Ocular Pathology

Use it to review eye pathology for Ophthalmology Board Review or OKAP. Anatomy and pathology of the human eye. Included solar-lentigo, phakomatous choristoma (phacomatous-choristoma), congenital hereditary endothelial dystrophy, Fuch's dystrophy, bullous keratopathy, conjunctival nevus, syringoma, primary acquired melanosis,carcinoma-in-situ, BIGH3 dystrophy, and other lesions seen in eye-pathology. The cornea, iris, lens, sclera, retina and optic nerve are all seen.

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Wednesday, March 29, 2006

What is conjunctival melanoma?

Conjunctival Melanoma
Definition:
Malignant tumor of melanocytes originating in the conjunctiva.
Incidence/ Prevalence: The incidence of conjunctival melanoma is based on 3 epidemiologic studies in Germany, Sweden and the Netherlands with an incidence of .080, .070, and .028 in 100,000 inhabitants, respectively. Conjunctival melanoma is about 1/500 as common as skin melanoma.
Etiology: The cause of conjunctival melanoma is largely debated but is strongly correlated with the presence of PAM, or acquired conjunctival lesions (manifested as detectable pigmentation), with atypia seen in these lesions. UVR exposure may induce conjunctival melanoma due to its correlation with atypical PAM. A population based study indicated that a focus of PAM with atypia co-existed in 71% of conjunctival melanomas. Several authors have reported conjunctival melanomas have arisen from benign conjunctival nevi in anywhere from 26-60% of cases (2,3,7,8). The evidence is usually based on co-existence.
Clinical Findings: Age of presentation: Most prevalent in elderly and middle-aged and is equally common to men and women. Pigmented lesions of the conjunctiva above the age of forty should be treated with suspicion; it is promulged that conjunctival nevus is unusual in this age group. However, Jakobiec reported the mean age of patients with conjunctiva nevi in his series was 40 and almost half the cases were well over 40 yrs!
Conjunctival melanoma occurs in all areas of conjunctiva including the tarsus, fornices, and caruncle. Melanocytic lesions in the palpebral conjunctiva are particular suspicious for PAM or malignant melanoma.
Tumors are usually nodular growths that may involve any portion of the conjunctiva; those not on the bulbar surface appear to behave more aggressively. The precursor to microinvasive melanoma may be a slight thickening of PAM observed through a histopathological examination of the lesion
Histopathology: In general, conjunctival melanomas feature infiltration of the substantia propria by atypical pigmented cells with prominent nucleoli and abundant cytoplasm containing brown granular pigment. The tumor may show pagetoid infiltration of the epithelium and there is often accompanying primary acquired melanosis or a nevus. The neoplasm shows atypical mitotic figures with abnormal forms (tripolar, hyperchromatic, ring forms). However the melanomas may include a variation of cell types such as spindle, epithelioid, and balloon cells. Melanomas may also contain polyhedral cells which are morphologically similar and may be confused with nevus cells or lymphocytes. In the image below and to the right, the epithelium is thin and poorly cohesive nests of tumor cells show atypical cells that vary from a small polygonal shape to a spindle cell shape in the lower portion. The image (high magnification) to the left shows atypical melanocytes that vary in shape and size and contain pigment. The tumor has infiltrated the sclera (low magnification image).
Immunohistochemical stains for S-100 protein, MART1, and HMB-45 may be used to verify Pagetoid spread. Ki67 has been touted as effective for differentiating nevus from melanoma (~19.7% positive cells in 4 high po wer fields versus 9% for junctional nevi).Ref.13 Tumor thickness can be measured objectively using a calibrated microscope; tumors thicker than 0.8 mm carry a greater risk for dissemination and death than thinner ones. However, even lesions less than 0.8 mm thick has resulted in patient mortality. Over history, various thicknesses have been assigned given a poor prognosis ranging from 0.8mm (2) to 4mm (5). Death due to metastatic conjunctival melanoma has been linked with other histologic characteristics as well: (1) invasion of the cornea, episclera, or sclera; (2) over five mitotic figures for every ten high-power fields; (3) involvement of the fornix, caruncle, or palpebral conjunctiva; (4) the presence of acute or moderate atypia; (5) the existence of melanoma cells permeating the entire thickness of the epithelium when PAM is present; (6) an overall absence of inflammation and lack of polyhedral cells exhibited in the invasive component.
Treatment: The primary treatment of conjunctival melanoma is surgical: all traces of invasive melanoma should be removed. Areas of adjacent PAM should also be extirpated by surgical excision, cryotherapy, laser ablation, perhaps topical chemotherapy, or a combination of methods. Cryotherapy is not a primary treatment for conjunctival melanoma and should be used only to treat extensive zones of primary acquired melanosis. Removal of the eye is not indicated unless the tumor invades the eye or the eye is otherwise blind and painful; intraocular invasion by conjunctival melanoma is extremely unusual, especially in the absence of any preexisting wounds such as cataract incisions. Exenteration may be indicated to manage large conjunctival melanomas but has little effect in controlling metastases once the orbit is invaded. It is considered a palliative approach (11). The treatment for conjunctival melanoma is complete surgical removal.
Prognosis: The overall mortality rate from conjunctival melanoma is about 25% (defined over various time periods in several studies showed survival ranging from 69-81% (2-8).
Typically, metastases first develop in parotid or submandibular lymph nodes. Unfavorable prognostic factors, in addition to conjunctival site as mentioned above, include orbital or scleral invasion, histopathologic identification of pagetoid or full-thickness intraepithelial spread, and involvement of the eyelid skin margin.


References:
1. Seregard S. Survey of Ophthalmology 1998:42;321.
2. Folberg R, McLean IW, Zimmerman LE. Conjunctival melanosis and melanoma.Ophthalmology. 1984 Jun;91(6):673-8.
3. Jay B. Br J Ophthalmol. 1965 Apr;49:169-204.
4. McGhee CN, Ni C, Albert DM, Chu FR. Int Ophthalmol Clin. 1982 ;22(3):35-56
5. Ash
6. Silvers
7. Liesegang TJ, Campbell RJ. Mayo Clinic experience with conjunctival melanomas.Arch Ophthalmol. 1980 Aug;98(8):1385-9.
8. Jeffrey
9. Werschnik C, Am J Clin Oncol. 2002 Jun;25(3):248-55
10. Paridaens AD, Minassian DC, McCartney AC, Hungerford JL.
Prognostic factors in primary malignant melanoma of the conjunctiva: a clinicopathological study of 256 cases.Br J Ophthalmol. 1994 Apr;78(4):252-9.
11. Paridaens AD, McCartney AC, Minassian DC, Hungerford JL. Orbital exenteration in 95 cases of primary conjunctival malignant melanoma. Br J Ophthalmol. 1994 Jul;78(7):520-8.
12. Jay B. Br J Ophthalmol. 1968 Jan;52(1):70-3
13. Jakobiec FA et al. Immunohistochemical Studies of Conjunctiva Nevi and Melanomas. Arch. Ophthalmol 128:174-183.

Tuesday, March 28, 2006

What is benign melanosis of the conjunctiva?


Benign Melanosis of the Conjunctiva
Definition: Pigmentation of the basal layer of the epithelium without a proliferation of melanocytes. This definition includes the ephelis or freckle, so called complexion-associated conjunctival pigmentation, and benign acquired melanosis because the three entities may be indistinguishable clinically and under the microscope.
Etiology: Benign melanosis is a normal phenomenon in heavily pigmented individuals and statistical data suggest that pigmentation may be protective from UV exposure (i.e. dramatically lower incidence of PAM with atypia and conjunctival melanoma). For those with less pigmentation, the etiology is unknown and unknown if such pigmentation is even abnormal.
Clinical Findings: Complexion associated pigmentation occurs mainly at the limbus (arrow 1 in this macrophotograph of an autopsy eye) and fans out to be lighter in color more peripherally toward the fornix (arrow 2 in the photo) shows that the pigment has dispersed just millimeters from the limbal pigmentation.
Ephelis is a circumscribed lesion.
Histopathology: As shown in the figure, there is increased pigmentation in the cells of the basal layer, i.e. squamous epithelium. There is no nested pattern and there is no increase in melanocytes. This is critical because the absence of the nesting distinguishes benign melanosis from primary acquired melanosis. The pigmented granules often are on the apical side of the nucleus as though protection is afforded by absorbing harmful UV radiation. If one looks carefully at the nuclei in the photograph(click on the image to enlarge) one will see the pigment is more concentrated above the nuclei.
Treatment: If recognized in the appropriate setting no treatment is generally needed. However, confusing cases of pigmentation arise that require biopsy. For example if the lesion is actively growing or documented by examination of remote photographs from the patient. In these cases a careful excision should be performed if the lesion is localized and placed flat on filter paper, bottom side down and fixed in formalin. It is very helpful to send a detailed sketch or photo to the eye pathologist to aid in recognizing the clinical problem, orienting the specimen to provide margins and performing careful analysis.

What is sarcoidosis of the conjunctiva?

Sarcoidosis
Definition: Sarcoidosis may involve any of a number of ocular tissues, including the conjunctiva. Conjunctival disease manifests small, tan nodules primarily within the fornix and tarsal regions.
Incidence/Prevalence: Sarcoidosis affects men and women of all races and ages. The condition usually presents in adults younger than 40 years, most frequently between 20 and 29 years of age. It is slightly more predominant in women than in men, with an incidence of 6.3 and 5.9 cases per 100,000 person-years, respectively. The lifetime risk of sarcoidosis for U.S. "whites" is estimated at 0.85 percent compared with 2.4 percent in U.S. "blacks". Sarcoidosis is most prevalent in Swedes, Danes, and U.S. blacks. Caution is advised in interpreting these figures as genetic studies have demonstrated that the U.S. population is much more heterogeneous with mixed ethnicity than previously realized. The artificial "racial" divisions are probably not warranted and may obfuscate understanding the etiology of the disease.
Etiology: Sarcoidosis is a multisystem granulomatous disease with an unknown etiology, characterized by the presence of non-caseating granulomas in involved organs.
Clinical Findings: Systemic sarcoidosis may present with bilateral hilar lymphadenopathy, pulmonary infiltrates, and ocular and skin lesions. The heart, liver, spleen, salivary glands, muscles, bones, kidneys, and central nervous system also may be involved.
Serum and tear levels of angiotensin converting enzyme are elevated. Conjunctival lesions often present as elevated nodules, single or multiple, of the palpebral surfaces. The lesions are yellow or tan in color and do not exhibit necrosis.
Histopathology: Histopathologically, non-caseating granulomas (aggregates of epithelioid histiocytes) may be present in the substantia propria. A minimal cuff of lymphocytes and plasma cells surround the lesions. Multinucleated giant cells may or may not be present within the granuloma. Star shaped asteroid bodies and calcific Schaumann bodies may be seen in epithelioid cells and particularly multinucleated cells but are not specific for sarcoidosis. Often one is faced with the random biopsy of conjunctiva in search of a granuloma of sarcoid. This procedure may be effective but the yield is exceedingly low in most hands despite step sectioning the entire tissue. Performing multiple (map biopsies) bilaterally will improve the yield. (1) Clinically performed confocal microscopy may be a more effective way to delineate tissue that is abnormal for biopsy. (2)

The diagnosis of sarcoidosis is one of exclusion from a pathologic standpoint; the diagnosis of sarcoidosis cannot be made on histologic grounds alone. Infectious etiologies of granulomatous disease include bacteria such as Francisella tularensis (tularemia) and Bartonella henselae (cat-scratch disease), mycobacteria, fungi, spirochetes, or parasites. Foreign body granuloma can usually be excluded if produced by suture and wood because they polarize light and can be viewed with 2 polarizing filters placed above the slide and below the substage condenser.

Treatment: Corticosteroids remain the mainstay of treatment. Methotrexate and antimalarial agents are also used in certain scenarios of the clinical disease.
Prognosis: The prognosis of systemic disease has some correlation with mode of onset, host characteristics, initial clinical course, and extent of disease. Mortality from sarcoidosis, usually respiratory failure, is between 1 and 5 percent.


References:
1. Leavitt JA, Campbell RJ.Cost-effectiveness in the diagnosis of sarcoidosis: the conjunctival biopsy.Eye. 1998;12 ( Pt 6):959-62.
2.Wertheim MS, Mathers WD, Suhler EB, Wilson DJ, Rosenbaum JT.
Histopathological features of conjunctival sarcoid nodules using noninvasive in vivo confocal microscopy. Arch Ophthalmol. 2005 Feb;123(2):274-6.

Dysplasia of Squamous Epithelium of the Conjunctiva

Definition: Dysplasia of the corneal epithelium refers to abnormal maturation of the epithelium as it differentiates from the basal layer in the superficial layers. Rarely, primary intraepithelial neoplasia may arise in the cornea.
Epidemiology: The incidence of dysplasia, carcinoma in situ, and invasive carcinoma of the cornea and conjunctiva was estimated to be 1.9 per 100,000 per year averaged for 10 years in a study from Brisbane, Australia. In a study from Queensland, Australia, 288 cases were identified 155 dysplasia, 71 carcinoma in situ, 62 squamous cell carcinoma. 78.5% of the cases occurred in males with an average age of 60.1 years. Squamous cell carcinoma was found to be most prevalent in the limbal region.
Etiology: precancerous lesions associated with dysplasia often appear in conjunction with preexisting pinguecula within the epithelium. Their development is strongly correlated to overexposure of the conjunctiva to ultraviolet light. The appearance of dysplasia has also been associated with human papillomavirus type 16 (HPV16). HPV is associated with bilateral conjunctival tumors manifested as multiple lesions of the tarsal and bulbar conjunctiva. In addition to these tumors, invading dysplasia and squamous cell carcinoma has been found in the eyes of patients harboring this disease. HPV 16 is also present in benign squamous papillomas (75%) in some series so that the role HPV 16 infection alone, in producing dysplasia has been questioned.
Clinical Findings:
Patients often present with irritation, reported in 40% of the cases. Dysplasia usually appears as a diffuse, gelatinous, and semitransparent epithelium. Most lesions originate at the limbus. Untreated lesions often involve the palpebral fissure and protrude between the eyelids. Recurrences occur in about 23% of the cases in some series.













Histopathology: At low magnification the epithelium shows acanthosis, cellular crowding and altered cellular polarity without maturation. There is nuclear enlargement, dyskeratosis, and often mitotic figures above the basal layer of the epithelium. There may be pleomorphism and abnormal mitoses. Squamous cell carcinoma are defined by invasion of the substantia propria and vary widely in size and often exhibit surface keratinization and squamous eddies and pearls.



















Treatment: Established treatment techniques include a careful excision using appropriate margins. Autografting may be necessary to close a large defect. Most small sized conjunctival intraepithelial neoplasia can be effectively treated with topical drops of Mitomycin C. Cryotherapy as well as application of topical conjunctival chemotherapy with 1% 5-FU may also be used as an adjunctive therapy to treat incompletely excised or recurrent carcinomas. In a study of ten patients with recurrent squamous cell carcinoma (average age 66 years) the tumor response to Mitomycin C was evaluated. Following six weeks of treatment cycles in which topical drops of .04% Mitomycin C were administered to the eye four times per day, all ten cases showed tumor regression. No complications were documented. The efficacy of topical 5-FU was also documented in a case study of eight patients with recurrent or untreated squamous cell carcinoma. The application of 1% 5-FU eye drops four times daily for four weeks resulted in clinical regression for all 8 patients. After three months the complete recovery of normal epithelium was observed in all cases with no long-term side effects.

References: Lee, GA Australian NZJ Opthamology 1997(4): 269-76
Spencer, Ophthalmic Pathology. W.B> Saunders Company, 1996(1): 113-115.
Shields CL, Am Journal of Ophthalmology 2002(5): 601-6
Edoardo Midena, Claudia Degli Angeli, Massimo Valenti, Valentina de Belvis, Paolo Boccato, Br Journal of Ophthamology 2000(84): 268-272

What is carcinoma-in-situ of the conjunctiva?

Squamous Carcinoma in Situ
Definition: Full thickness intraepithelial involvement by squamous dysplasia.

What is ligneous "conjunctivitis"?


LIGNEOUS CONJUNCTIVITIS
Definition: Ligneous conjunctivitis is a woody induration of the eyelid accompanied by a plasminogen defect that leads to fibrin deposition and a recurrent pseudomembranous conjunctivitis.
Etiology: Several mutations have been detected in the plasminogen gene of patients affected with ligneous conjunctivitis. The human plasminogen gene, located on chromosome 6, has a marked homology with the genes belonging to the plasminogen-apo(a) family, and with a number of pseudogenes and plasminogen-like genes located on chromosome 2. The result is that plasmin, the active form of enzyme that degrades fibrin, does not function and fibrin deposits accumulate.

Clinical Presentation: The median age at diagnosis is about 5 years, and patients present with papillary white red lesions of firm consistency. Below is an image of lesions in both eyelids.

Pathology: Fibrin is deposited in the substantia propria and epithelium may proliferate along the lobules of fibrin to become entrapped. The tissue may have a polypoid appearance and chronic inflammation and granulation tissue usually accompany the process. In the gross photograph islands of translucent granulation tissue and foci of inflammation (arrow 1) are surrounded by white fibrin (arrow 2). Note the lobulated appearance of the mass.











Under the microscope the H&E stain shows the amorphous eosinophilic substance in the substantia propria.


The PTAH stain demonstrates the abundance of fibrin in the lesion (blue color).

Treatment: The lesions generally respond well to fibrinolytic therapy, topical plasminogen and heparin.

What is primary acquired melanosis of the conjunctiva?

Primary acquired melanosis (PAM)
Definition: PAM is a controversial term used to describe increased brown pigmentation of the conjunctiva, usually flat and speckled, associated histologically with an increased number of melanocytes in the epithelium. The process is acquired after birth and generally in adulthood. It has been subdivided by Folberg et al. as PAM without atypia and PAM with atypia.
Incidence/ Prevalence: There is significant difficulty in interpreting the literature about the prevalence of PAM as it is generally definition dependent. Some prominent textbooks illustrate PAM as increased pigmentation of the basal layer. In one study the prevalence of PAM was 36% in patients with no known non-European ancestry. We reserve the diagnosis for a clear increase in the number of melanocytes in a specific pattern. Otherwise patients with a dark complexion who have incidental pigmentation of the conjunctiva, benign melanosis will be included in the group. Henkind noticed conjunctival pigmentation in 92.5 % of African Americans, 28% of Hispanics and 35.7% of Asians. PAM is most common in middle-aged persons.
Etiology: unknown.
Clinical Findings: PAM presents as a speckled brown flat lesion of the conjunctiva, often a unilateral flat patch, of golden brown pigmentation with an irregular margin in a middle aged person (see photograph below). Note in the image that the pigmentation does not diminish as one moves posteriorly from the limbus, a feature in distinction from complexion-related melanosis. The lesions may fluctuate in size or grow slowly for 10 years or more. 46% of patients with PAM that is histologically atypical as defined by Folberg et al (see below) progress to melanoma. Patients who have PAM without atypia tend to be younger than patients who have PAM with atypia.
Histopathology. Histologically, PAM without atypia (Figure below) is a histologic term denoting increased pigmentation within the epithelium with hyperplasia of the basal melanocytes lacking cytologic atypia. If one uses the term, PAM, for increased pigmentation of basal epithelial cells without a proliferation of melanocytes (benign melanosis) then entities other than our definition of PAM will be included such as complexion related melanosis. The histologic photograph from a case of PAM shows nests of melanocytes in the basal layer of epithelium (#1 in Figure) which are poorly cohesive but confined to the epithelium. Occasional pigmented macrophages lie within the substantia propria (number 2 in Figure below).
















PAM with atypia denotes atypical melanocytes which may involve or replace the epithelium with spindle or epithelioid cells. In the photograph below you see a densely pigmented lesion of conjunctiva with individual melanocytes infiltrating the epithelium. Although it is difficult to tell, the melanocyte is often surrounded by a clear space. In this case because the obvious melanocyte with a surrounding clear space is seen above the basal layer, it would meet the criteria for PAM with atypia. Of course bleaching the section would remove obfuscating pigment so cytologic atypia could be identified along with the architectural atypia that is evident here.
Treatment: In general a biopsy is required for proper diagnosis of PAM. A biopsy yields prognostic information. If the lesion is small complete excision may be possible on initial biopsy and that is preferred. Extirpation has been reported with topical mitomycin; chemotherapy was found to induce regression of conjunctival melanoma and primary acquired melanosis with atypia. Cryotherapy, laser ablation, and radiation may be indicated to treat large areas of affected conjunctiva and thus spare patients the potential complications of symblepharon and dry eye associated with large conjunctiva excision. Exenteration of the orbit is not indicated for PAM, a condition that by definition is entirely intraepithelial. Often PAM exists for many years and patients undergo many biopsies.

REFERENCES- Gloor et al: Clinical characterization of primary acquired melanosis.Invest Ophthalmol Vis Sci. 1995 Jul;36(8):1721-9.

Henkind P: Conjunctival melanocytic lesion , Natual History. In Jakobeic FA Ocular and Adnexal Tumors, Birmingham, Ala, 1978 572-582.

Folberg et al. Primary acquired melanosis of the conjunctiva. Hum Pathol. 1985 Feb;16(2):129-35.


Saturday, March 04, 2006

What is a phakomatous choristoma?

Definition: Phakomatous choristoma is considered a lens anlage tumor described in 1971 by Zimmerman (also coined Zimmerman’s tumor). The tumor is formed of proliferating tissue that recapitulates the lens in development. It may occur in the eyelid or orbit.

Epidemiology: The tumor occurs in infants and generally presents prior to 6 months of age (mean age at surgery=6.3 months). The oldest patient reported was operated at 13 months.

Etiology: Theories of pathogenesis include
1. surface ectoderm "dipping down" into the mesoderm of the developing eyelid,
2. migration of putative lens tissue through the closing optic fissure, and
3. the site of origin of the invaginating lens being located in the area destined to form the nasal lower lid
Histopathology: The tumor is composed of cuboidal (lens type) epithelium (#2 in the figure) that forms ducts in a fibrous stroma. There is exuberant basement membrane material reminiscent of lens capsule. This basement membrane material (recapitulating the lens capsule) lines the external surface of most of the ducts (arrowheads at 4 enclose). In addition the ducts may contain in their lumen proteinaceous material that include lens crystallins (#3 in figure). In addition you may be able to find calcific foci in the stroma (#1 in the figure). The basement membrane material is PAS positive and characteristic. There may be degenerate areas reminiscent of the Wedl or "bladder-like" cells of cataract. Previously reported cases have shown immunohistochemical staining for lens crystallins and ultrastructural appearances that feature interdigitating plasma membranes (folded plasmallema).
Clinical: Only about 20 cases have been reported in the literature and most are located in the inferior nasal aspect of the eyelid but at least one has been reported primarily in the orbit. One of the previously reported cases had a colobomatous hypoplastic optic disc with staphyloma, and severe myopia suggestive of abnormality of closure of the optic fissure. Other cases showed astigmatism or epiphora attributable to eyelid lesions that resolved postoperatively.
Prognosis: The cases in the literature have all behaved quite benignly. In fact even tumors that were incompletely excised (2) did not recur.