Freckle (the answers)

The eyelid freckle is characterized by the presence of increased amount of brown pigment (melanin) in the basal layers of epithelium (1). Note the cells of pigment are not melanocytes but rather epithelial cells. If the cells were all melanocytes an entirely different differential diagnosis becomes operative. There are also pigment containing melanophages (2) in the dermis and a superficial chronic perivascular dermatitis with lymphocytes and rare plasma cells (3). Freckles show hyperpigmentation of the basal layer but no elongation of the rete ridges as seen in lentigo simplex. Histologic evidence suggests that the actual number of melanocytes in freckles is decreased compared to normal adjacent epidermis. However, the melanocytes that are present in freckles have more intricately branched dendritic processes. This histologic picture may be quite difficult to distinguish from normal skin of pigmented individuals by light microscopy alone. However, the clinical appearance of discrete macules that are small and brown and generally deepened in sun-exposed areas is characteristic.

Eyelid Freckle

Click on the photograph to enlarge the image. Identify the pathology processes at the numbers that characterize this lesion. For the answers click here for the link.

Bullous Keratopathy of the Cornea

Bullous Keratopathy
Definition: Bullous keratopathy is a swelling of the cornea due to endothelial damage.
Incidence/Prevalence: Bullous keratopathy is most common in older people. Bullous keratopathy occurs after cataract surgery, its incidence has decreased since the advent of intraoperative viscoelastic agents that protect the corneal endothelium and the decreased use of iris plane and anterior chamber intraocular lenses. A review at the University of Toronto indicate that pseudophakic bullous keratopathy is the 3rd leading indication of penetrating keratoplasty. (Maeno et al.) In our material it is the most common diagnosis for corneal button specimens.
Etiology: Often the cause of bullous keratopathy is loss of endothelium from a malpositioned intraocular lens (pseudophakic bullous keratopathy). There is failure of the corneal endothelial cell layer to perform its normal pump function. The pumping failure can occur either because the cells themselves do not function normally or because the absolute number of endothelial cells has decreased below a critical level necessary to maintain corneal clarity. In addition retrocorneal fibrous membranes arise from uneven internal wounds and compromise the endothelium.
Clinical Presentation: Bullous keratopathy occurs most commonly after cataract removal. Bullous keratopathy is characterized by the formation of fluid-filled blisters on the surface of the cornea. The blisters rupture, causing pain, often with a foreign body sensation and impairment of vision. The diagnosis is made from the typical appearance of a swollen, cloudy cornea with blisters on the surface. Pachymetry will confirm a thicker cornea.
Histopathology: The changes observed include desquamating epithelial cells from the anterior surface (arrow 1), separation of epithelium from Bowman's layer creating the bullous detachment (number 2). There are hydropic changes (tiny bubbles) within the epithelium giving them less apparent staining (arrow 3). Bowman's layer is irregularly thinned probably related to the bullae (arrow 4). The stroma shows areas devoid of keratocyte nuclei and irregular lamellae (number 5), features indicative of scarring. The endothelium is markedly attenuated; there are fewer endothelial cells than normal. Here we find only a single endothelial cell in this view (arrow 6). Additional findings that may be seen include a thickened and redundant epithelial basement membrane. In general the key finding is a paucity of endothelial cells, and those cells remaining are flattened and attenuated. Descemet’s membrane is usually intact, except in cases triggered by a retrocorneal fibrous membrane.
Treatment: Bullous keratopathy is treated by reducing the amount of fluid in the cornea. Hypertonic eye drops can be used to draw the fluid out. Occasionally, soft contact lenses can be used to decrease discomfort. If vision is insufficient for daily activities or discomfort is significant, corneal transplantation may be indicated.



Compare to the normal cornea by clicking here.

Fuchs Corneal Endothelial Dystrophy

Fuchs Dystrophy
Definition: Fuchs corneal endothelial dystrophy features loss of endothelial cells controlling proper endothelial pump function; thus, malfunction permits marked edema. Vision progressively becomes blurrier and more indistinct as disease advances.
Incidence/Prevalence: Fuchs dystrophy has a variable inheritance pattern and occurs more commonly in women (12.5 to 1.0 in noted familial cases and 4 to 1 in sporadic cases). It is one of the leading causes of bullous keratopathy. Patients rarely present before 30 years and it usually manifests after 40 years of age.
Etiology: Fuchs is genetically inherited from affected parents and has high penetrance as an autosomal dominant disease.
Clinical Presentation: The condition is clinically recognizable by the appearance of guttae in Descemet’s membrane. Focal, anvil-shaped outgrowths are seen buried in the thickened Descemet’s membrane. The outgrowths can also be found protruding into the anterior chamber. The appearance of endothelial cells is sparse or non-existent.
Histopathology: In this disorder the corneal epithelium episodically separates from Bowman's layer and secondary changes occur that are featured here. The epithelial basement membrane reforms from epithelium as it reattaches leading to additional basement membrane material in the middle of the epithelium (number 1). The basal epithelium and sometimes the entire epithelium features a "washed out" appearance (number 2) which on close inspection is seen to be hydropic change. The epithelium is separated from Bowman's layer, a bullous detachment (number 3). Bowman's layer is irregularly thinned (arrowheads 4). The stroma is scarred as seen by irregularly contoured stromal lamellae and an uneven distribution of nuclei within the stroma (difficult to see on this PAS stain). The hallmark of Fuchs dystrophy is of course the guttata that can be seen clinically within Descemet's membrane. In this case the guttata are buried with Descemet's membrane or endophytic (5 and figure below arrows 1). The endothelium is quite sparse but the nuclei are much better seen in a routine H&E stain.

Treatment: Palliative treatment focuses on alleviating symptoms and improving vision after epithelial edema becomes distinct. 5% NaCl drops can be used to clear the epithelial edema or increase tonicity of tear film to prevent accumulation of corneal fluid during sleep. Surgical treatment include transplantion of the cornea or a more limited form of endothelial keratoplasty (DSEK).



Guttata may be seen clinically with retroillumination at the slit lamp (see Figure in link).


Usually, guttata in Fuchs dystrophy are exophytic as shown below.

Once again hydropic epithelial changes (1), and irregular Bowman's layer (2) , stromal scarring (3) and expophytic guttata that protrude posteriorly into the anterior chamber (4) are featured. The astute observer will notice that there is pigment in the endothelial cells.

Keratoconus

Definition: Noninflammatory condition characterized by the change in eye form from normal round shape to a cone shape. Cone shape results from the bilateral central or axial ectasia of the cornea with anterior protrusion of the cornea. Keratoconus results when the cornea thins and protrudes. Abnormal eye shape distorts visual images.
Incidence/Prevalence: Keratoconus usually manifest in adolescence with an incidence of about 1/2000.(1) About 70% of cases occur in females.
Etiology: The cause of keratoconus is unknown. Keratoconus has been associated with atopic dermatitis, vernal catarrh, Down's syndrome, retinitis pigmentosa, Marfan's syndrome, aniridia, blue sclera, infantile tapetoretinal degeneration, and mitral valve prolapse. The association with atopy and vernal has led to speculation that vigorous and frequent eye rubbing may aggravate or even cause keratoconus. The cause of the central thinning is unknown but the lamellae in keratoconus are reduced in thickness, particularly deep in the stroma. A small amount of stromal thinning can be attributed to reduced number of lamellae.
Clinical Presentation: Keratoconus often manifests during the late teens or early twenties, then progresses slowly for the next decade or two as the cornea scars and becomes more elongated. Although affecting both, one eye may be more severely affected than the other. Myopia and an irregular astigmatism may result from the alteration in the normal corneal contour. Keratoconus occurs mostly as an isolated finding, but can be associated with other ocular disorders or systemic conditions (i.e. Down syndrome).

Histopathology: The hallmark of keratoconus is thinning of the central stroma (arrows in the lower power photomicrograph). Changes in focal disruptions of the epithelial basement membrane and Bowman’s layer are initial indicators of keratoconus.
This macrophotograph of a bisected cornea is taken at the dissecting microscope with the cornea placed on edge. Here a brown ring called Fleisher's ring (black arrows) is evident on the surface of the cornea. At the very edge of the specimen (black arrow 1) the brown (oxidized iron) can be seen deposited within the epithelium. The white arrows show Descemet's membrane; click to enlarge. The central cornea (left side of photo) is thinner than the peripheral portion of the cornea.
The Prussian blue stain (Perls test) detects iron depositions in the basal epithelial layers. The image shows iron (blue staining at arrow 1) in the basal layer of the epithelium, which transitions to involve the entire epithelium in long standing and severe cases (arrow 2).
The earliest abnormalities of keratoconus occur in the epithelial basement membrane and Bowman's layer. The basement membrane





















may be disrupted (arrow 6) and duplicated. Bowman's layer (arrow 3) is disrupted (arrow 4) and fibrous tissue is interposed between the epithelial basement membrane and Bowman' layer (arrows 5). There is also stromal scarring. Note the endothelium is not significantly attenuated and the Descemet's membrane is thin (the patient is young).
One acute complication of keratoconus is corneal hydrops which is the sudden onset of corneal edema associated with a sudden break in Descemet's membrane. This occurs of course usually in the thinnest area of the stroma. While it can be managed medically in the acute phase, the cornea may not be able to recover as Descemet's membrane becomes scrolled and cannot heal. In this case a penetrating keratoplasty may be done. The patient whose penetrating keratoplasty specimen is shown had a history of corneal hydrops. Descemet's membrane is disrupted and folded back to rejoin the cornea in the wrong orientation (arrow 7) . There is marked stromal scarring (number 8).
Treatment: Some authors recommend cautioning patients about rubbing their eyelid as some believe this hastens progression of keratoconus. Mild cases of keratoconus can be treated with glasses or contact lenses. Often a rigid lens compensates for the irregular corneal astigmatism. Some have tried superficial keratectomy, epikeratoplasty and thermokeratoplasty with variable and often temporary improvement. Penetrating keratoplasty is considered very successful for long term rehabilitation in severe cases.

What is syringoma?

Definition: Syringoma is considered a benign neoplasm of the eccrine ducts in the skin.
Etiology: For most cases the etiology is unknown. Loss of heterozygosity of the familial gene for cylindromatosis has been reported at 16q or 16p in sporadic cases of syringoma. Familial cases of syringoma have been reported but are rare. Cases of eruptive syringomas have occurred in association with Down's syndrome (18-64%). Syringomas are part of the Nicolau-Balus syndrome (syringoma, milia, atrophodermis vermicula).
Incidence/Prevalence: Eruptive syringoma occurs with a frequency of 1/2500 in surgical biopsies.
Clinical: Click to enlarge photo.
Syringomas usually appear in crops on the patient's face especially the lower eyelids and are more common in women at puberty and beyond. For a clinical photograph please click here.
The lesions are soft in texture, similar in color to the normal skin or slightly yellow and measure about 1-2 mm in size.
Histopathology: Click on pictures for larger image. Identify the structures at the numbered arrows.


Both photographs feature ductular structures (1) and more solid appearing nests and strands (2) that are present within the dermis. Occasionally the ducts have solid extensions that have been likened to a comma in shape (3 below).

The ductular structures (1) are lined by bland cells with amphophilic cytoplasm (clear due to glycogen) and there is an eosinophilic lining internally and occasionally externally. The material in the lumen of the ducts (1) is keratinaceous. These structural features recapitulate the eccrine sweat gland apparatus.
A malignant syringoma, also known as sclerosing sweat duct carcinoma has been described in the eyelids.

Compound nevus- the answers

Conjunctival Nevus
Definition: Acquired benign proliferation of melanocytic cells in the conjunctiva
Incidence/Prevalence: Conjunctival nevi usually appear in childhood with an increasing rate per annum. In one series the nevus accounted for about 28% of biopsied conjunctival tumors(1) . The majority of patients in some series are white but this may reflect the patient population of the series. About 2% of clinically diagnosed conjunctival nevi progressed to melanoma in one series over 7 years(2).
Etiology: unknown but the location and increasing incidence with age may suggest sun exposure is related. An activating mutation in exon 15 of the BRAF gene is associated with 40% melanomas and 50% with conjunctival nevi but not in patients with PAM (3). This work is particularly interesting as some authors claim that 1/4-1/2 of melanomas arise from pre-existing nevi (see conjunctival melanoma in this tutorial).
Clinical Findings: The common acquired conjunctival nevus typically appears during the first decade of life. Conjunctival nevus usually (72%) develops in the bulbar conjunctiva nasally or temporally. Conjunctival nevi may also involve the plica semilunaris (11%), and the caruncle (15%). It is very unusual for limbal nevi to involve the corneal stroma, although clinically, nevi may appear to flop over onto the corneal surface. Typically the majority of nevi have cysts (65%) and about 1/3 of patients will have feeder or intrinsic vasculature. Nevi may grow, especially in children and adolescents. The sudden change in the size or color (especially towards pink or orange) in a nevus of a child or adolescent is more likely to reflect inflammation. Conjunctival melanoma is especially rare in children. Of the series reported for childhood conjunctival melanocytic lesions the incidence of melanoma was as follows:
•0/41 Bebe 1990-2001
•0/48 Goldenberg-Cohen 2005
•3/71 McDonnell 1989
•0/98 UCLA 1957-1982
One of the 3 cases in McDonnell's series developed metastases.
Age- In general the mean age of diagnosis for conjunctival nevi is younger than melanoma. In Jakobiec's recent series the mean age for nevi was 40 years of age with a range of 6-76 yrs compared to 62 yrs for melanoma with a range of 24-96 yrs. The criteria for diagnosis in this study was purely histologic and there was no meaningful patient follow up or documented history of growth.
Histopathology: The compound nevus of the conjunctiva features nests of nevus cells that are both at the junction of the epithelium and substantia propria and within the substantia propria. The lesion is often accompanied with cystic inclusions of epithelium not nevocytes which are sometimes misleading for the neophyte. The lumen of a very large cyst (1) is shown surrounded by squamous epithelium (2). The surface epithelium has been denuded partially (3) and there are few nevus cells at the base. The nevus cells form a nesting pattern (4).





















A slightly higher magnification shows the lumen of the cystic inclusion (1), the specialized stratified squamous epithelium (2), intracytoplasmic brown pigment (3) and an intranuclear cytoplasmic inclusion (4). Conjunctival nevi are believed to evolve from an initial junctional phase to a compound and finally subepithelial nevus. In the junctional phase, cells are confined to nests (theques) at the interface between the epithelium and the substantia propria. In the compound nevus phase, the nests are present in the substantia propria, as well as at the base of the epithelium and in the subepithelial phase the nests are confined to the substantia propria.
Given all of these criteria and those of immunohistochemistry, the diagnosis of conjunctival pigmented lesions remains a key problem for eye pathologists. Grossniklaus has identified discordance in diagnosis among experienced eye pathologists and has published that many melanocytic conjunctival lesions are indeterminant from the histologic findings alone.
Immunohistochemistry: Numerous studies on the immunohistochemistry of conjunctival nevi have differed in results for effectiveness. Both melanomas and nevi stain for MART-1 and S-100 and therefore have no predictive value in separating benign from malignant conjunctival lesions. Several studies have shown that HMB-45 also stains benign and malignant lesions. Two recent studies have touted that melanomas stain more intensely for HMB-45 and subepithelial nevi usually do not stain as well. These studies are all hampered by a lack of clear followup. In addition the centers reporting these studies were tertiary referral centers so that the sections had already been cut from the paraffin block and the immunohistochemistry was not performed on the same sections with the same fixation and processing. Most of the studies were not done in a stereologically sound manner. However, a recent study by Jakobiec found that Ki-67 (a proliferation marker) did distinguish nevi (6-9% positive cells in 4 high power fields) from melanomas (19.7-34.5%). However there was at least one exception in the series of 13 melanomas. One 59 year old patient with nodular epithelial melanoma showed only 7.1% Ki-67 positive cells. There was no clinical follow up on any of these cases. The study did not address the possibility of transformation in lesions or progression. However, a panel of markers Ki-67, CD45, HMB45, MART 1 and pankeratin may be useful to 1. identify the melanocytic cells from inflammatory cells and squamous epithelium, 2. accurately gauge the depth of the lesions, 3. determine if the proliferating cells are epithelial, inflammatory or melanocytic (dual immunostaining are performed on adjacent sections).
Treatment: The treatment of pigmented lesions of the conjunctiva is predicated on an accurate diagnosis. Some lesions simply require careful surveillance. If the pigmented lesion is clinically suspicious, i.e. growth, elevation, change in pigmentation then it should be completely excised if possible. A fine (10-0) suture should be placed at 12:00 o’clock for margin analysis. Because conjunctival tissue has a tendency to curl when placed into fixative, it is important to first flatten the specimen on filter paper or cardboard face up and to float this on formalin. In this way the specimen will fix in the flat state. These lesions are best handled by eye pathologist who are used to dealing with tiny specimens for margin analysis and are quite familiar with the specific attributes of conjunctival nevi.
Prognosis: Conjunctival nevi are thought by some to be a precursor to melanoma. Shields reports that ~2% of clinically diagnosed conjunctival nevi progress to melanoma over a mean of 7 years (Shields et al. Archives Ophthalmology 2004;122:167-75). This retrospective study is based on clinical chart review that spanned a mean of 11 years and 149 patients (3 patients developed melanoma). The caveate is that the diagnosis of nevus was made clinically and there is no histologic proof that these lesions were not melanoma from the beginning. No histology was provided in the paper to document the melanoma.

References:
Shields et al. Ophthalmology 2004;111:1747-54.
Shields et al. Archives Ophthalmology 2004;122:167-75.
Goldenberg-Cohen et al. Invest. Ophth. Vis. Sci 2005;46:3027-30.
JakobiecFA et al. Arch Ophthalmol. 2010;128:174-183.
Grossniklaus HE et al. AJO 2000;129:702. Indeterminant melanocytic proliferations of the conjunctiva.

Conjunctiva-Compound Nevus

Click on the photograph to see a higher magnification. Use "back" key to return.

Identify each of the structures that are numbered.

Then click here to link to the answers.