Case ReportDelayed metastasis of ocular squamous cell carcinomafollowing treatment in five horsesT. S. Mair†, C. E. Sherlock1*‡ and G. R. Pearson§

†Bell Equine Veterinary Clinic, Mereworth, Maidstone, Kent, UK; ‡University of Georgia, College ofVeterinary Medicine, Athens, Georgia, USA; and §Department of Clinical Veterinary Science,Comparative Pathology, University of Bristol, Langford House, Langford, Bristol, UK.

Keywords: horse; squamous cell carcinoma; eye; metastasis

Summary

Identification of regional and/or distant metastasisfollowing treatment and local resolution of primary ocularsquamous cell carcinoma (SCC) was observed in 5 horses.In all cases, identification of metastasis occurred at least18 months following treatment of the primary ocularlesions. In 3 cases, invasion of blood or lymphatic vesselsby neoplastic cells was identified in the excisional biopsiesof the primary tumour. Two horses developed SCC at 2or more separate sites. At the time metastases wereidentified, there was no evidence of local recurrence ofthe ocular tumour in any of the horses. These cases confirmthe importance of long-term monitoring of horses formetastatic disease following treatment of ocular SCC evenin the absence of local recurrence.

Introduction

Squamous cell carcinoma (SCC) is a common neoplasmwith malignant characteristics including anaplasia, localinvasion and metastatic potential (Thomas et al. 2008).Squamous cell carcinoma is generally locally invasive andslow to metastasise (Giuliano 2010) and local recurrence ismore commonly reported than metastasis. In the horse,SCC is reported to be the most common neoplasm of theeye and ocular adnexa and the second most commonlydiagnosed tumour overall (Strafuss 1976; Lavach andSeverin 1977; Sundberg et al. 1977; Junge et al. 1984;Giuliano 2010). Equine ocular and periocular SCC istypically invasive, resulting in discomfort and blindness ifuntreated (Fischer et al. 2002). The tumour may affect oneor more of the cornea; bulbar or palpebral conjunctiva;limbus; third eyelid and eyelids. Treatment generally

involves surgical excision of the affected area or laserablation, with or without adjunctive treatments such aschemotherapy, irradiation, cryotherapy, immunotherapyor photodynamic therapy (Giuliano 2010).

A better prognosis (with lower recurrence rates) hasbeen reported for SCC originating at the third eyelid, nasalcanthus or limbus compared to the eyelids (Duganet al. 1991; King et al. 1991). Reported recurrence ratesvary widely but within one year after treatment they aregenerally lower in cases where adjunctive therapy is usedcompared to surgery alone (Schwink 1987; Dugan et al.1991; King et al. 1991; Mosunic et al. 2004; Payne et al.2009; Giuliano 2010).

Local extension and subsequent tissue destruction canarise secondary to ocular SCC and may affect one ormore of the orbit, guttural pouch, nasal cavity, paranasalsinuses, nasolacrimal duct, temporomandibular joint andcalvarium (Gelatt et al. 1974; Eversole and Lavach 1978;Ellis 2006; D’Angelo et al. 2007; Perrier et al. 2010; Elce et al.2011). Metastasis of equine ocular SCC to the regionallymph nodes, salivary glands, thorax or elsewhere can alsooccur, with reported rates of metastasis up to 18.6% (Gelattet al. 1974; Schwink 1987; King et al. 1991). However, thereare few detailed descriptions of metastasis followingtreatment of primary ocular SCC in the horse and, inmost recorded cases, metastases have been identifiedin association with ocular recurrence or local extension ofthe tumour (Gelatt et al. 1974; Lavach and Severin 1977;Eversole and Lavach 1978; Schwink 1987; King et al. 1991).

Since SCC can be slow to both recur and metastasise,reappearance of the tumour, months to years after theinitial presentation and treatment, is recognised (Ellis 2006;Plummer et al. 2007). Recently, the delayed (occurring atleast one year after the initial presentation and treatment)local extension of ocular SCC to the maxillary sinus orperiorbital area and regional metastasis to the parotidlymph nodes have been reported in 4 horses (Elce et al.2011). Recognition of such delayed extension or metastasis

*Corresponding author email: cerisherlock@hotmail.com1Present address: School of Veterinary Medicine and Science, Universityof Nottingham, Sutton Bonington Campus, Leicestershire LE12 5RD, UK.

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EQUINE VETERINARY EDUCATION 1Equine vet. Educ. (2012) •• (••) ••-••doi: 10.1111/j.2042-3292.2012.00435.x

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of SCC has important implications for clinicians treating thistumour. The purpose of this report is to describe 5 furthercases of delayed metastasis (including distant metastasis)of SCC following treatment of ocular neoplasia. Localrecurrence at the ocular site was not identified in any ofthe cases at the time that the metastases were diagnosed.

Clinical histories

The medical records of 5 horses identified with delayedmetastasis of ocular SCC were reviewed. Relevantclinicopathological details are summarised in the followingparagraphs and Table 1. Tissue samples were fixed in 10%neutral buffered formalin, processed routinely to paraffinwax, sectioned at 4 mm and stained with haematoxylinand eosin (H&E) before histopathological examination.Representative slides from each case were reviewed byone author (GRP).

Case 1 was examined in 2002 with a purulent oculardischarge and a soft tissue mass involving the left thirdeyelid (Fig 1). The entire third eyelid was excised withthe horse standing and histopathological examinationrevealed the presence of foci of SCC in situ and invasiveSCC at the free margin. Tumour emboli were noted in asubmucosal lymphatic vessel (Fig 2). The horse made anuneventful recovery.

Eighteen months later the animal developed signs ofinappetence, weight loss, lethargy and dyspnoea. Clinicalexamination, thoracic radiography and ultrasonographyrevealed the presence of a cranial mediastinal massand the horse was subjected to euthanasia on humanegrounds. On post mortem examination, a multinodular,cranial mediastinal mass was identified, along withenlarged tracheobronchial lymph nodes and multiplesoft tissue masses (1–3 cm in diameter) scatteredthrough the lungs. Ocular lesions were not identifiedand parotid, retropharyngeal and submandibular lymphnodes appeared grossly normal. Remaining organsalso appeared normal. Histopathological examination of a

section of the mediastinal mass, an enlarged bronchiallymph node and a pulmonary nodule confirmed thepresence of SCC, with sheets of densely packedpleomorphic neoplastic cells, many with bizarre nuclei andfrequent mitotic figures (Fig 3).

Case 2 presented in 2002 with a pale pink, proliferative,soft tissue mass of the right third eyelid. The third eyelid wasexcised with the horse standing. Histological examinationof the excised tissues confirmed the presence of SCC withearly invasion of the sub-epithelial connective tissue (Fig 4).

Recurrence of the ocular tumour was not observedduring the follow-up period. However, 3 years later, aslow-growing mass of the right submandibular area wasidentified. The swelling did not improve with 3 courses ofi.m. procaine penicillin and, over the next 4 weeks, thehorse became dull and inappetent with some weightloss. A malodorous, blood-stained discharge was notedfrom the mouth. Oral examination revealed ulcerationand swelling of the buccal mucosa adjacent to the rightmandibular cheek teeth. A firm subcutaneous swellingsurrounded by pitting oedema was present in the rightsubmandibular region. In view of the probability ofneoplasia and the horse’s age, the owner electedto subject the horse to euthanasia without any furtherdiagnostic work-up. Post mortem examination revealed acream soft tissue mass in the submandibular tissues(including the submandibular lymph nodes), the parotidlymph nodes, oral cavity and oropharynx. Lesions were notidentified in the eyes or periocular tissues. Histologicalexamination of the submandibular, oral and pharyngealtissues (including the submandibular and parotid lymphnodes) confirmed the presence of SCC. Remaining organsappeared normal.

Case 3 presented initially in 2007 with a small, white, softtissue mass of the left third eyelid. A presumptive diagnosisof SCC was made and the entire third eyelid wasexcised with the horse standing. Histological examinationconfirmed SCC that had invaded the underlying dermis.

The horse remained fit and well, with no recurrenceof ocular signs for 2 years. However, in 2009, the horse

TABLE 1: Details of horses affected by ocular SCC

CaseNo.

Age at initialpresentation Breed Sex Colour

Location of primarySCC Location of metastasis

Presentationto metastasis

1 9 years Cob G Bay Third eyelid left eye Mediastinum, lungs and bronchiallymph node

1.5 years

2 20 years Anglo-Arab G Chestnut Third eyelid right eye Submandibular lymph nodes, oralcavity, oropharynx

3 years

3 16 years Thoroughbredcross

G Bay Third eyelid left eye Parotid and retropharyngeal gland 2 yearsRight thyroid gland

4 9 years Paint horse G Tan andwhite

Third eyelid and uppereyelid of both eyes

Submandibular, parotid,retropharyngeal and cervicallymph nodes; mediastinum; lungs

3 years

5 5 years Cob F Skewbald Bulbar conjunctiva left eye Right parotid and retropharyngealglands

11 yearsRight nostrilBulbar conjunctiva right eye

F, female; G, gelding.

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presented with signs of weight loss, depression, coughingand dysphagia. Diffuse bilateral swelling of the parotidand retropharyngeal regions, and a bilateral nasaldischarge containing food was observed (Figs 5a and b).On endoscopic examination, the walls of the nasopharynxappeared congested and oedematous and the gutturalpouches constricted. A transcutaneous wedge biopsyof the enlarged left parotid gland was obtained withthe horse standing. Histopathological examination of thebiopsy revealed salivary gland tissue, within which werevessels containing neoplastic epithelial cells (Fig 6). Adiagnosis of vascular metastases of SCC was madeand the horse was subjected to euthanasia at theowner’s request. Post mortem examination confirmedthe presence of extensive infiltration of the parotidand retropharyngeal tissues (including the parotid andretropharyngeal lymph nodes), by firm, cream tissue(Fig 7) which was confirmed to be SCC on histologicalexamination. Histological examination also revealeddeposits of SCC in the right thyroid gland with obviousvascular invasion. The eyes, periocular tissues andremaining organs were normal.

Case 4 was first examined in 2006 for evaluation ofmasses of the right third eyelid and medial, right, uppereyelid margin and the left third eyelid and upper eyelid.The horse was anaesthetised and the right third eyelidresected followed by the application of 4 radiation fieldsof strontium-90 beta irradiation to the remaining stump. Themedial, upper, eyelid margin lesion was also resected andthe eyelid received 2 more radiation fields of strontium-90beta irradiation. Routine transpalpebral enucleation ofthe left eye was performed, leaving 1 cm margins aroundthe nodular mass. Histological examination confirmed allexcised masses as SCC. In the right third eyelid there wasinvasion of neoplastic cells into the underlying stroma andinvasion of blood vessels. Excellent healing of the areaoccurred and a re-check examination of the ocularregion, 8 months post operatively, appeared normal.

Fig 1: Case 1. Purulent ocular discharge and soft tissue swelling ofthe left third eyelid.

Fig 2: Case 1. Third eyelid. Squamous cell carcinoma of thefree margin with tumour emboli in a submucosal lymphatic vessel(arrows). H&E. Bar, 200 mm.

Fig 3: Case 1. Lung. Metastasis of squamous cell carcinoma (arrow)adjacent to normal lung tissue. H&E. Bar, 200 mm.

Fig 4: Case 2. Biopsy of eyelid mass. Deposits of squamous cellcarcinoma in deep connective tissue (arrows). H&E. Bar, 200 mm.

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T. S. Mair et al. 3

Three years later, the horse re-presented with a onemonth history of intermittent fever, pectoral oedema andprogressive forelimb oedema. Several large, circumscribedmasses were palpable in the submandibular andretropharyngeal region with the largest located in theleft, lateral, cervical area just caudal to the ramus of themandible. The horse also demonstrated bilateral jugularvein distension. Radiography of the pharynx and thoraxrevealed a large, well circumscribed mass in the cranialmediastinum; irregular, nodular thickening of the floor of

both guttural pouches and poorly circumscribed massesin the pharyngeal region just caudal to the ramus ofthe mandible. Ultrasonography revealed several areasof well circumscribed, mixed echogenic masses in thesubmandibular and retropharyngeal regions. Mild pleuralroughening and a small volume of pleural effusionwere also identified bilaterally in the cranioventralthorax. Upper airway endoscopy revealed bilateralswellings along the ventral floor of the medialcompartment of the guttural pouches, consistent withretropharyngeal lymphadenopathy. Differential diagnosesincluded disseminated bacterial abscessation ormetastatic neoplasia. The owners elected not to pursuefurther diagnostic tests but to attempt long-term antibiotictreatment.

The horse deteriorated rapidly over the followingmonth with worsening cranioventral oedema and theowners elected for euthanasia. Post mortem examination

Fig 5: a) Case 3. Parotid swelling. b) Case 3. Bilateral nasaldischarge.

Fig 6: Case 3. Biopsy of parotid salivary gland. Vessels containsquamous cell carcinoma (arrows). H&E. Bar, 200 mm.

Fig 7: Case 3. Post mortem appearance of parotid region showingpale cream tissue (arrow) infiltrating between lobules of parotidgland (P).

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revealed a large mass adherent to the left mandiblethat compressed the oropharynx and infiltrated andeffaced the submandibular, parotid and retropharyngeallymph nodes. Numerous small, irregular, nodules wereobserved externally along the tracheal and oesophagealadventitia extending though the thoracic inlet, cranialto the base of the heart and involving the mediastinum.In addition, multiple nodules were present within thelung parenchyma. Histopathological examination ofrepresentative samples of the masses revealed a poorlydifferentiated metastatic SCC.

Case 5 was first examined in 1993 for a mass of the leftbulbar conjunctiva close to the lateral canthus, which wasexcised with the mare standing. Histological examinationconfirmed the diagnosis of SCC. Six weeks later, localrecurrence of the mass was noted and surgical excisionwas repeated with the horse under general anaesthesia,followed by 2 radiation fields of strontium-90 betairradiation. Healing of the area occurred and tumourrecurrence was not identified over the next 8 months.

Nine months after initial presentation, a 1 cm diameter,ulcerated area of the skin of the right external nostril wasnoted. A biopsy revealed a SCC in situ. The ulcerated areawith a 1 cm margin of normal skin was treated by a triplefreeze-thaw cycle of cryotherapy followed by topicalapplication of 5-fluorouracil ointment. The affected areahealed uneventfully over the next 3–4 weeks and no furtherrecurrence was noted at the site.

In 2002, 9 years after the appearance of the first SCClesion in the left eye, a soft tissue mass was identified onthe bulbar conjunctiva close to the lateral canthus of thecontralateral (right) eye. The mass was excised with thehorse under general anaesthesia; histological examinationconfirmed SCC and the presence of neoplastic cells withinblood vessels was noted. The owner declined furtheradjunctive treatments.

Recurrence of ocular lesions was not observed overthe next 2 years. The mare was subjected to euthanasiain 2004 for severe laminitis. At this time, mild enlargementof the right parotid region was present. Post mortemexamination revealed enlargement of the parotid glandand retropharyngeal lymph nodes on the right side andhistological examination revealed the presence of SCC inboth organs. The remaining organs were normal on grossexamination.

Discussion

The 5 cases reported herein demonstrate the potentialfor ocular SCC to metastasise to local lymph nodes or todistant sites following successful resolution of the primarytumour (i.e. without concurrent recurrence of ocularlesions). In 3 cases the metastasis was local to the parotidand/or retropharyngeal lymph nodes (one of these casesalso had metastasis to the thyroid glands); one case hadlocal and distant (thoracic) metastases and one case

had only distant (thoracic) metastases. Although localextension into adjacent and regional tissues (Elce et al.2011) and distant metastasis (Gelatt et al. 1974; Lavachand Severin 1977; Eversole and Lavach 1978; Schwink 1987;King et al. 1991) have been reported previously, localrecurrence of ocular SCC has been reported mostfrequently (Schwink 1987; Dugan et al. 1991; King et al.1991; Mosunic et al. 2004; Plummer et al. 2007). In thehorse, ocular lymphatic drainage is thought to involve theparotid, then retropharyngeal lymph nodes (Elce et al.2011). However, as noted in other species, there may besome individual variation in the order, as determined bylymphoscintigraphy (Nijhawan et al. 2010). It was notablethat the regional lymph nodes of the head (parotid,retropharyngeal and submandibular lymph nodes) wereaffected by metastasis in 4 of the 5 horses described in thepresent study. However, in one horse, (Case 1), metastasisto the thorax occurred in the absence of any detectableinvolvement of the regional lymph nodes of the head.There was no evidence of local recurrence of tumour in theocular tissues in any of these cases when the metastaseswere diagnosed. This suggests that the original treatmentwas effective at removing the primary tumour in its entiretybut that metastasis of tumour cells to a distant site hadalready occurred.

These 5 cases also highlight the fact that clinicalmanifestations of metastatic spread may occur a longtime after apparent resolution of the original tumour. In the5 cases reported here, identification of metastatic spreadof SCC occurred between 18 months and 9 years afterthe initial treatment of the ocular tumours. However,it is acknowledged that the first lesion on the left side ofCase 5 (ocular) and the uncommon right nasal SCC maynot have been associated with the right parotid andretropharangeal metastases. The right ocular SCC mayhave been the primary lesion for these metastases yieldingan interval of 2 years between resolution of ocular lesionsto detection of lymphadenopathy. The prolonged clinicalmanifestation of metastases in these cases warrantsrepeated regular re-examination of horses treated forocular SCC for several years (Plummer et al. 2007). Inhuman medicine, if the clinical, histopathological orcytological diagnosis is made >2 years after finishing theprimary treatment, metastases have been described asdelayed (Spector et al. 2001). It is unclear if the metastaticprocess itself is delayed or if clinical identification of themetastasis is delayed. It seems likely that the slow growthof SCC and the difficulties in identification of subtlelymph node enlargement in horses may permit subclinicalexistence of the tumours for a prolonged period of time,resulting in delayed identification of lymph nodemetastases.

There is currently no information available that couldbe used to predict the risk of recurrence or metastasis ofocular SCC following treatment in horses. It has been notedpreviously that eyelid SCC metastasises more frequentlythan limbal SCC (Hendrix 2005). This increased risk of

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metastasis has been hypothesised to be due to the easethat cords of tumour cells can spread from the eyelids intothe soft tissue, compared to the sclera and cornea wherethe sharp demarcation between normal, dense, fibroustissue and neoplastic tissue may act as a barrier to thepenetration of neoplastic cells (Hendrix 2005). In 3 horses(Cases 1, 4 and 5), there was histological evidence ofneoplastic cell infiltration of blood or lymphatic vessels inthe primary ocular tumours, which may have indicated apotential for more widespread dissemination of the tumour.This form of metastasis is believed to occur in 5–10% ofhuman cases of SCC metastasising from the skin (Thomaset al. 2008). It was of interest that in 2 of the 3 cases wherevascular or lymphatic emboli were observed, more distantmetastasis occurred (Cases 1 and 4). Apart from thepossible significance of this neoplastic invasion of blood/lymphatic vessels, no specific histopathological features(such as the mitotic rate or cytological appearance ofneoplastic cells) were detected in these 5 horses or in the4 horses described by Elce et al. (2011) to suggest anincreased risk of recurrence or metastasis. Whilst in people,microscopically controlled excision, or excision with frozensection analysis (Thosani et al. 2008), along with evaluationof the sentinel lymph nodes (Faustina et al. 2004), isperformed, such an approach would be hampered inthe horse by the surgical inaccessibility of the parotid andretropharyngeal lymph nodes in the absence of grosslymphadenopathy.

There are numerous different treatments that can beused for SCC in horses including surgery, cryotherapy,radiotherapy, immunotherapy, photodynamic therapy,radiofrequency hyperthermia, laser surgery andchemotherapy (Giuliano 2010). The use of combinationtherapies is common practice. Comparisons of recurrencerates between different combinations of therapies aredifficult to establish and studies documenting long-termand distant recurrence rates of ocular SCC are currentlylacking.

This case series has highlighted the importance of regularmonitoring of cases treated for ocular SCC even afterresolution of the primary tumour. As a minimum, the authorswould recommend prompt investigation of submandibular,retropharangeal or parotid lymphadenopathy in horsestreated for ocular SCC and long-term case follow-up.Additionally, multicentre prospective studies with regularfollow-up and particular attention to histopathologicalfeatures of excised SCC are warranted with the aim torecognise horses at risk for disease progression as well asidentify disease progression promptly.

In conclusion, the delayed identification of metastasisof neoplasia described by Elce et al. (2011), and the5 horses in the present study, illustrates the need forcounselling owners of affected horses and for long termcareful re-examination after treatment of ocular SCC notonly for local (ocular) recurrence of tumour but also formetastatic spread, both locally in sentinel lymph nodesand at distant sites. The identification of neoplastic invasion

of blood or lymphatic vessels in tissue samples of theprimary tumour may be considered as a marker forincreased risk of subsequent metastastic disease.

Authors’ declaration of interests

No conflicts of interest have been declared.

Acknowledgements

We thank colleagues at: the Bell Equine Veterinary Clinic; theDepartment of Clinical Veterinary Science, ComparativePathology, University of Bristol; Trevor Whitbread, AbbeyVeterinary Services; and The Department of Large AnimalMedicine, University of Georgia for assistance with theevaluation and treatment of these cases.

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