Malignant peripheral nerve sheath tumor in the kidney of a dog

Abstract

A 12-year-old castrated male poodle presented with vomiting and diarrhea. Ultrasonography and computed tomography revealed a protruding mass at the caudal pole of the left kidney. Grossly, the poorly circumscribed abnormal mass was 1.6 × 1.8 × 1.9 cm in size and had multifocal dark-red foci. Microscopically, it was composed of densely or loosely packed variable-sized short spindle or ovoid cells. These neoplastic cells showed high pleomorphism, mitotic figures, and invasive tendency to the adjacent tissue. Immunohistochemically, the neoplastic spindle cells expressed vimentin, S100, neuron-specific enolase, nerve growth factor receptor, and laminin. Therefore, the mass was diagnosed as a malignant peripheral nerve sheath tumor (MPNST). To our knowledge, this is the first report of primary renal MPNST in a dog.

Primary renal tumors are uncommonly diagnosed in dogs [6]. Tumors can arise from the renal epithelium (renal tubule or transitional epithelium of the renal pelvis), renal mesenchyme, or embryonal tissue of mixed origin [6]. Mesenchymal tumors are even rarer. The most common mesenchymal tumors in canine kidneys are undifferentiated sarcomas, fibromas, fibrosarcomas, hemangiomas, and hemangiosarcomas [11]. Primary renal tumors are usually unilateral [11]. The affected animals are typically middle-aged or older at diagnosis, with a mean age of 8.2 years for sarcomas [6]. Abnormalities in serum chemistry values are minor and nonspecific. The presenting symptoms, clinical signs, and clinicopathological findings are nonspecific [6].

Peripheral nerve tumors may originate exclusively within the nerve sheaths (peripheral nerve sheath tumors, PNST) from cells with Schwann cell characteristics (Schwann or perineurial cells), as in schwannomas and perineuriomas, or from mixtures of endoneurial, epineurial, or stromal fibroblasts in neurofibromas and malignant peripheral nerve sheath tumors (MPNST) [7]. A MPNST is relatively rare and excludes tumors originating from tissues outside the epineurium [19]. Although most MPNSTs occur in the paraspinal peripheral and spinal nerves, they may also occur in other uncommon sites such as the liver [15], spleen [3], adrenal gland [9], urinary bladder [10], diaphragm [16], and tongue [2]. Herein, we describe the first case of primary renal MPNST in a dog.

In July 2020, a 12-year-old castrated male poodle dog presented to a local animal hospital with a history of vomiting and diarrhea for 2–3 days. The hematological and biochemical examinations revealed mild elevation of blood urea nitrogen (35.2 mg/dL, reference range: 9.2–29.2 mg/dL). On ultrasonographic examination, a renal mass was incidentally found in the left kidney characterized by a heterogeneous lesion, including an anechoic cyst, at the caudal pole. Computed tomography revealed a large, abnormal, heterogeneous mass at the caudal pole of the left kidney. Differential diagnoses at that time included chronic renopathy due to senile changes, primary neoplasia, and edematous changes. At nephrectomy, the left kidney was dark reddish and enlarged compared with the normal kidney. An approximately 1.6 × 1.8 × 1.9 cm protruding mass was located at the caudal pole, and this mass was not covered with a renal capsule (Fig. 1A). There was no evidence of the tumor being attached to the surrounding vertebra on computed tomography or during the surgical procedure. Moreover, the tumor was not located inside the renal fascia. The remaining organs were unremarkable on clinical images and surgical procedures.

Fig. 1.

Gross findings. (A) The left kidney is dark reddish in color. Abnormal protruding mass uncovered with renal capsule in the caudal pole (circle). (B) The cut surface of the formalin-fixed left kidney. The poorly demarcated abnormal mass is located in the caudal renal parenchyma.

After surgery, the entire left kidney was immediately fixed in 10% neutral-buffered formalin. In the cut section of the formalin-fixed kidney, the mass was raised, solid, and poorly demarcated from the adjacent normal renal parenchyma, with multifocal dark-red foci (Fig. 1B). The tissue samples were processed routinely and embedded in paraffin. Sections (3–4 μm) were stained with hematoxylin and eosin.

Histopathologically, the abnormal mass occupied the renal parenchyma and was neither circumscribed nor encapsulated with the connective tissue. This renal mass was not covered with a renal capsule and had multifocal hemorrhagic foci and necrosis. Most of the abnormal mass was composed of densely or loosely packed variable-sized neoplastic spindle cells or ovoid cells arranged in bundles and short interlacing fascicles (Fig. 2A). These neoplastic cells had eosinophilic cytoplasm and concentric or eccentric nuclei with oval or elongated patterns. The neoplastic cells were pleomorphic (Fig. 2B) and showed strong invasion to the adjacent normal tissue (Fig. 2C). Mitotic figures counted in 10 high-power fields (2.37 mm²) (diameter of the field of view=0.55 mm; 40 objective and 10× ocular field number 22 mm; Olympus BX43 microscope) were 30.

Fig. 2.

Histopathologic findings. (A) Neoplastic spindle cells are arranged in short interlacing fascicle. HE. Bar, 100 µm. (B) Neoplastic spindle cells are pleomorphic and show high mitotic figures (arrows). HE. Bar, 20 µm. (C) Neoplastic cells show strong invasion to the adjacent renal tissues. HE. Bar, 100 µm. (D) The cytoplasm of neoplastic cells is stained red. Masson’s trichrome. Bar, 50 µm.

To determine the origin of the neoplastic cells, we performed Masson’s trichrome staining, Bielschowsky’s silver staining and immunohistochemistry (IHC) using several neurological, neuroendocrine, smooth muscle, and epithelial markers on serial sections of representative tumor tissues. The primary antibodies used for IHC are summarized in Table 1. Normal tissues of the dog were used as positive or negative controls.

Table 1. Information of primary antibodies to diagnose malignant peripheral nerve sheath tumor in this case.

Primary antibody (clone)	Clonality	Manufacturer	Antigen retrieval	Incubation (min)	Dilution
Vimentin (V9)	Monoclonal mouse	Dako, Glostrup, Denmark	Citrate, heating at 98°C in a water bath	60	1:100
S100	Polyclonal rabbit	Dako	Citrate, heating at 98°C in a water bath	60	1:400
Neuron specific enolase (BBS/NC/VI-H14)	Monoclonal mouse	Dako	EDTA, heating at 98°C in a water bath	60	1:200
Nerve growth factor receptor (ME20.4)	Monoclonal mouse	Santa Cruz, CA, USA	EDTA, heating at 98°C in a water bath	60	1:100
Laminin	Polyclonal rabbit	Dako	Proteinase K at 37°C drying oven	30	1:50
Glial fibrillary acidic protein	Polyclonal rabbit	Dako	Proteinase K at 37°C drying oven	30	1:500
PGP 9.5	Polyclonal rabbit	Dako	EDTA, heating at 98°C in a water bath	60	1:100
SOX-10 (EP268)	Monoclonal rabbit	Abcam, Cambridge, UK	Citrate, heating at 98°C in a water bath	60	1:200
Claudin-1	Polyclonal rabbit	Abcam	EDTA, heating at 98°C in a water bath	60	1:500
Desmin (D33)	Monoclonal mouse	Dako	EDTA, heating at 98°C in a water bath	60	1:100
Smooth muscle actin (1A4)	Monoclonal mouse	Dako	EDTA, heating at 98°C in a water bath	60	1:100
Synaptophysin (DAK-SYNAP)	Monoclonal mouse	Dako	EDTA, heating at 98°C in a water bath	60	1:50
Cytokeratin (AE1/AE3)	Monoclonal mouse	Dako	Citrate, heating at 98°C in a water bath	60	1:50

In Masson’s trichrome staining, the cytoplasm of neoplastic cells stained red (Fig. 2D), indicating that the cells were not producing collagen fibers. There were few collgen fibers in the tumor stroma. Bielschowsky’s staining revealed silver impregnated thin fibers in neoplastic cells (Supplementary Fig. 1). On immunohistochemical examination, neoplastic cells were diffusely positive for vimentin (Fig. 3A), S100 (Fig. 3B), neuron specific enolase (NSE) (Fig. 3C), nerve growth factor receptor (NGFR) (Fig. 3D), and laminin (Fig. 3E). In contrast, these cells were negative for glial fibrillary acidic protein (GFAP), protein gene product 9.5 (PGP 9.5), sox-10, claudin-1, desmin, smooth muscle actin (SMA), synaptophysin, and cytokeratin.

Fig. 3.

Immunohistochemical findings. Neoplastic cells show positive reactions for (A) vimentin, (B) S100, (C) neuron specific enolase, (D) nerve growth factor receptor, (E) laminin. Immunohistochemistry. Bars, 20 µm.

Based on histopathological and immunohistochemical features, the renal mass was diagnosed as a neoplasm of peripheral nerve sheath origin. The tumor showed pleomorphic histological characteristics, with a high mitotic index, necrosis, and invasion to the adjacent renal tissue. These histopathologic features support the malignant nature of this lesion. The kidney is an unusual primary location for MPNST; therefore, the possibility of metastasis of malignant tumor cells from other primary sites should be ruled out. However, computed tomography did not reveal the presence of neoplastic tissue in any other organs examined. Medical records for the dog did not mention a previous surgical biopsy. Therefore, the final diagnosis of the renal mass in this dog was primary renal MPNST.

After histopathological examination, the differential diagnosis of other soft tissue sarcomas, such as fibrosarcoma and leiomyosarcoma, can be successfully ruled out using Masson’s trichrome staining and IHC. Various immunohistochemical markers have been used to diagnose PNSTs in several studies. In the present case, the neoplastic cells were positive for vimentin, S100, NSE, NGFR, and laminin, similar to those reported previously. Vimentin and S100 are the most commonly used primary antibodies when diagnosing MPNST in solid organs [2, 3, 9, 10, 15, 16]. In canine MPNST of the liver [15] and tongue [2], NSE was positive, whereas NGFR was positive in canine MPNST of the adrenal gland [9]. Vimentin is used primarily to distinguish between epithelial and mesenchymal tumors [18]. In contrast, S100 is known to have a broad distribution in various tissues, including glial cells, neurons, chondrocytes, Schwann cells, melanocytes, fixed phagocytic or antigen-presenting cells, Langerhans cells, myoepithelial cells, notochord, and various epithelium but used mostly to distinguish schwannomas, neurofibromas, and fibrosarcomas in veterinary oncology [18, 22]. NSE is found predominantly in brain and neuroendocrine cells [18]. NGFR expression may influence tumorigenic potential, especially in those tumors of neural or neural crest origin. One study showed a high frequency of immunoreactivity by NGFR in both benign and malignant PNST [17]. Laminin is a routinely available antibody when making differential diagnosis of PNST [7]. Laminin shows immunoreactivity to the basal lamina in both normal and neoplastic Schwann cells [7]. Based on the results of the IHC analysis in the present case, the tumor can be diagnosed as a PNST.

During various tests to find the cause of vomiting and diarrhea that persisted for 2–3 days, the renal mass was incidentally found on ultrasound examination. The cause of vomiting and diarrhea is believed to be diet-related based on the patient’s history, and is unlikely related to the renal mass. Therapeutic options for MPNST include surgical resection, radiotherapy, and chemotherapy [21]. Generally canine MPNSTs are considered to have poor prognosis and a high recurrence rate after surgical resection [5, 13]. In this case, the dog did not receive any specific treatment for the renal tumor except nephrectomy. The dog had no evident disease recurrence at 1-year follow-up; there was no additional follow-up as the owner no longer visits the hospital.

In human medicine, MPNSTs are extremely rare, with an incidence of 1 per 1,000,000 and comprising 3–10% of soft tissue sarcomas of ectomesenchymal origin [4, 8]. There are few reports on MPNSTs of the kidneys in humans. The current treatment for MPNSTs involves surgical excision and adjuvant chemotherapy [23]. These tumors generally have a poor prognosis despite multimodal therapies, including aggressive surgical resection and adjuvant radiotherapy [1]. Five-year survival rates of 47–66% have been reported after complete resection of localized disease [14]. However, even with aggressive therapy, tumor recurrence has been observed in 50% of patients [12].

In veterinary medicine, primary renal MPNST has only been reported in a cat [20]. To the best of our knowledge, this is the first report of primary renal MPNST in a dog, suggesting that this tumor should be included as a differential diagnosis for renal spindle cell tumors.

CONFLICT OF INTEREST

The authors declared no conflicts of interest in relation to the research, authorship, and/or publication of this paper.