Concomitant Malignant Pulmonary Peripheral Nerve Sheath Tumour ...

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Summary. Peripheral nerve sheath tumours (PNSTs) are neoplastic growths derived from Schwann cells, perineural cells or both. Malignant PNSTs (MPNSTs) ...
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Author's Personal Copy J. Comp. Path. 2017, Vol. 157, 46e50

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NEOPLASTIC DISEASE

Concomitant Malignant Pulmonary Peripheral Nerve Sheath Tumour and Benign Cutaneous Peripheral Nerve Sheath Tumour in a Dog E. O. Silva*,†, P. F. I. Goiozo*, L. G. Pereira*, S. A. Headley† and A. F. R. L. Bracarense† * Laboratory of Animal Pathology, Universidade do Oeste Paulista, Rodovia Raposo Tavares KM 572, Presidente Prudente-S~ao Paulo and † Laboratory of Animal Pathology, Department of Veterinary Preventive Medicine, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid PR 445, Londrina, Parana, Brazil

Summary Peripheral nerve sheath tumours (PNSTs) are neoplastic growths derived from Schwann cells, perineural cells or both. Malignant PNSTs (MPNSTs) are uncommon in domestic animals. This report describes the concomitant occurrence of PNSTs in a 10-year-old female cocker spaniel with a clinical history of respiratory impairment. Grossly, there was a large infiltrative mass in the caudal lobe of the right lung; smaller nodules were observed in the other lobes of the right lung. Furthermore, a small encapsulated cutaneous nodule was observed on the left hindlimb. Histopathology of the pulmonary tumours revealed the proliferation of pleomorphic spindle-shaped cells with moderate mitotic index arranged in interwoven bundles and concentric Antoni A and Antoni B patterns; invasion of the adjacent pulmonary tissue was observed. The cutaneous nodule consisted of neoplastic mesenchymal cells in interwoven bundles with concentric whorls, but without the marked anisokaryosis, binucleation and infiltrative growth seen in the pulmonary tumour. Immunohistochemistry revealed that both tumours were immunoreactive for vimentin, glial fibrillary acidic protein and S100 protein, but were negative for factor VIII. These findings are indicative of a MPNST in the lung with a concomitant benign PNST in the limb. This case represents the first report of a primary MPNST in the lung of a dog. This neoplastic growth should be included in the differential diagnosis of primary malignant pulmonary tumours of dogs. Ó 2017 Elsevier Ltd. All rights reserved. Keywords: dog; immunohistochemistry; lung; malignant peripheral nerve sheath tumour

Peripheral nerve sheath tumours (PNSTs) are a heterogeneous group of neoplasms of the peripheral nerves that originate from Schwann cells, perineural cells or both (Gross et al., 2005; Suzuki et al., 2014). In veterinary medicine, this group of neoplasms is often referred to as PNSTs because there is no distinct histopathological subclassification and it is difficult to perform ancillary tests to determine the specific cell of origin; moreover, there are no prognostic differences between subtypes of PNSTs Correspondence to: E. O. Silva (e-mail: [email protected]). 0021-9975/$ - see front matter http://dx.doi.org/10.1016/j.jcpa.2017.05.002

(Koestner and Higgins, 2002; Gross et al., 2005). Although primary PNSTs are uncommon in domestic animals, there are reports in dogs, cats, pigs, sheep, horses, goats and cattle (Ramires et al., 2007; Sugiyama et al., 2008; Boonsriroj et al., 2014; Grossi et al., 2014; Kegler et al., 2014; Resende et al., 2015). Older dogs are more predisposed to develop PNSTs and there is no apparent sex predisposition (Koestner and Higgins, 2002). PNSTs described in domestic animals are frequently located unilaterally and originate from spinal nerves or the brachial plexus. Less Ó 2017 Elsevier Ltd. All rights reserved.

Author's Personal Copy Peripheral Nerve Sheath Tumours in a Dog

common sites of origin are the lumbosacral plexus, and subcutaneously at sites of distal peripheral nerves, on the trunk, distal legs or internal viscera (Brehm et al., 1995; Koestner and Higgins, 2002; Gross et al., 2005; Suzuki et al., 2014). In dogs, primary PNSTs have been described in the central nervous system (Pumarola et al., 1996), vagus nerve (Yap and Pratschke, 2016), myocardium (Wohlsein et al., 2005; Thomason et al., 2015), testis (Rothwell et al., 1986), liver (Park et al., 2011), ocular region (Duke et al., 2015; Kang et al., 2017), spleen (Bergmann et al., 2009; Suzuki et al., 2014), gingiva, nasal cavity (Suzuki et al., 2014), tongue (Baratt et al., 2015) and the diaphragm (Patterson et al., 2008). To our knowledge, there are no reports of a primary pulmonary PNST in the dog. PNSTs are usually nodular or lobulated masses that can range from soft to firm in consistency, white to grey in colour, and usually have a shiny and smooth surface (Koestner and Higgins, 2002; Gross et al., 2005). Benign PNTs are well-circumscribed, encapsulated nodules or masses that are microscopically composed predominantly of small spindle-shaped cells embedded in a delicate collagenous stroma (Koestner and Higgins, 2002). The tumour cells are arranged as interwoven bundles, streams or concentric whorls (Antoni type A pattern) and can have areas of reduced cellular density, where the cells have small dark nuclei and are embedded in a loose fibrous stroma (Antoni type B pattern). The neoplastic cells may also show palisading or herringbone patterns (Gross et al., 2005) and they have mild cellular pleomorphism and rare mitotic figures (Koestner and Higgins, 2002). Malignant PNSTs (MPNSTs) are rare in man (Farid et al., 2014) and domestic animals (Gross et al., 2005; Suzuki et al., 2014). Grossly, MPNSTs differ from benign PNSTs by being unencapsulated. Microscopically, MPNSTs consist of pleomorphic cellular populations with increased mitotic activity, intratumoural necrosis, haemosiderin deposition, infiltrative growth into surrounding tissue and metastasis to distant organs (Stoica et al., 2001; Gross et al., 2005). Moreover, MPNSTs may show areas of glandular, cartilaginous or osteoid differentiation (Chijiwa et al., 2004; Gross et al., 2005). This growth pattern explains the higher recurrence after surgical excision compared with benign PNSTs (Gross et al., 2005). A definitive diagnosis of PNST is obtained by histopathological evaluation, while immunohistochemistry (IHC) is required to distinguish these tumours from other sarcomas. PNSTs express S100 protein, glial fibrillary acidic protein (GFAP), vimentin, collagen IV and laminin (Koestner and Higgins,

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2002; Suzuki et al., 2014). This report describes the gross, histopathological and immunohistochemical findings in a primary pulmonary MPNST with a simultaneous benign cutaneous PNST in a dog. A 10-year-old female cocker spaniel dog was presented to the Veterinary Teaching Hospital, Universidade do Oeste Paulista, S~ao Paulo, Brazil, with a history of difficulty breathing. Clinical examination revealed tachypnoea and tachycardia. Thoracic radiography demonstrated a mass in the right lung with compression of the left lung and the heart. There was no history of previous tumours. The clinical status of the animal worsened, cardiorespiratory arrest was diagnosed and the dog died on the same day despite supportive therapy. A routine necropsy examination performed soon after death revealed a large, 13 cm diameter, multilobulated soft white mass with firm areas, in the right caudal pulmonary lobe (Fig. 1); similar but smaller (1e8 cm diameter) nodules were observed in other lobes of the same lung. The left lung was congested, without the presence of masses. In addition, a 0.5 cm diameter cutaneous nodule was observed on the left hindlimb. Other significant gross findings included mild left ventricular concentric myocardial hypertrophy. Lymph node enlargement was not observed. Samples of the lungs and the pulmonary mass, as well as the cutaneous nodule, were collected, fixed in 10% neutral buffered formalin and processed routinely for embedding in paraffin wax. Sections were stained by haematoxylin and eosin and subjected to IHC using primary antisera specific for vimentin (V9 antibody at 1 in 100 dilution; Invitrogen, S~ao Paulo, Brazil), GFAP (polyclonal antibody at 1 in 100 dilution; Zymed, San Francisco, California, USA), S100 protein (polyclonal antibody at 1 in 100 dilution; Zymed) and factor VIII

Fig. 1. White multilobular mass in the caudal right lung.

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(polyclonal antibody at 1 in 100 dilution; Dako, S~ao Paulo, Brazil). The protocols used and the positive and negative controls were according to the manufacturer’s recommendations. Histopathological evaluation of tissue samples from the mass in the right lung revealed spindle-shaped cells arranged in interwoven bundles and concentric whorls with occasional herringbone and palisading patterns (Fig. 2). The tumour was densely cellular and embedded in a background of moderate collagenous stroma (Antoni A pattern); in some areas, there were foci of low cellularity and a myxoid stroma (Antoni B pattern). The neoplastic cells showed marked anisokaryosis, conspicuous nucleoli, binucleation, an average of 1.8 mitotic figures per high-power field (HPF; 400) and infiltrative growth into the surrounding pulmonary parenchyma. In addition, there were intratumoral accumulations of haemosiderinladen macrophages, areas of necrosis and aggregates of lymphoplasmacytic cells. Furthermore, there was moderate oedema and vascular thrombosis of the surrounding pulmonary tissue. Oedema and marked vascular congestion were observed within the samples from the left lung, but there was no evidence of neoplastic growth. The cutaneous nodule was a well-demarcated, encapsulated tumour within the deep dermis that comprised of cells arranged as interwoven bundles and concentric whorls, embedded in a collagenous stroma; the neoplastic cells showed mild to moderate anisokaryosis, occasional conspicuous nucleoli and an average of 0.5 mitotic figures per HPF. By IHC, most neoplastic cells of the pulmonary and cutaneous tumours showed strong positivity to vimentin, GFAP and S100 protein (Figs. 3 and 4), but did

Fig. 2. Section from the pulmonary mass showing dense proliferation of neoplastic cells arranged in interwoven bundles and concentric whorls (Antoni A pattern). HE.

Fig. 3. Section from the pulmonary mass showing strong expression of GFAP. IHC.

not express factor VIII. A diagnosis of concomitant pulmonary and cutaneous PNSTs was made due to the anatomical location of the tumours and the histopathological and immunohistochemical features of each lesion. Neuronal and nerve cell tumours arise most frequently from the sympathetic and paraganglionic components of the autonomic nervous system (LeCouteur and Withrow, 2007). In dogs, MPNSTs are rare tumours that occur primarily in the nerve plexuses and spinal nerves (Koestner and Higgins, 2002; Suzuki et al., 2014). There are few reports (Wohlsein et al., 2005; Bergmann et al., 2009; Park et al., 2011; Duke et al., 2015) of primary MPNSTs in the organs of dogs, while descriptions of primary pulmonary MPNSTs in dogs were not found. Moreover, descriptions of pulmonary MPNSTs are rare in veterinary medicine, with only one report in

Fig. 4. Section from the pulmonary mass showing strong expression of S100. IHC.

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the lungs of a pig (Resende et al., 2015). In human pathology, pulmonary MPNSTs are also rare (Roviaro et al., 1983; McCluggage and Bharucha, 1995) and have been associated with neurofibromatosis type 1 (NF1), primarily in young persons (Boland et al., 2015). In animals, neurofibromatosis has been observed in cattle and dogs and is characterized by multiple neural tumours involving nerves, viscera and the skin (Goedegebuure, 1975; Ginn et al., 2007). The diagnosis of MPNST in the present case was based on the gross presentation and the histopathological and immunohistochemical features of the lung tumour (Koestner and Higgins, 2002; Chijiwa et al., 2004; Gross et al., 2005; Suzuki et al., 2014). There was gross evidence of pulmonary dissemination of the tumour. In addition, the histopathological features of the tumour, including the cellular pattern, cellular pleomorphism and mitotic activity, with associated intratumoural necrosis, favoured the diagnosis of a malignant lesion. Immunoreactivity for vimentin, GFAP and S100 protein supported the diagnosis of MPNST; similar features are described in cases of MPNST in man (Farid et al., 2014; Inci et al., 2014; Boland et al., 2015) and other domestic animals (Chijiwa et al., 2004; Suzuki et al., 2014; Resende et al., 2015). However, histopathological features described in other cases of MPNSTs (Pumarola et al., 1996; Patnaik et al., 2002; Chijiwa et al., 2004), such as epithelioid-like tumour cells, and glandular, cartilaginous or osseous differentiation, were not observed in this lesion. Moreover, the formation of Verocacy bodies (a double row of palisading tumour cells) described in human pathology (Roviaro et al., 1983; Inci et al., 2014) is rarely observed in animals with PNSTs (Gross et al., 2005); these bodies were not observed in the present tumour. Although the cutaneous nodule had similar histological and immunohistochemical features, it was well demarcated by a connective tissue capsule. The animal had no reported history of tumours and indications of previous surgical excision were not observed during the necropsy examination. Consequently, the gross and microscopical features of the tumours are suggestive of two independent lesions, one malignant (pulmonary) and the other benign (cutaneous). The differential diagnosis for MPNST should include tumours such as fibrosarcoma, myxosarcoma, haemangiopericytoma and histiocytic sarcoma (Koestner and Higgins, 2002; Gross et al., 2005). Fibrosarcomas do not normally demonstrate a palisading pattern (Gross et al., 2005; Ginn et al., 2007). Although MPNSTs may contain myxoid stroma, myxosarcomas have a larger amount of myxoid stroma and tumour cells are arranged haphazardly within the extracellular matrix and the neural patterns are not

present (Gross et al., 2005). The distinction between haemangiopericytoma and MPNST may be difficult; MPNSTs are characterized by fusiform and serpentine nuclei with smaller nucleoli, while haemangiopericytomas have predominantly round to oval nuclei, with neoplastic cells arranged around capillaries (Gross et al., 2005). Histiocytic sarcomas are composed of both spindle cells and large round cells and multinucleated giant cells are a common feature that are not described in MPNSTs (Koestner and Higgins, 2002; Gross et al., 2005). Although the immunohistochemical labelling characteristics for MPNSTs are not well defined, positive immunoreactivity for vimentin, GFAP and S100 protein, as observed in the present case, is described in domestic animals with similar tumours (Chijiwa et al., 2004; Park et al., 2011; Suzuki et al., 2014; Baratt et al., 2015; Resende et al., 2015). In addition, MPNSTs may have variable positive expression of GFAP and S100 (Chijiwa et al., 2004). In the absence of expression of these molecules, labelling for collagen IV and laminin is useful to differentiate between fibrosarcoma, myosarcoma and haemangiopericytoma (Gross et al., 2005; Boland et al., 2015). The expression of leucocyte markers such as CD45, CD18, CD1 and CD11c defines histiocytic sarcomas, but is not observed in MPNSTs (Gross et al., 2005). An important immunohistochemical tool used to differentiate between MPNST and haemangiopericytoma is that the latter tumour expresses factor VIII, highlighting the blood vessels around which the neoplastic cells are arranged (Koestner and Higgins, 2002; Gross et al., 2005). Despite the rare occurrence of MPNT in the lungs, this tumour should be included in the differential diagnosis of primary pulmonary tumours of dogs. The definitive diagnosis is obtained by histopathological and immunohistochemical examination and the prognosis of MPNST is guarded due its aggressive and infiltrative behaviour.

Conflict of Interest Statement This research did not receive any specific grant from funding agencies in the public, commercial or notfor-profit sections. The authors declare no conflicts of interest.

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February 2nd, 2017 ½ Received,  Accepted, May 19th, 2017