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Year : 2020  |  Volume : 2  |  Issue : 1  |  Page : 19

The clinical and histopathological features of patients with both uveal and cutaneous melanoma

1 Ocular Pathology and Translational Research Laboratory, MUHC–McGill University; Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Canada
2 Ocular Pathology and Translational Research Laboratory, MUHC–McGill University, Montréal, Canada

Date of Submission27-Apr-2020
Date of Acceptance07-May-2020
Date of Web Publication24-Jul-2020

Correspondence Address:
Dr. Anelise Savaris Dias
Department of Ocular Pathology, McGill University, 1001 Boul Decarie, Block E, E02.6217, Montreal, QC, H4A 3J1
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/PAJO.PAJO_23_20

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Introduction: It is unusual to have uveal and cutaneous melanoma in the same patient. It is challenging to differentiate between primary uveal melanoma (UM) and melanoma metastatic to the uvea.
Objective: The aim of this study is to evaluate the characteristics of patients who presented with concurrent melanomas (primary or metastatic) of the skin and uveal tract.
Materials and Methods: Eleven patients with both uveal and cutaneous melanomas were obtained from the McGill University Ocular Pathology Laboratory database. The characteristics included cell type, number of mitotic figures, presence of necrosis, the time interval between primary and secondary melanoma and the presence of metastasis in other organs.
Results: Five patients presented with both primary uveal and primary cutaneous melanoma, three patients with UM metastatic to the skin, and three patients with cutaneous melanoma metastatic to the uvea. In all of our cases, there was a time difference between the appearance of cutaneous and UM in the same patient.
Conclusion: Patients with two primary melanomas presented with spindle-cell type (uveal tumor), a Breslow index <1 mm, >7 years between tumors. Systemic disease was negative. Patients with metastasis from cutaneous melanoma to the eye and from ocular to the skin showed epithelioid cell type, a Breslow index >1.5 mm, <5 years between tumors and positive systemic disease.

Keywords: Cell type, metastases, primary melanoma, skin melanoma, uveal malignant melanoma

How to cite this article:
Dias AS, Burnier JV, Bergeron S, Miyamoto D, Campos Ferreira PC, Dantas CN, Coblentz J, Burnier MN. The clinical and histopathological features of patients with both uveal and cutaneous melanoma. Pan Am J Ophthalmol 2020;2:19

How to cite this URL:
Dias AS, Burnier JV, Bergeron S, Miyamoto D, Campos Ferreira PC, Dantas CN, Coblentz J, Burnier MN. The clinical and histopathological features of patients with both uveal and cutaneous melanoma. Pan Am J Ophthalmol [serial online] 2020 [cited 2021 Jun 23];2:19. Available from: https://www.thepajo.org/text.asp?2020/2/1/19/290580

  Introduction Top

Skin melanoma (SM), the most common form of melanoma, is a potentially fatal melanocytic neoplasm. Histopathological characteristics are Breslow level (thickness), mitotic rate, ulceration, regression, lymphovascular invasion, and histopathologic subtype.

The second-most common type of melanoma is uveal melanoma (UM), the most common primary intraocular malignant tumor in adults.[1] It largely derives from melanocytes of the uveal tract, which is composed of the iris, choroid, and ciliary body. There are some intrinsic factors that favoring melanoma formation, which are Caucasian race, family history of UM, blue-colored eyes, and red/blond hair individuals, fair skin, congenital ocular melanocytosis, melanocytoma, and the BAP1 cancer predisposition syndrome.[1] Histopathological subtypes are classified into the spindle, epithelioid, and mixed cells. Epithelioid cell tumors are associated with a worse prognosis.[2] The gold standard for the treatment for UM includes brachyradiotherapy, resection of the ocular tumor, or enucleation, which is usually reserved for large intraocular melanomas.[3]

While both SM and UM stem from melanocytes, the molecular characteristics that drive tumor development to differ. Recent genomic discoveries have revealed a high mutational burden and a distinct genomic landscape in SM, which highlights the genomic instability of this cancer type. Approximately 50% of patients harbor a mutation in BRAF at V600, which is thought to be a driver mutation. In contrast, UM is characterized by G protein-coupled singling changes, with mutations in the G protein-encoding genes GNAQ and GNA11 found in >80% of patients. Cytogenetic analysis of UM has been used for the prognostication of tumors, with chromosome 3 monosomy the single strongest cytogenic factor to predict UM metastasis. Somatic mutation in BAP1, resulting in loss of protein expression, is associated with an increased risk of metastasis, and approximately 84% of metastatic UM patients maintain only the mutated allele of BAP1.[4] PRAME (preferentially expressed antigen in melanoma) mRNA expression may also be an indicator of metastasis.[5] However, the use of tumor biomarkers and gene profiling is still limited in that it relies on enucleation or intraocular biopsy.

Intraocular metastases from SM are less common than primary UM. In general, intraocular metastases are flat tumors or rapidly enlarging nodules in the uveal tract, bilateral, and multiple.[2]

Differentiating between cases of two primary melanomas (uveal tract and skin) and metastatic melanoma can be challenging, especially given the rarity of such cases reported in the literature. In this report, we present 11 cases of uveal and cutaneous tumors that could be diagnosed as primary or metastatic melanoma based on clinical and histopathological findings.

  Materials and Methods Top

Clinical data of 11 patients with concurrent skin and UM, between 1997 and 2016, were obtained from the McGill University Ocular Pathology Laboratory database. Institutional review board approval was obtained. The data include histopathological features of both tumors, the time interval between the occurrence of the melanomas, ocular personal and family history of melanoma, and other cancers. These patients were classified into three groups: concurrent primary SM and primary UM, metastatic UM to the skin, and metastatic SM to the uveal tract.

  Results Top

Concurrent primary uveal melanoma and primary skin melanoma

Five patients had an interval between melanomas of 7 years or more. The average age of this group was 60.6 years. The ocular tumor was spindle cell type in 60% of these patients, and mixed cell type in the other 40%. There were no metastases in these five cases on systemic workup. Histopathologically, in all cases, the UM displayed a small number of mitotic figures (<2/40 high-power fields [HPF]), no necrosis, and represented a slow-growing tumor. The SM in all cases had a Breslow level (thickness) of <0.9 mm [Figure 1]. These characteristics were inconsistent with metastasis, and thus suggested concurrent primary melanomas of the skin and uveal tract.
Figure 1: Patient with primary uveal and primary skin melanoma. (a) Gross pathology of the iridocyclectomy specimen. (b) Iridocyclectomy specimen with free surgical margins. (c and d) Histopathology of the iridocyclectomy specimen displaying a spindle cell melanoma

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Primary uveal melanoma metastatic to the skin

One patient was diagnosed with epithelioid cell type UM, and two patients with mixed cell type UM. The average age corresponded to 77.3 years. The time interval between the occurrence of both melanomas was <4 years. All three patients developed metastases in several organs, including the liver. One of the patients had hepatic and pulmonary metastasis, another patient had involvement of multiple organs, including the skin after 3 years, whereas the other, had skin and liver metastases after 4 years [Figure 2]. Based on these characteristics and the aggressive nature of the ocular tumor cell type, they were diagnosed as primary UM metastatic to the skin.
Figure 2: Ciliary body melanoma metastatic from the skin. (a) Histopathology: low power view of the ciliary body tumor. (b) Histopathology: epithelioid cell melanoma with numerous mitotic figures. (c) Histopathological: extensive areas of necrosis. (d) Skin melanoma: Breslow 2.39 mm

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Primary skin melanoma metastatic to the uveal tract

Three patients had SM with a Breslow level >1 mm, followed by UM of epithelioid cells, with a large number of mitotic figures (>20/20 HPF) and large areas of necrosis, representing a rapidly growing tumor. The time interval between the occurrence of melanomas was <3.5 years. The mean age was 73.66 years. These patients showed clinical and histopathological characteristics consistent with primary SM metastatic to the uveal tract.

  Discussion Top

Distinguishing between a metastatic or primary UM is of prognostic importance since intraocular metastases of melanoma (IOMM) are associated with a survival average interval between the diagnosis of IOMM and death of 8.8 months. In contrast, in patients with primary UM, this time interval is more variable, with an accumulated 5-year survival rate reported to be up to 60%.[6] However, the clinical differentiation between metastatic melanoma and a second primary melanoma is challenging, as there are few cases reported in the literature, lack of complete data provided by the reports, and similarity of the histopathological features.

In this study, we used a combination of clinical and histopathological features to differentiate concurrent tumors from metastatic lesions.

Concurrent primary uveal melanoma and primary skin melanoma

In a literature search, we found only four more cases previously reported of this occurrence. Gilbert et al. described one case. This patient's past medical history included excision of cutaneous melanoma (Breslow 1.75), 20 years before the eye tumor. The histopathologic diagnosis was spindle-B malignant melanoma of the ciliary body and choroid. There was no evidence of metastasis.[7]

Augsburger et al. described an old patient who had a cutaneous melanoma (Breslow 1.73), that had been excised 11 years before the appearance of an ocular lesion. No evidence of metastasis was found. The right eye was enucleated and displayed a mixed cell type malignant melanoma with numerous mitotic figures and areas of necrosis. The pathological diagnosis was diffuse primary malignant melanoma of the uvea, mixed cell type.[8]

Paton and Thomas presented a case of an old Caucasian patient, with simultaneous occurrence of primary malignant melanomas of the eye and the skin. This patient observed a discrete nodule forming at the lateral canthus of the eyelid skin, and became aware of a progressive brown discoloration of the eyeball itself. The skin lesion was removed, and its diagnosis was SM. The tumor was composed of small oval and spindle - shaped cells. Enucleation was performed. Histopathological analysis revealed a choroidal melanoma. Bleached sections showed spindle cells with fine reticular pattern in the nucleus, and poorly defined nucleoli consistent with spindle A melanoma cells.[9]

Eide and Foerster reported a case of an old person with a retinal detachment presumed to be secondary to a juxta papillary tumor. A year before, a red nodule was detected, which was excised, and the following day the left eye was enucleated. A diagnosis was made of a cutaneous, superficial spreading malignant melanoma in situ with a satellite tumor to the dermal region. The histopathological pattern of the enucleated left eye was consistent with a primary mixed cell type choroidal melanoma.[10]

This group of patients with both primary cutaneous and UMs have in common spindle or mixed cell-type UM, small number of mitotic figures (<2/40 HPF), and no necrosis in the uveal tumor. The cutaneous melanoma displays a low Breslow level (<0.90mm). Interestingly, the time interval between the skin and the ocular melanoma was simultaneous or seven years or more. These characteristics were found in all patients in our group and are in accordance with the patients reported in the literature[11][Table 1].
Table 1: Concurrent primary uveal melanoma and primary cutaneous melanoma

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Primary uveal melanoma metastatic to the skin

Skin metastases are rare, and there are only 6 cases described in the literature with systemic metastasis of UM involving the skin.

UM metastasizes hematogenously, likely due to the lack of a draining lymphatic system in the eye, and almost exclusively to the liver. Experimental studies show that human UM cells injected via tail-vein in nude mice are found almost exclusively in the liver after 20 days.[12] We found only three cases reporting skin metastasis without hepatic involvement from UM.[13],[14] The mutations of GNAQ/GNA11 have been reported exclusively in primary UM, and hence, these mutations can be used as a tool to differentiate between primary uveal or metastatic melanoma.[15]

Zimmerman and McLean reported a case with decreased visual acuity in the right eye. After several years, this eye became glaucomatous. Three years after admission, a skin lesion was discovered and excised. It was initially interpreted as a primary SM. Ocular melanoma was diagnosed after 2 months, only when it spread to the sclera. Enucleation was performed. There was a large choroidal melanoma of mixed cell type. Two years after enucleation, the patient had evidence of widespread metastatic disease. On review of the cutaneous lesion, some consultants thought it could be a metastatic UM to the skin.[16]

Schwartz et al. described a patient complaining of a skin lesion. This person had an ocular melanoma treated 3 years earlier by enucleation. Histopathologically, the cutaneous tumor showed a collection of atypical, hyperchromatic cells in the deep dermis. HMB-45 staining was positive in most of these cells, revealing them to be melanocytes. The patient declined further evaluation and possible therapy and was lost to follow-up.[17]

Caminal Mitjana et al. presented an old patient with choroidal and ciliary body melanoma in the left eye. Pathological examination showed an epithelioid-cell melanoma. A year later, melanocytic skin lesions appeared on the scalp, as well as tumors in several organs, including the liver. Pathological examination of the subcutaneous lesions confirmed metastases of UM origin.[18]

Many cases of metastatic primary UM to other organs have been reported, but metastasis to the skin is rare. All patients reported here with metastatic disease to the skin showed liver involvement, with a time interval between UM and metastatic tumors of <4 years. Two patients were diagnosed with mixed cell type and the remaining as an epithelioid cell melanoma[Table 2]. Similar results have been reported by other authors.[13],[14],[17],[18]
Table 2: Primary uveal malignant melanoma metastatic to the skin

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Primary skin melanoma metastatic to the uvea

Malignant SM accounts for <5% of all metastasis to the eye and ocular adnexa and is usually associated with a poor prognosis.[3] Three patients, in our study, had this diagnosis, and in all of them, we found epithelioid cell type. The choroid lesion was solitary even when it was from skin to the uveal tract. None of the patients had lymph node involvement, which is a surprising characteristic in these patients. The longest time between primary and metastatic melanoma was 3.5 years.

Ten case reports have previously reported primary SM metastatic to the uveal tract.[19],[20],[21],[22],[23],[24],[25],[26],[27],[28] Five of these studies presented a time-interval of <5 years between the occurrence of the primary and metastatic tumors; none of them reported the cell type of the ocular tumor.[20],[21],[23],[24],[26] Four had metastases to other organs.[21],[22],[23],[24],[26]

Four cases described by Fernandez et al., Drummond et al., Hirst et al., and Küsters-Vandevelde reviewed that the time interval between melanomas was >6 years.[19],[20],[27],[28] Although we do not have data describing cell type, SM Breslow level, tumor growth rate, number of mitotic figure, and presence of necrosis, these cases could represent two independent primary tumors, particularly due to the long-time interval between both melanomas.

A case series, containing 14 patients, has also reported the presence of both SM and UM with no significant data to distinguish between primary and metastatic tumors.[29] Most of them have described only the diagnosis, without any other data [Table 3].
Table 3: Primary cutaneous malignant melanoma metastatic to the uvea

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  Conclusion Top

The combination of specific features of primary skin and UMs may help to differentiate those cases from metastatic UM to the skin and metastatic SM to the eye. Our cases of concurrent primary SM and UM were mostly composed of spindle cell ocular tumors with a low number of mitotic figures, no necrosis, slow growth, and a Breslow level <0.90 mm in the SM. These cases also showed simultaneous diagnosis or time interval between melanomas >5 years.

The patients with SM metastasis to the uveal tract presented with the following characteristics: epithelioid cell ocular tumors with a large number of mitotic figures, large areas of necrosis, and rapid growth, as well as high Breslow level in the SM. The interval between the skin and ocular lesions was <5 years and the presence of metastasis in other organs [Table 4].
Table 4: Primary skin and uveal melanoma

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Future use of molecular characteristics, such as cytogenetics, the presence of GNAQ/11 and BAP1 mutations, and PRAME expression in UM, BRAF mutations in SM, and other molecular indicators could help further to differentiate the origin of concurrent skin and ocular melanomas.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]


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