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• W2109181421 abstract "Most cutaneous melanomas (CMs) that metastasize to the conjunctiva are the result of hematogenous spread and are associated with short survival. We describe a patient with an unusual conjunctival metastasis from a CM of nearby temporal skin. The location of the 2 tumours raised the possibility of nonhematogenous spread, a distinctly uncommon event. A 61-year-old white male was referred from his oncologist for a new pigmented lesion on the surface of the left eye, discovered several weeks ago. The patient had no visual symptoms. His medical history was significant for nodular-ulcerative CM of the left temple skin roughly 4 cm from the eye. A biopsy was performed 4 months earlier. The Breslow depth of invasion was 6.9 mm, and the Clark level was IV. The deep and lateral surgical margins were involved; no lymphatic or vascular invasion was reported. After biopsy, positron emission tomography with computed tomography revealed hypermetabolic masses of the left parotid gland and liver. Fine-needle biopsies of both tissues showed metastatic melanoma with BRAF-v600E mutation. Because of liver involvement, he was not offered regional lymph node dissection, nor was the residual skin melanoma excised. Intervening skin between biopsy site and eye was grossly uninvolved. The patient was staged T4b/N1/M1 and then started on ipilimumab, a monoclonal antibody approved in 2013 for the treatment of metastatic melanoma. Ophthalmic examination at the time of referral revealed visual acuities of 20/30 OD and 20/25 OS. The left eye demonstrated a brown conjunctival nodule 4 mm in diameter at 3 o’clock (Fig. 1). The overlying epithelium was intact and glistening. The remainder of the ophthalmic examination was essentially normal. High-frequency ultrasound biomicroscopy showed no scleral or ciliary body involvement. The patient underwent complete excision with cryotherapy to the base and peripheral margins; the defect was covered with an amniotic membrane. Pathologic examination of the conjunctival tumour showed a 4.1-mm-thick melanoma. Tumour cells were large with irregular nuclei and prominent nucleoli, and were arranged in cords and ribbons (Fig. 2). The Ki-67 index was 29%. The overlying epithelium was intact but contained numerous large atypical melanocytes (pagetoid cells). Melanocytes both within the epithelium and substantia propria stained positive with HMB-45 and MART-1 (Fig. 2, inset). A pancytokeratin stain highlighted the interface of epithelium with substantia propria, which remained undisturbed (Fig. 3). Using appropriate immunohistochemical stains, tumour cells could not be found in lymphatic or vascular channels in the surrounding substantia propria. An assay for the BRAF-v600E mutation from a different laboratory and at a later date failed to detect the mutation.Fig. 3Pancytokeratin stain highlights the continuous and intact epithelium over the tumour. Atypical melanocytes are outlined by surrounding positive-staining keratinocytes (immunoperoxidase; scale bar = 90 μm). Inset, Higher magnification shows the abrupt delineation between epithelium (arrows) containing nonstaining pagetoid melanocytes and the underlying substantia propria (immunoperoxidase; scale bar = 30 μμm).View Large Image Figure ViewerDownload (PPT) This conjunctival melanoma was unusual because the tumour occupying the substantia propria was covered by an uninterrupted and nonulcerated epithelium containing malignant melanocytes. The epithelial–subepithelial interface was intact in all sections studied by light microscopy. When this phenomenon occurs in the skin it has been referred to as epidermotropic metastatic melanoma; the mechanism of intraepithelial metastasis is speculative.1Abernethy J.L. Soyer H.P. Kerl H. et al.Epidermotropic metastatic malignant melanoma simulating a melanoma in situ. A report of 10 examples from two patients.Am J Surg Pathol. 1994; 18: 1140-1149Crossref PubMed Scopus (50) Google Scholar, 2Kornberg R. Harris M. Ackerman A.B. Epidermotropically metastatic malignant melanoma. Differentiating malignant melanoma primary in the epidermis.Arch Dermatol. 1978; 114: 67-69Crossref PubMed Scopus (56) Google Scholar Some epidermotropic metastatic melanomas consist solely of in situ lesions.1Abernethy J.L. Soyer H.P. Kerl H. et al.Epidermotropic metastatic malignant melanoma simulating a melanoma in situ. A report of 10 examples from two patients.Am J Surg Pathol. 1994; 18: 1140-1149Crossref PubMed Scopus (50) Google Scholar We thought the possibility of melanoma arising in primary acquired melanosis unlikely given the recent history of white conjunctiva in the area of involvement and the lack of demonstrable connection between melanocytic proliferations in the epithelium and substantia propria. Before this case, 18 patients with CM metastatic to the conjunctiva had been reported in the literature (Table 1).3Dhar-Munshi S. Ameen M. Wilson R.S. Simultaneous metastases of cutaneous malignant melanoma to conjunctiva and choroid.Br J Ophthalmol. 2000; 84: 930-931Crossref PubMed Scopus (5) Google Scholar, 4Font R.L. Naumann G. Zimmerman L.E. Primary malignant melanoma of the skin metastatic to the eye and orbit. Report of ten cases and review of the literature.Am J Ophthalmol. 1967; 63: 738-754Abstract Full Text PDF PubMed Scopus (81) Google Scholar, 5Günther I. Ocular metastases in malignant melanoma of the skin [author’s transl].Klin Monbl Augenheilkd. 1973; 162: 821-823PubMed Google Scholar, 6Jakobiec F.A. Buckman G. Zimmerman L.E. et al.Metastatic melanoma within and to the conjunctiva.Ophthalmology. 1989; 96: 999-1005Abstract Full Text PDF PubMed Scopus (27) Google Scholar, 7Kiratli H. Shields C.L. Shields J.A. De Potter P. Metastatic tumours to the conjunctiva: report of 10 cases.Br J Ophthalmol. 1996; 80: 5-8Crossref PubMed Scopus (75) Google Scholar, 8Kwapiszeski B.R. Savitt M.L. Conjunctival metastasis from a cutaneous melanoma as the initial sign of dissemination.Am J Ophthalmol. 1997; 123: 266-268Abstract Full Text PDF PubMed Google Scholar, 9Lees V.A. Briggs J.C. Effects of initial biopsy procedure on prognosis in stage 1 invasive cutaneous malignant melanoma: review of 1086 patients.Br J Surg. 1991; 78: 1108-1110Crossref PubMed Scopus (95) Google Scholar, 10Shields J.A. Eagle Jr, R.C. Gausas R.E. et al.Retrograde metastasis of cutaneous melanoma to conjunctival lymphatics.Arch Ophthalmol. 2009; 127: 1222-1223Crossref PubMed Scopus (6) Google Scholar, 11Shields J.A. Shields C.L. Eagle Jr, R.C. Raber I.M. Conjunctival metastasis as initial sign of disseminated cutaneous melanoma.Ophthalmology. 2004; 111: 1933-1934Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 12Strempel I. Metastatic conjunctival tumor originating in a primary cutaneous malignant melanoma [author’s transl].Ophthalmologica. 1982; 185: 52-57Crossref PubMed Scopus (5) Google Scholar Clinically relevant information was extractable in 17 patients. Among these 17 patients, a prior diagnosis of CM was known in all but 3. The conjunctival tumour was the initial sign of metastatic melanoma in 3 other patients. Patients ranged in age from 18 to 70 years (mean 49 years); all but 3 were men. Seven patients had simultaneous intraocular metastases involving the iris, ciliary body, choroid, anterior chamber, vitreous, or retina. Time from diagnosis of primary CM ranged from less than 3 months to 5 years, with a mean of 24.2 months. Survival after diagnosis of conjunctival metastases ranged from 3 weeks to 16 months (median 4 months).Table 1Reported cases of cutaneous melanoma metastatic to the conjunctivaCase No.Age/Sex/RaceSite of Primary MelanomaTumour Morphology/Depth of Invasion*Clark level or Breslow thickness.Other Metastasis Known at Time of Conjunctival DiagnosisOther Ocular SitesTime Primary Diagnosis to Conjunctival Metastasis (mo)Survival after Conjunctival Metastasis (mo)Reference1———YesRetina——5Günther I. Ocular metastases in malignant melanoma of the skin [author’s transl].Klin Monbl Augenheilkd. 1973; 162: 821-823PubMed Google Scholar2—Calf——Bilateral ciliary body, angle——4Font R.L. Naumann G. Zimmerman L.E. Primary malignant melanoma of the skin metastatic to the eye and orbit. Report of ten cases and review of the literature.Am J Ophthalmol. 1967; 63: 738-754Abstract Full Text PDF PubMed Scopus (81) Google Scholar3—Shoulder——Ipsilateral choroid——4Font R.L. Naumann G. Zimmerman L.E. Primary malignant melanoma of the skin metastatic to the eye and orbit. Report of ten cases and review of the literature.Am J Ophthalmol. 1967; 63: 738-754Abstract Full Text PDF PubMed Scopus (81) Google Scholar418/M/WPreauricular—YesBilateral choroid, ciliary body19—4Font R.L. Naumann G. Zimmerman L.E. Primary malignant melanoma of the skin metastatic to the eye and orbit. Report of ten cases and review of the literature.Am J Ophthalmol. 1967; 63: 738-754Abstract Full Text PDF PubMed Scopus (81) Google Scholar556/M/WBack—YesBilateral choroid, ciliary body2.565Günther I. Ocular metastases in malignant melanoma of the skin [author’s transl].Klin Monbl Augenheilkd. 1973; 162: 821-823PubMed Google Scholar661/F/WBackSS/Clark VYesNone36—12Strempel I. Metastatic conjunctival tumor originating in a primary cutaneous malignant melanoma [author’s transl].Ophthalmologica. 1982; 185: 52-57Crossref PubMed Scopus (5) Google Scholar738/M/WBackNod/Clark IIIYesNone<1216Jakobiec F.A. Buckman G. Zimmerman L.E. et al.Metastatic melanoma within and to the conjunctiva.Ophthalmology. 1989; 96: 999-1005Abstract Full Text PDF PubMed Scopus (27) Google Scholar842/M/WBackYesIpsilateral iris746Jakobiec F.A. Buckman G. Zimmerman L.E. et al.Metastatic melanoma within and to the conjunctiva.Ophthalmology. 1989; 96: 999-1005Abstract Full Text PDF PubMed Scopus (27) Google Scholar955/M/WBackYesNone1166Jakobiec F.A. Buckman G. Zimmerman L.E. et al.Metastatic melanoma within and to the conjunctiva.Ophthalmology. 1989; 96: 999-1005Abstract Full Text PDF PubMed Scopus (27) Google Scholar1022/M/WAbdomenNod/Clark IVYesNone16106Jakobiec F.A. Buckman G. Zimmerman L.E. et al.Metastatic melanoma within and to the conjunctiva.Ophthalmology. 1989; 96: 999-1005Abstract Full Text PDF PubMed Scopus (27) Google Scholar1153/M/—BackNod/—YesBilateral anterior chamber, vitreous346Jakobiec F.A. Buckman G. Zimmerman L.E. et al.Metastatic melanoma within and to the conjunctiva.Ophthalmology. 1989; 96: 999-1005Abstract Full Text PDF PubMed Scopus (27) Google Scholar1254/F/———YesIris71167Kiratli H. Shields C.L. Shields J.A. De Potter P. Metastatic tumours to the conjunctiva: report of 10 cases.Br J Ophthalmol. 1996; 80: 5-8Crossref PubMed Scopus (75) Google Scholar1370/M/———YesIris, ciliary body1527Kiratli H. Shields C.L. Shields J.A. De Potter P. Metastatic tumours to the conjunctiva: report of 10 cases.Br J Ophthalmol. 1996; 80: 5-8Crossref PubMed Scopus (75) Google Scholar1452/M/—NeckNod/Clark IV/7 mmNoNone4218Kwapiszeski B.R. Savitt M.L. Conjunctival metastasis from a cutaneous melanoma as the initial sign of dissemination.Am J Ophthalmol. 1997; 123: 266-268Abstract Full Text PDF PubMed Google Scholar1542/M/WBackSS/Clark IV/3.5 mmNoBilateral choroid24<13Dhar-Munshi S. Ameen M. Wilson R.S. Simultaneous metastases of cutaneous malignant melanoma to conjunctiva and choroid.Br J Ophthalmol. 2000; 84: 930-931Crossref PubMed Scopus (5) Google Scholar1658/M/BHeelALYesNone48313Ziakas N.G. Eke T. Kendall C.H. Goulstine D.B. Metastatic cutaneous melanoma to the conjunctiva in an Afro-Caribbean patient.Eye (Lond). 2000; 14: 667-668Crossref PubMed Scopus (5) Google Scholar1748/F/—Axilla—NoNone48—11Shields J.A. Shields C.L. Eagle Jr, R.C. Raber I.M. Conjunctival metastasis as initial sign of disseminated cutaneous melanoma.Ophthalmology. 2004; 111: 1933-1934Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar1861/M/WPreauricular—NoNone181610Shields J.A. Eagle Jr, R.C. Gausas R.E. et al.Retrograde metastasis of cutaneous melanoma to conjunctival lymphatics.Arch Ophthalmol. 2009; 127: 1222-1223Crossref PubMed Scopus (6) Google Scholar1961/M/WTempleNod/Clark IV/6.9 mmYesNone44Current caseM, male; W, white; F, female; SS, superficial spreading; Nod, nodular; B, black; AL, acro-lentiginous. Clark level or Breslow thickness. Open table in a new tab M, male; W, white; F, female; SS, superficial spreading; Nod, nodular; B, black; AL, acro-lentiginous. Two previous cases arose on facial skin and within the network of periocular lymphatics. One patient with a facial CM (Patient 4) had a preauricular tumour that metastasized to ciliary body and choroid (sites theoretically outside the facial lymphatic network) 19 months after treatment of the primary tumour.4Font R.L. Naumann G. Zimmerman L.E. Primary malignant melanoma of the skin metastatic to the eye and orbit. Report of ten cases and review of the literature.Am J Ophthalmol. 1967; 63: 738-754Abstract Full Text PDF PubMed Scopus (81) Google Scholar The other patient (Patient 18) had a preauricular melanoma that spread to ipsilateral bulbar lymphatics, which were visible through intact, transparent epithelium.9Lees V.A. Briggs J.C. Effects of initial biopsy procedure on prognosis in stage 1 invasive cutaneous malignant melanoma: review of 1086 patients.Br J Surg. 1991; 78: 1108-1110Crossref PubMed Scopus (95) Google Scholar This process was deemed retrograde lymphatic spread because the eyelids lack afferent channels that open in the direction of the orbit. The case reported in this article may represent the only other CM metastatic to the conjunctiva not attributable to hematogenous spread. Three general mechanisms are thought to give rise to regional extranodal spread of CM: (i) in-transit metastasis, a phenomenon attributed to intralymphatic spread within the skin; (ii) extravascular migratory metastasis, in which tumour spreads along the external surfaces of vascular channels; and (iii) direct extension along or in peripheral nerves.14Van Es S.L. Colman M. Thompson J.F. et al.Angiotropism is an independent predictor of local recurrences and in-transit metastasis in primary cutaneous melanoma.Am J Surg Pathol. 2008; 32: 1396-1403Crossref PubMed Scopus (47) Google Scholar We found no evidence of these processes histologically, aided with immunohistochemical markers for vascular and lymphatic vessels. The inability to identify a structural conduit could reflect the relatively sparse amount of tissue that was available to study surrounding the skin and conjunctival tumours. This case also brings up a relevant issue concerning the risk for regional spread from incisional biopsy of CM. Several studies have addressed this question, but the most definitive answer comes from analysis of the Sunbelt Melanoma Trial. This large, multicentre, randomized, clinical trial involved 2164 patients with CM and found that incomplete excision of primary melanoma (incisional and shave biopsies) did not adversely affect locoregional or distant recurrence as long as appropriate treatment followed diagnostic biopsy.15Martin R.C.G. Scoggins C.R. Ross M.I. et al.Is incisional biopsy of melanoma harmful?.Am J Surg Pathol. 2005; 190: 913-917Google Scholar In summary, we describe a patient with CM of temporal skin that caused an ipsilateral conjunctiva melanoma with unusual compartmentalization of malignant melanocytes within the epithelium and substantia propria. This pattern of tissue involvement is similar to that described for epidermotropic metastatic melanoma of skin. Although definitive evidence of lymphatic, perivascular, or perineural spread was lacking, the proximity of the CM suggests regional rather than blood-borne spread." @default.
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• W2109181421 title "Conjunctival metastasis from a regional cutaneous melanoma" @default.
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