The Small Fatal Choroidal Melanoma Study. A Survey by The European Ophthalmic Oncology Group
The Small Fatal Choroidal Melanoma Study. A Survey by The European Ophthalmic Oncology Group
The Small Fatal Choroidal Melanoma Study. A Survey by The European Ophthalmic Oncology Group
SUSANNA JOUHI, MARTINE J. JAGER, STEFAN J.R. DE GEUS, LAURENCE DESJARDINS, NILS ANDREAS EIDE,
JEAN-DANIEL GRANGE, JENS FOLKE KIILGAARD, STEFAN SEREGARD, EDOARDO MIDENA,
RAFFAELE PARROZZANI, JEAN-PIERRE CAUJOLLE, IWONA ROSPOND-KUBIAK, AND TERO T. KIVELÄ
PURPOSE: To determine the size at which choroidal respectively. By the time of analysis, 37 patients had
melanomas can metastasize and to report the characteris- died of metastasis after a median of 7 months.
tics of small fatal choroidal melanomas (SFCM). CONCLUSIONS: Choroidal melanomas less than
DESIGN: Retrospective case series. 3.0 mm in LBD are highly unlikely to metastasize. Risk
METHODS: Ten ocular oncology services submitted 45 factors of an SFCM are similar to those for all choroidal
patients with a choroidal melanoma 3 mm or less in thick- melanomas of similar size. (Am J Ophthalmol
ness and 9 mm or less in largest basal diameter (LBD), 2019;202:100–108. Ó 2019 The Author(s). Published
when treated, who developed metastases. by Elsevier Inc. This is an open access article under the
RESULTS: Median tumor thickness was 2.4 mm (range, CC BY-NC-ND license (http://creativecommons.org/
1.0–3.0 mm) and LBD 7.3 mm (range, 3.0–9.0 mm). Of licenses/by-nc-nd/4.0/).)
14 (31%) tumors that were first observed, 12 grew a me-
dian of 0.5 mm (range, 0.1–1.2 mm) in thickness and
S
1.0 mm (range, 0–3.0 mm) in LBD within a median of MALL CHOROIDAL MELANOCYTIC TUMORS ARE
7 months; 3 were initially smaller than 3 mm in LBD. treated if their appearance or growth suggests malig-
Number of risk factors for growth and metastasis was nancy. Several studies have identified risk factors for
0 for 4% of the tumors; 60% were over 2 mm in thick- growth1–6 and metastasis3–5 of suspicious small melanocytic
ness, 63% had subretinal fluid, 84% caused symptoms, choroidal lesions so as to aid in making treatment
57% had orange pigment, and 92% were within 3 mm decisions. These include in particular tumor thickness
of the disc. Local recurrence occurred in 8 of 31 eyes over 2 mm, subretinal fluid, symptoms, orange pigment,
(26%) treated conservatively. Median metastasis-free and tumor margin either touching or within 3 mm from
survival was 4.5 years (range, 0.8–15.7 years). Kaplan- the optic disc margin, giving rise to the TFSOM (‘‘To
Meier estimate of metastasis developing was 15% (95% Find Small Ocular Melanoma’’) mnemonic.3,4 Small
confidence interval [CI], 7–26), 51% (95% CI, 36–64) choroidal melanocytic tumors, especially those without
and 85% (95% CI, 71–92) by 2, 5, and 10 years, risk factors, have frequently been observed for growth to
confirm diagnosis before being treated.7 Especially small
perifoveolar tumors have often been watched, because
treating them likely compromises vision. However, obser-
Supplemental Material available at AJO.com. vation before treatment might increase the risk for metas-
Accepted for publication Jan 30, 2019. tases.8 Consequently, the practice of observing suspicious
From the Ocular Oncology Service, Department of Ophthalmology, small melanocytic tumors of the choroid remains contro-
University of Helsinki and Helsinki University Hospital, Helsinki,
Finland (S.J., T.T.K.); Department of Ophthalmology, Leiden versial.7,9–13
University Medical Center, Leiden, The Netherlands (M.J.J.); In contrast to an abundance of case series that have
Department of Ophthalmology, Radbouc UMC, Nijmegen, The explored risk factors for growth and metastasis to tell small
Netherlands (S.J.R.G.); Department of Ophthalmology, Institute Curie,
Paris, France (L.D.); Department of Ophthalmology, Oslo University melanomas from other lesions, reports of small fatal
Hospital-HF, Oslo, Norway (N.A.E.); Department of Ophthalmology, choroidal melanomas (SFCM) that metastasized and killed
Croix-Rousse Hospital, Lyon, France (J.D.G.); Department of the patient are scarce and typically do not describe such tu-
Ophthalmology, Copenhagen University Hospital Glostrup,
Copenhagen, Denmark (J.F.K.); Department of Ophthalmic Oncology, mors in detail.3,14–25 Based on their size, one might infer
St. Erik’s Eye Hospital, Stockholm, Sweden (S.S.); Department of that the smallest choroidal melanomas that metastasize
Ophthalmology, University of Padova, Padova, Italy (E.M., R.P.); range from 1.7 to 2.5 mm in thickness and from 5.0 to
IRCCS - Fondazione Bietti, Rome, Italy (E.M.); Department of
Ophthalmology, Saint-Roch University Hospital, Nice, France (J.P.C.); 8.0 mm in largest basal diameter (LBD),14,19–26 and that
and Department of Ophthalmology, Poznan University of Medical several have shown evidence of growth before20,21 or—in
Sciences, , Poznan, Poland (I.R.K.). the form of local recurrence18,19,22,24—after they were
Inquiries to Susanna Jouhi, Department of Ophthalmology, Helsinki
University Hospital, Haartmaninkatu 4 C, PL 220, FI-00029 HUS, treated. Theoretical calculations based on tumor
Helsinki, Finland; e-mail: [email protected] doubling times have suggested that uveal melanomas as
DD ¼ disc diameters.
a
Seven tumors were up to 5.0 mm, 21 were 5.1–10.0 mm, and 7 were 10.1–15.0 mm in largest basal diameter.1
b
Percentages calculated from the number of patients with known data.
c
Fisher exact test.
d
Original criteria.3
e
Later criteria.4
developing a local recurrence was 17% (95% confidence Metastases were typically detected first by liver imaging
interval [CI], 7–29) by 5 years and 19% (95% CI, 9–32) (either ultrasonography, computed tomography, or mag-
by 10 years (Figure 3A). Twenty-seven patients died of netic resonance imaging) and when active treatment was
metastatic melanoma without developing a recurrence, considered for them, they were staged with imaging of
and 4 (9%) were lost to ocular follow-up. We did not other organs and typically confirmed through biopsy or by
have enough evidence to either confirm or exclude that tu- documenting progression. Metastases were diagnosed his-
mors with a local recurrence were more often located closer topathologically, by imaging, and clinically in 17 (38%),
to the optic disc (Table; P ¼ .14, Fisher exact test), more 20 (44%), and 2 (4%) patients, respectively
often had orange pigment (P ¼ .11) and subretinal fluid (Supplemental Table 2; Supplemental Material available
(P ¼ .11), and had more often been observed to grow at AJO.com). Metastases were hepatic in 28 (62%) pa-
(P ¼ .17). Two of the 8 recurrences were enucleated, 4 tients and hepatic and extrahepatic in 15 (33%) patients,
were treated with brachytherapy, and 2 received transpu- and the distribution was incompletely specified in 2 (4%)
pillary thermotherapy (1 was enucleated later). patients. The median metastasis-free survival was 4.5 years
(range, 10 months to 15.7 years). The cumulative inci-
HISTOPATHOLOGIC CHARACTERISTICS: Of 20 SFCM dence of metastasis developing was 15% (95% CI, 7–26)
with known histopathology, epithelioid cells were present by 2 years, 51% (95% CI, 36–64) by 5 years, and 85%
in 15 (75%), including those in all 3 eyes enucleated after (95% CI, 71–92) by 10 years after treatment. Of 33 patients
local recurrence, and 5 (25%) were of spindle cell type. with known data, 23 (70%) received active treatment for
One of the 3 enucleated recurrent tumors was found to metastatic disease while 10 (30%) received best supportive
have a 5-mm extrascleral extension following primary care (Supplemental Table 2). None of them had a known
brachytherapy and secondary transpupillary thermother- history of a second cancer, especially of cutaneous or mu-
apy. cous membrane melanoma.
METASTATIC DISEASE: By study design, all patients SURVIVAL OUTCOME: Thirty-seven (82%) patients died
developed metastatic uveal melanoma. Of 34 patients during follow-up, all of metastatic disease; 2 were lost to
with available data, 22 (65%) had participated in regular follow-up with progressive disease and are presumed dead;
surveillance and 19 (86%) of them remained asymptomatic and 6 are alive with metastases (Figure 3B). Median sur-
at the time of diagnosis of metastases. Of the 12 vival was 6.0 years (range, 1.6–16.7 years) from primary
patients who were not under regular surveillance, 1 was treatment and did not differ between patients who were
asymptomatic and the metastases were detected during treated with enucleation and conservatively with or
evaluation for an unrelated disease. without developing local tumor recurrence after treatment
(Figure 3C; P ¼ .80, log-rank test). Survival after devel- choroidal melanomas that metastasized were at least
oping systemic metastases was 8 months (range, 1 week 1.7 mm thick19 and 5.0 mm in LBD.21 To the best of our
to 3 years 9 months). The Kaplan-Meier estimate of meta- knowledge, our 3 smallest tumors, which were 3.0, 3.4
static death was 52% (95% CI, 37–66) at 1 year, 77% (95% (Figure 2D–F), and 4.8 mm (Figure 2B) in LBD, are the
CI, 60–88) at 2 years, and 84% (95% CI, 66–93) at 3 years smallest fatal choroidal melanomas reported.14,19–26 Their
(Figure 3D) after metastasis detection. thickness was 1.0 mm (in 1 case, 1.7 mm), 1 had
subretinal fluid, 2 caused blurred vision, and 1 touched
disc margin. The observational arm of the Collaborative
Ocular Melanoma Study defined a small choroidal
DISCUSSION melanoma as being 1–3 mm in thickness and 5–16 mm in
LBD; tumors smaller than this were regarded as probable
WE FOUND FROM 10 EUROPEAN OCULAR ONCOLOGY CEN- nevi.17 A large single-center study estimated that when
ters 3 patients with an SFCM that were less than 5 mm LBD is 5–6 mm, about 70 choroidal nevi are diagnosed
(about 3 DD) in LBD when treated, but none that was for every melanoma, and stated that few melanomas would
less than 3 mm (2 DD). In the literature the smallest be less than 5 mm in diameter.34 Our data confirm not only
FUNDING/SUPPORT: THE HELSINKI UNIVERSITY CENTRAL HOSPITAL RESEARCH FUND (TYH2013316, TYH2017218), THE SIGRID
Jusélius Foundation, Helsinki, Finland, and The Eye Foundation, Helsinki, Finland. The contribution of the Fondazione Bietti was supported by the Italian
Ministry of Health and Fondazione Roma. The funding organizations had no role in the design or conduct of this research. Financial Disclosures: Tero T.
Kivelä received lecture fees from Santen Finland. The following authors have no financial disclosures: Susanna Jouhi, Martine J. Jager, Stefan J.R. de Geus,
Laurence Desjardins, Nils Andreas Eide, Jean-Daniel Grange, Jens Folke Kiilgaard, Stefan Seregard, Edoardo Midena, Raffaele Parrozzani, Jean-Pierre
Caujolle, and Iwona Rospond-Kubiak. The authors attest that they meet the current ICMJE criteria for authorship.
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