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

Rummelt V, Folberg R, Woolson RF et al.: Relation between the microcirculation architecture and the aggressive behavior of ciliary body melanomas. Ophthalmology 102:844, 1995

Rummelt V, Naumann GOH, Folberg R et al.: Surgical management of melanocytoma of the ciliary body with extrascleral extension. Am J Ophthalmol 117:169, 1994

Sakamota T, Sakamota M, Yoshikawa H et al.: Histologic findings and prognosis of uveal malignant melanoma in Japanese patients. Am J Ophthalmol 121:276, 1996

Sandinha MT, Farquharson MA, McKay IC et al.: Monosomy 3 predicts death but not time until death in choroidal melanoma. Invest Ophthalmol Vis Sci 46:3497, 2005

Sandinha MT, Farquharson MA, Roberts F: Identification of monosomy 3 in choroidal melanoma by chromosome in situ hybridisation.

Br J Ophthalmol 88:1527, 2004

Sassani JW, Blankenship G: Disciform choroidal melanoma. Retina 14:177, 1994

Scheie HG, Yano M: Pseudomelanoma of ciliary body, report of a patient. Arch Ophthalmol 77:81, 1967

Schwartz GP, Schwartz LW: Acute angle closure glaucoma secondary to a choroidal melanoma. CLAO J 28:77, 2002

Scull JJ, Alcocer CE, Deschênes J et al.: Primary choroidal melanoma in a patient with previous cutaneous melanoma. Arch Ophthalmol 115:796, 1997

Seddon JM, Gragoudas ES, Glynn RJ et al.: Host factors, UV radiation, and risk of uveal melanoma. Arch Ophthalmol 108:1274, 1990

Seregard S, Daunius C, Kock E et al.: Two cases of primary bilateral malignant melanoma of the choroid. Br J Ophthalmol 72:244, 1988 Shields CL, Cater J, Shields JA et al.: Combination of clinical factors

predictive of growth of small choroidal melanocytic lesions. Arch Ophthalmol 118:360, 2000

Shields CL, Cater J, Shields JA et al.: Combined plaque radiotherapy and transpupillary thermotherapy for choroidal melanoma: tumor control and treatment complications in 270 consecutive patients. Arch Ophthalmol 120:933, 2002

Shields CL, Shields JA, dePotter P et al.: Di use choroidal melanoma: Clinical features predictive of metastasis. Arch Ophthalmol 114:956, 1996

Shields CL, Shields JA, Eagle RC et al.: Uveal melanoma and pregnancy. Ophthalmology 98:1667, 1991

Shields CL, Shields JA, Kiratli H et al.: Risk factors for growth and metastasis of small choroidal melanocytic lesions. Ophthalmology 102:1351, 1995

Shields CL, Shields JA, Milite J et al.: Uveal melanoma in teenagers and children. Ophthalmology 98:1662, 1991

Shields CL, Shields JA, Perez N et al.: Primary transpupillary thermotherapy for small choroidal melanoma in 256 consecutive cases: outcomes and limitations. Ophthalmology 109:225, 2002

Shields CL, Shields JA, Shields MB et al.: Prevalence and mechanisms of secondary intraocular pressure elevation in eyes with intraocular tumors. Ophthalmology 94:839, 1987

Shields JA, McDonald PR, Leonard BC et al.: The diagnosis of uveal malignant melanomas in eyes with opaque media. Am J Ophthalmol 83:95, 1977

Shields JA, Shields CL, Eagle RC et al.: Malignant melanoma arising from a large uveal melanocytoma in a patient with oculodermal melanocytosis. Arch Ophthalmol 118:990, 2000

Singh AD, Eagle RC Jr, Shields CL et al.: Clinicopathologic reports, case reports, and small case series: enucleation following transpupillary thermotherapy of choroidal melanoma: clinicopathologic correlations.

Arch Ophthalmol 121:397, 2003

Singh AD, Shields CL, dePotter P et al.: Familial uveal melanomas: Clinical observations on 56 patients. Arch Ophthalmol 114:392, 1996

Singh AD, Shields CL, Shields JA et al.: Bilateral primary uveal melanoma: Bad luck or bad genes? Ophthalmology 103:256, 1996

Singh AD, Shields CL, Shields JA et al.: Uveal melanoma in young patients. Arch Ophthalmol 118:918, 2000

Singh AD, Topham A: Incidence of uveal melanomas in the United States: 1973–1997. Ophthalmology 110:956, 2003

Singh AD, Topham A: Survival rates with uveal melanomas in the United States: 1973–1997. Ophthalmology 110:962, 2003

Sneed SR, Byrne SF, Mieler WF et al.: Choroidal detachment associated with malignant choroidal tumors. Ophthalmology 98:963, 1991

Steuhl KP, Rohrbach JM, Knorr M et al.: Significance, specificity, and ultrastructural localization of HMB-45 antigen in pigmented ocular tumors. Ophthalmology 100:208, 1993

Sumich P, Mitchell P, Wang JJ: Choroidal nevi in a white population: The Blue Mountain Eye Study. Arch Ophthalmol 116:645, 1998

Tabassian A, Zuravle JJ: Necrotic choroidal melanoma with orbital inflammation. Arch Ophthalmol 113:1576, 1995

Teichmann KD, Karcioglu ZA: Melanocytoma of the iris with rapidly developing secondary glaucoma. Surv Ophthalmol 40:136, 1995

ten Berge PJM, Danen EHJ, van Muijen GNP et al.: Integrin expression in uveal melanoma di ers from cutaneous melanoma. Invest Ophthalmol Vis Sci 34:3635, 1993

The Collaborative Ocular Melanoma Study Group: Accuracy of diagnosis of choroidal melanomas in the collaborative ocular melanoma study. Arch Ophthalmol 108:1268, 1990

The Collaborative Ocular Melanoma Study Group: The COMS randomixed trial of iodine 125 brachytherapy for choroidal melanoma, III: Initial mortality findings. COMS report no. 18. Arch Ophthalmol 118:969, 2001

Toivonen P, Mäkitie T, Kujala E et al.: Microcirculation and tumorinfiltrating macrophages in choroidal and ciliary body melanoma and corresponding metastases. Invest Ophthalmol Vis Sci 45:1, 2004

Tsai JC, Sivak-Callcott JA, Haik BG et al.: Latanoprost-induced iris heterochromia and open-angle glaucoma: a clinicopathologic report. J Glaucoma 10:411, 2001

Tschentscher F, Husing J, Holter T et al.: Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities. Cancer Res 63:2578, 2003

Tschentscher F, Prescher G, Zeschnigk M et al.: Identification of chromosomes 3, 6, and 8 aberrations in uveal melanoma by microsatellite analysis in comparison to comparative genomic hybridization. Cancer Genet Cytogenet 122:13, 2000

Vajdic CM, Kricker A, Giblin M et al.: Eye color and cutaneous nevi predict risk of ocular melanoma in Australia. Int J Cancer 92:906, 2001

Vajdic CM, Kricker A, Giblin M et al.: Sun exposure predicts risk of ocular melanoma in Australia. Int J Cancer 101:175, 2002

Warwar RE, Bullock JD, Shields JA et al.: Coexistence of 3 tumors of neural crest origin: Neurofibroma, meningioma, and uveal melanoma.

Arch Ophthalmol 116:1241, 1978

Weber A, Hengge UR, Urbanik D et al.: Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. Lab Invest 83:1771, 2003

Weiss E, Shah CP, Lajous M et al.: T he association between host susceptibility factors and uveal melanomas. Arch Ophthalmol 124:54, 2006

Whelchel JC, Farah SE, McLean IW et al.: Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. Invest Ophthalmol Vis Sci 34:2603, 1993

White JS, Becker RL, McLean IW et al.: Molecular cytogenetic evaluation of 10 uveal melanoma cell lines. Cancer Genet Cytogenet 168:11, 2006

White VA, Chambers JD, Courtright PD et al.: Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma. Cancer 83:354, 1998

White VA, McNeil BK, Horsman DE: Acquired homozygosity (isodisomy) of chromosome 3 in uveal melanoma. Cancer Genet Cytogenet

102:40, 1998

White VA, McNeil BK, Thiberville L et al.: Acquired homozygosity (isodisomy) of chromosome 3 during clonal evolution of a uveal melanoma: association with morphologic heterogeneity. Genes Chromosomes Cancer 15:138, 1996

Wilkes SR, Robertson DM, Kurland LT et al.: Incidence of uveal malignant melanoma in the resident population of Rochester and Olmsted County, Minnesota. Am J Ophthalmol 87:639, 1979

Yano M: Melanomas and the incidence of neoplastic disease (letter). N Engl J Med 273:284, 1965

Yano M: Glaucoma mechanisms in ocular malignant melanomas. Am J Ophthalmol 70:898, 1970

Yano M: In discussion of Kersten RC, Tse DT, Anderson RL et al.: The role of orbital exenteration in choroidal melanoma with extrascleral extension. Ophthalmology 92:442, 1985

Yano M, Scheie HG: Melanomalytic glaucoma: Report of patient. Arch Ophthalmol 84:471, 1970

Yano M, Zimmerman LE: Histogenesis of malignant melanomas of the uvea: II. Relationship of uveal nevi to malignant melanomas. Cancer 20:493, 1967

Yano M, Zimmerman LE: Histogenesis of malignant melanomas of uvea: III. The relationship of congenital ocular melanocytosis and neurofibromatosis to uveal melanomas. Arch Ophthalmol 77:331, 1967 Young TA, Rao NP, Glasgow BJ et al.: Fluorescent in situ hybridization for monosomy 3 via 30-gauge fine-needle aspiration biopsy of choroi-

dal melanoma in vivo. Ophthalmology 114:142, 2007

Zaldivar RA, Aaberg TM, Sternberg P Jr et al.: Clinicopathologic findings in choroidal melanomas after failed transpupillary thermotherapy.

Am J Ophthalmol 135:657, 2003

Zimmerman LE, McLean IW, Foster WD: Statistical analysis of follow-up data concerning uveal melanomas and the influence of enucleation. Ophthalmology 87:557, 1980

Melanotic Tumors of the Optic Disc and

Optic Nerve

de Potter D, Shields CL, Eagle RC Jr et al.: Malignant melanoma of the optic nerve. Arch Ophthalmol 114:608, 1996

Demirci H, Shields CL, Shields JA: Bilateral optic disc melanocytoma in a 10-month-old infant. Am J Ophthalmol 136:190, 2003

García-Arumí J, Salvador F, Corcostegui B et al.: Neuroretinitis associated with a melanocytoma of the optic disk. Retina 14:173, 1994

Haas BD, Jakobiec FA, Iwamoto T et al.: Di use choroidal melanocytoma in a child: A lesion extending the spectrum of melanocytic hamartomas. Ophthalmology 93:1632, 1986

Hiscott P, Campbell RJ, Robertson DM et al.: Intraocular melanocytoma in association with bone formation. Arch Ophthalmol 121:1791, 2003

Kurli M, Finger PT, Manor T et al.: Finding malignant change in a necrotic choroidal melanocytoma: a clinical challenge. Br J Ophthalmol

89:921, 2005

LaRusso FL, Bomiuk M, Font RL: Melanocytoma (magnocellular nevus) of the ciliary body: Report of 10 cases and review of the literature. Ophthalmology 107:795, 2000

Lauritzen K, Augsburger JJ,Timmes J: Vitreous seeding associated with melanocytoma of the optic disc. Retina 10:60, 1990

Meyer D, Ge J, Blinder KI et al.: Malignant transformation of an optic disk melanocytoma. Am J Ophthalmol 127:710, 1999

Robertson DM, Campbell RJ, Salomào DR: Mushroom-shaped melanocytoma mimicking malignant melanoma. Arch Ophthalmol 120:82, 2002

Scheie HG, Yano M: Pseudomelanoma of ciliary body, report of a patient. Arch Ophthalmol 77:81, 1967

Shields CL, Eagle RC Jr, Shields JA et al.: Progressive growth of an iris melanocytoma in a child. Am J Ophthalmol 133:287, 2002

Shields JA, Demirci H, Mashayekhi A et al.: Melanocytoma of optic disc in 115 cases: The 2004 Samuel Johnson Memorial Lecture, Part 1. Ophthalmology 111:1739, 2004

Shields JA, Shields CL, Eagle RC et al.: Malignant melanoma associated with melanocytoma of the optic disc. Ophthalmology 97:225, 1990

Shields JA, Shields CL, Eagle RC et al.: Malignant melanoma arising from a large uveal melanocytoma in a patient with oculodermal melanocytosis. Arch Ophthalmol 118:990, 2000

Shields JA, Shields CL, Eagle RC et al.: Central retinal vascular obstruction secondary to melanocytoma of the optic disc. Arch Ophthalmol 119:12, 2001

Teichmann KD, Karcioglu ZA: Melanocytoma of the iris with rapidly developing secondary glaucoma. Surv Ophthalmol 40:136, 1995

Zimmerman LE: Melanocytes, melanocytic nevi and melanocytomas.

Invest Ophthalmol 4:11, 1965

Zografos L, Othenin-Girard CB, Desjardin L et al.: Melanocytoma of the optic disk. Am J Ophthalmol 138:964, 2004

Melanotic Tumors of the Orbit

Delaney YM, Hague S, McDonald B: Aggressive primary orbital melanomna in a young white man with no predisposing ocular features.

Arch Ophthalmol 122:118, 2004

Dutton JJ, Anderson RL, Schelper RL et al.: Orbital malignant melanoma and oculodermal melanocytosis: Report of two cases and review of the literature. Ophthalmology 91:497, 1984

Lloyd WC III, Leone CR Jr: Malignant melanoma of the lacrimal sac.

Arch Ophthalmol 102:104, 1984

Mandeville JT, Grove AS JR, Dadras SS et al.: Primary orbital melanoma associated with an occult episcleral nevus. Arch Ophthalmol

122:287, 2004

Rice CD, Brown H: Primary orbital melanoma associated with orbital melanocytosis. Arch Ophthalmol 108:1130, 1990

Tellado M, Specht CS, McLean IW et al.: Primary orbital melanomas.

Ophthalmology 103:929, 1996

RETINOBLASTOMA

General Information

I.Retinoblastoma, along with leukemia and neuroblastoma, is one of the most common childhood malignancies and is the most common childhood intraocular neoplasm.

II.It is third to uveal malignant melanoma and metastatic carcinoma as the most common intraocular malignancy in

humans of any age.

III. The incidence is approximately 1 in 18 000 live births in the United States, with a trend toward a higher prevalence than historically found (because of increased survival rate).

The average annual incidence of retinoblastoma is 5.8 per million for children younger than 10 years and 10.9 per million for children younger than 5 years of age.

A.Reese–Ellsworth system relates clinical tumor characteristics to visual prognosis.

Group I: very favorable for maintenance of sight

1.Solitary tumor, smaller than 4 disc diameters, at or behind the equator.

2.Multiple tumors, none larger than 4 disc diameters,

all at or behind the equator.

Group II: favorable for maintenance of sight

1.Solitary tumor, 4 to 10 disc diameters at or behind the equator.

2.Multiple tumors, 4 to 10 disc diameters behind the

equator.

Group III: possible for maintenance of sight

1.Any lesion anterior to the equator.

2.Solitary tumor, larger than 10 disc diameters behind

the equator.

Group IV: unfavorable for maintenance of sight

1.Multiple tumors, some larger than 10 disc diameters.

2.Any lesion extending anteriorly to the ora

serrata.

Group V: very unfavorable for maintenance of sight

1.Massive tumors involving more than one-half the retina.

2.Vitreous seeding.

B.Other classification systems predicting visual and ocular prognosis have been reported.

IV. No significant race or sex predilection exists.

V.Bilaterality occurs in 20% to 35% of all cases and is a useful marker for patients with hereditary retinoblastoma.

VI. The eye is a normal size at birth, but later may become phthisical or buphthalmic.

A rare exception to the normal size at birth is a microphthalmic eye that contains both a retinoblastoma and persistent hyperplastic primary vitreous (PHPV). Microphthalmia, retinoblastoma, and 13q deletion syndrome can also occur and have been accompanied by colobomas.

VII. Age at initial diagnosis

A.Average age is 13 months, with 89% diagnosed before 3 years of age.

B.It is rare after 7 years of age, but has been reported in patients past 50 years of age.

Approximately 8.5% of patients are older than 5 years of age at the time of diagnosis. It is quite rare after the age of 20 years.

VIII. Children with retinoblastoma may have other congenital abnormalities such as the 13q deletion (deletion of chromosomal region 13q14) syndrome, 13qXp translocation, 21 trisomy, 47,XXX, 47,XXY, PHPV, the Pierre Robin syndrome, or hereditary congenital cataracts.

All children with 13q14 deletions should have an ophthalmologic examination to rule out retinoblastoma.

IX. Immune complexes may be present in the serum of patients with retinoblastoma. Populations of major histocompatibility complex (MHC)-II-positive cells are also found within the tumor, which may have significance for possible immunomodulation of these tumors.

Extraocular muscle biopsies obtained at enucleation for retinoblastoma in patients who had clinical signs of slight limitation of extraocular movements or strabismus exhibited muscle fibers with slight to severe atrophy and myopathic structures such as nemaline, filamentous and zebra bodies. Fiber necrosis and capillary abnormalities accompanied by inflammation were also noted. No direct tumor invasion was present. An extraocular paraneoplastic process related to the retinoblastoma was postulated as the cause of the findings. Also, DNA from oncogenic papilloma viruses 16 and 35 has been detected in 27.9% of 43 sporadic retinoblastoma specimens examined. Viral DNA was found in 63.3% of the more differentiated tumors.

X.Genetic cases have an increased prevalence of nonocular cancers, especially of the pineal gland (bilateral retinoblastoma plus pineal tumor comprise trilateral retinoblastoma),

and sarcomas.

XI. Trilateral retinoblastoma

1.As noted above, the association of a midline intracranial neoplasm with bilateral retinoblastomas is known as trilateral retinoblastoma and is found in

4% to 8% of patients with hereditary retinoblastoma.

2.The intracranial neoplasm is most often an undifferentiated neuroblastic pineal tumor, or suprasellar or parasellar neuroblastoma.

Pineal cysts are significantly more common in patients who have bilateral retinoblastoma than in those with unilateral tumor, thereby suggesting a benign variant of trilateral retinoblastoma, or possibly a hereditary influence.

3.Loss of the retinoblastoma “genes” is thought to confer an increased susceptibility to the development of an intracranial neoplasm.

About 95% of patients who have trilateral reti-

noblastoma have a positive family history of retinoblastoma, bilateral retinoblastoma, or both.

XII. Retinoblastoma, which behaves as an autosomal-dominant trait with 90% penetrance, represents a prototype of a class of human cancers characterized by a loss of genetic

information at the constitutional or tumor level. Other cancers in this class include Wilms’ tumor, neuroblastoma, small cell carcinoma of the lung, pulmonary carcinoid, breast and bladder cancer, osteosarcoma, and renal cell carcinoma.

Two leiomyosarcomas of the bladder at ages 17 and 39 years developed in a twin with bilateral retinoblastoma.

Heredity

I. “Two-hit” model

Knudson’s two-hit model states that retinoblastoma arises as a result of two mutational events (see discussion of chromosomal region 13q14, later).

Inactivation of both retinoblastoma 1 alleles may not be sufficient in itself to cause tumors in patients with hereditary retinoblastoma. On the other hand, some tumors that develop in patients with tuberous sclerosis complex or neurofibromato- sis-1 may not require the “second hit”. Retinoblastoma has developed in a boy diagnosed with macrocephaly–cutis marmorata telangiectatica congenita (M-CMTC). The child had macrosomy, body asymmetry, cutis marmorata, and tall stature. The diagnosis of M-CMTC was made even though macrocephaly was not noted. Retinoblastoma is usually said not to be associated with overgrowth syndromes; however, it has been suggested that M-CMTC may be a tumor-prone syndrome. Similarly, there is an increased incidence of multiple cutaneous malignant melanomas among individuals with retinoblastoma and dysplastic nevus syndrome, and among their family members. It has been recommended that survivors of inherited retinoblastoma and their families be screened for dysplastic nevus syndrome.

Speculation, with some preliminary evidence, suggests that inactivation of the chromosomal region 13q14 (the

“retinoblastoma gene” that regulates normal development) by an oncogenic virus can produce the mutation.

1.If both mutations occur in the same somatic

(postzygotic) cell, a single, unifocal, unilateral retinoblastoma results. Because the mutations occur in a somatic cell, the resultant condition is nonheritable.

The nonheritable form arises through two unrelated events occurring at homologous loci in a single neural retinal cell. Double such sporadic mutations are highly unlikely; hence, a unifocal, unilateral retinoblastoma results.

2.In the hereditary form, the first mutation occurs in a germinal (prezygotic) cell (which, therefore, would mean that the mutation would be present in all resulting somatic cells), and the second mutation occurs in a somatic (postzygotic) neural retinal cell, resulting in multiple neural retinal tumors (multifocal in one eye, bilateral, or both), as well as in

primary tumors elsewhere in the body (e.g., pineal tumors and sarcomas).

The heritable form arises through transmission of a mutant allele from a carrier parent or through a new mutation, which appears in the germline of the child, and is then carried in every cell. A second, somatic mutation occurs in the neural retina at a locus homologous to the mutant locus, triggering tumorigenesis (retinoblastoma) in different areas in the same eye as well as in the other eye (multifocal and bilateral).

a.The probability that in the inherited form the tumor will develop in the patient (i.e., genotypically and phenotypically abnormal) is 90 in 100 (penetrance is estimated at 90%).

b.Occasionally, a generation may be skipped, and the retinoblastoma may be transmitted to a genotypically abnormal but phenotypically normal family member.

II.The chromosomal region 13q14 (the retinoblastoma gene—Rb gene) regulates the development of normality

(i.e., the region acts as an antioncogene).

Tumor suppressor genes, of which the Rb gene is one, are the “opposite numbers” of oncogenes, because their normal role is to inhibit cell growth; oncogenes, conversely, stimulate cell growth.

A.If both chromosomal 13q14 regions are normal, no retinoblastoma will develop.

B.If one of the two 13 chromosomes has a 13q14 deletion, duplication, or point mutation (a heterozygous condition), a retinoblastoma will still not result.

C.If both 13 chromosomes have a 13q14 deletion, duplication, or point mutation (a homozygous condition), retinoblastoma results.

D.Therefore, retinoblastoma is inherited as an auto- somal-recessive trait at the cellular level; nevertheless, retinoblastoma behaves clinically as if it has an autosomal-dominant inheritance pattern with 90% penetrance.

E.Gain of chromosome 1q31–1q32 is found in >50% of retinoblastoma, and also is common in other tumors. A determination of the minimal 1q region of gain reveals that 71% of retinoblastoma gained sequence-tagged sites (STS) at 1q32.1, which defines a 3.06 Mbp minimal region of gain between flanking markers and contained 14 genes. Of these genes, only KIF14, which is a putative chromokinesin, was overexpressed in various cancers.

F.“Fragile-site” loci probably contribute synergistically to the development and progression of the cytogenetics of retinoblastoma malignancy.

G.A facial phenotype for retinoblastoma patients having interstitial 13q14 deletions has been described in Japanese and then in Caucasian individuals, and includes cranial anomalies, frontal bossing, deeply grooved and long philtrum, depressed and broad nasal bridge, bulbous tip of the nose, thick lower lip, thin

upper lip, broad cheeks, and large ears and lobules. Its recognition in newborns with no known family history of retinoblastoma may be helpful in making the diagnosis.

Retinoblastoma has recurred 12 years following multiple therapies for retinoblastoma in the second eye of a 25-year-old man with a g.153211T > A (p.Tyr606X) mutation in the retinoblastoma 1 gene whose fellow left eye was enucleated at age 2 years for two retinoblastomas. The patient was alive and without recurrence 11 years after the second eye was enucleated.

III.Hereditary cases (approximately 40% of cases)

A.Approximately 10% of all retinoblastomas are inherited (familial). All are multifocal in one eye, bilateral, or both.

The clinical characteristics of patients who have retinoblastoma and a unilaterally affected parent are similar to those in all patients who have retinoblastoma and a positive family history.

B.Another 30% are caused by a new germline mutation

(see later discussion of sporadic cases). Although most of these mutations are multifocal in one eye, bilateral, or both, unilateral retinoblastoma, lack of family history, and older age do not exclude the possibility of a germline retinoblastoma 1 gene mutation.

C.Retinoblastoma and hypochondroplasia have occurred as two clinically distinct heritable germline mutations

arising de novo in a single individual. IV. Sporadic cases

A.Approximately 90% of all retinoblastomas develop by mutation (sporadic cases).

The mutation rate is approximately 2 × 10−5 (1 in 36 000 births), with, perhaps, a third representing a genetic mutation in a germinal cell capable of transmitting the retinoblastoma to offspring. The remaining two-thirds represent a somatic mutation incapable of transmitting the tumor.

B.The retinoblastoma in sporadic somatic mutation cases is unifocal and unilateral (approximately 60% of the total cases); in the sporadic genetic mutation cases, it is usually multifocal in one eye, bilateral, or both (approximately 30% of the total cases).

The other 10% are the inherited familial cases.

V.Genetic counseling

A.Healthy parents with one a ected child run approximately a 6% risk of producing more a ected children (the parent may be genotypically abnormal but phenotypically normal).

B.If two or more siblings are a ected, approximately a 50% risk exists that each additional child will be a ected.

C.A retinoblastoma survivor with the hereditary type has approximately a 50% chance of producing a ected children.

Phetotypically normal children of an a ected parent may be genetically abnormal.

D.A patient with sporadic disease has approximately a

12.5% chance of producing a ected children.

E.Preimplantation genetic diagnosis has been helpful in genetic counseling in heritable retinoblastoma.

Clinical Features

I.Strabismus and leukokoria are the most common clinical manifestations of retinoblastoma in the typical tumor-

prone age group

II. Early lesions may present with visual di culties or strabismus. They may also be completely asymptomatic, as are small fundus lesions found on routine eye examination.

III.Moderate lesions may present as:

A.Leukokoria (i.e., “cat’s-eye reflex”; Figs 18.1 and 18.2)

The term leukokoria is derived from the Greek leukos, meaning “white,” and kor , meaning “pupil.”

1.Computed tomography (CT) and magnetic resonance imaging (MRI):

a.CT detects intraocular calcium with a high level of accuracy.

b.MRI has superior contrast resolution to CT and, therefore, although not as specific as CT (MRI does not detect calcium), o ers more information than CT on the di erent pathologic intraocular conditions that cause leukokoria.

MRI can also be helpful in tumor staging and detection of metastatic risk factors; however, detection of intraocular

tumor infiltration is difficult. Some MRI techniques may be particularly helpful in detecting optic nerve or scleral infiltration. Three-dimensional high-resolution MRI provides superior resolution for intraocular and orbital structures, and can be very useful in the evaluation of intraocular tumors and the nerve sheath complex. High-frequency ultrasound may be particularly helpful in evaluating anteriorly located tumors. Three-dimensional ultrasound may have some advantages for patient care, teaching, tumor volume analysis, and telemedicine. Rarely is fine-needle aspiration biopsy indicated to rule out retinoblastoma.

B.“Pseudoinflammation,” i.e., simulating uveitis, endophthalmitis, or panophthalmitis with or without pseudohypopyon (Fig. 18.3)

1.Any childhood intraocular inflammation should be considered retinoblastoma until proven otherwise.

2.Orbital inflammation can occur even when the retinoblastoma is confined to the eye; signs of orbital cellulitis therefore do not necessarily mean orbital extension of the tumor.

C.Iris neovascularization (rubeosis iridis; Fig. 18.4A and

B)with a hyphema, chronic secondary closed-angle glaucoma, or both

1.Vascular endothelial growth factor, secreted by hypoxic retina, may play a role in the development of iris neovascularization. The glaucoma may lead to symptoms of photophobia and, if prolonged, buphthalmos may develop.

2.Glaucoma and secondary hyphema may result from the iris neovascularization.

3.Spontaneous hyphema in a child should always alert the physician to suspect retinoblastoma, juvenile xanthogranuloma, or nonaccidental trauma.

D.Phthisis bulbi

IV.Advanced lesions may present with proptosis (see Fig. 18.4C and D), distant metastases, or both.

An advanced tumor at presentation in uncommon in the

United States; however, it is a tragic fact of international ophthalmology that advanced tumors are relatively common at the time of diagnosis in many nonwestern countries. Proptosis is the most common presentation of retinoblastoma in eastern Nepal and is associated with orbital extension and tumor at the cut end of the optic nerve. In Ethiopia, retinoblastoma is

the most common orbital tumor in children. Similarly, an Indian study reported a higher incidence of choroidal and optic nerve invasion in Asian Indian children than among children from the west. Whether this finding was secondary to delay in diagnosis or to ethnic differences in the tumor biology could not be determined. Advanced tumor at presentation and increased mortality appear to be common problems in countries such as Taiwan compared to western countries and to Japan, and in more rural areas of countries such as Mexico.

Histology

I.Growth pattern

A.Multifocal growth (i.e., spontaneous development from more than one region of the same neural retina; Fig. 18.5)

B.Bilateral involvement is, itself, a reflection of multifocal neural retinal involvement.

C.Exophytic retinoblastoma (see Fig. 18.1) grows predominantly toward the subneural retinal space and detaches the neural retina.

D.Endophytic retinoblastoma (see Fig. 18.2) grows predominantly toward the vitreous.The neural retina is not detached.

Most retinoblastomas have both endophytic and exophytic components. Diffuse infiltrating retinoblastoma is a rare subtype of retinoblastoma, comprising approximately 1.5% of the total.

E.Rarely, retinal neovascularization may be found with retinoblastoma.

The histopathology of retinoblastoma can be helpful in suggesting in vitro drug resistance. Undifferentiated tumors are more sensitive to several cytostatic drugs. Calcification and apoptosis reflect an inverse relation to in vitro drug resistance to ifosfamide and vincristine. Extreme drug resistance to cytarabine has been observed.

II.The basic cell type is the radiosensitive undi erentiated retinoblastoma cell (Fig. 18.6).

A.Retinoblastoma cells seem to be neuron-committed cells that arise from photoreceptor progenitor cells or from primitive stem cells that are capable of di erentiation along both neuronal and glial cell lines. Mucin-like glycoprotein associated with photoreceptor cells is an immunohistochemical marker that is specific for retinal photoreceptor cells. Its use demonstrates photoreceptor di erentiation even in apparently “undi erentiated” retinoblastomas.

B.The cell of origin of retinoblastoma is not known with certainty. Evidence suggests that it may be the rod photoreceptor cell; however, polymerase chain reaction for interphotoreceptor retinoid-binding protein gene transcript is a useful method for detecting metastatic retinoblastoma cells, but rod beta-subunit of cyclic guanosine monophosphate (cGMP) was not found. Retinoblastomas can also express markers for other retinal nuclear cells, suggesting that the tumor may develop from visual stem cells that are progenitors of photoreceptor cells, intermediate neurons, and ganglion cells.

C.The primitive cells may be di cult to di erentiate from other soft-tissue sarcomas. Immunohistochemistry, electron microscopy, and molecular assays for specific gene fusion may all be helpful in establishing the diagnosis.

D.The cells (bipolar-like) are positive for neuron-specific enolase, class III β-tubulin isotype (hβ4), microtubuleassociated protein 2 (MAP2), and synaptophysin; they are negative for glial fibrillary acidic protein and S-100 protein.

Neuron-specific enolase is present in the aqueous humor of patients who have intraocular retinoblastomas.

E.The product of the retinoblastoma susceptibility gene, p110RB1, can be identified in para n-embedded tissues with commercially available techniques.

F.The Y79 retinoblastoma cell line, a prototype for retinoblastoma cells, shows decreased adhesion of the cells to extracellular matrix because of a deficit of integrin receptors; this may explain, in part, how the cells metastasize.

G.Apoptosis is more frequently found in tumors of young patients and to be distributed within rosettes.

III.Rosettes are of two types:

A.Flexner–Wintersteiner rosettes (Figs 18.7 and 18.8; see also Fig. 18.6C) are the characteristic rosettes of retinoblastoma, but are not always present.

1.In the rosettes, the cells line up around an apparently empty central lumen.

2.Special stains show that the lumen contains a hyal- uronidase-resistant acid mucopolysaccharide.

B.Homer Wright rosettes (see Fig. 18.7) are found in medulloblastomas and neuroblastomas, and occasionally, in retinoblastomas.

1.In 1910, John Homer Wright described the structure that bears his name in a series of cases of adrenal gland tumors that he called neurocytoma or neuroblastoma.

2.In Homer Wright rosettes, the cells line up around an area containing cobweb-like material but no acid mucopolysaccharides.

IV. Pseudorosette—this very poor and confusing term is often used to refer to arrangements in the tumor that on cursory examination may resemble the aforementioned rosettes.

The structures are formed by:

A. Viable tumor cells that cluster around blood vessels

A B

C

Fig. 18.7 Types of rosettes. A, A Flexner–Wintersteiner rosette consists of a central lumen lined by cuboidal tumor cells that contain nuclei positioned basally (away from the lumen). Delicate limiting membranes are seen at the apices of the cells that surround the lumen. B, Homer Wright rosettes are found more frequently in medulloblastomas and neuroblastomas than in retinoblastomas. In these rosettes, the cells line up around an acellular area that contains cobweb-like material.

C, Fleurettes are flower-like groupings of tumor cells in the retinoblastoma. The cells of fleurettes show clear evidence of differentiation into photoreceptor elements.

The cu of retinoblastoma cells surrounding the blood vessels is rather uniform within the tumor, and from tumor to tumor, with a mean thickness of 98.7 μm.

B.Small foci of necrotic cells between larger masses of viable tumor cells

C.Incompletely formed Flexner–Wintersteiner or Homer

Wright rosettes

V.Fleurettes and retinocytoma (Fig. 18.9; see also Figs 18.7 and 18.8)

A.Fleurettes are flower-like groupings of tumor cells in the retinoblastoma that clearly show evidence of differentiation into photoreceptor elements.

B.Fleurettes may be absent, may be present in small nodules, or rarely, may be present as the only cells in the tumor, so that the entire tumor has di erentiated into photoreceptor-like elements.

1.The fully di erentiated retinoblastoma is called a retinocytoma (retinoma).

2.Retinocytomas have a uniformly bland cytology, photoreceptor di erentiation, abundant fibrillar eosinophilic stroma, absence of mitotic activity, and occasional foci of calcification.

3.Cells in the di erentiated part of the tumor show immunoreactivity for retinal S antigen, S-100 protein, and glial fibrillary acidic protein.

The histopathology and immunocytohistochemistry support the concept that retinocytomas arise de novo rather than from retinoblastomas that have undergone spontaneous regression.