Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003
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Figure 15 Fleurette. Electron micrographic evidence of photoreceptor differentiation. The bulbous process is composed of two components. The inner part has numerous mitochondrialike the inner segment of retinal cones and the outer part has a stack of lamella like the outer segments of cones.
contain structures that resemble retinal cones [5]. The bulbous eosinophilic processes contained numerous mitochondria (Fig. 15) and resembled cone inner segments.
In a subsequent study, Tso et al. [24] examined retinoblastomas in 54 eyes enucleated after having been irradiated. Of these, 42 eyes contained viable tumor cells and 17 of these tumors (40%) exhibited photoreceptor differentiation. In seven cases, the residual tumor was composed entirely of cells showing photoreceptor differentiation. Consequently, these investigators suggested that tumors containing such benign components might be incompletely radioresponsive because, as a general rule, benign and highly differentiated tumors are more radioresistant. Follow-up information was obtained in 13 of the 17 cases; there was only one tumor death. Despite uncontrolled tumor growth, the parents of this child refused to permit enucleation. The patient died of intracranial extension of the retinoblastoma. Histological study revealed this tumor to be composed of areas of undifferentiated retinoblastoma and areas of benign-appearing cells that exhibited photoreceptor differentiation.
Tumors composed entirely of benign-appearing cells are now diagnosed as retinocytomas. In addition to the cells exhibiting photoreceptor differentiation, there are cells that resemble bipolar neurons, astrocytes, and Mu¨ller cells [6]. The presence of glia has been demonstrated using glial fibrillary acid protein immunohistochemistry and electron microscopy and probably represents reactive gliosis in these benign variants of retinoblastoma [6].
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In phthisic eyes with totally necrotic ‘‘regressed’’ retinoblastomas, it may be difficult to diagnose the retinoblastoma. Histological examination reveals dense calcification in a tumor that exhibits complete coagulative necrosis (Figures 8 and 9). Under high magnification, one can usually make out the ghostly outlines of fossilized tumor cells. Further confusion may be created by exuberant reactive proliferation of retinal pigment epithelial cells, ciliary epithelial cells, and glial cells and by ossification [25].
II.EXTRAOCULAR EXTENSION, SPREAD, AND METASTASIS
Most retinoblastomas exhibit relentlessly progressive, rapidly invasive growth. If left untreated, they usually fill the eye and completely destroy the internal architecture of the globe (Fig. 16). The most common method of spread is by invasion through the optic disc into the optic nerve (Figs. 17 and 18). Once into the nerve, the tumor may spread directly along the nerve fiber bundles back toward the optic chiasm, or it may infiltrate through the pia into the subarachnoid space. From the subarachnoid space, tumor cells may be carried via the circulating cerebrospinal fluid to the brain and spinal cord. Once the tumor has invaded the choroid (Fig. 19), it may then spread into the orbit via the scleral canals or by massively replacing the sclera (Fig. 16). It has been estimated that an average of approximately 6 months is required from when the retinoblastoma produces its first symptoms to when it invades beyond the eye [26]. Extraocular invasion dramatically increases the chances of hematogenous
Figure 16 Advanced retinoblastoma. The bisected eye shows that the tumor has destroyed the intraocular structures and cornea. It has invaded outside the eye to form extraocular masses anteriorly and posteriorly.
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Figure 17 Retinoblastoma. Minimal optic nerve invasion. Centrally there are a few retinoblasts posterior to the lamina cribrosa.
Figure 18 Retinoblastoma. Optic nerve invasion has not reached the resection margin. Tumor cells have come very close to the subarachnoid space.
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Figure 19 Exophytic retinoblastoma. Retinoblasts have completely infiltrated the choroid. An unusual feature in this tumor is the presence of Flexner-Wintersteiner rosettes within the choroidal infiltrate.
dissemination and permits access to conjunctival lymphatics and metastasis to regional lymph nodes.
Retinoblastomas exhibit metastatic potential in four ways:
1.Direct infiltrative spread may occur along the optic nerve from the eye to the brain. Once the orbital soft tissues have been invaded, the tumor may spread directly into the orbital bones, through the sinuses into the nasopharynx, or via the various foramina into the cranium.
2.Dispersion of tumor cells may occur after cells in the optic nerve have invaded the leptomeninges and gained access to the circulating subarachnoid fluid. This may occur without involvement of cut end of the optic nerve. Flow of cerebrospinal fluid can carry tumor cells from the eye to the brain and spinal cord; in monocular cases, spread to the optic nerve on the opposite side has been observed.
3.Hematogenous dissemination leads to widespread metastasis to the lungs, bones, brain, and other viscera. Extraocular invasion and to a lesser degree choroidal invasion increase the risk for hematogenous spread.
4.Lymphatic spread occurs in those cases in which there has been anteriorly located or massive extraocular extension. There are no intraocular or posterior orbital lymphatic channels, but the lacrimal gland, bulbar conjunctiva, and eyelids are richly supplied with lymphatic vessels.
When metastasis occurs, it is generally becomes symptomatic and kills within the first year or two following treatment. Kopelman et al. [27] found that the median
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time to death with fatal retinoblastoma was 6.4 months in unilateral cases and 14.2 months in bilateral cases. In contrast, Gamel et al. [28] estimated the median time to death for patients dying of metastatic uveal melanoma to be 7.2 years. Late death from metastasis, which occurs so frequently following enucleation for uveal melanomas, is rare after treatment for retinoblastoma—so much so that when late metastasis is suspected, the question of an independent new primary tumor must be considered. Hematogenous metastasis from retinoblastoma is characteristically widespread, but—unlike uveal melanoma—is frequently preceded by spread to regional lymph nodes. The brain may be selectively affected when spread has occurred via the optic nerve. Invasion of leptomeninges of the optic nerve typically gives rise to a thick accumulation of tumor cells in the meninges along the basilar surface of the brain and in the ventricles, which can be detected by computed tomography [29].
In metastatic lesions, retinoblastoma typically appears much less differentiated than in the intraocular primary tumor. Rosettes, which may be numerous and highly organized in the primary tumors, are typically very difficult to find and poorly formed in metastatic lesions. Fleurettes are never observed in metastatic lesions. In a study of 17 autopsies [30] on children who died of metastatic retinoblastoma, 9 had distant bone involvement, 8 had visceral involvement, and 8 had lymph node involvement. The metastases of retinoblastoma, unlike those of uveal melanoma, do not home to the liver.
The primary retinoblastoma-like tumors observed in the pineal and in parasellar sites [27,31] and primitive neuroectodermal tumors that have been encountered as second primary neoplasms in patients with heritable retinoblastoma have been confused with metastatic retinoblastoma. In distinction from metastatic retinoblastoma, these second primary tumors are initially solitary and frequently not located in sites of predilection for metastatic retinoblastoma. They often appear several years after the successful treatment of intraocular retinoblastomas that do not have a high risk of metastasis. The intracranial primary tumors may exhibit photoreceptor differentiation, with numerous rosettes and fleurettes, which one would not expect in a metastatic retinoblastoma.
Recurrence of retinoblastoma in the orbit following enucleation is usually the result of tumor cells that were left untreated in the orbit. In some instances this may be the result of subclinical orbital involvement that also may have escaped histopathological recognition. More frequently, it has been a consequence of incomplete initial treatment of known invasion of the orbit or optic nerve beyond the margin of surgical transection. Very rarely, orbital recurrence may be the result of lymphatic or hematogenous spread to the bony walls and soft tissues of the orbit or the lids.
III.PROGNOSIS
There are many risk factors affecting prognosis, but most important is the extent of invasion by the retinoblastoma outside of the eye. Kopelman et al. [27], in an analysis of cases from the Registry of Ophthalmic Pathology, found that the extent of invasion into the optic nerve and through the ocular coats were the two most important predictors of patient outcome. Extraocular invasion as the most
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important predictor of death is supported by a number of studies [32–36]. When the data were evaluated by multivariate analysis, bilaterality was the only variable that proved to be more significantly associated with a fatal outcome than in univariate analysis, suggesting that bilaterality is related to death for reasons unrelated to the primary tumor. In some of these cases the cause of death was attributed to spread of retinoblastoma to the brain, yet there was no optic nerve invasion. One must consider the possibility that new intracranial primary tumors (trilateral retinoblastomas) were responsible for the deaths in these cases.
A problem with the study by Kopelman et al. [27] was that it was based on cases of retinoblastoma that were treated prior to 1962, and the possibility existed that more modern treatment could affect the results. A more recent study was performed in Germany [37], but in this study there were few deaths, making statistically significant inferences about prognostic factors difficult. Mclean et al. [38] compared 514 cases of retinoblastoma from the Registry of Ophthalmic Pathology obtained between 1917 and 1962 (mean, 1945) with 460 cases from Germany obtained between 1963 to 1986 (mean, 1976). The cause-specific survival rate, in which only deaths attributed to spread or metastasis of the retinoblastoma are considered, was lower in the older sample from the United States (66% at 5 years) than that in the German sample (93% at 5 years). Because of the rapid growth rate of retinoblastoma, 5-year survival rates essentially represent cure rates. Invasion of the ocular coats and invasion into the optic nerve were the most significant prognostic factors in both samples. A multivariate logistic model using seven variables (post1962 German versus pre-1963 American case, unilateral versus bilateral, invasion of choroid, invasion of sclera, invasion of orbit, invasion of retrolaminar optic nerve, and invasion of the resected margin of the optic nerve) described well the observed mortality patterns (Table 1). In the absence of these prognostic factors, there were no deaths in the German series and eight deaths in the series from the Registry of Ophthalmic Pathology. Because metastasis of retinoblastoma is very unlikely in the absence of extraocular invasion, many oncologists no longer recommend lumbar punctures and bone marrow aspirates when retinoblastoma does not invade outside the eye [39].
Table 1 Prognostic Factors Determined by Logistic Regression of 514 American Cases Obtained Prior to 1963 and 460 German Cases Obtained After 1962
Variable |
Odds ratio |
p Value |
|
|
|
Invasion of ocular coats |
|
|
Into choroid |
2.9 |
<0.0001 |
Into sclera |
9.1 |
<0.0001 |
Into orbit |
37.6 |
<0.0001 |
Invasion of optic nerve |
|
|
Resected |
4.4 |
<0.0001 |
Unresected |
13.3 |
<0.0001 |
Bilaterality |
2.9 |
0.0001 |
Pre-1963 American case |
4.1 |
<0.0001 |
|
|
|
Source: Ref. 38.
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McLean et al. [1] have reviewed 12 cases of fatal unilateral retinoblastoma from the Registry of Ophthalmic Pathology in which the tumors were believed to be confined to the eye without invasion into the optic nerve or sclera. In 6 of the 12 cases, there was choroidal invasion. In 8 cases, 4 with choroidal invasion and 4 without choroidal invasion, there was an orbital recurrence, which preceded the development of distant metastasis. These histories suggest that there was probably microscopic extraocular spread that was not detected by histological examination. This emphasizes the importance of extraocular invasion as the pathway leading to metastasis of retinoblastoma and the great need for careful histological examination aimed at the detection of microscopic extraocular extension for accurate staging. A problem arises when globes are opened to get fresh tissue for genetic and molecular biology studies. This often spreads tumor cells to suprachoroidal and episcleral locations, making it very difficult to tell if there was extraocular invasion by the tumor.
IV. UNSUSPECTED RETINOBLASTOMA
Stafford and coworkers [40], in their analysis of 618 histologically proven cases of retinoblastoma for which adequate clinical data were available, found that almost 15% had been misdiagnosed initially. In 6.6% of the 618 cases, the incorrect initial diagnosis had led to a delay in enucleation while treatment was given for panophthalmitis, endophthalmitis, tuberculosis, or other forms of uveitis. In the other 8.3%, a variety of noninflammatory, nonneoplastic conditions had been diagnosed. Shields et al. [41] described five patients with retinoblastoma who presented with orbital cellulitis without extraocular extension of the tumor. In all five cases, the retinoblastoma was large and had undergone extensive necrosis. Delays in enucleation were associated with a greater mortality than in the cases where a correct initial diagnosis had been followed promptly by enucleation. Kopelman et al. [27] found that the odds of death were 2.5 times greater with clinically undiagnosed retinoblastoma.
REFERENCES
1.McLean IW, Burnier MN, Zimmerman LE, Jakobiec FA. Tumors of the eye and ocular adnexa. In: Atlas of Tumor Pathology, 3rd Series, Fascicle 12. Washington, DC: Armed Forces Institute of Pathology, 1994; pp 101–127.
2.Klauss V, Chana HS. Ocular tumors in Africa. Soc Sci Med 1983; 17:1743–1750.
3.Tso MOM, Fine BS, Zimmerman LE, et al. Photoreceptor elements in retinoblastoma. A preliminary report. Arch Ophthalmol 1969; 82:57–59.
4.Tso MOM, Zimmerman LE, Fine BS. The nature of retinoblastoma: I. Photoreceptor differentiation: A clinical and histologic study. Am J Ophthalmol 1970; 69:339–649.
5.Tso MOM, Fine BS, Zimmerman LE. The nature of retinoblastoma: II. Photoreceptor differentiation: An electron microscopic study. Am J Ophthalmol 1970; 69:350–359.
6.Margo C, Hidayat A, Kopelman J, Zimmerman LE. Retinocytoma: A benign variant of retinoblastoma. Arch Ophthalmol 1983; 101:1519–1531.
7.Gallie BL, Phillips RA, Ellsworth RM, et al. Significance of retinoma and phthisis bulbi for retinoblastoma. Ophthalmology 1982; 89:1393–1399.
446 |
McLean |
8.Abramson DH, McCormick B, Fass D, et al. Retinoblastoma. The long-term appearance of radiated intraocular tumors. Cancer 1991; 67:2753–2755.
9.Eagle RC Jr, Shields JA, Donoso L, Milner RS. Malignant transformation of spontaneously regressed retinoblastoma, retinoma/retinocytoma variant. Ophthalmology 1989; 96:1389–1395.
10.Shields JA, Shields CL. Intraocular Tumors: A Text and Atlas. Philadelphia: Saunders, 1992.
11.Mansour AM, Greenwald MJ, O’Grady R. Diffuse infiltrating retinoblastoma. J Pediatr Ophthalmol Strabismus 1989; 26:152–154.
12.Nicholson DH, Norton EW. Diffuse infiltrating retinoblastoma. Trans Am Ophthalmol Soc 1980; 78:265–289.
13.Shields JA, Shields CL, Eagle RC, Blair CJ. Spontaneous pseudohypopyon secondary to diffuse infiltrating retinoblastoma. Arch Ophthalmol 1988; 106:1301–1302.
14.Boniuk M, Zimmerman LE. Spontaneous regression of retinoblastoma. Int Ophthalmol Clin 1962; 2:525–542.
15.Schipper J. Retinoblastoma: A medical and Experimental Study (thesis). Utrecht: University of Utrecht, 1980, p 144.
16.Burnier MN, McLean IW, Zimmerman LE, Rosenberg SH. Retinoblastoma. The relationship of proliferating cells to blood vessels. Invest Ophthalmol Vis Sci 1990; 31:2037–2040.
17.Bunt AH, Tso MO. Feulgen-positive deposits in retinoblastoma. Incidence, composition, and ultrastructure. Arch Ophthalmol 1981; 99:144–150.
18.Zimmerman LE. Retinoblastoma and retinocytoma. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook. Philadelphia: Saunders, 1985, pp 1292–1351.
19.Tso MOM, Fine BS, Zimmerman LE. The Flexner-Wintersteiner rosettes in retinoblastoma. Arch Pathol 1969; 88:665–671.
20.Donoso LA, Shields CL, Lee EY. Immunohistochemistry of retinoblastoma. A review. Ophthalm Paediatr Genet 1989; 10:3–32.
21.Kivela T. Glycoconjugates in retinoblastoma. A lectin histochemical study of ten formalin-fixed and paraffin-embedded tumours. Virchows Arch [A] 1987; 410:471–479.
22.Vrabec T, Arbizo V, Adamus G, McDowell JH, Hargrave PA, Donoso LA. Rod cellspecific antigens in retinoblastoma. Arch Ophthalmol 1989; 107:1061–1063.
23.Rubinstein LJ. Tumors of the central nervous system. In: Atlas of Tumor Pathology, Suppl to Fascicle 6, 2nd Series. Washington, DC: Armed Forces Institute of Pathology, 1982, pp 15–20.
24.Tso MOM, Zimmerman LE, Fine BS, et al. A cause of radioresistance in retinoblastoma: Photoreceptor differentiation. Trans Am Acad Ophthalmol Otolaryngol 1970; 74:959– 969.
25.Smith JLS. Histology and spontaneous regression of retinoblastoma. Trans Ophthalmol Soc UK 1974; 94:953–967.
26.Erwenne CM, Franco EL. Age and lateness of referral as determinants of extra-ocular retinoblastoma. Ophthalm Paediatr Genet 1989; 10:179–184.
27.Kopelman JE, McLean IW, Rosenberg SH. Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmology 1987; 94:371–377.
28.Gamel JW, McLean IW, Rosenberg SH. Proportion cured and mean log survival time as functions of tumor size. Statist Med 1990; 9:999–1006.
29.Meli FJ, Boccaleri CA, Manzitti J, Lylyk P. Meningeal dissemination of retinoblastoma: CT findings in eight patients. AJNR 1990; 11:983–986.
30.Merriam GR. Retinoblastoma: Analysis of 17 autopsies. Arch Ophthalmol 1950; 44:71– 108.
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447 |
31.Bader JL, Meadows AT, Zimmerman LE, et al. Bilateral retinoblastoma with ectopic intracranial retinoblastoma: Trilateral retinoblastoma. Cancer Genet Cytogenet 1982; 5:203–213.
32.The Committee for the National Registry of Retinoblastoma. Survival rate and risk factors for patients with retinoblastoma in Japan. Jpn J Ophthalmol 1992; 36:121–131.
33.Hungerford J, Kingston J, Plowman N. Orbital recurrence of retinoblastoma. Ophthalm Paediatr Genet 1987; 8:63–68.
34.Magramm I, Abramson DH, Ellsworth RM. Optic nerve involvement in retinoblastoma. Ophthalmology 1989; 96:217–222.
35.Messmer EP, Heinrich T, Ho¨pping W, de Sutter E, Havers W, Sauerwein W. Risk factors for metastases in patients with retinoblastoma. Ophthalmology 1991; 98:136–141.
36.Stannard C, Lipper S, Sealy R, Sevel D. Retinoblastoma: Correlation of invasion of the optic nerve and choroid with prognosis and metastases. Br J Ophthalmol 1979; 63:560– 570.
37.Messmer EP, Heinrich T, Ho¨pping W, de Sutter E, Havers W, Sauerwein W. Risk factors for metastases in patients with retinoblastoma. Ophthalmology 1991; 98:136–141.
38.McLean IW, Rosenberg SH, Messmer EP, Heinrich T, Hopping W, Havers W. Prognostic factors in cases of retinoblastoma: Analysis of 974 patients from Germany and the United States treated by enucleation. In: Bornfeld N, Gragoudas ES, Lommatzsch PK., eds. Tumors of the Eye. Proceedings of the International Symposium on Tumors of the Eye. Amsterdam: Kugler Publications, 1991, pp 69–72.
39.Pratt CB, Meyer D, Chenaille P, Crom DB. The use of bone marrow aspirations and lumbar punctures at the time of diagnosis of retinoblastoma. J Clin Oncol 1989; 7:140– 143.
40.Stafford WR, Yanoff M, Parnell B. Retinoblastoma initially misdiagnosed as primary ocular inflammation. Arch Ophthalmol 1969; 82:771–773.
41.Shields JA, Shields CL, Suvarnamani C, Schroeder RP, DePotter P. Retinoblastoma manifesting as orbital cellulitis. Am J Ophthalmol 1991; 112:442–449.
