Congenital Hypertrophy of the RPE : 32027-PD / 102646

Introduction

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