Canine cutaneous histiocytoma is one of the most common benign tumors (2,7). Cutaneous histiocytoma is known to originate from epidermal Langerhans cells, indicated by expression of CD1, CD11c and major histocompatibility complex (MHC) class II (10). Purebred dogs such as Dachshunds and Boxers are predisposed, although these cutaneous neoplasms occur in dogs of all breeds with all ages (7).

Histiocytoma often occurs as solitary lesion in dogs (2,7). Multiple histiocytomas are known to occur in less than 1% of cases and are commonly reported in Shar Peis (7). Postoperative recurrence at the surgical removal site is reported to be extremely low with low incidence of development at a new site (7,11).

Histiocytoma involving the eyelid occasionally occurs in young dogs (2,7). Lesions of these tumors are usually presented at the cranial portion of the body, predominantly on the head and pinna, although lesions can occur in any region of the body (5,10,11). This tumor grows rapidly but is usually benign. Histiocytoma may regress spontaneously without any medical or surgical treatment (2,7). The cytological examination could be helpful for the diagnosis and staging of histiocytoma (2,10).

Even though spontaneous regression and typical benign behavior of histiocytomas have been widely reported, canine cases of solitary cutaneous histiocytoma with regional lymph node metastasis identified by histopathology have also been reported (3). Lymph node metastasis is known as an unfavorable prognostic indicator in multiple cutaneous histiocytoma (3), but spontaneous regression of solitary metastatic histiocytoma was also reported (7).

This case study reports a case of cutaneous histiocytoma on the upper eyelid of the left eye (OS) in a Maltese dog. Along with presenting the diagnostic process for this eyelid tumor, the role of cytological examination in determining treatment options will be discussed.

A 1-year-old neutered male Maltese dog was referred to the Veterinary Medical Teaching Hospital in Seoul National University with a mass on the upper eyelid of OS. The owners’ concern was the progressive appearance of the mass during two-month on. Previous therapy with 0.5 mg/kg prednisolone (Solondo^® 5 mg tablets, Yuhanyanghaeng, Korea), 20 mg/kg cephalexin (Falexin^® 500 mg capsules, Donghwa, Korea) and 0.05 mg/kg clemastine fumarate (Masgil^® 1 mg tablets, Taiguk, Korea), twice a day orally, by referring veterinarian, had not relieved the lesion.

The standard physical examination showed no abnormalities. A complete ophthalmic examination, including a tear production test (Schirmer tear test^®, Intervet, NJ, USA), neuro-ophthalmic examinations, rebound tonometry (Tonovet^®, Icare Oy, Finland), fluorescein staining, slit lamp biomicroscopy (Topcon^®-Model SL-D7, Topcon Corp., Japan) and indirect ophthalmoscopy (Vantage^®, Keeler Instruments Inc., PA, USA) were performed. No abnormalities of both eyes were detected in the examinations, with the exception of a mass on the upper eyelid of OS. A pinkish and alopecic mass was located in the nasal portion of the upper eyelid of OS (Fig. 1). The mass was not painful and it was firmly attached to the eyelid and round-shaped with a diameter of 11 mm (Fig. 1). No spread to conjunctiva was identified.

Figure 1. Clinical appearances at initial presentation. (A) A pinkish and alopecic mass is located in the nasal portion of the upper eyelid of the left eye. (B) The mass is firmly attached to the eyelid and round-shaped with a diameter of 11 mm.

Cytological examination of samples obtained by fine-needle aspiration of the mass was performed. The majority of the cells had moderate amounts of light-colored cytoplasm and round to oval nuclei in slides stained with hematoxylin and eosin (Fig. 2). These cells were revealed as histiocytes, and more small lymphocytes were infiltrated (Fig. 2). There were no microorganisms nor marked neoplastic cells. The dog was diagnosed as cutaneous histiocytoma with late regressive stage. The dog received no treatment and complete regression of the mass was verified 2 months later (Fig. 3).

Figure 2. Cytology stained with hematoxylin and eosin. Small lymphocytes (arrow) and histiocytes (arrow head) are infiltrated.

Figure 3. Clinical appearances at 2 months later. Complete spontaneous regression of the mass was verified.

Canine cutaneous histiocytomas were known to occur in dogs of all ages, but especially common in dogs under 3 years of age (2,7). Canine cutaneous histiocytomas are usually well circumscribed, dome-shaped lesions that may reach 4 cm, but mostly 1 to 2 cm in diameter (10,11). This tumor grows rapidly as indicated by multiple mitotic figures in histopathological examinations (4,10,11). It was reported that most canine cutaneous histiocytomas regress within few weeks, but the factors associated with the onset of regression in canine histiocytoma are yet to be confirmed (2,10). In this case, the mass was completely regressed within 2 months.

The regression of canine cutaneous histiocytomas is characterized by progressive infiltration of lymphocytes (2). It is revealed by immunophenotype that the majority of infiltrating lymphocytes are mainly CD8⁺ T lymphocytes (10). It has been shown that tumor tissue and / or tumor-infiltrating reactive interstitial dendritic cells in histiocytoma migrate to draining lymph nodes. The migration likely activates CD4⁺ T lymphocytes and leads to recruitment of CD8⁺ cytotoxic T lymphocytes. It was known to mediate regression by massive infiltration of CD8⁺ T lymphocytes capable of lysis of neoplastic histiocytes (7,12). This reaction has been interpreted as a signal of host immune response (2,10,11). Therefore, in some studies, it has been reported that immunosuppression treatment for the therapeutic intervention of histiocytoma, which would interrupt neoplastic cell regression, should be avoided (12). This may be the reason why previous steroid treatment by RDVM failed to alleviate the lesion in the current case, even though the dose was lower than the immunosuppressive dose. Although spontaneous regression of histiocytoma was widely reported within 1-2 months after onset (3), in the present case, spontaneous regression occurred later than 2 months.

The regression of cutaneous histiocytoma is also associated with up-regulation of cytokines, such as interleukin-2, tumor necrosis factor-α, interferon-γ and inducible nitric oxide synthase (5,10). In addition, lymphocytic infiltrate and increased cytokines has been reported to mediate necrosis of tumor tissue cells at all stage on regression of histiocytoma. Especially, in late stages, it was revealed that lymphocytic infiltrates consist mainly of CD8⁺ T lymphocytes and has few or none CD4⁺ T lymphocytes and B lymphocytes (5,10). However, in the late phase of histiocytoma regression, these heavy lymphocytic infiltrates can be mistaken for a non-epitheliotropic T cell lymphoma (7). It was reported that non-epitheliotropic T cell lymphoma with inflammation had a number of reactive histiocytes and T lymphocytes, which may be recognized by significant histiocytoma (7). It has been studied that this problem would be resolved by using molecular clonality analysis of the T lymphocyte receptor locus (TRG), even though clonal T lymphocyte expansion can be associated with cytotoxic T lymphocyte responses to histiocytoma (7).

Histiocytoma can exhibit various cytological features. There are characteristic cells which have round to oval nuclei with indistinct nucleoli and fine chromatin and usually have abundant and clear to lightly acidophilic cytoplasm (7,8). The mitotic index of cutaneous histiocytoma is very variable, but often high. However, multinucleated histiocytes may be noted with low frequency in cutaneous histiocytoma. Cytologic atypia as hyperchromatic nuclei and anisokaryosis is not common (7). Most of cutaneous histiocytoma may show invasion into the epidermis by individual histiocytes or lump of histiocytes. It is mostly not prevalent, but should be evaluated due to diagnostic features of cutaneous histiocytoma (7).

The majority of canine histiocytic diseases develop in most of the dendritic cell lineages (7,12). However, based on ultrastructural and immunophenotypic features, canine cutaneous histiocytoma is known to originate from Langerhans cells which are indicated as expression of CD1a and E-cadherin (7). The expression of E-cadherin is a characteristic marker in cutaneous histiocytoma. It may help to differentiate histiocytomas from reactive histiocytosis, such as systemic histiocytosis and cutaneous histiocytosis (12). Expression of E-cadherin has been studied to decrease in relation to degree of lymphocyte infiltration into cutaneous histiocytoma. Recent studies have shown that decreased E-cadherin staining correlates with the regression phase of cutaneous histiocytoma. The decrease in E-cadherin expression is associated with spontaneous regression of cutaneous histiocytoma (12). However, E-cadherin expression can be limited to infiltration of histiocytes around the epidermis, and the pattern of E-cadherin staining is often not uniform. This issue can be clearly solved by analyzing the immunophenotyping with several other markers (7).

Eyelid tumors are reported as a common adnexal disease in dogs, and benign tumors comprise more than 75% of canine eyelid tumors (6). Clinical management of eyelid tumors in dogs is mainly surgical removal, sometimes accompanied by blepharoplasty (6). The primary treatment modality of cutaneous histiocytoma is also surgical excision (3,7). Recurrence for cutaneous histiocytomas with surgical excision and development of a cutaneous histiocytoma at a new site is very rare (7). In few cases, however, metastasis of cutaneous histiocytoma to lymph nodes and multiple histiocytoma have been reported, especially in aged dogs (7,12). In such cases, the process may rapidly undergo malignant transformation with the involvement of lymph nodes and even with distant metastases (9). Hence, manifestation of cutaneous histiocytoma in older dogs, even solitary lesion, is associated with much more unfavorable prognosis (1,9). In contrast, this case, which was younger, showed a spontaneous regression of cutaneous histiocytoma on the upper eyelid of OS in a Maltese.

Solitary histiocytoma developed in a Maltese dog, and cytological examination was helpful in determining treatment. Although surgical removal was known as the most reliable treatment for eyelid mass, spontaneous regression could be expected without any treatment because it was judged to be a regression stage through cytological examination.

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1I1A1A 01058695).

The authors have no conflicting interests.