Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009

6.Classification and prognosis summary

a.A little less than 50% of ciliary body and choroidal malignant melanomas are of the spindlecell variety with an excellent prognosis (i.e., approximately 73% survival).

b.A little more than 50% are of the nonspindlecell variety (epithelioid, mixed, or necrotic) and have a poor prognosis (i.e., approximately 35% survive).

E.Other classifications and prognosis

1.Wilder’s stain for reticulum: in general, heavily

fibered malignant melanomas have a better prognosis than lightly fibered ones, but this is not a very reliable criterion.

2.Degree of pigmentation

a.In general, lightly pigmented tumors have a better prognosis than heavily pigmented ones, but this is not a very reliable criterion.

b.The pigmentation may vary greatly from cell to cell, region to region, and tumor to tumor.

1). Unless serial sections are made, one may see only the pigmented part of the tumor or the nonpigmented (amelanotic) part.

2). Some tumors are completely amelanotic,* others are maximally pigmented, and others show variable pigmentation.

3.Size of tumor

a.Size seems to be the most reliable prognostic sign, even more reliable than cell type.

Posterior choroidal melanomas with ciliary body involvement have a greater mortality than “pure” choroidal melanomas, most likely because of their greater size.

b.The four factors for predicting prognosis best appear to be size (dimension), cell type, scleral extension, and mitotic activity.

Size of tumors based on echographic tumor elevation differs from that based on measurements from histologic slides because of variable shrinkage in the latter.

*Even in tumor cells considered completely amelanotic by light microscopy, some poorly formed, immature melanosomes are frequently found by electron microscopy.

c.Malignant melanomas under 1 cm3 (approximately 6 × 6 × 6 DD or smaller clinically) have a very favorable prognosis.

Of this group of small tumors, 69% are of the spindlecell types.

d.Malignant melanomas over 1 cm3 (10 × 10 ×

10 mm) have a poor prognosis.

Of this group of large tumors, 57% are of the nonspin- dle-cell types. The poor prognosis in the large tumor

group reflects the preponderance of epithelioid cellcontaining melanomas.

e. For practical clinical purposes, a solid uveal tumor under 6 DD in greatest diameter and less than 3 mm in height has a favorable prognosis, with a survival rate of approximately

73%.

f.Clinical features that may help predict metastases in small choroidal melanocytic tumors include posterior tumor location touching the optic nerve, increased tumor thickness, symp-

A

C

toms of blurred vision, and documented tumor enlargement.

4.Nucleolar area

a.Di erent techniques can measure the nucleolar area of melanoma cells directly from para n- embedded microsections.

b.The standard deviation of nucleolar area is an extremely accurate predictor of death from tumor.

Automated image analysis may be more sensitive than flow cytometry in detecting euploidy in determining DNA quantification. Also, cytomorphometric analysis of nuclear characteristics may be easier than determining nucleolar characteristics, and equally accurate.

5.Vascular patterns in melanoma (Figs 17.42 and

17.43)

Different vascular patterns can be seen in melanomas, including zones of avascularity (silent pattern), straight pattern, parallel pattern with cross-linking, arcs (fragments of curved vessels or incompletely closed loops), loops (island of tumor surrounded by a large, closed vascular loop), and networks (back-to-back adjacent loops). The presence of vascular arcs with or without branching on

B

Fig. 17.42 Seven morphologic vascular patterns in uveal melanoma (see Fig. 17.43). A, Normal: tumor cells grow around normal choroidal vessels that are either filled with blood (n) or vacant (N). B, Silent (zones of avascularity): no normal vessels or new vessels are identified. C, Straight pattern: a straight vessel connects with a normal vessel (n). Straight vessels can also run in a parallel array. (From Folberg R et al: Ophthalmology 100:1389. © Elsevier 1993.)

histopathologic examination implies that loops or networks will be detected in the same section plane, reflecting the architectural potential in aggressive tumors.

a.A closed vascular loop is a large vascular space occluded (closed) by melanoma cells.

b.A network is composed of at least three back- to-back closed vascular loops.

c.The presence of vascular networks provides a most significant association with death from metastatic melanoma.

d.It is important to distinguish vasculogenic mimicry patterns from fibrovascular septa when examining tumors for vascular patterns.

e.Alterations in p53 expression in uveal melanoma are associated with the expression of the cellular proliferation marker, Ki-67, but not with the presence of microvascular patterns.

Ezrin, radixin, and moesin form the ERN protein family, which mediates interaction between actin filaments and cell membranes. Ezrin immunoreactivity in uveal melanomas is associated with higher mortality and two independent high-risk characteristics: microvascular density and number of infiltrating macrophages.

6.Nucleolar organizer region

a.Nucleolar organizer regions are outpouchings of nucleolar DNA that direct ribosomal RNA transcription.

b.Silver staining of nucleolar organizer regions can be helpful in di erentiating benign from malignant pigmented uveal tumors.

7.Iris color

Patients who have blue or gray irises appear to be at increased risk of metastatic death from choroidal melanomas, independent of other risk factors.

8.Di use melanomas carry a metastatic potential of 24% at 5 years.

a.Iris pigment and texture changes secondary to topically applied prostaglandin analogues may simulate a di use iris melanoma.

9.Epidermal growth factor receptor (EGFR)

a.EGFR is a transmembrane glycoprotein that is correlated with the development of metastases in various human malignancies.

b.Expression of EGFR is significantly correlated with death caused by metastases (strong preference for liver metastases) from primary uveal melanoma.

10.Tumors, Nodes Metastases (TNM) classification

a.The TNM classification takes into consideration standardized definitions of di erent-size melanomas (small, medium, and large) based on

LBD, height, and extraocular extension.

b.The TNM is still a work in progress.

F. Prognosis without enucleation

1.Because the natural history of uveal melanomas is not known, the prognosis is speculative when based on data after therapy.

2.The mortality rate before enucleation, as extrapolated from incomplete data, seems to be 1% per year.

3.The mortality rate after enucleation reaches a peak of approximately 8% during the second year after enucleation.

Based on the preceding statistical analysis, two-thirds of the fatalities could be attributed to tumor emboli being disseminated at the time of enucleation. Only a long-term follow-up study of untreated patients with uveal melanomas can clarify the situation.

G.Associated findings

1.Invasion of Bruch’s membrane occurs in approximately 63% of tumors (Fig. 17.44).

a.When Bruch’s membrane is intact, the tumor usually has an oval shape.

b.When Bruch’s membrane is ruptured, the tumor assumes a mushroom shape.

c.When the elastic Bruch’s membrane is ruptured, it acts as a tourniquet around the base of the tumor so that:

1). Arterial blood can easily be pumped into the mushroom head, but the venous return is obstructed, thereby leading to dilated, tortuous venous channels.

2). The vascular abnormalities account for prolonged fluorescein staining, and the dilated,

thin veins may also lead to intravitreal hemorrhage (see p. 705 in this chapter).

2.Invasion of the scleral canals (Fig. 17.45A and B) occurs in approximately 32% of tumors and provides one route for tumor access to the orbit.

3.Invasion of scleral tissue occurs directly in approximately 15% of tumors.

4.Invasion of the optic nerve (see Fig. 17.45C and D) occurs in approximately 5% of tumors.

Peripapillary uveal melanomas tend to invade the optic nerve. Therefore, a long piece of optic nerve should be excised when an eye with such a tumor is enucleated.

5.Invasion of the vortex veins (Fig. 17.46) occurs in approximately 13% of tumors.

a.Sampling of the vortex veins should be taken routinely for histology on all enucleated globes suspected of harboring an intraocular tumor.

b.Vortex vein invasion carries an extremely unfavorable prognosis.

6.A neural retinal detachment (Fig. 17.47) is present in approximately 75% of cases, but in approximately 83% of those cases, the detachment is localized rather than total.

7.Extraocular extension (Fig. 17.48) occurs in approximately 13% of tumors.

a.Following failed transpupillary thermotherapy, the melanoma may continue to grow along the paths of least resistance to extend laterally in the choroid or through scleral emissary canals, resulting in extrascleral extension, which may be di cult to detect by ultrasonography. Nevertheless, ultrasonography should be performed periodically to attempt to detect such extrascleral extension. Similarly, extrascleral extension of

uveal melanoma may occur following failed proton beam therapy. Factors associated with local failure of proton beam radiotherapy for uveal melanoma include reduced safety margins, large ciliary body tumors, eyelids within the treatment field, inadequate positioning of tantalum clips, and male gender. Viable tumor cells may remain even in apparently nonrecurrent uveal melanoma treated with Ru-106 brachytherapy. A combination of plaque radiotherapy and transpupillary thermography has resulted in

cm

s

v

Fig. 17.46 Invasion of vortex vein. A large pigmented choroidal melanoma (cm) is present in the eye and is filling most of an intrascleral vortex vein (v). Obviously, vortex vein invasion, like extraocular extension into the orbit, carries a life-threatening prognosis (s, sclera).

only a 3% local recurrence rate in choroidal melanoma at 5-year follow-up. Transpupillary thermotherapy is not the therapy of choice for di use choroidal melanoma. Subretinal pigment dispersion is an uncommon complication of the procedure.

b.After extraocular extension, the tumor orbital recurrence rate is 18%, compared with 0.7% in the absence of detectable extraocular extension.

c.If the extraocular portion of the tumor is incised or transected (rather than small or well encapsulated) at the time of enucleation, or if it is nonencapsulated, the tumor orbital recurrence rate is at least 50%.

d.Frequently, discovery of an orbital recurrence precedes the discovery of a metastatic lesion.

Because the orbital recurrence often precedes the metastasis, exenteration seems to be the treatment of choice when extraocular extension is significant, especially in cases that have nonencapsulated or surgically transected tumors. However, the efficacy of orbital exenteration for primary extraocular extension or for orbital recurrence of a uveal melanoma is still not known.

8.Reaction of overlying RPE

a.Secondary drusen

b.Orange pigment overlying choroidal melanomas is seen clinically in approximately 47% of cases (Fig. 17.49).

Fluorescein angiography shows that the orange pigment is hypofluorescent. Orange pigment may also occur over a choroidal nevus. Histologically, the orange appearance results from aggregates of RPE cells and lipofuscin-containing macrophages overlying the melanoma.

c.Placoid or adenomatous proliferations are often accompanied by degenerative changes in the overlying retina.

H.Associated cytology

1.Cytogenetic studies show a consistent occurrence of monosomy 3 and trisomy 8q (i.e., the loss of gene sequences on chromosome 3 and the duplication of gene sequences on chromosome 8).

a.Monosomy for chromosome 3, particularly as detected by fine-needle aspiration biopsy of uveal melanoma and analyzed by fluorescent in situ hybridization (FISH) analysis, may provide important information regarding prognosis for these tumors. Moreover, indicative chromosomal studies for monosomy of chromosome 3 can also be performed on glutaraldehyde or formalin-

fixed, para n-embedded tissue using chromosome in situ hybridization (CISH). Loss of chromosome 3 may be associated with a reduction of 5-year survival from 95% to less than

50%.

b.Several tumor suppressor loci on chromosome 3 are targets of specific deletions associated with uveal melanoma.

2.Uveal melanoma cells are positive for S-100 protein,

HMB-45, and Ki-67.

3.Lymphocytes found in uveal melanomas (tumorinfiltrating lymphocytes) are predominantly T-sup- pressor/cytotoxic cells; B-cell lymphocytes are scarce.

I.Unsuspected malignant melanomas

1.Approximately 12% of ciliary body and choroid malignant melanomas proven histologically were unsuspected before surgery; most were in glaucoma eyes with opaque media.

Many of the eyes have a total neural retinal detachment. A patient who has a neural retinal detachment plus glaucoma, especially with no prior history of glaucoma and no glaucoma in the other eye, should be considered to have a uveal malignant melanoma until proven otherwise.

2.Approximately 4% of eyes that have opaque media and are enucleated from white patients (blind for at least 6 months) harbor a malignant melanoma.

This does not mean that 4% of enucleated blind eyes that have opaque media harbor a malignant melanoma, because the statistics are derived from a study done on enucleated eyes. The eyes were obviously enucleated for some reason. Therefore, if a blind eye that has opaque media becomes clinically symptomatic, a malignant melanoma should be considered. Ultrasonography is helpful in this situation.

J.Di erential diagnosis of malignant melanomas of ciliary body and choroid

1.Hemorrhages: choroidal, sub-RPE, neural retinal or subneural retinal, and vitreous

2.Cysts: congenital, retinoschisis, solitary, and parasitic

Ciliary body melanomas can acquire an intralesional cavity (cavitary melanomas) and mimic a ciliary body cyst.

3.Serous detachment: neural retinal and choroidal

4.Subretinal neovascularization, especially with hemorrhage

5.Tumors: hemangioma, nevus, metastatic carcinoma (Fig. 17.50), lymphoma, and lesions of PE

a.The typical “mushroom” or “collar button” con-

figuration of an expanding choroidal melanoma has been simulated by metastatic adenocarcinoma to the choroid that ruptured through

Bruch membrane.

6.Ultrasonography, fluorescein angiography, transillumination, and, to a much lesser extent, 32P uptake are helpful methods of determining the correct diagnosis.

K.Primary, bilateral, di use, uveal, melanocytic lesions may occur along with another systemic primary tumor.

L.Melanoma-associated spongiform scleropathy

1.This condition is characterized by areas within the sclera where collagen bundles appear to have disintegrated into loose fibres

2.The extent of these scleral changes is proportional to the extent of direct contact between the tumor and sclera

3.It has been observed in 33% to 38.5% of cases examined, and is particularly common in eyes with tumor scleral extension (91.5%)

4.There is a significantly higher incidence in older patients

5.The incidence is reduced by pre-enucleation radiation

6.It is not correlated with tumor cell type

7.There are significantly lower levels of major amino acids of scleral collagen and total proteins in the involved areas, presumably indicating collagen degradation

8.Specific glycosaminoglycans (GAGs) and total GAGS are increased in these regions, resulting in localized water accumulation, which may further separate collagen bundles