Uveal melanoma pathobiology: Metastasis to the liver
Introduction
Uveal melanoma (UM) is the most common primary intraocular tumor in adults [1], and the second most common type of melanoma, after that of the skin [2]. The tumor originates within the pigmented uveal tract [choroid (90 %), ciliary body (6 %), and iris (4 %)] [3,4]. UM tumors are often asymptomatic and are thus frequently discovered during a routine ophthalmic examination [5,6]. The diagnosis is made primarily based on imaging modalities, including fundus photography, fluorescein angiography, fundus autofluorescence imaging, optical coherence tomography, and ultrasound imaging, making UM one of the few cancers generally diagnosed without a tissue biopsy. In Canada, the average-annual incidence rate of UM is 3.75 cases per million [7]. The mean age-adjusted incidence of UM in United States is 5.2 cases per million [8], while in Europe it varies according to latitude, with more than 8 cases per million in Northern countries and around 2 cases per million in Southern Europe [9]. Caucasian ethnicity is the most affected population (98 % of cases), with a male predominance [10]. The cause of UM remains unclear. Predisposing factors have been proposed and include light iris color [11], fair skin color [12], choroidal nevus [13], and ocular melanocytosis [4]. Among environmental factors, exposure to blue light has been suggested as a risk factor [14], while the role of ultraviolet (UV) radiation remains controversial in UM [15]. UV-hallmark mutations were found at codon 183 of G protein subunit alpha Q and 11 (GNAQ/GNA11), codon 182 of GNA11, and codon 29 of Rac family small GTPase 1 (RAC1) in UM, with typical C < T transitions at dipyrimidine sites, but these mutations account only for a small percentage of those found in UM [[16], [17], [18], [19], [20]]. No evidence of an UV radiation mutational signature was found in molecular data from 80 primary UMs available through The Cancer Genome Atlas (TCGA) [21]. Previous studies have associated UM with welding [15], a source of artificial UV radiation and blue light.
Treatment modalities for the intraocular tumor comprise radiotherapy, laser therapy, which preserve the eye, or surgical resection (enucleation) [22]. The latter treatment is considered for large tumors or blind painful eyes secondary to neovascular glaucoma or post-irradiation effects, and accounts for about 30 % of cases [3]. As such, eye-conserving alternatives such as radioactive plaque (brachytherapy) are the preferred approaches and result in effective control of the primary tumor. Despite current treatments that achieve excellent local tumor control, up to 50 % of patients develop metastasis within 15 years, which are generally asymptomatic at detection and associated with high mortality [23]. In fact, while UM accounts for only 5 % of melanoma cases, it represents 13 % of mortality from melanoma [2,24]. Therefore, this relatively rare cancer is marked by a high rate of metastasis and associated mortality. Moreover, UM has a very high predilection to metastasize to the liver, with over 90 % of metastatic cases showing hepatic lesions.
In this review, we will present an overview of prognostic indicators associated with metastasis in UM, and factors that likely play a role at the metastatic site, with a particular emphasis on the liver microenvironment given the remarkable hepatotropism of UM. We will also describe the experimental models used to study metastatic UM. Finally, we will summarize current and prospective treatments for this deadly metastatic cancer.
Section snippets
Organotropism and dormancy of metastatic uveal melanoma
Metastatic disease is detectable at diagnosis in less than 4 % of UM cases [25]. Interestingly, UM metastasizes preferentially and almost exclusively to the liver, with up to 90 % of metastatic UM associated with hepatic lesions, and in most cases, the liver is the only affected organ [26,27]. Other sites such as the lungs (24 %), bones (16 %), skin/subcutaneous tissues (11 %) and lymph nodes (10 %) can also be affected [27], while involvement of brain and fellow eye are rare (reviewed in Table
Prognostic indicators of metastasis in uveal melanoma
The poor prognosis of UM is linked to the challenge in its early diagnosis due to the lack of symptoms, few sensitive biomarkers to monitor the progression of the disease, and no effective treatments for the metastatic stage [38]. In this section, we will summarize prognostic indicators of metastasis in UM, including clinical/histopathological factors, genetic indicators, and serological biomarkers.
Metastatic cascade and liver microenvironment
Various studies agree that UM cells escape the eye through hematogenous dissemination. CTCs and other oncogenic molecules have been detected in the blood of UM patients at diagnosis, suggesting that the systemic nature of UM is an early phenomenon [35,127]. For successful metastasis, tumor cells must complete a complex sequential cascade: detachment from the primary tumor, intravasation into the vascular system, survival in the circulation, extravasation and colonization of the target organ [163
Experimental models of metastatic uveal melanoma: strengths and limitations
A major limitation in our ability to study UM metastasis is the difficulty in obtaining and assessing samples from patients with micro-metastatic or end-stage disease. Experimental models are thus essential to mimic and better understand the biology of metastasis as well as to test new therapeutic approaches for UM. Currently, there are various in vitro-based and animal models (Table 3) [[219], [220], [221]], and each has its advantages and limitations, which should be considered to choose the
Current treatments
Once metastasis is diagnosed, effective treatment options are currently limited in UM. However, some studies have reported better median survival in treated patients compared to untreated cases [290]. While UM primary tumors can be successfully controlled with radiotherapy or by surgical resection, response rates to chemotherapy or immunotherapy remain low in patients with metastases [38,291].
A surgical approach is the gold standard for patients with resectable liver metastasis but these
Conclusion
Up to 50 % of UM patients develop metastases mainly to the liver. Several primary tumor characteristics help to predict the risk of metastasis. However, there is a lack of imaging modalities or sensitive and accurate biomarkers for the early stages of metastasis, namely during the appropriate therapeutic window to begin treating the patient. There is no approved standard of care for metastatic UM, even if various treatments have been evaluated such as liver-directed therapies and immunotherapy
Funding
The Fonds de recherche du Québec – Santé (FRQS, Canada, #30903 and #32608; S.L.) and the Eye Disease Foundation (Canada, #FO115923; S.L.). The FRQS Vision Health Research Networkfinancially supports the Quebec Uveal Melanoma Biobank(Canada, #IF-2019-3; S.L. and J.V.B.). P.B. is the recipient of a CONACYT award (2019-000021-01EXTF-00293). L.P. is the recipient of a FRQS Postdoctoral Training Award (Canada, #277722).
Declaration of Competing Interest
None.
Acknowledgements
The authors would like to thank Dr. Ioana Fugaru and Mrs. Julie Bérubé for their helpful contributions to the development of the tissue-engineered hepatic stroma.
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