In dogs, the most common periocular tumors are eyelid neoplasms (13). Eyelid neoplasms can develop from epithelial, mesenchymal and round cell origin (8). Most eyelid tumors are benign, usually with unilateral involvement, and slow growing over months to years (1). As the sizes of the eyelid tumors increase, it can cause ocular discharge and conjunctival hyperemia and damage the cornea, causing corneal ulceration in severe cases (14,22). In studies reporting the prevalence of eyelid tumors, the most common eyelid tumor was sebaceous adenoma, consisting of 31-60% of cases (14,22). Other tumors that arise in the eyelids included sebaceous epithelioma, sebaceous carcinoma, melanoma, basal cell tumor, mastocytoma, and histiocytoma (1,11,12).

Plasmacytoma originates from mature and differentiated B lymphocytes, and occurs in low-frequency in dogs (18,19). The neoplastic cells are plasma cell-like or plasma cells that occur from excessive multiplication, which affect soft tissues at various stages of differentiation (18). Extramedullary plasmacytoma (EMP) is the most common form of this neoplasm without bone marrow involvement. Most EMPs are covered by sometimes ulcerated and alopecic skin, and occur as a single, slightly raised, small dermal nodule (19). Multiple EMPs may also be presented in some animals (18).

In humans, EMPs occur commonly in the submucosal layer of the upper respiratory tract and oral cavity, but rarely in the lacrimal gland (2). In dogs, EMPs are common in skin and mucous membrane, particularly affecting face, ears, oral cavity, and the digits (6,7,20). EMP occurs more frequently in senile dogs, whereas it is rarely reported in cats with an average age of 8 or 10 years (5,15). Some canine breeds, such as American and English cocker spaniels and West Highland white terriers, are known to be predisposed (5,23). Canine EMP is reported as usually benign neoplasm that may be cured with surgical excision (9).

The purpose of this study is to report an EMP that occurred in the eyelid of a dog and to describe the clinical and histopathological aspects.

A 9–year-old spayed female Shih-Tzu was presented with glaucoma in the left eye (OS). After 1.5 years of glaucoma management OS, a mass was identified in the upper eyelid of the right eye (OD) on slit-lamp biomicroscopy (SL-D7; Topcon, Tokyo, Japan) (Fig. 1A). At the time the mass was first observed, Schirmer tear test-1 (STT; Merck Animal Health, Madison, NJ, USA) results were normal with values of 20 (OD) and 20 (OS) mm/min. Rebound tonometry (Icare^® Tonovet; Icare, Helsinki, Finland) showed intraocular pressure values of 12 (OD) and 4 (OS) mmHg; phthisis bulbi was observed OS due to previous intravitreal cidofovir injection for the treatment of glaucoma. The results of fluorescein dye test (Fluorescein paper; Haag-Streit, Koenitz, Switzerland) were negative OU. The results of physical examinations, including regional lymph node palpation, were normal.

Figure 1. The slit-lamp biomicroscopy photographs of the case during the follow-up in the right eye. (A) A small mass (red arrowhead) was first observed in the nasal margin of the upper eyelid. (B) After 4 months, the mass was slightly enlarged (yellow arrowhead). (C) Seven months later, the size of the mass was large enough to be visible without slit-lamp biomicroscopy, along the margin of the eyelid. (D) After 9 months, the size of the mass increased, and contact with the cornea was observed. (E) After 11 months, the mass size increased not only along the eyelid margin but also along the skin above the eyelid margin. (F) Thirteen months after first identified, the mass was enlarged along the upper skin part of the eyelid and along the eyelid margin. EMP did not invade into the palpebral conjunctiva during the follow-up period.

Clinical photographs of the eye were taken at the same magnification with slit lamp biomicroscopy at each visit. After 4 months, the mass was slightly enlarged (Fig. 1B). Three months later, the size of the mass was larger along the margin of the eyelid on gross examination, while the conjunctival surface appeared to be intact (Fig. 1C). After 2 months, the size of the mass increased, and contact with the cornea was observed, but no related clinical signs were identified (Fig. 1D). However, on the follow-up examination after 2 months, the mass size increased not only along the eyelid margin but also along the skin above the eyelid margin, and OD showed symptoms of discomfort. There was no epiphora, conjunctival hyperemia, corneal edema, corneal vascularization, or corneal ulceration on ophthalmic examination (Fig. 1E), because the conjunctival surface of the eyelid remained intact despite the increased mass size. However, as the size of the mass increased, erythema and swelling of the surrounding skin were observed, and the owner complained that the patient showed signs of discomfort. Surgery was planned; however, during preoperative general examination, hematuria was discovered. The patient was transferred to the department of internal medicine. The results of complete blood count and serum chemistry were within normal range. On radiographic and ultrasonographic examinations, bilateral nephrolithiasis, left ureteric and cystic caliculi, and microhepatica were identified, so computed tomography (CT) scan was ordered for tumor metastasis evaluation as well as kidney and liver imaging. Surgery was planned immediately after the CT scan. On the day of surgery, which was two months after the last ophthalmic examination, the mass was enlarged along the upper eyelid skin and along the eyelid margin, but there was still no palpebral conjunctival involvement (Fig. 1F).

The dog was pre-medicated with an intravenous (IV) bolus of cefazolin (22 mg/kg; Cefazolin, Chong Kun Dang, Seoul, Korea) and medetomidine hydrochloride (Domitor, Zoetis Animal Health, Sandton, South Africa) and a constant rate infusion (CRI) of remifentanil (0.1 μg/kg/min; Ulitiva, GlaxoSmithKline, Co., Genval, Belgium), ketamine (0.6 mg/kg/hr; Ketalar, Youhan, Seoul, Korea), and midazolam (0.02 mg/kg/hr; Bukwang Pharmaceutical Co., Seoul, Korea).

General anesthesia was induced with alfaxalone (IV, 2.0 mg/kg; Alfaxan, Jurox Pty Ltd., Rutherford, Australia) and maintained with isoflurane at a 1.0-1.4% end tidal concentration of isoflurane (Ifran, Hana Pharm, Seoul, Korea) in 100% oxygen (3 L/min), delivered through a circle rebreathing system. During anesthesia, the dog was monitored using electrocardiography, pulse oximetry, capnography, invasive blood pressure, spirometry, blood gas analysis, and measurement of body temperature. Plasma solution was administered IV route at a rate of 5.0-10.0 mL/kg/h.

After the anesthetic induction phase, CT scan was performed first. On CT images, small round nodular shadows were found in the renal cortex, but there was no evidence of metastasis. Fine needle aspiration (FNA) was performed and the FNA findings showed predominant epithelial cells and an increase in heteronuclear cells without malignant cells.

After the CT scan, the patient was moved to the operating room. The patient was positioned in dorsal recumbency, and the eyes and adnexa OD were prepared aseptically with 0.5% povidone-iodine solution. The pentagonal resection was performed to remove the mass in the upper eyelid OD. A 6-0 round Vicryl (Johnson & Johnson, New Brunswick, New Jersey) was used to suture a few stitches, starting with a buried horizontal mattress suture followed by a figure-8 suture to accurately appose the resected eyelid margin (Fig. 2A). Postoperatively, as oral medication, amoxicillin and clavulanic acid (Augmentin; Il Sung Pharmaceutical, Seoul, Korea) 12.5 mg/kg, streptokinase (Retonase; Withus Pharmaceutical, Seoul, Korea) 0.5 mg/kg, and famotidine (Gaster; Dong-A ST, Seoul, Korea) 0.5 mg/kg were prescribed twice a day for 7 days. In addition, 0.5% levofloxacin (Cravit; Santen Pharmaceutical, Osaka, Japan) twice a day was also topically administrated. Two weeks after the surgery, the surgical area healed well. To relieve possible inflammation and patient discomfort caused by absorbable sutures, stitch-out of the sutures was performed (Fig. 2B). There was no recurrence of the eyelid mass 6 months after the surgery Two weeks after the surgery, the surgical area healed well and stitch-out of the sutures was performed (Fig. 2C, D), and the relief of previous inflammation and discomfort was observed OD.

Figure 2. Clinical photographs after the pentagonal resection surgery. (A) Surgical site (red arrowhead) right after the surgery. (B) Two weeks after the surgery, the surgical site healed well. Notice the neatly arranged meibomian ducts (two yellow arrowhead) between the resected incision lines. (C, D) No recurrence of the mass six months following the surgery. A normal eyelid margin without defects or mass is observed.

The mass removed from the eyelid was fixed in 10% neutral buffered formalin, processed routinely, embedded in paraffin, sectioned at 4 um, and stained with hematoxylin and eosin (H&E). Standard avidin-biotin-peroxidase technique was used to identify the presence of multiple myeloma oncogene-1 (MUM-1) with commercially available antibody. Microscopically, the neoplastic mass was exophytic and consisted of solid population of plasmacytoid cells with clean deep surgical margin (Fig. 3A). The neoplastic cells contained eccentrically located nuclei and a moderate amount of eosinophilic cytoplasm (Fig. 3C). The neoplastic cells were consistently and strongly positive for MUM-1 (Fig. 3B, D).

Figure 3. Histopathological examination and immunohistochemistry. Note the exophytic mass with clean surgical margin (A, B). The neoplastic cells had eccentric nucleus with a moderate amount of eosinophilic cytoplasm (C) and were positive to MUM-1 (D). (A) and (C) were H&E and (B) and (D) were MUM-1 immunohistochemistry.

EMP is a benign tumor of the B-lymphocyte cell line unlike multiple myeloma. However, previous canine reports have suggested that non-cutaneous EMPs may be more aggressive and exhibit distant metastases (19,20). The current case presents an eyelid EMP that continued to enlarge along the eyelid margin, surrounding the eyelid skin without affecting the conjunctiva, and showed no evidence of systemic multiple myeloma. EMP of the eyelid is rare, but as with EMPs of other sites (9), there was no recurrence upon complete resection in the current case.

In the case of EMP that occurred in the 3rd eyelid, the tumor cells were infiltrated into the lesion’s margin, whereas in this study, margin was clear (19). Despite these differences, tumor recurrence was not confirmed in the two cases. Although this is a small number of cases, EMP is thought to show a low metastatic potential and a low potential for local recurrence in the canine eye.

Similar to several previous studies, the EMP on the eyelid in this case was benign on pathology, appeared in a senile dog, and was slowly and peripherally invasive (5-7,15,20). Most EMPs are known to occur in the skin and mucocutaneous area (5,15). However, in this case, the size increased only along the eyelid margin and skin. No invasion was observed in the palpebral conjunctiva.

The eyelids play a very important role in maintaining healthy corneal surface (4). They protect the ocular surface from physical damage, reduce pre-corneal tear film (PTF) evaporation to prevent dryness, and evenly distribute the PTF to nourish and hydrate the ocular surface (4,16). Therefore, when the size of the eyelid mass increases, an abnormality occurs in the shape of the eyelid, which leads to ocular discharge, conjunctival hyperemia and even corneal ulceration (14,22). In this case, clinical symptoms did not appear until the mass grew to about 1/5 of the length of the eyelid margin. Although no clinical symptoms may be apparent, as the size of the mass increases, the movement of the upper eyelid could be affected, making blinking difficult and leading to discomfort. In this case, clinical signs caused by the mass was not detected on the initial ophthalmic examination due to intact palpebral conjunctiva with small size of the mass. The corneal dryness parallel to the eyelids in the central part of the eye observed on slit-lamp biomicroscopy even before the growth of the mass appeared to be due to the characteristics of the brachycephalic breed possessed by Shih-Tzus (10). However, the possibility that it was aggravated due to the eyelid mass cannot be completely excluded (3).

Although the biological behavior of EMPs in humans is reported with high variability, it is known that EMPs in dogs are not as aggressive as in humans (9). The predilection pattern and gross appearance of EMP may resemble histiocytoma (17). However, in the current case, the two neoplasms were differentiated via histopathology, and histological differences were evident at low magnification (Fig. 3). A typical EMP has distinct histological features, so histopathological differentiation is usually not difficult, although, markedly anaplastic tumors can be misdiagnosed as disseminated histiocytic sarcoma (17). MUM-1, labeling nucleus with a weak cytoplasmic component, is an excellent and highly specific plasma cell marker for normal and neoplastic plasma cells (17). In this case, strong positive stain with MUM-1 was observed.

However, well-differentiated plasmacytoma is difficult to distinguish from an inflammatory lesion in which plasma cells predominate (19). MUM-1 expressed in EMP was strongly detected using the standard avidin-biotin-peroxidase technique to differentiate the inflammatory lesions and plasmacytoma. In the past study, MUM-1 was positive in 94% of plasma cell tumors, whereas CD20 and CD79a, other B-cell markers commonly used, were positive in 19% and 56%, respectively, of the tumors (21). Therefore, only MUM-1 was used to differentiate inflammation and plasmacytoma in this study.

In this case, the neoplastic mass was exophytic and consisted of solid population of plasmacytoid cells with clean deep surgical margin. Only surgical removal of the neoplastic lesion of the eyelid was proposed to prevent recurrence, and was well-finished. The neoplastic mass was clearly excised, and it was confirmed that eyelid area recovered well without recurrence after surgery. Although EMP can occur throughout the whole body, to the author’s knowledge, this canine report is the first case report of an EMP in the eyelid in dogs. Although EMP is a benign tumor, the mass showed invasive growth and grew toward the skin rather than the palpebral conjunctiva in this case.

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1I1A1A01058695).

The authors have no conflicting interests.