TGFBI Corneal Dystrophy- Avellino Phenotype

Transforming Growth Factor Beta Induced Gene (TGFBI) Corneal dystrophy
Definition: TGFBI also known as BIGH3 may have a number of phenotypes. The lattice phenotype shows deposits indicative of amyloid deposition without a red color upon trichrome stain. The Avellino phenotype shows both characteristics. In fact the gene defects encompass the same gene and the protein sequence of keratoepithelin is similar if not identical.
Incidence/Prevalence:
Etiology:Features of both granular and lattice dystrophy appear in Avelino dystrophy, first described in patients tracing their ancestry to Avellino, Italy. Histologically, both hyaline deposits (typical of granular dystrophy) and amyloid deposits (characteristic of lattice dystrophy) are present within the corneal stroma. This dystrophy, like granular and lattice dystrophy, has been mapped to chromosome 5q.

Histopathology: The cornea shows stromal linear deposits (arrow 1) that are present similar to lattice dystrophy as well as discrete intrastromal deposits (arrow 2) that appear white in gross specimen on cross-section. All of the deposits stain similarly. Trichrome stains the deposits bright red. The fluorescent dye Congo red binds to the protein and exhibits dichroism (circular and linear) with a Cotton effect as well as optical rotary dispersion.


Treatment:

What is an actinic keratosis of the eyelid?

Actinic Keratosis (Solar Keratosis)
Definition: a premalignant condition characterized by dysplasia of the basal cell layer of the skin.
Incidence/Prevalence: Prevalence for actinic keratosis of the skin in general ranges from 0.3% of the general population in Italy to about 3% in patients over 40 in Germany.
Etiology: Ultraviolet radiation induced oxidative damage is the predominant current etiologic hypothesis. Actinic keratosis as the name suggests is related to solar exposure.
Clinical Findings: Actinic keratoses range from millimeters up to 1 cm in size. They usually present as erythematous, scaly macules or papules in middle age on sun-exposed skin. Frequently the keratosis, or an elevated white flaky crust is seen on the surface.
Histopathology: The sine qua non for diagnosis in actinic keratosis is the presence of dysplasia of the basal cell layer of the epidermis. Accompanying architectural features include cellular and nuclear crowding with alteration of the polarity or maturation of the cells; cells fail to flatten at the higher layers of the epithelium. Cytologic findings include nuclear enlargement, nuclear hyperchromasia, nuclear membrane irregularity, mitotic figures, and increased nuclear-to-cytoplasmic ratios. Nuclear changes in actinic keratosis range from mild (involving only the basal epithelial layers) to frank carcinoma in situ, or full-thickness involvement of the epidermis. The underlying dermis shows solar elastosis (fragmentation, clumping, and loss of eosinophilia) of dermal collagen and a lichenoid chronic inflammatory infiltrate of varying intensity. Several subtypes have been described with the following features:
acantholytic- clefts in the epithelium above the atypical cells in the basal layer
atrophic- minimal hyperkeratosis, loss of rete ridges, a single layer of atypical basal cells
Bowenoid - carcinoma in situ; involves the entire epithelium
hypertrophic- hyperkeratosis, hypergranulosis, parakeratosis and papillomatosis. In the figure below, one sees a typical actinic keratosis with downward budding or elongation










of rete pegs (arrows 1), atypia of the basal layer that extends along the rete pegs (arrows 2) acanthosis, marked hyperkeratosis, and parakeratosis (arrows 3). In addition there is a chronic inflammatory infiltrate at the base of the epidermis. Some of the enlarged and atypical basal cells extend along the adnexal structures as well.
pigmented type- melanin in the basal layer and dendritic cells within the epithelium, dermal pigment laden macrophages.
Treatment: Biopsy of suspicious lesions and follow-up are prudent in patients with this condition. The base of the lesion must be examined histopathologically to exclude invasive squamous cell carcinoma. Therefore, biopsies of suspected actinic keratoses should include the base of the lesion; shave biopsies should be avoided. Treatment alternatives include excision, cryotherapy and a variety of topical agents to extirpate the lesions.
Prognosis: Some authors state that in about 20% of patients with actinic keratoses, squamous carcinoma may develop in one or more of the lesions. However, when squamous cell carcinoma arises in actinic keratosis, the risk of subsequent metastatic dissemination is very low (0.5%-3.0%).

Methods and Conjunctiva Study Guide

Name the precise events and their time course for wound healing of the following tissues and the operations:
1. Cornea
a. LASIK
b. Clear cornea cataract surgery
c. Limbal incision cataract surgery
d. penetrating keratoplasty
2. Sclera
3. Iris
4. Retina

5. Name the strict definition of a "granuloma."

6. What are the definitions of choristoma, hamartoma, teratoma. Be able to classify lesions into these categories... for example capillary hemangioma.

7. What is the histological appearance of Berlin's edema? (Commotio retinae)
8. What is the rate of penetration of formalin in tissue specimen?

9. What are the histological features of phthisis bulbi? What is the single most important key histology finding that pervades all of the cases? Hint: ciliary body
10. What is the standard thickness of tissue sections in histology?
11 Arrange the following in order of increasing sizes: neutrophil, lymphocyte, plasma cell, monocytes, red blood cell, basophil, eosinophil, giant cell, epithelioid histiocyte.
12. What is the histological appearance of dermolipoma?
13. Describe the histological appearance of eye in expulsive choroidal hemorrhage.
14. Name the etiology, clinical findings, histologic findings, associations, treatment and prognosis for the following conjunctival lesions:
a. amyloidosis
b. oncocytoma
c. squamous carcinoma
d. allergic conjunctivitis
e. ligneous conjunctivitis
f. complexion associated melanosis
g. PAM
h. PAM with atypia
i. Melanoma
j. lymphoma
k. superior limbic keratoconjunctivitis
l. sarcoidosis
m. cat scratch fever
n. mucoepidermoid carcinoma
o. spindle cell carcinoma
p. choristoma

15. Special stains
a. best overall stain to give general morphology, stains nuclei blue and proteins red.
b. stain to identify calcification(as black in color), such as in band keratopathy.
c.. that turns Aspergillus black.
d. stain to identify lipid as green globules in formalin fixed tissue
e. special stain to identify melanocytes in a case of PAM
f. panel of special stains to identify Rosai Dorfman disease.

16. Trauma
a. What is iridodialysis?
b. What is a Vossius Ring?
c. What are the causes of Descemet's membrane rupture and what is the appearance histologically? How is forceps injury discernible microscopically?
d. What is proliferative vitreoretinopathy?
e. What is sclopetaria?
f. What is a retinodialysis?

What is Melkersson-Rosenthal syndrome?

Melkersson Rosenthal Syndrome
Definition: First described in 1928, the syndrome is characterized by orofacial edema swelling, facial nerve paralysis and a fissured tongue. Histologically there are dilated lymphatics with perivascular and occasional intralymphatic vascular granulomatous inflammation.
Incidence/Prevalence: More common in females than males by a ratio of 3:1. This syndrome is quite rare and seems to be more prevalent in Europe than in the U.S.
Etiology: The etiology of Melkersson-Rosenthal syndrome remains controversial. No convincing evidence exists for any infectious, allergic or hereditary origin. There is a familial tendency and some authors claim there is an autosomal dominant pattern of inheritance with variable penetrance.
Clinical Findings: Generally occurs more commonly in women. The syndrome does occur in children but is much more common in adults. Non-pitting facial edema, facial nerve paralysis (left side of face in the image to the left and a fissured tongue ( arrows 1 below) form the classic triad. The upper lid is more often involved than the lower lid (see image to the left). The facial nerve paralysis (shown in the image) is often delayed in onset, years after the facial edema and is indistinguishable from Bell’s palsy. The onset of the disease episode is sudden and may last hours to weeks.
In addition migraine headaches and constitutional symptoms such as hyperpyrexia have been described. Fibrosis may ensue. Distinguished from angioedema, Melkersson-Rosenthal syndrome lasts longer and is unresponsive to antihistamines.
Histopathology: A skin biopsy is usually performed to aid in the diagnosis. Typical histopathological findings include edema, non-caseating epithelioid cell granulomas, multinucleate Langerhans-type giant cells, perivascular mononuclear infiltration and fibrosis. The low power image of the skin shows some thickening of collagen bundles (fibrosis) and an increased distance between them (suggestive of edema). There is a dilated lymphatic in the deep dermis that is filled with epithelioid histiocytes. (Click to enlarge the photograph.) There are sparse extravascular infiltrates of lymphocytes and histiocytes in this image. Lymphocytic and histiocytic infiltration of lymphatics may be seen in the early stages of the disease. At higher magnification one sees that the intralymphatic infiltrate is composed of single epithelioid histiocytes (arrow 3) with bean shaped nuclei that are eccentric in the cells and abundant foamy cytoplasm. Note that the infiltrate is accompanied by some lymphocytes. One can see the spindle cells lining the blood vessels of these lymphatics (arrow 2). Intralymphatic and perilymphatic granulomatous infiltrates (arrow 4) are very characteristic of this disorder.
Treatment: Some authors have had success with short doses of corticosteroids during attacks but otherwise the treatment is largely symptomatic.
Prognosis: Recurrent episodes are likely.

What is a rhabdomyosarcoma?

Rhabdomyosarcoma of the Orbit
Definition: malignant neoplasm with skeletal muscle differentiation
Incidence/Prevalence: the most common primary malignant orbital tumor of childhood
Etiology: The alveolar subtype of rhabdomyosarcoma has a consistent chromosomal translocation, t(2;13)(q35;q14). PAX3 and FKHR genes on respective chromosomes 2 and 13 are juxtaposed as a result of the translocation.
Clinical Findings: Rhabdomyosarcomas of the orbit usually present with sudden and rapidly progressive proptosis. As shown in the image, there is accompanying swelling of the eyelids, and conjunctival chemosis. The average age of onset is 7-8 years. The tumor is slightly more common in boys. Rhabdomyosarcomas usually involve the superior part of the orbit, so the eye may be displaced downward as in the case shown. The notable absence of erythema, calor and fever separates rhabdomyosarcoma from cellulitis due to an adjacent sinus infection.
Radiologic Studies: The tumor often appears deceptively well circumscribed on scan. The lamina papyracea is often eroded in up to 60% of patients. The lateral orbital wall should be carefully examined for erosion. Rhabdomyosarcoma is not a highly vascular tumor.
Histopathology: Orbital rhabdomyosarcomas are classified slightly differently and have a better prognosis (overall five-year survival of 92%) than do their extraorbital counterparts.
Three histologic types of orbital rhabdomyosarcoma are recognized:
1. embryonal (the most common),
2. alveolar, and
3. differentiated.
Embryonal rhabdomyosarcoma may develop in the conjunctiva and may present as grapelike submucosal clusters (botryoid variant). Histologically, spindle cells are arranged in a loose syncytium with occasional cells bearing cross-striations, which are found in about 69% of embryonal rhabdomyosarcomas.
Alveolar rhabdomyosarcoma has the worst prognosis in untreated or non-orbital rhabdomyosarcomas, but in recent studies the prognosis is no different than for other orbital types. The pattern produced is alveolar, with tumor cells forming and lining trabecular spaces. A reticulin stain shows thin septae that mark this tumor.
Differentiated rhabdomyosarcomas feature numerous cells with striking cross-striations, muscle differentiation. In the image series here, one sees a cellular tumor with a slightly myxoid background (arrow 1), hemorrhage (arrow 2). At higher magnification numerous strap cells with abundant pink cytoplasm are seen in the H&E stained section (arrow 3). A trichrome stain reveals numerous cells with clear cross striations (arrow 4) . Note also that the nuclei are extremely atypical with marked enlargement, variation in size and shape, numerous dark chromocenters and nucleoli and irregular chromatinic rims (arrow 5). Immunohistochemical reactivity for desmin and muscle-specific actin may be identified. Electron microscopy is often helpful, especially in the less well-differentiated cases of embryonal rhabdomyosarcoma, to demonstrate the typical sarcomeric banding pattern.
Treatment: A combination of surgical intervention, chemotherapy and radiotherapy has been very effective.
Prognosis: Orbital rhabdomyosarcomas are classified slightly differently and have a better prognosis (overall five-year survival of 92%) than do their non-orbital tumors.

What is a nevus of the eyelid?

Eyelid Nevi
Definition: Nevocellular nevi are benign proliferations of melanocytic cells divided into 3 categories depending on their architecture: junctional, compound and intradermal. The congenital nevus of the eyelid is a special category with implications for malignant transformation.
Incidence/Prevalence: The intradermal nevus is by far the most common nevus seen on the eyelid.
Etiology: There is some controversy whether nevocytes arise from melanocytic precursors in the nerve sheaths or in the epidermis.
Clinical Findings: On the eyelid the nevus often arises at the eyelid margin and may be flat, elevated, dome-shaped, and even pedunculated. The flat lesions are often junctional nevi. The domeshaped lesions are often intradermal or compound nevi and the pedunculated lesions are usually intradermal nevi. The image shows a dome-shaped pedicle at the eyelid margin which was diagnosed clinically as a “squamous papilloma”. Close examination reveals subtle brown areas on the surface and a tan color. Histology showed an intradermal nevus. Generally nevi will be tan in color and often will feature deep brown pigmentation. The nevus is generally well circumscribed and not associated with ulceration.
The congenital nevus of the eyelids may present as a "kissing nevus" in which the melanocytes are present symmetrically on the upper and lower eyelids. Presumably this nevus was present prior to eyelid separation (9 -20 weeks of gestation).
Gross Findings: As shown in the macroscopic image of a bisected eyelid lesion, the surface of the lesion may be domeshaped or irregular (arrows 1) and in this nevus, nests of cells near the surface are more darkly pigmented (arrow 2). The lesion is elevated as nest of cells begin to fill the dermis (arrow 3).
Histopathology: Nests of nevocytes may be present at the epidermal-dermal junction (hence junctional nevus), confined to the dermis (intradermal) or both (compound). The nevus shown in the image is an intradermal nevus. Nests are composed of uniform cells with bland nuclei and variable amount of cytoplasmic pigmentation (number 1). Cells deeper in the lesion tend to have smaller nuclei, be less pigmented and the cells appear more organoid in architecture and more spread out. The nuclei may show invaginated cytoplasm that give the appearance of a vacoule or an inclusion within the nucleus (arrows 3). The invaginated cytoplasm may contain brown pigment. Some cells may contain clumps of pigment (number 2). There are usually very few if any mitotic figures. Nevi are believed to progress over time from junctional nests, or theques, to nests that migrate into the superficial dermis. Eventually the nevus becomes a dome-shaped as it expands and fills the dermis locally and finally as a pedunculated lesion.
The kissing nevus or congenital nevus of the eyelid will have similar features to the compound nevus but may show extensive pilosebaceous apparatus involvement.
Treatment: Suspicious pigmented lesions of the eyelid, that have a history of growth, alteration in pigment pattern, vascularity, associated inflammation should be removed as the early diagnosis of melanoma is critical and may be confused with a nevus. Some nevi in which the diagnosis is obvious may be cosmetically unacceptable to the patient or may cause irritation, particularly if they are pedunculated. These are easily removed at the slit lamp.

Prognosis: Most nevi of the skin are not considered to be at increased risk of malignancy. However, the large congenital melanocytic nevus appears to have an increased risk of malignant
transformation of 4.6% during a 30 year period in a Danish study (see Wu-Chen et al.). The risk of transformation of the kissing nevus of the eyelid has never been firmly established; a single case was published in 1950 by Fuchs, but this was anecdotal and no pathology was provided.

Retina Uvea Study Guide

STUDY GUIDE
Describe and be able to recognize the clinical gross and histological features of the following entities:
1. PHPV
2. Bergmeister’s papilla
3. CMV retinitis
4. ARN
5. Toxoplasmosis
6. Coccidioidomycosis
7. Aspergillus
8. Candida uveitis
9. Ophthalmomyiasis, due to Cuterebri and Ovis Oestris
10. Chronic vitreous hemorrhage
11. Asteroid hyalosis
12. Vitreous amyloidosis
13. Posterior vitreous detachment
14. Retinal tear flap
15. Retinal hole
16. Lattice degeneration of the retina
17. Chronic retinal detachment
18. Macular hole
19. Surface wrinkling retinopathy
20. Intraocular lymphoma
21. Retinal features of glaucoma
22. Myelinated nerve fibers
23. Hemangioblastoma
24. Sturge Weber
25. Wyburn Mason
26. Congenital Hypertrophy of the RPE
27. Radiation retinopathy
28. Sarcoidosis
29. Typical cystoid degeneration
30. Reticular cystoid degeneration
31. Cystic retinal tuft
32. Retinoschisis
33. Pavingstone degeneration
34. Retinopathy of prematurity
35. Diabetic retinopathy
36. Macular degeneration
37. Central retinal vein occlusion
38. Central retinal artery occlusion
39. Cotton wool spots
40. Retinal microaneurysm
41. Retinoblastoma
42. Medulloepithelioma
43. VKH syndrome
44. Sympathetic uveitis
45. Uveal nevi
46. Uveal melanoma
47. Melanocytoma
48. Metastatic choroidal lesions
49. Choroidal osteoma
50. Leiomyoma of the ciliary body
51. Schwannoma of the ciliary body
52. Hemangioma of the choroid
53. Retinal glioma
54. Fuch’s adenoma
55. Dentate pearl
56. Learn the predisposing lesions for retinal detachment.
57. Commotio Retina