Radiotherapy of Conjunctival Melanoma: Role and Challenges of Brachytherapy, Photon-Beam and Protontherapy
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applied sciences Review Radiotherapy of Conjunctival Melanoma: Role and Challenges of Brachytherapy, Photon-Beam and Protontherapy Corrado Spatola 1,2, Rocco Luca Emanuele Liardo 2, Roberto Milazzotto 2 , Luigi Raffaele 2, Vincenzo Salamone 2, Antonio Basile 1,2, Pietro Valerio Foti 1,2, Stefano Palmucci 1,2 , Giuseppe Antonio Pablo Cirrone 3, Giacomo Cuttone 3, Andrea Russo 4 , Teresio Avitabile 4, Michele Reibaldi 5 , Antonio Longo 4, Giuseppe Broggi 1 , Vincenza Bonfiglio 6, Rosario Caltabiano 1 , Stefano Pergolizzi 7 and Floriana Arena 7,* 1 Dipartimento di Scienze Mediche, Chirurgiche e Tecnologie Avanzate “G.F. Ingrassia”, Università di Catania, 95125 Catania, Italy; [email protected] (C.S.); [email protected] (A.B.); [email protected] (P.V.F.); [email protected] (S.P.); [email protected] (G.B.); [email protected] (R.C.) 2 UO Radiodiagnostica e Radioterapia Oncologica AOU Policlinico-S.Marco Catania, 95125 Catania, Italy; [email protected] (R.L.E.L.); [email protected] (R.M.); raff[email protected] (L.R.); [email protected] (V.S.) 3 Istituto Nazionale di Fisica Nucleare-LNS Catania, 95125 Catania, Italy; [email protected] (G.A.P.C.); [email protected] (G.C.) 4 Dipartimento di Chirurgia Generale e Specialità Medico-Chirurgiche, Università di Catania, 95125 Catania, Italy; [email protected] (A.R.); [email protected] (T.A.); [email protected] (A.L.) 5 Dipartimento di Oftalmologia, Università di Torino, 10124 Torino, Italy; [email protected] 6 Dipartimento di Oftalmologia, Università di Palermo, 90133 Palermo, Italy; vincenzamariaelena.bonfi[email protected] 7 Department Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali, Università di Messina, 98100 Messina, Italy; [email protected] * Correspondence: [email protected] Received: 15 October 2020; Accepted: 14 December 2020; Published: 18 December 2020 Abstract: Conjunctival melanoma is a rare neoplasia, whose therapeutic management is generally of ophthalmological relevance, through radical surgical resection. The high incidence of local relapses after surgery, has made it necessary to combine various types of adjuvant treatments, which in some cases take on the role of radical treatments. Among these non-surgical treatments, those involving the application of ionizing radiation are becoming particularly important. In this review, we discuss the role of episcleral brachytherapy, external photon-beam radiotherapy, also made through stereotactic or radiosurgical modality, and of proton-beam radiotherapy. We try also to take stock of the benefits of the different irradiation modalities and the application difficulties of each. Keywords: Conjunctival melanoma; episcleral brachytherapy; proton-beam radiotherapy 1. Introduction and General Overview Conjunctival melanoma (CM) is a rare ocular disease, accounting for about 2% of all ocular malignancies. Its incidence has been increasing in recent years, with 0.3–0.8 cases per million people in Western countries, mainly in Caucasian ethnicity, but can occur in African or in Afro-Americans as well. It most commonly appears in middle-aged or elderly white individuals. In the US, the incidence increased by 295% from 1973 to 1999 [1–3]. Appl. Sci. 2020, 10, 9071; doi:10.3390/app10249071 www.mdpi.com/journal/applsci Appl. Sci. 2020, 10, 9071 2 of 8 Appl. Sci. 2020, 10, x FOR PEER REVIEW 2 of 8 Usually, itit arisesarises from primary acquired melanosis (PAM), inin about 75% of cases, less frequently from a pre-existingpre‐existing conjunctivalconjunctival nevus or de novo.novo. CM arising from PAM appears as a thickeningthickening lesion. Histopathologically, PAM withwith mildmild atypiaatypia hashas lessless likelihood of transformation to melanoma than PAM withwith severesevere atypiaatypia [[4].4]. De novo melanomas melanomas carry carry a a higher higher risk risk of of metastasis metastasis and and death. death. As in As cutaneous in cutaneous melanoma, melanoma, sun sunexposure exposure is a high is a high risk riskfactor factor and andplays plays an important an important role role in the in pathogenesis the pathogenesis of CM. of CM. Clinically, CMCM appearsappears asas aa nodularnodular oror flatflat pigmentedpigmented lesion, commonly located on the nasal or temporal bulbarbulbar conjunctivaconjunctiva (Figure (Figure1 ),1), and, and, less less frequently, frequently, as as amelanotic amelanotic tumors. tumors. It has It has a tendency a tendency to spreadto spread directly directly to any to any part part of conjunctiva, of conjunctiva, to the to cornea, the cornea, globe, eyelid,globe, orbit,eyelid, sinus orbit, or sinus central or nervous central system,nervous and system, through and through lympho-vascular lympho‐vascular drainage drainage to the laterocervical to the laterocervical lymph nodes lymph or nodes distant or organs,distant asorgans, reported as reported in the AJCC in the eighth AJCC edition eighth stagingedition systemstaging [ system5,6]. Pathologic [5,6]. Pathologic staging isstaging based is on based vertical on thickness and depth of invasion, and, consequently, it is classified as follows: 0.5, 0.5–1.5, and >1.5 mm. vertical thickness and depth of invasion, and, consequently, it is classified≤ as follows: ≤0.5, 0.5–1.5, Breslowand >1.5 stagesmm. Breslow are not routinelystages are used not routinely to classify used CM. to classify CM. Figure 1. Slitlamp photographphotograph ofof a a conjuntival conjuntival melanoma, melanoma, histologically histologically confirmed, confirmed, with with a tendency a tendency to invadeto invade the the limbus limbus and and cornea. cornea. Biologically, CM shows shows different different behavior behavior than than uveal uveal melanoma, melanoma, while while it is it quite is quite similar similar to that to thatof its of cutaneous its cutaneous counterpart. counterpart. Molecular Molecular characterization characterization studies, studies, developed developed to understand to understand the tumor the tumorbiology biology and possibly and possibly to implement to implement any new anytherapeutic new therapeutic approaches, approaches, have confirmed have confirmed this similitude this similitudewith cutaneous with cutaneousmelanoma. melanoma. In particular, In particular, Griewank Griewank et al. found et al. BRAF found (of BRAF which, (of 91% which, were 91% V600E) were V600E)mutations mutations in 29% in and 29% NRAS and NRAS in 18% in 18% of conjunctival of conjunctival melanoma melanoma analyzed, analyzed, similar similar to to cutaneous melanomas [[7].7]. Diagnosis requires a complete examination of bulbar and tarsal conjunctiva, as well as orbitalorbital rim, due to the high rate of recurrence in that region. Opthalmic examination, slit slit-lamp‐lamp photography with clinical drawing, in vivovivo confocalconfocal microscopymicroscopy (IVCM),(IVCM), optical coherence tomography (OCT), and ultrasound biomicroscopy biomicroscopy (UBM) (UBM) are are variably variably used used for for documenting documenting the the localization localization and and size size of ofthe the lesion lesion and and to study to study its itslocal local extension. extension. These These non non-invasive‐invasive imaging imaging techniques techniques could could support support the thediagnosis, diagnosis, but butthe theexcisional excisional biopsy biopsy of a of clinically a clinically suspicious suspicious lesion lesion is undoubtedly is undoubtedly the the standard standard of ofcare. care. CT and MRI of thethe orbit,orbit, maxillofacialmaxillofacial region and brain are useful when an orbital,orbital, nasal and paranasal sinussinus or or central central nervous nervous system system involvement involvement is suspected. is suspected. Whole Whole body body PET /PET/CTCT scan scan or MRI or ofMRI the of neck the canneck reveal can reveal lymphatic lymphatic spread spread to proximal to proximal nodes, nodes, and metastatic and metastatic disease disease to regional to regional lymph nodeslymph is nodes accessed is accessed using sentinel using sentinel lymph nodelymph biopsy node (SLNB)biopsy (SLNB) [8]. [8]. Surgery is thethe mainstaymainstay ofof treatment.treatment. Shields Shields introduced introduced in in 1997 the “no touch” technique, describing surgicalsurgical guidelines guidelines to allowto allow a complete a complete en-bloc en tumor‐bloc tumor removal removal with wide with margins, wide avoidingmargins, directavoiding tumor direct manipulation tumor manipulation [9]. This technique [9]. This technique is widely is accepted widely andaccepted applied, and in applied, order to in minimise order to cellminimise seeding cell and seeding reduce and the reduce likelihood the likelihood of recurrence. of recurrence. Incisional Incisional biopsy is biopsy discouraged, is discouraged, as well as narrow-marginwell as narrow‐ resection;margin resection; a margin a ofmargin at least of 2at mm least is generally2 mm is generally advised, thoughadvised, some though surgeons some surgeons suggest 5 mm when possible. In case of suspect involvement of the Tenon capsule, or when Appl. Sci. 2020, 10, 9071 3 of 8 suggest 5 mm when possible. In case of suspect involvement of the Tenon capsule, or when there is any evidence of scleral adhesion or pigment, a local dissection to these structures should also be performed. Less frequently, CM presents as extensive infiltrating tumor, requiring enucleation or orbital exenteration. This is the case of eyes with limbal lesion,