palliate clinical signs of pericardial effusion and eliminate the risk of cardiac tamponade (13). During the surgical procedure, excised pericardial tissue, along with pleural and lymph node biopsies, can be used to provide a definitive diagnosis by histopathological examination (13). Port-site metastasis following diagnostic thoracoscopy has been reported in 1 dog with mesothelioma and is a reported complication in the human literature (14,15). To the authors’ knowledge, there have been no reports of metastatic seeding following pericardiocentesis in cases of canine mesothelioma.

This case report describes a presumptive extra-thoracic metastatic spread of mesothelioma that seeded following repeated pericardiocentesis, which should be considered in cases with recurrent pericardial effusions.

Case description

An 8-year-old, spayed female, mixed breed dog was presented to the surgical service at the Ontario Veterinary College Health Sciences Centre (OVCHSC) for further evaluation of recurrent pericardial effusion diagnosed 10 mo previously. Within this time, 3 events of pericardial effusion requiring pericardiocentesis were recorded following clinical signs of weakness, lethargy, hyporexia, and tachypnea. A diagnostic work-up including echocardiogram, abdominal ultrasound, and pericardial fluid cytology was performed at initial presentation by the referring veterinarian. There were no structural abnormalities noted during echocardiography, abdominal ultrasound did not reveal any abnormal findings, and pericardial fluid was cytologically unremarkable. Two months prior to referral to the OVCHSC, after the third pericardiocentesis event, an echocardiogram and thoracic radiographs were repeated and did not reveal any abnormalities. The exact location of catheter placement for each pericardiocentesis event was unknown. Thoracoscopic pericardiectomy was recommended by the referring veterinarian for palliation of clinical signs for presumptive IPE.

At the time of presentation to the OVCHSC, the dog was bright, alert, and responsive, with normal vital parameters and unremarkable cardiothoracic auscultation. The owner reported occasional vocalization associated with perceived pain when manipulating the forelimbs for the 4 wk prior to presentation; however, orthopedic examination was unremarkable. A newly palpable subcutaneous mass, measuring 3 cm × 3 cm in diameter was present over the right mid-thorax at the region of the 5th costochondral junction that elicited a pain response upon deep palpation. No other abnormalities were observed on physical examination. Initial diagnostic testing included a complete blood (cell) count (CBC), serum biochemistry, thoracic and cervical radiographs, abdominal ultrasound, and fine-needle aspiration of the subcutaneous mass. The CBC and serum biochemistry revealed a mild thrombocytosis [464 × 10⁹ platelets/L; reference interval (RI): 117 to 418 × 10⁹ platelets/L] and mild hypercholesterolemia (10.72 mmol/L; RI: 3.6 to 10.2 mmol/L), considered consistent with reactive thrombocytosis and post-prandial sampling, respectively. Three-view thoracic radiographs revealed mild generalized cardiomegaly, considered to relate either to mild pericardial effusion, or normal diastolic phase of the cardiac cycle. Cervical radiographs were unremarkable. Abdominal ultrasound revealed isoechoic and hypoechoic hepatic nodules consistent with nodular hyperplasia or extra-medullary hematopoiesis. Cytological examination of fine-needle aspirates from the right cranial thoracic mass revealed sheets of epithelial cells with prominent intracellular bridging and lobule formation (Figure 1). The cells were round to polygonal with a moderate nuclear to cytoplasmic ratio and amphophilic granular cytoplasm with occasional perinuclear vacuolation and pink extracellular material resembling a fringe around the cell. The cells had an oval to amoeboid nucleus with finely stippled chromatin and multiple variably distinct nucleoli. Marked anisocytosis, anisokaryosis, occasional multinucleation, rare mitotic figures, and emperipolesis were observed. Admixed were abundant non-degenerate neutrophils and moderate numbers of macrophages with frequent erythrocytophagy. Given the location, the interpretation was carcinoma and mixed (suppurative and macrophagic) inflammation.

Figure 1.

Cytology by fine-needle aspiration of the right lateral thoracic mass at 100× magnification (Wright’s stain).

The results were discussed with the owner and thoracoscopic pericardiectomy was elected the following day to eliminate the risk of cardiac tamponade. Surgical treatment of the subcutaneous thoracic mass was to be performed at a later date.

An uncomplicated thoracoscopic pericardiectomy using a transdiaphragmatic approach was performed as previously described (16). The pericardium was markedly thickened and biopsy samples were submitted for histopathological evaluation. Five-millimeter laparoscopic cup biopsy forceps (Karl Storz, Charlton, Massachusetts, USA) were used to obtain multiple pleural biopsies for histopathology. A 16-gauge Mila thoracic drain (Mila International, Florence, Kentucky, USA) was placed using endoscopic guidance. Instruments and ports were removed, and incisions were closed routinely. The thoracic cavity was evacuated until negative pressure was obtained. The patient recovered uneventfully from the procedure. Post-operative analgesia was provided with hydromorphone (Sandoz Canada, Boucherville, Quebec) boluses, 0.025 to 0.05 mg/kg body weight (BW), q4 to 6 h, as required, and meloxicam (Boehringer Ingelheim Canada, Burlington, Ontario) 0.1 mg/kg BW, PO, q24h. The thoracic drain was removed 36 h after surgery due to minimal fluid/air evacuation. The patient was discharged to the care of her owners 48 h after surgery.

Histopathology of the pericardial and pleural tissues revealed packets of polygonal neoplastic mesothelial cells often occluding or distending small to intermediate caliber vessels in underlying connective tissues (Figure 2). The cells had abundant, lightly vacuolated eosinophilic cytoplasm, distinct cell borders and 1 to 2 round central nuclei with finely stippled chromatin and 1 to 5 nucleoli. There was up to 4-fold anisocytosis and anisokaryosis, and occasional mitotic figures. These findings were consistent with malignant mesothelioma and vascular invasion. With the diagnosis of thoracic mesothelioma, and given the history and cellular phenotype, a seeded mesothelioma and not carcinoma was considered the top differential diagnosis for the thoracic wall mass.

Figure 2.

Histopathology of the pericardium at 20× magnification depicting vascular invasion of malignant mesothelioma (Hematoxylin & Eosin stain).

The dog recovered without complication, but continued to show progressive non-specific pain described by the owners as difficulty moving up and down stairs despite additional analgesia. The owners elected euthanasia 6 wk after surgery due to the pain related to the presumptive seeding metastasis of the mesothelioma in the right thoracic wall. Necropsy was not permitted.

Discussion

A case of pericardial mesothelioma with presumptive metastatic seeding to the right lateral thorax following pericardiocentesis is described in the dog of this report. This is a known complication in human medicine for pleural mesothelioma, with an incidence of 4% when an image-guided needle core biopsy is taken, and 22% with surgical biopsies and has also been reported following thoracocentesis in 1 case of pleural mesothelioma (14,17). This patient developed an erythematous swelling within her chest wall 2 wk following thoracocentesis. Fine-needle aspiration of this swelling was consistent with cells of mesothelioma lineage, confirmed with immunohistochemistry (17). In veterinary medicine, there are no reports of seeding mesothelioma to the body wall during pericardiocentesis, which is an uncommon consideration when performing therapeutic and diagnostic pericardio- or thoraco-centesis.

A definitive diagnosis of the thoracic wall mass was not made as surgical removal was not performed, and necropsy was not permitted by the owner of the dog in this report. As previously discussed, diagnosis of mesothelioma requires tissue architecture to evaluate for features including mass formation and vascular invasion, as differentiating reactive mesothelial cells from mesothelioma is otherwise impossible (1,3,10). The cytological features of cells with distinct cytoplasmic margins, perinuclear vacuolation, and a fringed cytoplasm, as well as marked anisocytosis, multinucleation, multiple distinct nucleoli, and mitotic figures are supportive of mesothelioma and were found in the dog of this report (18). This, in combination with a confirmed diagnosis of pericardial mesothelioma and the development of a mass in the location of repeated pericardiocentesis in the right lateral thoracic wall, is highly suspicious for a seeded metastasis. It is believed the metastasis occurred through transplantation of tumor cells from the pericardium or neoplastic effusion by the catheter used to perform pericardiocentesis. Although the precise insertion point of each pericardiocentesis event is unknown, the location of the subcutaneous mass is compatible with well-described pericardiocentesis recommendations. This site is the right thorax, at the level of the costochondral junction in the 4th or 5th intercostal space (19).

Portal site metastasis following a thoracoscopic pericardiectomy with pleural and mediastinal biopsies has been reported in a single case of invasive canine mesothelioma (15). Contamination of intercostal thoracoscopic ports and surgical instruments resulting in seeding of tumor cells against disrupted serosal surfaces was a proposed mechanism of tumor metastasis (15). Furthermore, it has been demonstrated that traumatized mesothelial lining, like that of a port site, allows for easier tumor cell implantation resulting in the metastatic spread of disease compared to intact serosal surfaces (15,20,21). It is theorized that a similar mechanism occurred in this case, in which repeated pericardiocentesis allowed transposition of neoplastic cells from a damaged serosal lining to the external thoracic wall. Transplantation of neoplastic cells along needle tracts is a known complication, albeit rare, seen with percutaneous sampling of transitional cell carcinomas of the lower urinary system (bladder, urethra, and prostate) (22).

Mesothelioma generally has a grave prognosis with median survival time following pericardiectomy alone being 60 d in 1 case series of 8 dogs (1). However, palliative pericardiectomy followed by chemotherapy (intracavitary followed by systemic, due to the diffuse nature of the disease) has shown some efficacy in a small number of cases (5,12). One case that had a disease-free interval longer than 27 mo received intracavitary cisplatin followed immediately by intravenous doxorubicin and intravenous cisplatin after 45 d (5). Two other dogs were given intracavitary carboplatin followed by daily piroxicam PO: 1 of the dogs survived for 8 mo and the other survived beyond 3 y (12). Both case reports had histopathological diagnosis of mesothelioma and show a potential area for improvement in the management of these cases.

Pericardial effusion secondary to mesothelioma typically goes undiagnosed until multiple pericardiocenteses are performed prompting pericardiectomy. The dog in this report developed an extrathoracic mass that was consistent with metastasis that seeded following pericardiocentesis. To the authors’ knowledge, this is the first report of extrathoracic metastasis of pericardial mesothelioma following repeated pericardiocentesis in the dog. Previous reports described spread across serosal surfaces, but not extra-cavitary tissue layers. The potential for tumor seeding should be a consideration in cases of recurrent pericardial effusions. CVJ