Peripapillary and circumpapillary retinal intraocular metastases are rare and present a treatment challenge for ophthalmologists because of the high risk of iatrogenic injury to the optic nerve. There are no clear guidelines on the management of these lesions, and many clinicians will initially observe for improvement of the metastases with systemic chemotherapy before considering local therapy with external beam radiation. Radiation to the optic disc carries a significant risk of injuring the optic nerve, leading to worsening of vision. Alternative treatment approaches are needed. We present a patient with large-cell neuroendocrine carcinoma with metastasis to the peripapillary retina who was treated with intravitreal topotecan and with intravitreal aflibercept. Serial fundus photos, ultrasound, and optical coherence tomography demonstrated a reduction in size of the lesion and a decrease in subretinal fluid with intravitreal topotecan and aflibercept. In addition, visual acuity was stabilized during treatment. Intravitreal chemotherapy for intraocular metastases in vision-sensitive areas such as the peripapillary retina may be a viable alternative for patients who seek to preserve their vision and maintain their quality of life.

Established Facts

  • Neuroendocrine carcinoma metastases to the eye are rare.

  • There are no current guidelines on the management of retinal metastases.

  • Topoisomerase I inhibitors are used in the systemic chemotherapy regimen for high-grade neuroendocrine carcinomas.

  • Intravitreal bevacizumab has been used to treat neuroendocrine carcinoma metastases to the iris with success.

Novel Insights

  • Intravitreal topotecan reduced the intraocular neuroendocrine tumor size and associated subretinal fluid.

  • Intravitreal aflibercept reduced the intraocular neuroendocrine tumor size and associated subretinal fluid.

  • Intravitreal chemotherapy is a viable alternative to treat intraocular metastases, especially in areas with increased risk for vision loss with external beam radiation.

Large-cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive malignancy that arises from various tissues, including the lung and prostate. Patients with LCNEC have a poor prognosis and tend to have widely metastatic disease at initial presentation [1, 2]. Neuroendocrine tumors rarely metastasize to the eye, and there are only 2 case reports of intraocular LCNEC metastases [3-5]. In addition, there are no reported cases of LCNEC metastases to the peripapillary retina, and there are no current guidelines on the management of any metastases to this location. In part, few guidelines exist because most metastases to the eye occur in the choroid, due to its rich vascular supply.

LCNECs are considered grade 3 neuroendocrine tumors, which is the highest grade and the least differentiated. First-line systemic therapy for these cancers is etoposide-platinum chemotherapy. Patients who fail this therapy have a poor prognosis, and there are currently no guidelines for second-line therapy. A study showed that some patients with grade 3 neuroendocrine tumors respond to the FOLFIRI chemotherapy regimen [6]. The FOLFIRI regimen includes leucovorin calcium, 5-fluorouracil, and the topoisomerase I inhibitor irinotecan. Topotecan is a topoisomerase I inhibitor that is used extensively in retinoblastoma in systemic, intra-arterial, and intravitreal forms [7, 8]. To our knowledge, intravitreal topotecan for LCNEC intraocular metastases has not been described in the literature. Intravitreal injections of anti-VEGF agents have been used in the treatment of choroidal metastases from various cancers [9, 10]. In addition, there is 1 reported use of intravitreal bevacizumab for the treatment of LCNEC metastasis to the iris with success [5]. We report a case of LCNEC metastasis to the peripapillary retina treated with both intravitreal topotecan and intravitreal aflibercept.

A 70-year-old man with a history of resected prostate cancer 6 months prior presented to the ophthalmology clinic with decreased vision in the left eye. Visual acuity was 20/40 in the left eye, and an amelanotic peripapillary retinal lesion with subretinal fluid was found in the same eye. Fundus photography, ultrasound, enhanced depth imaging optical coherence tomography (OCT), and OCT of the macula were done to further characterize the lesion and to document changes over time (Fig. 1a). Initial systemic imaging demonstrated widely metastatic disease of unknown primary origin involving the brain, liver, and lungs. There was no bony metastatic involvement. Liver biopsy of a metastatic lesion revealed LCNEC with an immunohistochemical profile most consistent with prostate cancer metastasis with LCNEC transformation. In the setting of diffusely metastatic LCNEC, the peripapillary lesion was inferred to be a metastasis of LCNEC. He was started on a systemic regimen of carboplatin and etoposide for the systemic disease.

Fig. 1.

a Fundus photography, OCT of the macula, EDI-OCT of the lesion, and ultrasound imaging at initial presentation prior to systemic or intravitreal chemotherapy showing a large peripapillary metastatic lesion with subretinal fluid. b Repeat imaging after 2 cycles of systemic chemotherapy demonstrating an enlarging peripapillary metastatic lesion and worsening subretinal fluid. OCT, optical coherence tomography; EDI, enhanced depth imaging.

Fig. 1.

a Fundus photography, OCT of the macula, EDI-OCT of the lesion, and ultrasound imaging at initial presentation prior to systemic or intravitreal chemotherapy showing a large peripapillary metastatic lesion with subretinal fluid. b Repeat imaging after 2 cycles of systemic chemotherapy demonstrating an enlarging peripapillary metastatic lesion and worsening subretinal fluid. OCT, optical coherence tomography; EDI, enhanced depth imaging.

Close modal

After 2 cycles of the carboplatin-etoposide therapy, his corrected vision had decreased to finger-counting at 2 feet. The peripapillary lesion had increased in size during this time (Fig. 1b). Intravitreal topotecan (30 μg/0.1 mg) was administered in the left eye. At the follow-up visit 1 week later, his visual acuity improved to 20/400 and a second topotecan intravitreal injection was given. Follow-up systemic imaging was performed and demonstrated that the systemic metastatic disease had progressed, despite the initial 2 cycles of systemic carboplatin-etoposide therapy. He was then transitioned to a systemic FOLFIRI chemotherapy regimen.

A month after the initial topotecan intravitreal injection, the size of the peripapillary lesion was reduced and subretinal fluid had improved (Fig. 2a). He was given a third intravitreal injection of topotecan as well as an intravitreal injection aflibercept (2 mg/0.05). Aflibercept was added to the regimen to speed the resolution of the hemorrhages and subretinal fluid. The patient then received intravitreal injections of both topotecan and aflibercept every 2 weeks for 2 additional visits and then spaced out to every month for a combined total of 7 injections of topotecan and 5 injections of aflibercept. The peripapillary lesion size decreased further and subretinal fluid resolved with this treatment regimen (Fig. 2b). He subjectively noted that his vision had improved, and his corrected measured visual acuity fluctuated between finger-counting and 20/400. He was started on systemic pembrolizumab shortly after the last intravitreal injection visit as he had failed systemic FOLFIRI chemotherapy. The patient passed away from systemic involvement of his cancer 1 month after his last clinic visit, which was 9 months after his initial presentation.

Fig. 2.

a Fundus photography, OCT of the macula, EDI-OCT of the lesion, and ultrasound imaging after 2 intravitreal topotecan injections demonstrating a shrinking peripapillary metastatic lesion and an improvement of subretinal fluid. b Repeat imaging after a total of 7 intravitreal injections of topotecan and 5 intravitreal injections of aflibercept showing further reduction in the size of the peripapillary metastatic lesion and significant improvement in subretinal fluid. OCT, optical coherence tomography; EDI, enhanced depth imaging.

Fig. 2.

a Fundus photography, OCT of the macula, EDI-OCT of the lesion, and ultrasound imaging after 2 intravitreal topotecan injections demonstrating a shrinking peripapillary metastatic lesion and an improvement of subretinal fluid. b Repeat imaging after a total of 7 intravitreal injections of topotecan and 5 intravitreal injections of aflibercept showing further reduction in the size of the peripapillary metastatic lesion and significant improvement in subretinal fluid. OCT, optical coherence tomography; EDI, enhanced depth imaging.

Close modal

Historically, patients with intraocular metastases have widely metastatic disease and a poor prognosis at the time of presentation. With advancement in cancer therapies, the life expectancy of many of these patients is improving and the management of intraocular metastases has become more relevant in contributing to patients’ quality of life. Cases in which patients have a possibility of significant survival of the primary disease and valuable vision to be preserved, local therapy such as external beam radiation, plaque brachytherapy, photodynamic therapy, and transpupillary thermotherapy can be used [11-14]. Despite these options, there are no established guidelines specifically for the treatment of retinal metastases. Most cases of retinal metastases are treated with observation or radiotherapy [11, 12]. However, local therapy with radiation is limited when the metastatic lesion involves the peripapillary retina because of the high risk of damaging the optic nerve [15-17].

An alternative therapy that does not carry the risk of radiation optic neuropathy is intravitreal injections of chemotherapy. Intravitreal injections of anti-VEGF have been used to treat intraocular metastases with mixed success [9, 10]. Yokouchi et al. [5] reported 1 case of a lung LCNEC with metastasis to the iris that was treated with intravitreal bevacizumab. After systemic chemotherapy for multiple metastases outside of the eye, the patient presented to the ophthalmologist with an iris lesion, iris neovascularization, increased intraocular pressure, and blurred vision. After 3 monthly intravitreal injections of bevacizumab, the lesion size, iris neovascularization, intraocular pressure, and vision all improved without adverse effects [5].

Our patient failed first-line systemic therapy for LCNEC and was then treated with the FOLFIRI regimen as second line. FOLFIRI includes irinotecan, a topoisomerase I inhibitor, the same class of drug as topotecan. Intravitreal topotecan is used extensively in the treatment of retinoblastoma, but it has not been reported to be used for intraocular metastases in adult primary cancers [7, 8]. Since systemic topoisomerase I inhibitors have shown activity against LCNECs systemically, there was mechanistic logic to using this agent. To our knowledge, this is the first case report of intravitreal topotecan treatment of LCNEC metastasis to the eye.

Our patient noticed an improvement in vision with intravitreal topotecan, and his measured visual acuity was slightly improved. Notably, the lesion regressed dramatically, and no additional lesions developed. Intravitreal aflibercept injections were also added, given the previous report of anti-VEGF use for a LCNEC metastasis to the iris. To what extent the anti-VEGF agent played a role in the improvement and regression of the lesion in addition to the effect of the topotecan is unknown. Certainly, topotecan seemed to have a significant effect on the lesion size before aflibercept was added.

This case, as all single case reports, has limitations. We did not confirm the pathologic origin of the lesion with a biopsy. We do not have a large series of patients or a randomized control, and we do not know the relative effect of each agent since 2 were used. Given the rare nature of this disease, treating a larger series of these patients is unlikely.

In conclusion, this case demonstrates that local intravitreal chemotherapy can be effective for peripapillary metastatic lesions of the retina. Ocular oncologists may consider intravitreal chemotherapy to preserve vision and improve quality of life in these challenging situations as the procedure is simple, has low risk, and has a lower chance of causing iatrogenic damage than traditional alternative local therapies.

No individuals in addition to the authors contributed to this manuscript.

Prior to his death, the subject gave his written informed consent to publish his case (including publication of images). All efforts were made to prevent the subject’s identity from being revealed.

The authors have no conflicts of interest to declare.

Funding was not required for this study.

Colin S. Ip, MD – drafting/writing of the manuscript. Yuval Raizen, MD – editing of the manuscript. David Goldfarb, MD – editing of the manuscript. Eric Kegley – editing of the manuscript and imaging. Jose Munoz – editing of the manuscript. Amy C. Schefler, MD – conception of study and editing of the manuscript.

1.
Iyoda
A
,
Hiroshima
K
,
Nakatani
Y
,
Fujisawa
T
.
Pulmonary large cell neuroendocrine carcinoma: its place in the spectrum of pulmonary carcinoma
.
Ann Thorac Surg
.
2007 Aug
;
84
(
2
):
702
7
. .
2.
Evans
AJ
,
Humphrey
PA
,
Belani
J
,
van der Kwast
TH
,
Srigley
JR
.
Large cell neuroendocrine carcinoma of prostate: a clinicopathologic summary of 7 cases of a rare manifestation of advanced prostate cancer
.
Am J Surg Pathol
.
2006 Jun
;
30
(
6
):
684
93
. .
3.
Shields
CL
,
Say
EA
,
Stanciu
NA
,
Bianciotto
C
,
Danzig
CJ
,
Shields
JA
.
Cavitary choroidal metastasis from lung neuroendocrine tumor: report of 3 cases
.
Arch Ophthalmol
.
2011 Jan
;
129
(
1
):
102
4
. .
4.
Parra-Medina
R
,
Melo-Uribe
M
,
Romero-Rojas
AE
.
Bilateral invasive orbital metastases from a poorly differentiated large cell neuroendocrine carcinoma of the esophagus
.
Interdiscip J Gastroenterol Hepatol Endosc
.
2018 Oct
;
2
(
2
):
10
.
5.
Yokouchi
H
,
Kitahashi
M
,
Oshitari
T
,
Yamamoto
S
.
Intravitreal bevacizumab for iris tumor metastasized from large cell neuroendocrine carcinoma of lung
.
Graefes Arch Clin Exp Ophthalmol
.
2013 Sep
;
251
(
9
):
2243
5
. .
6.
Hentic
O
,
Hammel
P
,
Couvelard
A
,
Rebours
V
,
Zappa
M
,
Palazzo
M
,
FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3
.
Endocr Relat Cancer
.
2012 Dec
;
19
(
6
):
751
7
. .
7.
Dalvin
LA
,
Kumari
M
,
Essuman
VA
,
Shohelly Shipa
S
,
Ancona-Lezama
D
,
Lucio-Alvarez
JA
,
Primary intra-arterial chemotherapy for retinoblastoma in the intravitreal chemotherapy era: five years of experience
.
Ocul Oncol Pathol
.
2019 Feb
;
5
(
2
):
139
46
. .
8.
Schefler
AC
,
Kim
RS
.
Recent advancements in the management of retinoblastoma and uveal melanoma
.
F1000Res
.
2018
;
7
. .
9.
Cohen
VM
.
Ocular metastases
.
Eye
.
2013 Feb
;
27
(
2
):
137
41
. .
10.
Maudgil
A
,
Sears
KS
,
Rundle
PA
,
Rennie
IG
,
Salvi
SM
.
Failure of intravitreal bevacizumab in the treatment of choroidal metastasis
.
Eye
.
2015 May
;
29
(
5
):
707
11
. .
11.
Arepalli
S
,
Kaliki
S
,
Shields
CL
.
Choroidal metastases: origin, features, and therapy
.
Indian J Ophthalmol
.
2015 Feb
;
63
(
2
):
122
7
. .
12.
Mathis
T
,
Jardel
P
,
Loria
O
,
Delaunay
B
,
Nguyen
AM
,
Lanza
F
,
New concepts in the diagnosis and management of choroidal metastases
.
Prog Retin Eye Res
.
2019 Jan
;
68
:
144
76
. .
13.
Shields
CL
,
McMahon
JF
,
Atalay
HT
,
Hasanreisoglu
M
,
Shields
JA
.
Retinal metastasis from systemic cancer in 8 cases
.
JAMA Ophthalmol
.
2014 Nov
;
132
(
11
):
1303
8
. .
14.
Taubenslag
KJ
,
Kim
SJ
,
Attia
A
,
Abel
TW
,
Nickols
HH
,
Ancell
KK
,
Retinal metastasis from unknown primary: diagnosis, management, and clinicopathologic correlation
.
Digit J Ophthalmol
.
2015
;
21
(
4
):
1
10
. .
15.
Wang
W
,
Yang
H
,
Guo
L
,
Su
H
,
Wei
S
,
Zhang
X
.
Radiation-induced optic neuropathy following external beam radiation therapy for nasopharyngeal carcinoma: a retrospective case-control study
.
Mol Clin Oncol
.
2016 May
;
4
(
5
):
868
72
. .
16.
Ferguson
I
,
Huecker
J
,
Huang
J
,
McClelland
C
,
Van Stavern
G
.
Risk factors for radiation-induced optic neuropathy: a case-control study
.
Clin Exp Ophthalmol
.
2017 Aug
;
45
(
6
):
592
7
. .
17.
Brown
GC
,
Shields
JA
,
Sanborn
G
,
Augsburger
JJ
,
Savino
PJ
,
Schatz
NJ
.
Radiation retinopathy
.
Ophthalmology
.
1982 Dec
;
89
(
12
):
1494
501
. .
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