Learning Objectives:
- To review the demographics, pathophysiology, and characteristics of congenital hypertrophy of the retinal pigment epithelium (CHRPE)
- To review the association between CHRPE and colon cancer
- To review features and purpose of a Cochrane Review
Course Credit:
2 hours
Case
A 40 year old female presents to your
office for a routine eye exam. She
has no specific concerns. She has
not seen an optometrist in over 20 years, and has no history of any eye
problems. She is healthy apart
from well-controlled hypertension and migraines.
On dilated exam, a large pigmented
lesion is seen in the superotemporal retina. What is the most likely diagnosis?
Select your answer:
• Choroidal melanoma
Incorrect - Choroidal melanoma should be considered in the differential diagnosis of any pigmented fundal lesion. Choroidal melanoma is less likely in this case due to the absence of drusen, orange pigment, or elevation of the lesion.
• Choroidal nevus
Incorrect - Choroidal nevus is a common cause of pigmented fundal lesions. However, the appearance in this example is more in keeping with CHRPE.
• Congenital hypertrophy of the retinal pigment epithelium
CORRECT
• RPE adenocarcinoma
Incorrect - Although extremely rarely RPE adenocarcinoma may arise from a CHRPE lesion, there are no signs to suggest this is the case in this example. Specifically, the lesion here is not raised and there does not appear to be abnormal vasculature supplying the lesion.
Introduction
Congenital hypertrophy of the retinal
pigment epithelium (CHRPE) is a benign lesion of the fundus that most often appears
as a flat, pigmented spot.1 Its prevalence
is highly variable and difficult to determine- studies quote a highly variable
prevalence ranging from 0.3-40% of the population.2-4 It is more common in
females by a ratio of 2:1.5
CHRPE can be broken down into three
subtypes which include solitary CHRPE (which is most often referred to with the
term “CHRPE”), grouped CHRPE (“bear tracks”), and multiple CHRPE. The latter 2 subtypes are often
considered distinct entities, and this module will focus primarily on the
solitary type. Typically, CHRPE has no clinical significance, however the
recent development of multiple CHRPE is often associated with the cancer
syndrome familial adenomatous polyposis
(FAP).1
Presentation
CHRPE lesions are most commonly an
incidental finding discovered on dilated fundus examination. In its most common form, CHRPE (i.e.
solitary CHRPE) presents as a flat, pigmented, well defined fundus lesion.6 It is usually solitary
and more commonly seen in the temporal rather than nasal retina.7 8 It is also most
commonly seen in the mid-periphery but on rare occasion may involve the
posterior pole and even the macula.
Most cases are unilateral.9 Approximately 88% of
lesions are pigmented, which are brown in about ½ of cases, black in 1/3 of
cases and the remaining gray.5 Rarely, it may be
present without pigmentation.5 The lesions are often
round or oval in shape and have sharply demarcated smooth or scalloped margins.10 In a series of 330
patients with CHRPE lesions, Shields et al found the mean basal diameter of the
lesions to be 4.7 mm (range 0.2-13 mm) and mean thickness by ultrasound 0.8 mm
(range 0-2.1 mm).5 Drusen and
pigmentary mottling do not occur over CHRPE lesions, and the presence of such
features should prompt suspicion for melanoma.11
CHRPE lesions are usually asymptomatic
and do not cause a decrease in vision unless they involve the macula, which is
rare.12 However, peripheral
lesions can cause a related visual field defect that evolves from a relative
scotoma in youth to an absolute scotoma in adulthood. 13
Approximately half of CHRPE lesions
contain lacunae, which are atrophied window-like defects in the lesion. Histologically they represent segmental
loss of RPE where the inner retina is fused to Bruch’s membrane over a bed of
bare sclera with segmental absence of choroidal tissue.14 Lacunae vary in shape,
size, and percentage of the lesion which they cover and are especially seen in
elderly patients.10 There is likely no clinical
significance of them.
Most CHRPE lesions also feature a
pigmented or nonpigmented halo just inside the margin of the lesion which
produces a halo or double outline of the lesion, accounting for its nickname of
“halo nevus”.13
Classically, it was thought that CHRPE
lesions were stationary with no potential to grow or undergo malignant
transformation.7 However, it is now
known that over time 75-80% of lesions
will slowly grow in diameter.5,
15 Provided such enlargement is slow
and flat, it is not a cause of concern.
The number and size of lacunae also typically increases over time. 5
Most often, CHRPE lesions do not grow in
vertical dimensions but rarely progression to an elevated nodule has been noted. Histological examination of such
lesions has found nodular transformation in CHRPE to be due to the formation of
a primary malignant adenocarcinoma of the RPE.16 17 Such lesions can
invade the sensory retina and develop a retinal blood supply.16 With continued
tumor growth subsequent complications may develop including exudative retinal
detachment, intraocular inflammation, vitreous traction, posterior synechiae,
cataract, and vision loss.6 18 Generally
inflammation worsens as the tumor grows, however it is unclear if the tumor
causes inflammation, or inflammation promotes growth of the tumor.18
Features which suggest a tumor of the
RPE (including originating from CHRPE) include development of retinal blood vessels
that supply and drain the tumor, and yellow lipoproteinaceous retinal and
subretinal exudation.7 Choroidal melanoma
rarely has feeder vessels or signifiant exudation.7 It should be noted
that with respect to nomenclature of a neoplasm originating from RPE cells
without glandular features, the terms benign epithelioma or malignant
epithelioma are more correct, however by convention the term RPE adenocarcinoma
is used.7
Pathology
Histologically, CHPRE lesions are
composed of intensely pigmented, hypertrophied RPE cells that are 1.5-2x the
height of normal RPE cells.14 Pigmentation in
the form of multiple round melanin granules (macromelanosomes) is heavy
throughout the cytoplasm of the cells, as opposed to normal RPE cells which
display apical polarization of pigment. There is also a lack of lipofuscin, which manifests
clinically as a complete lack of autofluorescence of the lesions.19
It is also known that CHRPE lesions cause
a progressive loss of photoreceptors in the overlying retina (this can readily be seen on OCT).20 It is thought that
there is a defect in the capacity of phagocytosis and digestion of
photoreceptor outer segments which leads to photoreceptor degeneration of the
overlying retina and the associated visual field defect.20 There is usually a
normal choriocapillaris and thickened RPE basement membrane.13 Histology shows an abrupt change from
abnormal to normal cellular architecture at the edges of the lesion.13
Grouped
CHRPE
Grouped CHRPE, also known as congenital
grouped pigmentation of the RPE (CGP-RPE) is a variant of CHRPE that appears
similar but is often considered a separate entity.10 CGP-RPE is
characterized as sectorially-oriented hyperpigmentation in one or more
quadrants of the fundus.8 21 The lesions are
multiple, small, brown-black in colour, and often resemble footprints (the
condition is often called “bear tracks”).
Typically such bear tracks are larger in the periphery and decrease in
size towards the optic disc.
Histologically, CGP-RPE is dissimilar
from CHRPE. RPE cells in CGP-RPE
display hyperpigmentation as in CHRPE but are normal in size (i.e. no true
hypertrophy).8 Embryologically the condition is likely
due to clusters of pigmented RPE cells that develop with the secondary optic
vesicle during the evolution of the two retinal layers.21 They are derived from the
edge of optic nerve with smaller clusters and larger lesions in the periphery,
which are surrounded by normal somatic cells with wild-type pigmentation.21
Familial
Adenomatous Polyposis and Multiple CHRPE
Familial adenomatous polyposis (FAP) is
an autosomal dominant condition characterized by the development of hundreds to
thousands of polyps (adenomas) in the rectum and colon.22 Although these polyps
are initially benign, almost all patients will eventually develop colorectal
cancer if left untreated.22 The fatality rate is as high as 100% for
untreated patients by the age of 50.23 Overall, FAP accounts
for only about 1% of all cases of colorectal cancer but accounts for 5% of
familial colorectal cancer.22 The prevalence is
between 1 in 11 300 to 1 in 37 600.22 It usually manifests
by the late teens to early twenties and occurs in males and females at an equal
rate.22
FAP is caused by a mutation in the APC
gene on the long arm of chromosome 5.
APC (adenomatous polyposis coli) encodes a tumor suppressor
protein. Over 800 mutations in the
APC gene have been noted to cause FAP.
Virtually 100% of patients will eventually develop colorectal cancer due
to a “2 hit mechanism” in which further mutations (e.g. p53, kRAS) cause
APC-mutated cells to be more likely to be malignant.
FAP usually does not cause symptoms
until the polyps are large or numerous enough to cause rectal bleeding and/or
resultant iron-deficiency anemia.
Patients may also have non-specific gastrointestinal complaints such as
changes in bowel habits, constipation, diarrhea, or abdominal pain.22 Rarely, patients
may initially present with constitutional symptoms such as weight loss however
it should be noted that a family history of the disorder is often known and
rarely do patients present with advanced disease.
The diagnosis of FAP is made by a suggestive family
history and clinical findings.22 Colonoscopy is
performed to identify the number of polyps and biopsy the lesions. Most patients will also have genetic
testing as the diagnosis of FAP is important both in terms of treatment for the
individual and family planning.
The treatment of FAP-related colorectal
cancer involves regular colonoscopies and usually prophylactic proctocolectomy
by the age of 25. Non-steroidal
anti-inflammatory drugs (NSAIDs) are often prescribed to decrease the number of
polyps but they do not negate the need for surgery.
Patients with FAP may also have
malignancies develop in the small bowel or stomach, and often display
extra-intestinal manifestations.
These include CHRPE (see below), osteomas, dental abnormalities, desmoids
tumors, and/or extracolonic cancers (thyroid, liver, bile ducts, CNS).22
CHRPE is the most common extra-colonic
manifestation of FAP, occurring in 70-75% of patients.24 CHRPE lesions in FAP
are atypical in that they are multiple, bilateral, and familial (i.e. the name
“multiple CHRPE”).25 Studies have also
shown that the lesions differ in both histology and appearance on fluorescein
angiography from standard solitary CHRPE.
As such, many consider these lesions to be a different entity altogether,
using the term “pigmented ocular fundus lesions of familial adenomatous
polyposis” or POFLs.26
The presence of CHRPE/POFLs in
individuals with a family history of FAP but no known APC mutations themselves
is significant as it indicates the patient is an asymptomatic carrier of FAP
(i.e. the lesions are clinical marker for FAP in CHRPE-positive families).27 28 The occurrence of CHRPE
with FAP is related to a distinct region of the APC gene, specifically between
codons 311 and 1444.24 It has been proposed
that the presence of CHRPE can be used to direct mutation analysis to a
specific region of the APC gene.24
There is no association between CHRPE
characteristics and specific FAP variants.29 Pigmented fundal
lesions are highly pleomorphic and represent the variable expression of a
common genetic defect of growth regulation.29
The development of new CHRPE-like
lesions are strongly associated with FAP (or related disorders, see below) and
usually occur as multiple bilateral lesions as opposed to the often solitary
unilateral normal CHRPE lesions.
The sensitivity of such new-onset bilateral CHRPE-like lesions in
diagnosing FAP is 65-84%, with a
specificity of greater than 94%.4,
29-31
There are also several other variants of
FAP that should be noted:
·
Attenuated FAP: milder form of disease
characterized by fewer adenomas, later age of adenoma development and cancer
diagnosis.22
·
Gardner syndrome: Gardner syndrome (also
known as Gardner’s syndrome or familial colorectal polyposis) is a clinical
variant of FAP where extra-colonic features (e.g. fibromas of the scalp,
shoulders, arms, and back; dental abnormalities; and osteomas of the skull and
mandible) are prominent.22 CHRPE-like lesions occur in 75% of
patients with Gardner’s syndrome.
·
Turcot syndrome: extremely rare variant
of FAP with various neuroepithelial tumors of the central nervous system
including medulloblastomas and/or astrocytomas, without soft tissue, bony, or
dental abnoramlities.22 32
CHRPE lesions in patients with Gardner
and Turcot syndrome are also unique histologically and on fluorescein
angiography. They show RPE
hyperplasia and hamartomatous changes in addition to RPE hypertrophy and
hyperpigmentation.33 Bruch’s membrane is
often thickened.
CHRPE lesions may also be a marker of a solitary
precancerous colon mass, without a cancer syndrome.1 Patients with
colorectal cancer have been found to have a higher prevalence of CHRPE than
healthy controls (19.5 vs. 7.5%).1