Skip to main content
Top
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology 5/2018

01-05-2018 | Pathology

Conjunctival melanoma: association of cyclooxygenase-2 tumor expression to prognosis

Authors: Rita Pinto-Proença, Mariana Santos, Cristina Fonseca, Júlia Fernandes, Maria Filomena Gaspar, Rui Proença

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 5/2018

Login to get access

Abstract

Purpose

Conjunctival melanoma is a rare but potentially lethal tumor. Its biologic profile is still largely unknown, with recent studies aiming at establishing histopathological and genetic tumor profiles. The aim of this study was to analyze the association between clinicopathological characteristics and tumor expression of cyclooxygenase-2 (COX-2) to prognosis, assessing its usefulness as a possible prognostic marker.

Methods

Case series of 50 patients from 1991 to 2008 with pathologically proven conjunctival melanoma. Demographic, clinical, and pathological characteristics were evaluated by reviewing clinical files and pathology. Expression of COX-2 was studied by immunohistochemistry of formalin-fixed paraffin-embedded tissue samples of 20 melanomas. Samples were classified in a score which included intensity of staining and percentage of cells with positive reactivity.

Results

Clinicopathological features significantly associated (p < .05) with a poor prognosis (death) included involvement of fornix and tarsal conjunctiva, tumor thickness exceeding 2 mm, local tumor recurrence, lymph node, and systemic metastasis. In the immunohistochemistry study (n = 20), 18 cases expressed COX-2 although with different scores. However, only cases with a high score were associated with a poor outcome. Multivariate association analysis revealed that recurrence rate, metastasis, corneal invasion, and tumor thickness were associated with high score cases and, therefore, with a clinical profile with a higher risk of death.

Conclusions

Results suggest that higher COX-2 expression may be a negative prognostic factor in conjunctival melanoma. Further studies can address the potential use of anti-COX-2 drugs as adjuvant therapy of this disease.
Literature
1.
go back to reference Lim LA, Madigan MC, Conway RM (2013) Conjunctival melanoma: a review of conceptual and treatment advances. Clin Ophthalmol 6:521–531CrossRefPubMed Lim LA, Madigan MC, Conway RM (2013) Conjunctival melanoma: a review of conceptual and treatment advances. Clin Ophthalmol 6:521–531CrossRefPubMed
2.
4.
go back to reference Novais GA, Fernandes BF, Belfort RN, Castiglione E, Cheema DP, Burnier MN Jr (2010) Incidence of melanocytic lesions of the conjunctiva in a review of 10,675 ophthalmic specimens. Int J Surg Pathol 18(1):60–63CrossRefPubMed Novais GA, Fernandes BF, Belfort RN, Castiglione E, Cheema DP, Burnier MN Jr (2010) Incidence of melanocytic lesions of the conjunctiva in a review of 10,675 ophthalmic specimens. Int J Surg Pathol 18(1):60–63CrossRefPubMed
5.
go back to reference Kao A, Afshar A, Bloomer M, Damato B (2016) Management of primary acquired melanosis, nevus, and conjunctival melanoma. Cancer Control 23:117–125CrossRefPubMed Kao A, Afshar A, Bloomer M, Damato B (2016) Management of primary acquired melanosis, nevus, and conjunctival melanoma. Cancer Control 23:117–125CrossRefPubMed
6.
go back to reference Zembowicz A, Mandal RV, Choopong P (2010) Melanocytic lesions of the conjunctiva. Arch Pathol Lab Med 134(12):1785–1792PubMed Zembowicz A, Mandal RV, Choopong P (2010) Melanocytic lesions of the conjunctiva. Arch Pathol Lab Med 134(12):1785–1792PubMed
7.
go back to reference Damato B, Coupland SE (2009) Management of conjunctival melanoma. Expert Rev Anticancer Ther 9(9):1227–1239CrossRefPubMed Damato B, Coupland SE (2009) Management of conjunctival melanoma. Expert Rev Anticancer Ther 9(9):1227–1239CrossRefPubMed
8.
go back to reference Shildkrot Y, Wilson MW (2010) Conjunctival melanoma: pitfalls and dilemmas in management. Curr Opin Ophthalmol 21(5):380–386CrossRefPubMed Shildkrot Y, Wilson MW (2010) Conjunctival melanoma: pitfalls and dilemmas in management. Curr Opin Ophthalmol 21(5):380–386CrossRefPubMed
9.
go back to reference Savar A, Esmaeli B, Ho H, Liu S, Prieto VG (2011) Conjunctival melanoma: local-regional control rates, and impact of high-risk histopathologic features. J Cutan Pathol 38(1):18–24CrossRefPubMed Savar A, Esmaeli B, Ho H, Liu S, Prieto VG (2011) Conjunctival melanoma: local-regional control rates, and impact of high-risk histopathologic features. J Cutan Pathol 38(1):18–24CrossRefPubMed
10.
go back to reference Missotten GS, Keijser S, De Keizer RJ, De Wolff-Rouendaal D (2005) Conjunctival melanoma in the Netherlands: a nationwide study. Invest Ophthalmol Vis Sci 46(1):75–82CrossRefPubMed Missotten GS, Keijser S, De Keizer RJ, De Wolff-Rouendaal D (2005) Conjunctival melanoma in the Netherlands: a nationwide study. Invest Ophthalmol Vis Sci 46(1):75–82CrossRefPubMed
11.
go back to reference Esmaeli B, Roberts D, Ross M et al (2012) Histologic features of conjunctival melanoma predictive of metastasis and death (an American ophthalmological thesis). Trans Am Ophthalmol Soc 110:64–73PubMedPubMedCentral Esmaeli B, Roberts D, Ross M et al (2012) Histologic features of conjunctival melanoma predictive of metastasis and death (an American ophthalmological thesis). Trans Am Ophthalmol Soc 110:64–73PubMedPubMedCentral
12.
go back to reference Sheng X, Li S, Chi Z, Si L, Cui C, Mao L et al (2015) Prognostic factors for conjunctival melanoma: a study in ethnic Chinese patients. Br J Ophthalmol 99(7):990–996CrossRefPubMed Sheng X, Li S, Chi Z, Si L, Cui C, Mao L et al (2015) Prognostic factors for conjunctival melanoma: a study in ethnic Chinese patients. Br J Ophthalmol 99(7):990–996CrossRefPubMed
13.
go back to reference Heindl LM, Hofmann-Rummelt C, Adler W, Bosch JJ, Holbach LM, Naumann GO et al (2011) Prognostic significance of tumor-associated lymphangiogenesis in malignant melanomas of the conjunctiva. Ophthalmology 118(12):2351–2360CrossRefPubMed Heindl LM, Hofmann-Rummelt C, Adler W, Bosch JJ, Holbach LM, Naumann GO et al (2011) Prognostic significance of tumor-associated lymphangiogenesis in malignant melanomas of the conjunctiva. Ophthalmology 118(12):2351–2360CrossRefPubMed
14.
go back to reference Kenawy N, Lake SL, Coupland SE, Damato BE (2013) Conjunctival melanoma and melanocytic intra-epithelial neoplasia. Eye (Lond). 27(2):142–152CrossRefPubMed Kenawy N, Lake SL, Coupland SE, Damato BE (2013) Conjunctival melanoma and melanocytic intra-epithelial neoplasia. Eye (Lond). 27(2):142–152CrossRefPubMed
15.
go back to reference Lake SL, Jmor F, Dopierala J, Taktak AF, Coupland SE, Damato BE (2011) Multiplex ligation-dependent probe amplification of conjunctival melanoma reveals common BRAF V600E gene mutation and gene copy number changes. Invest Ophthalmol Vis Sci 52(8):5598–5604CrossRefPubMed Lake SL, Jmor F, Dopierala J, Taktak AF, Coupland SE, Damato BE (2011) Multiplex ligation-dependent probe amplification of conjunctival melanoma reveals common BRAF V600E gene mutation and gene copy number changes. Invest Ophthalmol Vis Sci 52(8):5598–5604CrossRefPubMed
16.
go back to reference Griewank KG, Westekemper H, Murali R, Mach M, Schilling B, Wiesner T et al (2013) Conjunctival melanomas harbor BRAF and NRAS mutations and copy number changes similar to cutaneous and mucosal melanomas. Clin Cancer Res 19(12):3143–3152CrossRefPubMed Griewank KG, Westekemper H, Murali R, Mach M, Schilling B, Wiesner T et al (2013) Conjunctival melanomas harbor BRAF and NRAS mutations and copy number changes similar to cutaneous and mucosal melanomas. Clin Cancer Res 19(12):3143–3152CrossRefPubMed
17.
go back to reference Larsen AC, Dahl C, Dahmcke CM, Lade-Keller J, Siersma VD, Toft PB et al (2016) BRAF mutations in conjunctival melanoma: investigation of incidence, clinicopathological features, prognosis and paired premalignant lesions. Acta Ophthalmol 94(5):463–470CrossRefPubMed Larsen AC, Dahl C, Dahmcke CM, Lade-Keller J, Siersma VD, Toft PB et al (2016) BRAF mutations in conjunctival melanoma: investigation of incidence, clinicopathological features, prognosis and paired premalignant lesions. Acta Ophthalmol 94(5):463–470CrossRefPubMed
18.
go back to reference Blum ES, Yang J, Komatsubara KM et al (2016) Clinical management of uveal and conjunctival melanoma. Oncology 30(1):29–32 34–43, 48PubMed Blum ES, Yang J, Komatsubara KM et al (2016) Clinical management of uveal and conjunctival melanoma. Oncology 30(1):29–32 34–43, 48PubMed
19.
go back to reference Chwirot BW, Kuźbicki Ł (2007) Cyclooxygenase-2 (COX-2): first immunohistochemical marker distinguishing early cutaneous melanomas from benign melanocytic skin tumours. Melanoma Res 17(3):139–145CrossRefPubMed Chwirot BW, Kuźbicki Ł (2007) Cyclooxygenase-2 (COX-2): first immunohistochemical marker distinguishing early cutaneous melanomas from benign melanocytic skin tumours. Melanoma Res 17(3):139–145CrossRefPubMed
20.
go back to reference Figueiredo A, Caissie AL, Callejo SA, McLean IW, Gold P, Burnier MN Jr (2003) Cyclooxygenase-2 expression in uveal melanoma: novel classification of mixed-cell-type tumours. Can J Ophthalmol 38(5):352–356CrossRefPubMed Figueiredo A, Caissie AL, Callejo SA, McLean IW, Gold P, Burnier MN Jr (2003) Cyclooxygenase-2 expression in uveal melanoma: novel classification of mixed-cell-type tumours. Can J Ophthalmol 38(5):352–356CrossRefPubMed
21.
go back to reference Marshall JC, Caissie AL, Cruess SR, Cools-Lartigue J, Burnier MN Jr (2007) The effects of a cyclooxygenase-2 (COX-2) expression and inhibition on human uveal melanoma cell proliferation and macrophage nitric oxide production. J Carcinog 6:17CrossRefPubMedPubMedCentral Marshall JC, Caissie AL, Cruess SR, Cools-Lartigue J, Burnier MN Jr (2007) The effects of a cyclooxygenase-2 (COX-2) expression and inhibition on human uveal melanoma cell proliferation and macrophage nitric oxide production. J Carcinog 6:17CrossRefPubMedPubMedCentral
22.
go back to reference Edge SB (2010) Malignant melanoma of the conjunctiva. In: Edge SB, Byrd DR, Compton CC et al (eds) American Joint Committee on Cancer staging manual, 7th edn. Springer, New York, pp 539–546 Edge SB (2010) Malignant melanoma of the conjunctiva. In: Edge SB, Byrd DR, Compton CC et al (eds) American Joint Committee on Cancer staging manual, 7th edn. Springer, New York, pp 539–546
23.
go back to reference Remmele W, Schicketanz KH (1993) Immunohistochemical determination of estrogen and progesterone receptor content in human breast cancer. Computer-assisted image analysis (QIC score) vs. subjective grading (IRS). Pathol Res Pract 189(8):862–866CrossRefPubMed Remmele W, Schicketanz KH (1993) Immunohistochemical determination of estrogen and progesterone receptor content in human breast cancer. Computer-assisted image analysis (QIC score) vs. subjective grading (IRS). Pathol Res Pract 189(8):862–866CrossRefPubMed
24.
go back to reference Mougiakakos D, Johansson CC, Trocme E, All-Ericsson C, Economou MA, Larsson O et al (2010) Intratumoral forkhead box P3-positive regulatory T cells predict poor survival in cyclooxygenase-2-positive uveal melanoma. Cancer 116(9):2224–2233PubMed Mougiakakos D, Johansson CC, Trocme E, All-Ericsson C, Economou MA, Larsson O et al (2010) Intratumoral forkhead box P3-positive regulatory T cells predict poor survival in cyclooxygenase-2-positive uveal melanoma. Cancer 116(9):2224–2233PubMed
25.
go back to reference Shields CL, Kaliki S, Al-Dahmash SA, Lally SE, Shields JA (2012) American Joint Committee on Cancer (AJCC) clinical classification predicts conjunctival melanoma outcomes. Ophthal Plast Reconstr Surg 28(5):313–323CrossRefPubMed Shields CL, Kaliki S, Al-Dahmash SA, Lally SE, Shields JA (2012) American Joint Committee on Cancer (AJCC) clinical classification predicts conjunctival melanoma outcomes. Ophthal Plast Reconstr Surg 28(5):313–323CrossRefPubMed
26.
go back to reference Yousef YA, Finger PT (2012) Predictive value of the seventh edition American Joint Committee on Cancer staging system for conjunctival melanoma. Arch Ophthalmol 130(5):599–606CrossRefPubMed Yousef YA, Finger PT (2012) Predictive value of the seventh edition American Joint Committee on Cancer staging system for conjunctival melanoma. Arch Ophthalmol 130(5):599–606CrossRefPubMed
27.
go back to reference Damato B, Coupland SE (2008) Conjunctival melanoma and melanosis: a reappraisal of terminology, classification and staging. Clin Exp Ophthalmol 36(8):786–795CrossRefPubMed Damato B, Coupland SE (2008) Conjunctival melanoma and melanosis: a reappraisal of terminology, classification and staging. Clin Exp Ophthalmol 36(8):786–795CrossRefPubMed
28.
go back to reference Damato B, Coupland SE (2008) Clinical mapping of conjunctival melanomas. Br J Ophthalmol 92(11):1545–1549CrossRefPubMed Damato B, Coupland SE (2008) Clinical mapping of conjunctival melanomas. Br J Ophthalmol 92(11):1545–1549CrossRefPubMed
29.
go back to reference Shields CL (2000) Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Trans Am Ophthalmol Soc 98:471–492PubMedPubMedCentral Shields CL (2000) Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Trans Am Ophthalmol Soc 98:471–492PubMedPubMedCentral
30.
go back to reference Shields CL, Markowitz JS, Belinsky I, Schwartzstein H, George NS, Lally SE et al (2011) Conjunctival melanoma: outcomes based on tumor origin in 382 consecutive cases. Ophthalmology 118(2):389–395CrossRefPubMed Shields CL, Markowitz JS, Belinsky I, Schwartzstein H, George NS, Lally SE et al (2011) Conjunctival melanoma: outcomes based on tumor origin in 382 consecutive cases. Ophthalmology 118(2):389–395CrossRefPubMed
31.
go back to reference Tuomaala S, Eskelin S, Tarkkanen A, Kivelä T (2002) Population-based assessment of clinical characteristics predicting outcome of conjunctival melanoma in whites. Invest Ophthalmol Vis Sci 43(11):3399–3408PubMed Tuomaala S, Eskelin S, Tarkkanen A, Kivelä T (2002) Population-based assessment of clinical characteristics predicting outcome of conjunctival melanoma in whites. Invest Ophthalmol Vis Sci 43(11):3399–3408PubMed
33.
go back to reference Kivelä T, Kujala E (2013) Prognostication in eye cancer: the latest tumor, node, metastasis classification and beyond. Eye (Lond) 27(2):243–252CrossRef Kivelä T, Kujala E (2013) Prognostication in eye cancer: the latest tumor, node, metastasis classification and beyond. Eye (Lond) 27(2):243–252CrossRef
34.
go back to reference Anastassiou G, Heiligenhaus A, Bechrakis N, Bader E, Bornfeld N, Steuhl KP (2002) Prognostic value of clinical and histopathological parameters in conjunctival melanomas: a retrospective study. Br J Ophthalmol 86(2):163–167CrossRefPubMedPubMedCentral Anastassiou G, Heiligenhaus A, Bechrakis N, Bader E, Bornfeld N, Steuhl KP (2002) Prognostic value of clinical and histopathological parameters in conjunctival melanomas: a retrospective study. Br J Ophthalmol 86(2):163–167CrossRefPubMedPubMedCentral
35.
go back to reference Seregard S, Kock E (1992) Conjunctival malignant melanoma in Sweden 1969–91. Acta Ophthalmol 70:289–296CrossRef Seregard S, Kock E (1992) Conjunctival malignant melanoma in Sweden 1969–91. Acta Ophthalmol 70:289–296CrossRef
36.
go back to reference Paridaens AD, McCartney AC, Minassian DC, Hungerford JL (1994) Orbital exenteration in 95 cases of primary conjunctival malignant melanoma. Br J Ophthalmol 78(7):520–528CrossRefPubMedPubMedCentral Paridaens AD, McCartney AC, Minassian DC, Hungerford JL (1994) Orbital exenteration in 95 cases of primary conjunctival malignant melanoma. Br J Ophthalmol 78(7):520–528CrossRefPubMedPubMedCentral
37.
go back to reference Marshall JC, Fernandes BF, Di Cesare S, Maloney SC, Logan PT, Antecka E, Burnier MN Jr (2007) The use of a cyclooxygenase-2 inhibitor (Nepafenac) in an ocular and metastatic animal model of uveal melanoma. Carcinogenesis 28(9):2053–2058CrossRefPubMed Marshall JC, Fernandes BF, Di Cesare S, Maloney SC, Logan PT, Antecka E, Burnier MN Jr (2007) The use of a cyclooxygenase-2 inhibitor (Nepafenac) in an ocular and metastatic animal model of uveal melanoma. Carcinogenesis 28(9):2053–2058CrossRefPubMed
38.
go back to reference Kuźbicki Ł, Chwirot BW (2016) Intratumoral expression of cyclooxygenase-2 (COX-2) is a negative prognostic marker for patients with cutaneous melanoma. Melanoma Res 26(5):448–456CrossRefPubMed Kuźbicki Ł, Chwirot BW (2016) Intratumoral expression of cyclooxygenase-2 (COX-2) is a negative prognostic marker for patients with cutaneous melanoma. Melanoma Res 26(5):448–456CrossRefPubMed
39.
go back to reference Muraki C, Ohga N, Hida Y, Nishihara H, Kato Y, Tsuchiya K et al (2012) Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells. Int J Cancer 130(1):59–70CrossRefPubMed Muraki C, Ohga N, Hida Y, Nishihara H, Kato Y, Tsuchiya K et al (2012) Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells. Int J Cancer 130(1):59–70CrossRefPubMed
41.
go back to reference Cryan LM, Paraoan L, Hiscott P, Damato BE, Grierson I, Gray D et al (2008) Expression of COX-2 and prognostic outcome in uveal melanoma. Curr Eye Res 33(2):177–184CrossRefPubMed Cryan LM, Paraoan L, Hiscott P, Damato BE, Grierson I, Gray D et al (2008) Expression of COX-2 and prognostic outcome in uveal melanoma. Curr Eye Res 33(2):177–184CrossRefPubMed
Metadata
Title
Conjunctival melanoma: association of cyclooxygenase-2 tumor expression to prognosis
Authors
Rita Pinto-Proença
Mariana Santos
Cristina Fonseca
Júlia Fernandes
Maria Filomena Gaspar
Rui Proença
Publication date
01-05-2018
Publisher
Springer Berlin Heidelberg
Published in
Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 5/2018
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI
https://doi.org/10.1007/s00417-017-3864-x

Other articles of this Issue 5/2018

Graefe's Archive for Clinical and Experimental Ophthalmology 5/2018 Go to the issue