Lacrimal Sac Malignant Melanoma in 15 Japanese Patients: Case Report and Literature Review

Background. Primary malignant melanoma of the lacrimal sac is rare. A patient with lacrimal sac melanoma was presented, and 14 Japanese patients with lacrimal sac melanoma in the literature were reviewed. Case Presentation. A 78-year-old Japanese man was presented with painless swelling of the lacrimal sac on the left side. Dacryocystectomy revealed diffuse infiltration with large epithelioid cells, sometimes with pigments, which were positive for cocktail mix of antibodies to tyrosinase, melan A (MART-1), and HMB45, leading to pathological diagnosis of melanoma. One month later, positron emission tomography (PET) revealed 2 high-uptake sites (SUVmax = 10.29 and 15.38) at the levels of medial canthus and nasolacrimal duct, but no abnormal uptake in the other site of the body. The lesion had the BRAF V600E mutation. He began to take daily oral dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor), leading to no abnormal uptake on PET in half a year. He had stable disease in good physical status with small and weak uptake sites of lymph nodes on PET 1 year later. Results. In the review of 15 Japanese patients, including this patient, local recurrence was noted in 4 patients, regional lymph node metastasis only in 3, distant metastasis in 6, and no metastasis in 6. Five patients died within 2 years and the others were alive in short follow-up periods. Conclusions. Chemotherapy was the standard for local recurrence or metastasis. Emerging molecular target drugs, as shown in the present patient, would change the strategy for management of lacrimal sac melanoma.

previously and endoscopic colon polypectomy 4 months previously. His medication was daily amlodipine 5 mg only. Computed tomographic scan showed a 1-cm-sized round homogeneous mass with no bony change on the left lacrimal fossa ( Figure 1A). He underwent left lacrimal sac tumor extirpation under general anesthesia. The lacrimal sac filled with black mass was carefully separated from the surrounding tissue, and pigmented epithelial lesions along the nasolacrimal duct were removed as deep as possible into the duct.
The pathological examination showed malignant melanoma. The entire lacrimal sac was infiltrated with large epithelioid cells with anomalous nuclei, sometimes, multinucleated large cells in a diffuse pattern (Figure 2A and B). Pigmented abnormal cells were also present in foci. Infiltrating cells were positive for cocktail-mix antibodies against tyrosinase, melan A (MART-1, melanoma antigen recognized by T cells-1), and HMB45 ( Figure 2D), but negative for cytokeratin AE1/AE3 ( Figure 2C) or CAM5.2. A cluster of small lymphocytes were noted among the large neoplastic cells ( Figure 2B).
One month later, he developed subcutaneous pigmented bumpy lesions surrounding the medial canthus ( Figure   1F), and whole-body 2-[ 18 F]fluoro-2-deoxy-D-glucose positron emission tomography fused with computed tomography (PET/CT) showed 2 high-uptake sites (SUV max = 10. 29 and 15.38) at the levels of the medial canthus ( Figure 1B) and nasolacrimal duct ( Figure 1C), with no abnormal uptake found in the other sites of the body. The lesion had the BRAF V600E mutation by a US Food and Drug Administration-approved test (the cobas 4800 BRAF V600 Mutation Test; Roche Molecular Diagnostics, Pleasanton, CA), and he showed no rise of serum 5-S-cysteinyldopa at 5.7 nmol/L (normal range = 1.5-8.0). Two months after the surgery, he began to take oral dabrafenib (Tafinlar) 300 mg daily plus trametinib (Mekinist) 2 mg daily. In half a year, the subcutaneous and nasolacrimal ductal recurrent lesions resolved ( Figure 1G), and PET/CT showed no abnormal uptake in the orbit on the left side ( Figure 1D), with no abnormal uptake at other sites of the body. Conjunctival pigmentation in the lacrimal caruncle on the left side ( Figure 1H) remained unchanged in comparison with the initial visit. At the last visit, 1½ years after the initial visit, PET/CT showed small weak uptake sites in cervical and axillary lymph nodes. He had the stable disease in good physical status with the continuing medications at the same doses. No adverse event, except for occasional mild nausea, was noted throughout the course.

Methods
To analyze historical cases from the literature, the Japanese literature was searched for the key words "lacrimal sac melanoma (in Japanese)" in Igaku Chuo Zasshi (Japana Centra Revuo Medicina). Old literatures were further collected from references cited in the articles identified during the literature search. PubMed was also searched for the key words "lacrimal sac melanoma."

Results
The 15 Japanese patients with lacrimal sac malignant melanoma, including the present patient, were 7 men and 8 women, with the age at the initial presentation ranging from 41 to 80 (median = 60) years ( Table 1). The tumor was present on the right side in 6 patients, and on the left side in 8 patients, with unknown laterality in 1 patient (Case 9). Local recurrence was noted in 4 patients including the present case, regional lymph node metastasis only in 3 patients, distant metastasis in 6 patients, and no metastasis in 6 patients. As an initial surgery, all 15 patients underwent dacryocystectomy, except for 1 patient with orbital exenteration (Case 5). Lymph node dissection was done in 3 patients. Chemotherapy as a standard regimen at that time, including dacarbazine alone or combination of dacarbazine and nimustine, or further combined with vincristine or carboplatin was done in 7 patients. Additional surgeries for local recurrence were done in 2 patients. Local radiotherapy was applied to metastatic lesions, including the brain, in 2 patients. Two patients had both local recurrence and metastasis. Five patients died within 2 years and the others were alive although the follow-up periods were short. Pathologically, all patients showed epithelioid-type melanoma cells, except for one (Case 8) with spindle cell melanoma.

Discussion
The present patient showed local recurrence of malignant melanoma along the nasolacrimal duct in addition to the subcutaneous infiltration. The recurrent melanoma was unresectable, and thus, a combined therapy with oral dabrafenib and trametinib was applicable since the tumor had the BRAF mutation. 38,39 The patient maintained the stable disease with no local recurrence but with small lymphadenopathy later in one and a half year after the initial surgery of dacryocystectomy. He was in good quality of life and had only tolerable adverse event as mild nausea. In the development of distant lymphadenopathy with mild abnormal uptake on PET/CT, we decided to continue dabrafenib and trametinib and not to switch to PD-1 or PD-L1anitbodies because PD-1 or PD-L1 antibodies might cause adverse event, resulting in poor quality of life. It should be noted that foci of infiltration with small lymphocytes were present among the large melanoma cells. This fact suggests that PD-1 or PD-L1 antibodies might work in recovering the immune surveillance to neoplastic cells.
In literature review of Japanese patients with lacrimal sac melanoma, only 14 patients were found as case reports. The main features of lacrimal sac melanoma in 15 patients, including the present patient, were no dominance in gender and laterality. One third of patients had neither local recurrence nor distant metastasis after the initial surgery of dacryocystectomy. The patients with lymphadenopathy or distant metastasis or their combination usually underwent systemic chemotherapy based on dacarbazine and nimustine at that time, but died within 2 years after the initial surgery. Therefore, the prognosis was basically poor when metastasis was present.
In the emerging trend with new therapeutic drugs, BRAF inhibitor and MEK inhibitor, 38,39 the strategy for management of lacrimal sac melanoma would be drastically changing. As complete as possible extirpation of the lacrimal sac remains the basis for local control and pathological diagnosis. In the case of nasolacrimal duct epithelial infiltration noted during the surgery, removal of pigmented lesions as deep in the nasolacrimal duct as possible would be recommended. In case of local recurrence mainly from the nasolacrimal duct lesion, further radical surgery would not be recommended and molecular target drugs would be better tried in the situation of unresectable tumor after the BRAF mutation is confirmed. Lymph node metastasis and distant metastasis are, of course, the indication of chemotherapy with molecular target drugs. Clinical staging by PET/CT is the standard in the assessment of lacrimal sac melanoma as are melanomas which arise in other sites of the body, including conjunctival melanoma 39 and choroidal melanoma 40 in the field of ophthalmology.

Authors' Note
Data are available on reasonable request to the corresponding author.

Author Contributions
TM as an ophthalmologist followed the patient and did the surgery. TT as a pathologist made pathological diagnosis. OY as a dermatologist prescribed molecular target drugs and followed the patient. TM wrote the manuscript; TT and OY did critical review of the manuscript. All authors read and approved the manuscript.

Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article:

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article:

Ethics Approval
Not applicable to case reports, based on ethical guidelines for medical and health research involving human subjects issued by the Government of Japan.

Informed Consent
Oral informed consent was obtained from the patient.