Combined hamartoma of the retina and the retinal pigment epithelium (CHRRPE) is a benign proliferation of the pigment epithelium, neurosensory retina, retinal vasculature, and adjacent vitreous.1,2 It is usually solitary, unilateral, and can be located on or adjacent to the optic disc, at the macula, or in the peripheral retina.1 The clinical appearance of the lesion falls on a spectrum depending on the predominating tissue subtype: melanocytic, vascular, or glial.3 Common characteristics include vascular tortuosity (93%), variable pigmentation (87%), elevation (80%), and epiretinal membrane (ERM) formation (78%).3
Visual impairment may occur from direct involvement of the tumor on the optic nerve head, papillomacular bundle, or fovea. Or in cases where the lesion is located elsewhere, visual loss can be due to foveal distortion from ERM formation leading to tractional retinal elevation via tumor or ERM contraction. Diagnosis is typically made in early childhood speculating the congenital nature of CHRRPE, but visual acuity (VA) may continue to deteriorate over time secondary to progressive distortion of the retinal architecture.3,4
These hamartomas are relatively uncommon with an unknown prevalence. Literature on the benefit of surgery in the management of ERMs in combined hamartoma has historically been controversial and is currently limited. The purpose of this study is to describe the surgical outcomes in CHRRPE patients with dense ERMs that were visually significant and progressive who underwent vitrectomy with membrane peeling surgery without the use of adjunctive autologous plasmin enzyme.
Patients and Methods
This is a retrospective chart review study approved by the institutional review board at the North-well Health System. The medical records of all patients at our tertiary vitreoretinal referral service with the database keyword of “ERM” from 2006 to 2019 were reviewed. Inclusion criteria were the diagnosis of combined hamartoma and surgical intervention by pars plana vitrectomy (PPV) with membrane peeling. Exclusion criteria were all other diagnosis causative of ERMs and those without surgical intervention. A minimum of 1 year of follow-up was required.
Fifteen eyes of 15 patients were identified with CHRRPE that underwent PPV and membrane peeling. Diagnosis was based on full ophthalmologic evaluations along with fundus photography, optical coherence tomography (OCT), and fluorescein angiography. The decision for surgery was based on preoperative worsening VA and macula-involving or threatening ERM progression as judged with color fundus photos, OCT, and clinical exam. The amblyopic risk of each patient was also considered. No autologous plasmin enzyme was used in any of our patients. Fluid-air exchange and gas tamponade were performed when necessary.
Medical records were analyzed for age, gender, location of lesion, preoperative and postoperative VA, preoperative and postoperative macular architecture, length of follow-up, presence of amblyopia, and complications.
Mean VAs were determined by calculating the geometric mean with standard deviation in the logMAR format, as defined by Holladay.5 The Kolmogorov-Smirnov test was used to assess the normality of the preoperative and postoperative VAs in logMAR Format (SPSS, Armonk, NY). The Mann–Whitney (Wilcoxon) rank-sum test was used to compare the visual acuities for non-normally distributed data. Results were considered statistically significant when P values were less than .05.
A total of 15 eyes of 15 patients were analyzed; 10 patients (76%) were male and five patients (33%) were female. The mean age at surgery was 10 years old (median: 9 years; range: 1 year to 25 years), with an average follow-up of 5.7 years (median: 4 years; range: 1.25 years to 20 years). Three patients (20%) were in the high amblyopic risk age (< 6 years old), eight patients (53%) in the mild amblyopic risk age (7 to 12 years old), and the remaining four patients (27%) were past the amblyopia risk age at the time of surgery. Eight of the patients (53%) had amblyopia, and four out of the eight amblyopic patients had evidence of strabismus. Table 1 summarizes the key data collected for each case.
Summary of Patient Case Details
All lesions were unilateral and there was no significant laterality. Eight of the 15 patients (53%) had right eye involvement, and seven of the 15 patients (47%) had left eye involvement. Fourteen patients (93%) had solitary lesions, and one patient (7%) had two CHRRPE lesions in the same eye. The patient with two lesions also has a diagnosis of neurofibromatosis type 1 (NF1), with a strong family history of NF1 (his father and brother). The rest of the cohort did not have any known diagnosis of systemic syndromes or systemic disease.
With regard to the location of the lesions in the 15 patients, 10 (67%) were located in the macula, one (7%) in the macula and posterior pole, two (13%) in the peripapillary region and macula, and two patients (13%) had involvement of the midperiphery, which affected the macula (Table 2). We define macula as involving the macula and up to one vascular arcade, whereas macula and posterior pole is defined as involving the macula and both superior and inferior arcades. One patient had two lesions in the same eye, and they were located in the temporal midperiphery and superonasal midperiphery.
Summary of the Locations of the Combined Hamartoma Lesions
The average preoperative VA was 20/514, and the average postoperative VA was 20/138 (P = .0251) at 1 year and 20/89 (P = .0025) on the final follow-up exam. The median preoperative VA was 20/400, and the median postoperative VA was 20/70 at 1 year and 20/60 on the final exam. Dramatic improvements in VA were seen in 14 of the 15 patients (93%). One patient (7%) had VA loss despite membrane peeling treatment, but this case was complicated by concomitant pars planitis in the same eye that was being treated with adalimumab (Humira; AbbVie, North Chicago, IL). Time of surgery in this patient was at 7 years of age; his preoperative VA was count fingers at 3 feet, and postoperative VA was count fingers at 2 feet. The CHRRPE lesion involved the peripapillary region and macula with an associated tractional detachment involving the macula. It was likely he had significant dense preoperative amblyopia. Two months subsequent to the membrane peeling, the patient suffered an inferior macula-on rhegmatogenous retinal detachment secondary to pars planitis vitreous base contraction. The macula on retinal detachment was repaired with one surgery, by revision vitrectomy, scleral buckle, laser, and gas tamponade. His postoperative VA was count fingers at 2 feet 1.5 years after retinal detachment repair.
Figure 1 shows the breakdown of the preoperative and postoperative VA in the cohort. Specifically, zero patients (0%) had good preoperative VA (range: 20/20 to 20/40), and 10 patients (67%) had poor pre-operative VA (range: ≤ 20/200). Postoperatively, seven patients (47%) achieved good VA (range: 20/20 to 20/40), and only three patients (20%) remained in the poor VA (range: ≤ 20/200) group at last follow-up.
Breakdown of preoperative and final postoperative visual acuity in the cohort; 93% of the patients had visual improvement, and 7% of the patients had decreased vision postoperatively.
All patients (100%) had improved macular anatomy postoperatively. Nine patients (60%) had complete removal of ERM (Figure 2), and six patients (40%) had near-complete removal of ERM, as seen in this representative postoperative example (Figure 3). The six patients with near complete ERM removal did not have recurrence, and their postoperative VA remained excellent, with an average postoperative VA of 20/40, from an average preoperative VA of 20/590. ERM recurred in one of the 15 patients (7%), but this was the case complicated by concomitant pars planitis in the same eye. OCT preoperatively showed retinal thickening with ERM and disorganization of the retinal layers in all cases. Some patients also had localized TRD. These findings improved in all patients after surgery. One patient was not able to obtain a pre-operative OCT (Patient 1, due to his age and cooperation level at the time).
Patient 13, preoperative visual acuity (VA) 20/70 and postoperative VA 20/20. (A) Preoperative color fundus photo demonstrating combined hamartoma of the retina and retinal pigment epithelium lesion in the peripapillary region with vascular tortuosity and overlying gliosis extending along the inferotemporal arcade causing distortion of the macular architecture. (B) Preoperative optical coherence tomography (OCT) showing epiretinal membrane (ERM) with retinal thickening, macula edema, and retinal layer disorganization. (C) Preoperative fluorescein angiography (FA) showing ERM and large tortuous retinal vessels at location of the tumor without late leakage. (D) Postoperative color fundus photo demonstrating relief of macular distortion, improvement of vascular tortuosity, and removal of ERM. (E) Postoperative OCT demonstrating improved macular architecture. (F) Postoperative FA showing significant decrease in retinal vascular tortuosity and small window defect nasal to the fovea.
Patient 10, preoperative visual acuity (VA) 20/100 and postoperative VA 20/20. (A) Preoperative color fundus photo demonstrating combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) lesion with overlying gliosis component causing distortion of the macular architecture with a traction retinal detachment of the macula present. (B) Preoperative optical coherence tomography (OCT) thickness map of the CHRRPE lesion. (C, D) Preoperative OCT showing epiretinal membrane (ERM) with macula schisis and a tractional retinal detachment over the fovea and along the inferotemporal arcade. (E) Postoperative color fundus photo demonstrating reduction of macula distortion as well as residual ERM along the inferotemporal arcade (arrow). (F) Postoperative OCT map showing significant reduction of retinal thickness at the fovea and location of CHRRPE. (G, H) Postoperative OCT demonstrating restored macula architecture with resolution of the ERM, macular schisis, and traction retinal detachment.
Two patients encountered complications during the treatment course and needed further surgery. One patient had both CHRRPE and pre-existing pars planitis in the same eye, and 2 months after the vitrectomy and membrane peeling procedure for CHRRPE, the patient was found to have an inferior macula-on retinal detachment secondary to pars planitis. He required retinal reattachment surgery consisting of vitrectomy, scleral buckle, laser, and gas tamponade. He remained attached 1.5 years later. Another patient had a midperipheral CHRRPE with significant proliferative tissue that caused a tractional retinal detachment and affected his macula. Subsequently, after his original surgery for the CHRRPE, this patient developed a retinal tear with a localized macula-on retinal detachment requiring a second operation consisting of vitrectomy, scleral buckle, lensectomy, laser, and silicone oil. The silicone oil was subsequently removed a short time later and the retina remained attached.
ERMs are a common feature of CHRRPE. Contraction of these membranes can lead to the secondary formation of retinal folds, traction retinal detachment, macular schisis, and chronic macular edema, which can cause significant VA loss and metamorphopsia in these patients. The utility of surgical membrane peeling to improve visual outcomes has been scarcely reported in these patients partly due to the rarity of this condition, and additionally the results have been mixed.
In 1973, Gass stated that the overlying sheet of ERM is intertwined with the underlying anterior surface of the lesion and therefore questioned the role of surgical intervention.1 Then a decade later in 1984, the Macula Society published a review of 60 patients with CHRRPE.3 In that report, three of the 60 patients underwent membrane peeling and only one of out of the three surgical patients had improvement in visual outcome. Based on these three patients, the authors concluded that if the ERM is not directly entwined with the underlying retinal component of the lesion, surgery might be beneficial.
Since then, there have been 11 other small, sporadic case reports in the literature (with nine of the 11 having three or fewer patients with surgical intervention reported) demonstrating mixed visual outcome results after membrane peeling (Table 3). McDonald et al.6 and Sappenfield and Gitter7 did not find objective improvement in VA after surgery, whereas Mason and Kleiner,8 Mason,9 Benhamou et al.,10 Stallman et al.,11 Konstantinidis et al.,12 and Sanchez-Vicente et al.13 reported success in visual outcome after surgery. Shields et al. reported mixed outcomes of three surgical patients included in a series of 77 patients they reported with CHRRPE.14
Details of Previously Reported Cases of Combined Hamartomas That Underwent Membrane Peeling Surgery
Cohn et al.15 in 2009 reported outcomes of 11 patients with CHRRPE who underwent membrane peeling, with the majority of their patients having had autologous plasmin enzyme used adjunctively at surgery (six of 11 patients). All 11 patients (100%) had “complete macular reattachment,” and eight of 11 patients (73%) had improvement in VA. Their average follow-up duration was 15.6 months.
In 2010, Zhang et al.16 reported five patients with CHRRPE who underwent membrane peeling, with the difference being that plasmin enzyme was not used. All of the patients (100%) had anatomical improvement, but only three of the five patients had improvement in VA postoperatively. The duration of follow-up for this small series was 3 months to 5 years, with the average follow-up not reported in this series.
Our study is the largest series to date, consisting of 15 surgical patients, compared to 11 patients in the Cohn group and five patients in the Zhang group. All of our patients (100%) had macular anatomical improvement including reattachment and improved retinal anatomy with removal of the ERM. Fourteen of the 15 patients (93%) had objective improvement in VA (Figure 1). This is a significant improvement in visual outcome compared to the prior two studies by Cohn and Zhang, in which 73% and 60% of patients experienced VA improvement, respectively. All patients in our study had worsening VA preoperatively with significantly affected retinal anatomy changes, and eight of the 15 patients (53%) had amblyopia at time of surgery, although only three patients were 6 years old or younger at the time of surgery — the most densely affected amblyopic age range. Despite the effects of amblyopia in the remaining five patients of this group, dramatic improvements in VA were noted postoperatively. Overall, the average preoperative VA was 20/514, and the average postoperative final VA was 20/89 (P = .0025). The results of our study demonstrate that visual loss due to combined hamartoma with ERM can be treated effectively with surgery. Patients of amblyogenic age can do very well with surgical repair and subsequent postoperative amblyopia therapy.
None of our patients received adjunctive autologous plasmin enzyme. The rate of complete ERM removal was 60% in our study. Six patients (40%) had near complete removal of ERM without recurrence, and with an excellent visual outcome (average postoperative VA of 20/40, from an average preoperative VA of 20/590). The Zhang group had a similar incomplete ERM removal rate of 40%. In our series, one patient had a mild recurrence of ERM; however, this case was complicated by concomitant pars planitis in the same eye and was being treated with adalimumab for his pars planitis. This is compared to a 37% ERM recurrence rate in the Cohn study, which used plasmin enzyme in more than half of the patients. It should be mentioned that the average age at the time of surgery was 10 years in our study, compared to 5 years in the Cohn study and 13 years in the Zhang study.
We had a long follow-up period averaging 5.7 years, with a median follow-up of 4 years, and a minimum follow-up period of 1 year. Most patients obtained an improved outcome after the initial surgery; two patients required subsequent surgeries.
The main limitations of our study were the small patient population and its retrospective design. This was in part due to the rarity of combined hamartomas. To date, this is the largest series of patients with ERM due to CHRRPE lesions undergoing surgical repair.
In summary, vitrectomy with membrane peeling is beneficial in patients with worsening VA secondary to epiretinal proliferation associated with CHRRPE. In children of amblyogenic age, deprivational amblyopia is a concern; therefore, earlier surgical repair should be considered to maximize visual potential.
- Gass JD. An unusual hamartoma of the pigment epithelium and retina simulating choroidal melanoma and retinoblastoma. Trans Am Ophthalmol Soc. 1973;71:171–183; discussions 184–175. PMID: 10949597
- Dedania VS, Ozgonul C, Zacks DN, Besirli CG. Novel Classification System for Combined Hamartoma of the Retina and Retinal Pigment Epithelium. Retina. 2018;38(1):12–19. doi:10.1097/IAE.0000000000001499 [CrossRef] PMID:
- Schachat AP, Shields JA, Fine SL, et al. Combined hamartomas of the retina and retinal pigment epithelium. Ophthalmology. 1984;91(12):1609–1615. doi:10.1016/S0161-6420(84)34094-5 [CrossRef] PMID:6521994
- Font RL, Moura RA, Shetlar DJ, Martinez JA, McPherson AR. Combined hamartoma of sensory retina and retinal pigment epithelium. Retina. 1989;9(4):302–311. doi:10.1097/00006982-198909040-00011 [CrossRef] PMID:2697919
- Holladay JT. Proper method for calculating average visual acuity. J Refract Surg. 1997;13(4):388–391. PMID:9268940
- McDonald HR, Abrams GW, Burke JM, Neuwirth J. Clinicopathologic results of vitreous surgery for epiretinal membranes in patients with combined retinal and retinal pigment epithelial hamartomas. Am J Ophthalmol. 1985;100(6):806–813. doi:10.1016/S0002-9394(14)73372-0 [CrossRef] PMID:4073178
- Sappenfield DL, Gitter KA. Surgical intervention for combined retinal-retinal pigment epithelial hamartoma. Retina. 1990;10(2):119–124. doi:10.1097/00006982-199004000-00006 [CrossRef] PMID:2402552
- Mason JO III, Kleiner R. Combined hamartoma of the retina and retinal pigment epithelium associated with epiretinal membrane and macular hole. Retina. 1997;17(2):160–162. PMID:9143046
- Mason JO III, . Visual improvement after pars plana vitrectomy and membrane peeling for vitreoretinal traction associated with combined hamartoma of the retina and retinal pigment epithelium. Retina. 2002;22(6):824–825. doi:10.1097/00006982-200212000-00028 [CrossRef] PMID:12476119
- Benhamou N, Massin P, Spolaore R, Paques M, Gaudric A. Surgical management of epiretinal membrane in young patients. Am J Ophthalmol. 2002;133(3):358–364. doi:10.1016/S0002-9394(01)01422-2 [CrossRef] PMID:11860973
- Stallman JB. Visual improvement after pars plana vitrectomy and membrane peeling for vitreoretinal traction associated with combined hamartoma of the retina and retinal pigment epithelium. Retina. 2002;22(1):101–104. doi:10.1097/00006982-200202000-00017 [CrossRef] PMID:11884886
- Konstantinidis L, Chamot L, Zografos L, Wolfensberger TJ. Pars Plana vitrectomy and epiretinal membrane peeling for vitreoretinal traction associated with combined hamartoma of the retina and retinal pigment epithelium (CHRRPE). Klin Monatsbl Augenheilkd. 2007;224(4):356–359. doi:10.1055/s-2007-962840 [CrossRef] PMID:17458814
- Sánchez-Vicente JL, Rueda-Rueda T, Llerena-Manzorro L, et al. Surgical treatment in combined hamartoma of the retina and retinal pigment epithelium. Arch Soc Esp Oftalmol. 2017;92(3):137–140. doi:10.1016/j.oftal.2016.07.007 [CrossRef] PMID:
- Shields CL, Thangappan A, Hartzell K, Valente P, Pirondini C, Shields JA. Combined hamartoma of the retina and retinal pigment epithelium in 77 consecutive patients visual outcome based on macular versus extramacular tumor location. Ophthalmology. 2008;115(12):2246–2252.e3. doi:10.1016/j.ophtha.2008.08.008 [CrossRef] PMID:18995912
- Cohn AD, Quiram PA, Drenser KA, Trese MT, Capone A Jr, . Surgical outcomes of epiretinal membranes associated with combined hamartoma of the retina and retinal pigment epithelium. Retina. 2009;29(6):825–830. doi:10.1097/IAE.0b013e31819b1788 [CrossRef] PMID:19276871
- Zhang X, Dong F, Dai R, Yu W. Surgical management of epiretinal membrane in combined hamartomas of the retina and retinal pigment epithelium. Retina. 2010;30(2):305–309. doi:10.1097/IAE.0b013e3181b85f2d [CrossRef] PMID:20175272
Summary of Patient Case Details
|Patient||Eye||Age (Years)||Sex||Hamartoma Location||Preoperative VA||1-Year Postoperative VA||Latest Postoperative VA||Clinical Exam (1 Year - Last Follow-Up#)||Follow-Up Duration (Years)||Amblyopia/Strabismus||Notes/Surgical Complications|
|1||OD||1||M||Macula & ST arcade||LP||CF 2 ft||20/100||Decreased TRD, residual membrane||2.5||Yes, esotropia|
|2||OD||4||M||Macula||CF 3ft||20/80||20/70||Macula flat||3||Yes, esotropia|
|3||OS||4||M||SN midperiphery & temporal midperiphery; associated VH||LP||20/80||20/70||Good macula anatomy, residual membrane||4||Yes||Additionally diagnosed with Neurofibromatosis Type 1|
|4||OD||7||M||Macula||LP||HM||HM||Macula flat||2||Yes, esotropia|
|5||OD||7||M||Peripapillary with TRD involving macula||CF 3ft||CF 1ft||CF 2ft||Good macula anatomy, no residual ERM but mild recurrent ERM||4||Yes||Concurrent pars planitis OD on adalimumab. Inferior macula on RRD secondary to pars planitis successfully treated with PPV/SB/EL/gas.|
|6||OD||7||M||Macula & IT and ST arcades||20/150||20/60||20/60||Macula flat||1.3||No|
|7||OS||8||M||Macula & ST arcade||20/200||20/30||20/30||Good macula anatomy, residual membrane||14||No|
|8||OS||9||M||Macula & IT arcade||20/50||20/50||20/30||Good macula anatomy, residual membrane||2.7||Yes|
|9||OS||9||M||Midperiphery||20/400||20/200||20/150||Macula flat||8||No||Cataract formation after initial PPV/MP/EL/SF6. Postoperative retinal detachment led to PPV/lensectomy/SB/oil. Silicone oil was subsequently removedwith continued attachment.|
|10||OS||11||M||Macula & IT arcade||20/100||20/70||20/20||Good macula anatomy, residual membrane||5||No|
|11||OD||12||F||Macula & ST arcade||20/400||20/40||20/30||Good macula anatomy, residual membrane||20||No|
|13||OD||14||F||Papillary & macula & IT arcade||20/70||20/20||20/20||Focal retinal thickening inferiorly||10||No|
|14||OS||18||F||Macula||20/70||20/40||20/40||Focal retinal thickening||2||Yes|
|15||OS||25||F||Macula||CF 6ft||20/400||20/400||Inferior macular thickening||4||Yes, exotropia|
|Mean VA logMAR ± SD||1.41 + 0.82||0.84 + 0.69*||0.65 + 0.67**|
Summary of the Locations of the Combined Hamartoma Lesions
|Location of Combined Hamartomas||Percentage of Patients (n/15 Total Patients)|
|Macula only||67% (10/15)|
|Macula and posterior pole||7% (1/15)|
|Macula and peripapillary||13% (2/15)|
Details of Previously Reported Cases of Combined Hamartomas That Underwent Membrane Peeling Surgery
|Reference, Year||Number of Eyes||Location of Lesion||Average Age at Surgery, Range (Years)||Visual Acuity Improvement||Improvement in Macular Anatomy||Follow-Up, Range (Months)||Comments|
|Schachat et al.,3 1984||3||NA||NA||1 of 3||NA||NA|
|McDonald et al.,5 1985||2||Macula||35, (26–44)||0 of 2||Persistent CME; Yes, small persistent fold in fovea||6, (3–9)|
|Sappenfield and Gitter, 6 1990||1||Macula||27||0 of 1||Yes||6||Subjective visual acuity improvement (but no objective improvement)|
|Mason and Kleiner,7 1997||1||Peripapillary, with associated macular hole||37||1 of 1||Yes||4|
|Mason,8 2002||1||Macula||20||1 of 1||Yes||3|
|Benhamou et al.,9 2002||1||Macula||7||1 of 1||NA||53|
|Stallman,10 2002||1||Macula||10||1 of 1||Yes||9|
|Konstantinidis et al., 11 2006||2||One peripapillary, one macula||13, (12–14)||2 of 2||Yes||9, (6–12)|
|Shields et al.,13 2008||3||Macula||NA||1 of 2; 3rd eye data-NA||NA||NA|
|Cohn et al.,14 2009||11||73% Macula, 27% macula & posterior pole||4.6, (1–14)||8 of 11 (73%)||Yes, 100%||15.6, (6–42)||6 of 11 eyes (55%) used plasmin; 4 of 11 eyes (37%) had ERM recurrence and 3 of the 4 underwent repeat surgery|
|Zhang et al.,15 2010||5||60% Peripapillary, 40% macula||12.6, (6–21)||3 of 5 (60%)||Yes, 100%||NA, (3–60)||No plasmin use; 2 of 5 (40%) had residual ERM|
|Sanchez-Vicente et al., 12 2017||1||Macula||39||1 of 1||Yes||15|
|Our study, 2020||15||67% Macula, 7% macula & posterior pole; 13% peri-papillary & macula; 13% midperiphery||10, (1–25)||14 of 15 (93%)||Yes, 100%||68.4, (15–240)||No plasmin use; 6 of 15 (40%) had residual ERM; 1 of 15 (7%) had mild ERM recurrence|