A total of 359 patients with histopathologically diagnosed malignant conjunctival tumors were included in this study. All patients were Japanese. The mean age of all patients at the time of diagnosis was 61.5 ± 16.8 years. There were 162 men (45.1%) and 197 women (54.9%). Forty patients (10.6%) had bilateral conjunctival lesion.

Table 1 shows the number of patients, mean age, sex ratio, and tumor laterality of different tumor types. The most common tumor was lymphoma (n = 197, 54.9%), followed by SCC (n = 97, 27.0%), melanoma (n = 60, 16.7%), basal cell carcinoma (BCC) (n = 2, 0.6%), Kaposi’s sarcoma (n = 2, 0.6%), and solitary fibrous tumor (SFT) (n = 1, 0.3%). The top three diseases; lymphoma, SCC, and melanoma, totaled 354 cases (98.6%).

Figure 1 shows the age distribution of all patients. The peak age of patients diagnosed with primary conjunctival malignant tumors was in the 60s. The youngest patient was an 18-year-old woman with lymphoma, and the oldest patient was a 101-year-old man with lymphoma. There were no significant differences in age between the three major malignant conjunctival tumors (lymphoma, SCC, and melanoma, t test).

Age distribution of all patients with primary malignant conjunctival tumors

Detailed clinical data and treatment outcomes of each tumor are described below.

The mean age at the time of diagnosis of lymphoma was 60.5 ± 17.4 (range: 18–101) years. There were 77 men (39.1%) and 120 women (60.9%), and the proportion of women was significantly higher than of men (P = 0.0012, Chi-square test). Bilateral disease was observed in 35 patients (17.8%). Histopathologically, extranodal marginal zone lymphoma (EMZL) was the most prevalent type (176 patients, 89.3%), followed by follicular lymphoma (14 patients, 7.1%), mantle cell lymphoma (3 patients, 1.5%), diffuse large B cell lymphoma (2 patients, 1.0%), and T cell lymphoma (2 patients, 1.0%). Systemic work up at the time of diagnosis confirmed the presence of extraocular lymphoma in 19 cases (9.6%).

Among 197 patients, 104 (52.8%) were treated with external beam radiation therapy (EBRT) at a dose of 20–30 Gy using electron beams (Fig. 2), 79 (40.1%) were treated with surgical resection with or without cryopexy (Fig. 3), 7 were treated with systemic chemotherapy, and 1 was treated with EBRT and systemic chemotherapy. The remaining 6 patients were treated at other hospitals or were lost to follow-up.

Conjunctival lymphoma: before treatment (a) and after treatment with 20 Gy of electron beams (b)

Conjunctival lymphoma: before treatment (a) and after extraction of the tumor located underneath the bulbar conjunctiva (a). No recurrence was observed for 24 months

Treatment outcomes of 178 patients followed for 12 months or longer at our hospital were analyzed. The mean follow-up period was 28.3 ± 22.4 months. Local recurrence was observed in 15 patients (8.4%), and novel extraocular lymphoma was confirmed in 4 patients (1.7%) after treatment. None of the 178 patients died from lymphoma during the follow-up period, although the exact mortality status is unknown, as a few patients were transferred to other hospitals when systemic lymphoma was confirmed.

The mean age of patients when diagnosed with SCC was 60.2 ± 15.8 (range: 27–95) years. There were 54 men and 43 women, with no significant difference in proportions of men and women. Bilateral lesion was observed in 5 patients (5.2%). Thirteen patients (13.4%) had a medical history of atopic dermatitis.

Primarily, treatment consisted of surgical excision of the tumor with sufficient safety margin, cryopexy in cases with broad expansion or unclear lesion boundaries, and intraoperative application of 0.04% mitomycin C (MMC) for 4 min (Fig. 4). In some cases, the lesions were reduced in size by preoperative instillation of 0.04% MMC eye drops. Postoperative instillation of 0.04% MMC or interferon (IFN)-α2b eye drops was used in advanced cases and recurrent lesions.

Squamous cell carcinoma: before treatment (a) and after resection of the tumor with cryopexy and 0.04% mitomycin C (MMC) application, followed by ocular surface re-construction by transplantation of free conjunctival graft from the same eye (a)

Among the 97 patients, 4 were treated at other hospitals. Of the remaining 93 patients, 9 (9.7%) received only 0.04% MMC or IFN-α2b instillation alone after incisional biopsy, and 84 patients (90.3%) underwent surgical excision with adjuvant therapy as described above. Re-construction after resection of the pathological conjunctiva was performed by transplantation of free bulbar conjunctiva, free tarsal plate with palpebral conjunctiva, or amniotic membrane, as needed. Three patients (3.2%) who had broad lesions at initial presentation were treated by EBRT alone. Seven patients (7.5%) required enucleation of the eyeball or orbital exenteration as the initial treatment.

Treatment outcome of 77 patients followed for 12 months or longer at our hospital were analyzed. The mean follow-up period was 35.6 ± 42.9 months. Local recurrence occurred in 24 patients (31.1%) and metastasis to regional lymph nodes was observed in 6 patients (6.2%). No metastasis to distant organs was found, and no patient died from SCC during the follow-up period.

The mean age of patients diagnosed with melanoma was 65.8 ± 15.7 (range: 28–96) years. There were 32 men and 28 women, with no significant difference in proportion of men and women. No patient had bilateral lesion. Fifty patients (83.3%) had preexisting conjunctival melanosis.

Incisional biopsy for diagnostic purpose was not done for any case of melanoma. Surgical excision of the tumor with sufficient safety margin, cryopexy, and intraoperative 0.04% MMC application were performed as eye-preserving treatment. Carbon dioxide laser was also used in some eyes with palpebral conjunctival melanoma (Fig. 5). Postoperative instillation of 0.04% MMC or IFN-α2b eye drops was used in patients with broad lesions before treatment and patients who showed local recurrence. Orbital exenteration was performed as the initial treatment in 4 patients (6.7%) with broad lesions involving the eyelid and/or infraorbital invasion. Two patients who had advanced disease and several systemic disorders at the initial presentation did not receive any curative treatment, and opted for best supportive care.

Melanoma: before treatment (a) and after resection of the tumor with carbon dioxide laser, cryopexy, and 0.04% MMC application (b). No recurrence and metastasis were observed for more than 3 years

Treatment outcomes of 45 patients who were followed for 24 months or longer at our hospital were analyzed. The mean follow-up period was 44.0 ± 21.2 months (24–105 months). Local recurrence was observed in 13 patients (28.9%) and metastases to regional lymph nodes or distant organs were confirmed in 13 patients (28.9%).　Seven patients (15.6%) died from tumor-related cause.

Two patients with BCC (one man and one woman) were aged 76 years (Fig. 6) and 52 years, respectively. The BCC arose from the caruncle. One patient underwent simple resection of the caruncle lesion. Another patient underwent extended resection including the lacrimal sac due to invasive lesion [14], and this patient showed local recurrence 18 months after the initial treatment and required additional resection.

Basal cell carcinoma. Tiny, brown colored tumor arising from caruncle (a). Histopathology was compatible with basal cell carcinoma with palisading

The two patients with Kaposi’s sarcoma were aged 44 years (Fig. 7) and 28 years. Both patients were men, and were positive for serum antihuman immunodeficiency virus (HIV) antibody. Both patients were treated with surgical resection, followed by systemic anti-retrovirus therapy and anti-human herpes virus (HHV)-8 therapy, with no recurrence for more than 12 months.

Kaposi’s sarcoma. Red, nodular lesion arising from palpebral conjunctiva (a). Characteristic histopathological findings with spindle cell proliferation and vascular clefts (a). Immunostaining is positive for HHV-8 (inset)

The patient with SFT was a 35-year-old woman (Fig. 8). She was treated with simple excision of the conjunctival lesion, and no recurrence was observed during 24 months after surgery.

Solitary fibrous tumor. Red-pink, dome shaped lesion of the bulbar conjunctiva with dilated vessels (a). Spindle to ovoid cell proliferation surrounding blood vessels (b). Immunostaining is positive for STAT6 (inset)