Rare Lacrimal Gland Melanoma: A Case Report and Treatment Insights

Introduction

We present a case of primary melanoma of the lacrimal gland, an extremely rare entity; to the best of our knowledge previously reported only once [1].

Melanoma emanates from the malignant transformation of melanocytes. Its relentless nature lies in its capacity to metastasize, necessitating early diagnosis and intervention. Over 97% of all melanomas are diagnosed with a known primary site of origin, most often involving the skin, but also the eye or mucous membranes [2]. Rarely, melanoma is classified as melanoma of unknown primary (MUP), which was initially defined as melanoma of the subcutaneous tissue, lymph nodes, or visceral organs, lacking a cutaneous, ocular, or mucosal site of origin [3]. However, there is no consensus on the extent of the physical examination, which may result from incomplete examination of all cutaneous, ocular, and mucosal areas [4]. This report describes a 68-year-old woman with a 4-week history of swelling and discoloration of the left upper eyelid and a diagnosis of melanoma of the lacrimal gland, undergoing a comprehensive work-up.

Case Report

In January 2023 a 68-year-old woman presented to her ophthalmologist with a 4-week history of left-sided, reddish-livid, and increasing eyelid swelling (Figure 1A). She was consequently referred to our institution. There was no history of previous malignancy reported. She underwent thyroidectomy due to a nodule, appendectomy, and gallbladder removal. She was taking levothyroxine 100 µg once per day and zolpidem due to a sleeping disorder. She was a smoker (5–7 cigarettes a day, 10 pack years) and reported no allergies.

Clinical examination showed a hard, livid mass at the left upper eyelid, with no clinical sign of local inflammation as the underlying cause. Ophthalmologic examination was normal apart from a pseudo-ptosis due to the swelling; there was no conjunctival involvement. Ultrasonography of the regional and remote lymph nodes was negative. She denied weight loss and pain. MRI revealed a mass of suspected malignancy, which was located within the lacrimal gland, which is located in the anterior, superotemporal orbit within the lacrimal fossa of the frontal bone. The suspect lesion extended to the anterior surface of the temporal tarsus of the upper eye lid, leading to a reddish-livid eyelid swelling, which was noted on initial presentation; the largest diameter was 21 mm (Figure 1B).

After informed consent was obtained, the patient underwent surgery under general anesthesia in February 2023. An incision at the lid crease was chosen, a 3.5×2.5 cm pigmented mass was removed from the periosteum and the tarsal plane facing the lacrimal gland. Although the whole mass comprising the lacrimal gland could be excised en bloc (Figure 1C), there was pigmentation throughout the adjacent tissues. Histopathology revealed lacrimal gland parenchyma with infiltration of epithelioid cell melanoma (Figure 2A, 2B). Immunohistochemistry work-up showed expression of vimentin, S100, melan-A, HMB-45, and SOX10 (Figure 2C–2F).

Consequently, a thorough work-up was initiated. Examination at the dermatologist showed solar elastosis as a sign of chronic sun damage but no other signs of melanoma. Screening of mucosal tissue with her gastroenterologist, gynecologist, and otolaryngologist showed no sign of melanoma. A computed tomography (CT) scan assured her lymph nodes were negative, but revealed angiolipoma of her right kidney, calcified uterus myoma, and signs of osteoporosis. A positron emission tomography (PET)-CT scan using 221MBq (Megabecquerel) F (fluor)-18 FDG (fluorodeoxyglucose) contrast agent showed a local hypermetabolism at the excision site only; no suspect lymph nodes and no other suspect areas were detected.

The patient was evaluated at the local tumor board. Two options were proposed: local radical excision (exenteration), or radiation therapy. The patient decided to undergo proton radiotherapy (64.25Gy using simultaneous integrated boost (SIB) technique, May and June 2023). In August 2023, the patient returned with a solid nodule at her right temporal upper eyelid (Figure 3A).

She was scheduled for excision-biopsy of the lesion 1 week later. On the day of surgery, close inspection showed that almost the whole tarsal plate has turned into a pigmented lesion (Figure 3B). The nodule was excised and histopathology revealed an infiltration of the eyelid in the course of the preexisting melanoma (Figure 2G, 2H). No BRAF, cKIT, or NRAS mutations were found. A subsequent restaging of the patient using CT revealed metastatic spread to the lungs. The pulmonal filiae were <0.5 mm, which made them inaccessible to CT-guided biopsy. Video-assisted thoracoscopic surgery (VATS) was scheduled in September 2023 to perform extra-anatomical segment resections of her right upper and middle lung lobes. Histopathology revealed 3 intrapulmonary and 1 lymph node metastasis of melanoma (Figure 2I, 2J).

A re-evaluation at the local tumor board showed a metastatic spread not only to the right side of her lung, but also multiple small lesions in the left pulmonary lobes (TNM (tumor, nodes, metastasis) staging: pTxN0M1b, AJCC IV (American Joint Commission on Cancer Staging Version 4): M1b, ECOG (Eastern Cooperative Oncology Group – Performance Scale): 0). The patient agreed to participate in a randomized and patient-blinded study between November 2023 and January 2024 comparing a PD-1 antibody in combination with a LAG-3 antibody to a PD-1 antibody monotherapy. Four cycles were applied. Restaging in January 2024 showed an increasing left-sided orbital mass on MRI, as well as growing lesions in the lung and mediastinal lymph nodes on CT scans. The tumor marker S100 (0.05µg/l; ULN (upper limit of normal) 0.105µg/l) and LDH (lactate dehydrogenase) (205U/l, ULN 250U/l) were not elevated at the time of progression. She subsequently received 2 cycles of ipilimumab 3 mg/kg + nivolumab 1 mg/kg showing a near complete clinical regression of the orbital tumor. In February 2024, she was hospitalized due to hypophysitis and anterior pituitary deficiency followed by lung infection, metabolic acidosis, fever, and acute kidney failure in March 2024. In April 2024 a cytologic work-up of her spinal fluid showed acute-onset viral meningitis. She died on 19 April 2024.

Discussion

The distribution of lacrimal gland tumors has been roughly estimated based on a literature review by Shields et al [5]: 10% of orbital lesions occur in the lacrimal gland, 80% of solid lacrimal gland masses are of nonepithelial origin and 20% are of epithelial origin; 55% of epithelial tumors are benign and 45% are malignant lesions. A detailed overview on lesion subtypes can be found elsewhere [6,7]. Although rare, secondary metastasis to the lacrimal gland should be considered, which mostly originate from breast and lung carcinomas [8].

Melanoma of unknown primary (MUP) [4] is defined as melanoma without a cutaneous, ocular, or mucosal primary site, most often occurring in lymph nodes, subcutaneous sites, or visceral organs. MUP accounts for approximately 3% of melanoma diagnoses. Scott and Gerstenblith state that there is common misclassification as MUP, as the lack of true primary site of the melanoma is the result of an incomplete physical examination of all cutaneous, ocular, and mucosal surfaces, or from the history omitting a previously treated or regressed melanoma [4]. Hence, Dasgupta stated in 1963 [3] that a history “of previous orbital exenteration or enucleation; evidence of previous skin excision, electrodessication, cauterization, or other surgical manipulation of a mole, freckle, birthmark, paronychia, or skin blemish; evidence of metastatic melanoma in a draining lymph node with a scar in the area of skin supplying that lymph node basin” [4]; and a “lack of a non-thorough physical examination, including the absence of an ophthalmologic, anal, and genital exam” [4] are exclusion criteria for MUP. However, heterogeneous definitions of MUP have been used in studies, and the thoroughness of the clinical examination lacks uniform standards [9].

Various hypotheses regarding the origin of MUP have been proposed: First, the spontaneous, immune-mediated regression of primary melanoma is well documented [10–13]. Second, the presence of ectopic melanocytes in lymph nodes or mucosal tissue such as the conjunctiva and gastrointestinal mucosa may be the origin of melanoma, [14,15] as melanoblastic cells are known to migrate predominately to the ileum and potentially differentiate into ectopic melanocytes [15]. Third, in primary salivary gland melanoma, a possible explanation may be the descent of melanoblasts along the downgrowth of the oral epithelium into the salivary glands [16], which is supported by the literature reporting cases of primary malignant melanomas of the parotid gland [16] and submandibular gland [17]. Due to their shared embryologic origins, tumors of the lacrimal and salivary glands share histopathologic similarities [18]. Whether a similar mechanism may underlie lacrimal gland melanomas remains to be elucidated.

Melanoma of the lacrimal gland is an extremely rare condition and to the best of your knowledge has only been reported once so far, in a case report [1]. A 50-year-old woman presented with a swelling in her left eye. The patient underwent successful surgery and adjuvant radiotherapy, as histopathological examination confirmed the diagnosis of melanoma of the lacrimal gland. A good recovery and no symptoms were reported at 3 months of follow-up.

In our patient immunohistochemistry work-up showed expression of vimentin, S100, melan-A, HMB-45, and SOX10 within the initial melanoma of the lacrimal gland. There was no staining with antibodies against AE1/3 (antibody against pan-cytokeratin), CK7 (antibody against cytokeratin), CK20, and EMA (epithelial membrane antigen). The proliferation rate (Ki67) was 40%. PD-L1 TPS was 90%. The recurrence of the tumor after radiation therapy showed positive expression of melan-A, HMB-45, and panmelanoma. The tissue was not reactive for AE1/3. Metastases in the lung were positive for melan-A, HMB-45, and S100. Again, there was no staining for AE1/3. PD-L1 TPS was 5%.

FISH examination of the melanoma of the lacrimal gland with LSI (Locus-Specific Identifier) probes against 1p36/1q25, and 8q24 and probes against centromere 3 and 8 showed polysomy of chromosomes 8 and 3. There was no deletion of 1p and no gain of 8q as expected in uveal melanoma [19].

Cutaneous, ocular, acral, and mucosal melanomas have distinct genetic profiles [20,21]. MUP shows similarities with cutaneous melanoma, in particular cutaneous sun-exposed melanoma. A study characterizing patients with MUP showed that BRAF and NRAS mutations occurred in 53% and 14% of MUP cases, respectively [22]. In our patient, the evaluation of the primary lesion revealed no mutation of BRAF (exon 11 and 15), NRAS (exon 2, 3, 4 and 5), or KIT (exon 9, 11, 13, 17, and 18) using Sanger sequencing. Analysis of the pulmonary metastasis showed pathogenic mutations in KIT exon 17: p.D816V and CTNNB1 exon 3: p.G34R using Next Generation Panel Sequencing (Ion AmpliSeq™ Cancer Hotspot Panel v2, Thermo Fisher Scientific) comprising 50 genes. This is an interesting finding and may possibly be traced back to tumor evolution after radiotherapy. Although there is a difference in techniques used, even Sanger sequencing should have detected a KIT mutation considering a tumor cell content of 90%. The lack of BRAF and NRAS mutation differs from the published genetic profile of melanoma from chronic sun-damaged skin, comprising BRAF, NRAS, and KIT mutations. However, the presence of KIT mutation usually occurs in cutaneous or mucosal melanomas rather than uveal melanoma, which shows changes in BAP1, SF3B1, and GNAQ/11 [21]. These findings may suggest a true primary melanoma of the lacrimal gland. The KIT mutation could be an indicator of tumor evolution, which was not present in Sanger sequencing as it has not yet been a dominant clone in the primary tumor, but later appeared in the pulmonary metastasis.

Conclusions

Differentiating between melanoma of known or unknown primary is a diagnostic dilemma, as melanoma can clinically appear similar to other lesions of the eyelid [23]. Although melanoma of the lacrimal gland is extremely rare, a fair degree of suspicion with histological work-up should lead to a swift diagnosis, considering its capacity to metastasize. Increased awareness of this rare condition will hopefully support early referral and treatment initiation in a tumor board setting and finally considering the patient’s treatment choice.