Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

p53 and p21. The concurrent loss of squamous potential and loss of tumor suppressor activity can push mutant multipotent cells toward sebaceous tumorigenesis. The regulatory roles of the nuclear receptors for retinoic acid, vitamin D, and other nuclear receptor ligands are unknown, but they are likely to interact genetically with the major transcriptional signaling pathways to regulate proliferation and differentiation. It is important to note that, while sebaceous cells are distributed across the entire body, the eyelids give rise to far more sebaceous cell carcinomas than any other locations. It is tempting to speculate about the reasons for this propensity, with a likely explanation being the high concentration of sebaceous cells in the eyelids, along with the anatomic exposure to mutagenic solar radiation, which combine to create the environment in which sebaceous cell carcinomas can arise. We now have substantial tools to dissect carefully the molecular pathways and cellular environments to shed light on the processes involved in dermatologic carcinogenesis, and to permit the development of diagnostic and therapeutic strategies for the successful medical treatment of sebaceous cell carcinoma.

Conclusion

Sebaceous cell carcinomas account for 1–5% of all eyelid malignancies and proper identification and treatment of these tumors are critical because the rate of misdiagnosis has been estimated to be as high as 50%, with a mortality rate of at least 20%. The diagnosis of sebaceous cell carcinoma

is difficult as it often masquerades as more common processes. This can lead to critical delay in the diagnosis and contribute to the morbidity and mortality associated with the disease. Sebaceous cell carcinomas result from dysregulation of glandular stem cells, involving the Hedgehog, Notch, and Wnt signaling pathways. Poorly differentiated carcinomas have large cells, greater pleomorphism, higher mitotic rates, and disorganized architectures. Intraepithelial spread, also called pagetoid invasion – an important hallmark of sebaceous cell carcinoma – is known to occur in 44–80% of cases. The level of differentiation appears to correlate well with the aggressiveness of the tumor. At the present time there is a suggestion that, in experienced hands, traditional excision with permanent section control of the margins provides the best chance of avoiding recurrence. Given the likelihood of pagetoid invasion, map biopsies of the skin and conjunctiva are essential to determining the extent of the disease and treatment options.

Acknowledgment

The authors would like to acknowledge the generosity of Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences at the University of Michigan. Figure 52.9 was kindly provided by Professor Fiona Watt, Wellcome Trust Centre for Stem Cell Research, University of Cambridge, UK. Alon Kahana and Victor Elner gratefully acknowledge research support from the National Institutes of Health, USA.

3.Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the ocular region: a review. Surv Ophthalmol 2005;50:103–122.

4.Thody AJ, Shuster S. Control and function of sebaceous glands. Physiol Rev 1989;69:383–416.

5.Porter AM. Why do we have apocrine and sebaceous glands? J R Soc Med 2001;94:236–237.

12.Chao AN, Shields CL, Krema H, et al. Outcome of patients with periocular sebaceous gland carcinoma with and without conjunctival intraepithelial invasion. Ophthalmology 2001;108: 1877–1883.

22.Johnson JS, Lee JA, Cotton DW, et al. Dimorphic immunohistochemical staining in ocular sebaceous neoplasms: a useful diagnostic aid. Eye 1999;13: 104–108.

23.Murata T, Nakashima Y, Takeuchi M, et al. The diagnostic use of low molecular weight keratin expression in

sebaceous carcinoma. Pathol Res Pract 1993;189:888–893.

24.Sinard JH. Immunohistochemical distinction of ocular sebaceous carcinoma from basal cell and squamous cell carcinoma. Arch Ophthalmol 1999;117:776–783.

28.Ho VH, Ross MI, Prieto VG, et al. Sentinel lymph node biopsy for sebaceous cell carcinoma and melanoma of the ocular adnexa. Arch Otolaryngol Head Neck Surg 2007;133: 820–826.

30.Yeatts RP, Waller RR. Sebaceous carcinoma of the eyelid: pitfalls in diagnosis. Ophthalm Plast Reconstr Surg 1985;1:35–42.

32.Folberg R, Whitaker DC, Tse DT, et al. Recurrent and residual sebaceous carcinoma after Mohs’ excision of the primary lesion. Am J Ophthalmol 1987;103:817–823.

36.Putterman AM. Conjunctival map biopsy to determine pagetoid

spread. Am J Ophthalmol 1986;102: 87–90.

37.Lisman RD, Jakobiec FA, Small P. Sebaceous carcinoma of the eyelids. The role of adjunctive cryotherapy in the management of conjunctival pagetoid spread. Ophthalmology 1989;96:1021– 1026.

38.Shields CL, Naseripour M, Shields JA, et al. Topical mitomycin-C for pagetoid invasion of the conjunctiva by eyelid sebaceous gland carcinoma. Ophthalmology 2002;109:2129–2133.

48.Blanpain C, Lowry WE, Geoghegan A, et al. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 2004;118:635–648.

51.Ohyama M, Terunuma A, Tock CL,

et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest 2006;116:249– 260.

Neurofibromatosis type 1 (NF1) is an autosomal-dominant tumor predisposition syndrome in which affected children are prone to the development of low-grade astrocytic (glial) neoplasms along the optic pathway (optic pathway glioma, OPG). In this regard, 30% of OPGs are found in children with NF1, making NF1 the most common genetic cause for this visual pathway tumor. The protean manifestations and unpredictability of the clinical course of an individual with NF1 often make this complex condition challenging to manage for the practitioner.

Clinical background

Historical development

Historical depictions of individuals who clearly display manifestations of NF1 can be found in art dating back to as early as the 15th century. Frederick Daniel von Recklinghausen provided the first complete pathologic description of NF1 (1881), reporting both the gross and histologic features, and demonstrating for the first time that the cutaneous masses contained neural elements. Although Crowe (1953)1 emphasized the importance of the café-au-lait spot in the diagnosis of “von Recklinghausen disease,” the recognition of NF1 as a distinct clinical entity did not occur until 1981. Finally, in 1987 the National Institutes of Health Consensus Development Conference2 defined the seven diagnostic criteria for NF1, of which two must be present to confirm the diagnosis (Box 53.1).

Key signs and symptoms of NF1

Café-au-lait spots and intertriginous freckling

(Figure 53.1A)

Café-au-lait spots are flat, pigmented macules, and are generally the first cutaneous manifestation of NF1. Often present at birth, they become apparent during the first few years of life. As many as 97% of children who are eventually diagnosed with NF1 will have six or more café-au-lait spots by the time they are 6 years of age.3 Patients with greater numbers of café-au-lait spots are not at risk for the develop-

ment of more severe disease. While freckling is common in sun-exposed areas of individuals without NF1, smaller café- au-lait spots or freckling may be seen in areas not directly exposed to the sun in individuals with NF1, and constitutes the second most common diagnostic criterion found in young children. These freckles typically occur in skinfolds, including the axilla, inguinal creases, submammary regions, and the neck.

Dermal neurofibromas (Figure 53.1B)

Neurofibromas, the hallmark lesion of NF1, are benign nerve sheath tumors arising from peripheral nerves. These tumors are composed of neoplastic Schwann cells as well as numerous stromal cell types (i.e., mast cells, fibroblasts, and perineural cells). Cutaneous neurofibromas arise from small superficial nerves; they are soft, protrude just above the skin’s surface, and often display a violaceous hue. In contrast, subcutaneous neurofibromas arise from deeper nerves and are generally firm. Deep visceral neurofibromas may cause symptoms by compressing vital structures, such as is seen in spinal cord compression from dorsal root neurofibromas. Although young children may have some neurofibromas, these tumors tend to appear with the onset of puberty and increase in both size and number with advancing age.

Plexiform neurofibromas (Figure 53.1C)

Although plexiform neurofibromas are histologically similar to dermal neurofibromas, they are clinically quite distinct. They are often present at birth or develop in the first several years of life, undergoing a phase of rapid growth during childhood. Although these tumors are generally soft, the observer can often feel multiple firmer thickened nerves within the tumor, described as a “bag of worms.” Overlying hyperpigmentation or fine hair growth may be a clue to the presence of an underlying plexiform neurofibroma. Often arising from branches of major nerves, they can become large and cause significant dysfunction. Plexiform neurofibromas involving the eyelid or orbit may lead to visual loss from associated glaucoma, amblyopia secondary to proptosis, or optic nerve damage. Internal plexiform neurofibromas can cause morbidity as a result of spinal cord compression, erosion of contiguous bone, or ureteral/bladder outlet obstruction.

Box 53.1  Neurofibromatosis type 1 (NF1)

diagnostic criteria

Two or more of the following must be present to establish the diagnosis of NF1:

•Six or more café-au-lait macules >5 mm in prepubertal individuals, or >15 mm in postpubertal individuals

•Two or more neurofibromas, or one plexiform neurofibroma

•Freckling in the axillary or inguinal region

•Optic glioma

•Two or more Lisch nodules

•A distinctive osseous lesion (sphenoid dysplasia or thinning of long bone cortex with or without pseudarthrosis)

•A first-degree relative with NF1 by above criteria

A

Clinical background

Lisch nodules (Figure 53.1D)

Lisch nodules are dome-shaped melanocytic hamartomas of the iris, and are virtually pathognomonic of NF1. Not associated with any visual abnormalities, they are present in 90– 95% of adults with NF1. They are best visualized using a slit lamp by an experienced ophthalmologist.

Optic pathway gliomas

Although children 6 years of age and younger with NF1 are at greatest risk for the development of an OPG, new symptomatic OPGs may also arise in older children and adults.4 If neuroimaging is performed on all children with NF1 at the time of diagnosis, 15–20% of these children will harbor an OPG. However, only half of these tumors will ever become symptomatic, giving an overall incidence of symptomatic OPGs of 7%.5

B

optic track

Optic

chiasm

B

Figure 53.2  Visual pathway anatomy. (A) Visual information is transmitted from the retina by the optic nerves whose fibers cross at the optic chiasm and proceed to the lateral geniculate bodies before coursing to the visual cortex. (B) Optic pathway gliomas in individuals with neurofibromatosis type 1 may involve the optic nerves, optic chiasm, postchiasmatic optic tracks, and hypothalamus (highlighted in yellow) in sagittal (left) and coronal (right) orientations.

NF1-associated OPGs are usually to the anterior visual pathway, including the intraorbital optic nerve, intracranial optic nerve, and the optic chiasm (Figure 53.2). In contrast, sporadic OPGs not associated with NF1 commonly involve the optic tracts and postchiasmatic optic radiations as well. Bilateral intraorbital OPGs are virtually pathognomonic of NF1 (Figure 53.3A).

Symptomatic OPGs may become apparent in one of several ways. Approximately 30% of such tumors will present with the rapid onset of unilateral proptosis and significantly decreased visual acuity secondary to large intraorbital tumors. An additional 30% of patients will have an abnormal ophthalmologic examination without any visual symptoms, since young children rarely complain of gradual visual loss. Abnormal ophthalmologic signs may include optic nerve atrophy or pallor, an afferent pupillary defect, uncorrectable decreased visual acuity, strabismus, or papilledema.5 The remaining 40% of children will present with signs of precocious puberty, usually with accelerated linear growth. Such children invariably harbor chiasmatic tumors which can affect the hypothalamic–pituitary–gonadal axis (Figure 53.3B). Thus, it is essential that all young children with NF1 have annual assessments of linear growth plotted on standardized pediatric growth charts.6

Natural history of OPG

Predicting the natural history of an individual OPG is impossible. For example, rapidly progressive intraorbital tumors

410

A

B

Figure 53.3  Optic pathway gliomas (OPGs) in children with neurofibromatosis 1. (A) Representative bilateral orbital OPG (denoted by the arrows). (B) Representative chiasmatic OPG (denoted by the dotted line).

which cause proptosis and significant visual loss may stop growing following initial presentation. While progressive disease following the diagnosis of a symptomatic OPG occurs in 35–52% of cases, OPGs found by screening neuroimaging of asymptomatic individuals with NF1 rarely progress.5,7 Most importantly, the natural history of NF1associated OPGs is markedly different from that of sporadic OPG. The latter are significantly more likely to progress radiographically and clinically, leading to the development of increased intracranial pressure and hydrocephalus with substantially greater ophthalmologic morbidity.8

Diagnostic evaluation of asymptomatic children with NF1

All young children with NF1 should undergo complete yearly ophthalmologic examinations in order to identify the earliest manifestations of a symptomatic OPG. Complete

examinations including ocular alignment and rotations, assessment of color vision, pupillary light response, refractive status, and fundoscopic evaluation should be performed. Visual acuity should be measured using ageappropriate testing (i.e., preferential looking tests in infants, Lea figure, or HOTV matching in preliterate children, Snellen charts in older children). Routine measurement of visual fields is unnecessary as clinically important visual field compromise without concomitant loss of visual acuity is rare. There is no reliable evidence supporting the routine use of visual evoked potentials in the diagnosis of NF1-associated OPG.7

There has been considerable debate as to the role of neuroimaging of asymptomatic children with NF1. Routine “screening” neuroimaging would be important if it led to the early detection of OPG which, in turn, led to significantly decreased ophthalmologic morbidity. However, there are substantial data showing that such a strategy would fail; in previous studies, many tumors were detected that never progressed and some children developed symptomatic OPG after a normal visual screening examination. Thus, there is no conclusive evidence that the early detection of OPGs leads to improved outcome. For these reasons, screening “baseline” neuroimaging of asymptomatic children with NF1 is not recommended.7

Follow-up of an asymptomatic OPG

Once an asymptomatic NF1-associated OPG has been identified, close follow-up is warranted, as the natural history of an individual tumor cannot be predicted. Generally, ophthalmologic examinations should be performed every 3 months during the first year following diagnosis. Magnetic resonance imaging should also be performed at frequent intervals; the exact protocols vary among institutions. As the child gets older without evidence of either clinical or radiographic progression, the intervals between examinations can be progressively lengthened.

Treatment

There are scant data as to what constitutes sufficient clinical or radiographic progression to warrant treatment. Radiographic progression without a concomitant change in the child’s visual examination may not be sufficiently compelling to mandate treatment. Additionally, the appearance of clinical signs, such as the development of precocious puberty, does not constitute in itself a reason for treatment. However, once the decision to undergo treatment has been made, certain truths exist.

There is a limited role for surgery in the management of NF1-associated OPG. Partial removal of an intraorbital optic nerve glioma is usually reserved for cosmetic purposes only. On occasion, surgical decompression of a hypothalamic glioma may be necessary to treat hydrocephalus secondary to third ventricular compression. Biopsy is only recommended in very atypical cases as NF1-associated OPG are most often low-grade juvenile pilocytic astrocytomas.7 Similarly, radiotherapy in children with NF1 is not recommended, because of the unacceptable neurovascular (cerebral occlusive vasculopathy), endocrinologic, and neuropsychologic sequelae. Moreover, recent evidence suggests that children with NF1 treated with radiation therapy develop secondary brain malignancies later in life.9

Pathophysiology

Chemotherapy has become the mainstay of treatment for NF1-associated OPGs. The most commonly used chemotherapeutic regimen is the combination of carboplatin and vincristine. This combination is effective in controlling the growth of most NF1-associated OPGs, and is typically well tolerated in this age group. Other chemotherapies have also been used; however, there is no consensus on which secondline therapy is most effective for these tumors.7

Pathology

The vast majority of NF1-associated OPGs are classified by the World Health Organization (WHO) as grade I astrocytic neoplasms (pilocytic astrocytomas). Similar to pilocytic astrocytomas arising in other brain regions in individuals with NF1, these low-grade gliomas are characterized by a biphasic histologic pattern of more cellular areas alternating with looser cystic regions.10 Within the less compact areas, there are Rosenthal fibers (tapered corkscrew-shaped hyaline masses) and eosinophilic granular bodies (globular aggregates). These tumors exhibit low mitotic indices with rare mitoses and occasional hyperchromatic nuclei. Despite their benign nature, pilocytic astrocytomas are rather infiltrative tumors with significant microvascular proliferation and the presence of microglia. Immunohistochemical analyses of these tumors reveal robust staining with glial fibrillary acidic protein antibodies, characteristic of astrocytic neoplasms.

Etiology

NF1 is caused by a germline mutation in the NF1 gene; however, only 50% of all individuals with NF1 have an affected parent.11 These individuals without a family history of NF1 represent new mutations, which presumably arise from a mutation in the NF1 during spermatogenesis in the male.12 Since NF1 is an autosomal-dominant disorder with complete penetrance, the risk of transmitting NF1 is 50% with each pregnancy. Children who inherit a mutated (nonfunctional) copy of the NF1 gene have NF1, yet the clinical manifestations may be variable. In this regard, a child with NF1 with the identical NF1 gene mutation as a parent or sibling can be more severely or more mildly affected. More­ over, there are no obvious genotype–phenotype correlations that predict disease severity, with the exception of children with large chromosomal deletions surrounding the NF1 gene. These children frequently have mental retardation and distinctive facial features, and may be at risk for the development of malignancy.13,14 Finally, there are no known environmental risk factors and NF1 has been described in all ethnic and racial groups worldwide.

Pathophysiology

With the identification of the NF1 gene and its protein product, neurofibromin, there is renewed excitement that future therapies for NF1-associated OPG might involve treatments that target the pathways deregulated in these tumors. The NF1 gene is classified as a tumor suppressor gene, since patients affected with NF1 develop benign and malignant

Unaffected individual

Cancer

Individual with NF1

Figure 53.4  Knudson two-hit hypothesis. Individuals with neurofibromatosis type 1 (NF1) begin life with one functional and one nonfunctional (denoted by the X) copy of the NF1 gene. Tumors result from somatic mutation of the remaining functional copy of the NF1 gene.

tumors at an elevated rate. Consistent with Knudson’s two-hit hypothesis for inherited cancer syndromes,15 individuals with NF1 start life with one functional and one mutated copy of the NF1 gene in every cell of their body. Tumors form when the remaining functional NF1 gene undergoes somatic mutation and is rendered nonfunctional (Figure 53.4). Examination of tumors from patients with NF1, including OPGs,16 has demonstrated biallelic inactivation of the NF1 gene and loss of NF1 gene expression.

Function of the NF1 protein

The NF1 gene resides on chromosome 17q and encodes a large cytoplasmic protein (neurofibromin) of 220–250 kDa.17–20 Examination of the predicted protein sequence of neurofibromin revealed that a small region of the protein shares striking sequence similarity with the catalytic domain of a family of proteins known to regulate the RAS protooncogene negatively (Figure 53.5).21–23 RAS is an intracellular signaling molecule that exists in an active guanosine triphosphate (GTP)-bound conformation and an inactive guanosine diphosphate (GDP)-bound state. Active GTPbound RAS provides a strong mitogenic growth signal, such that constitutive RAS activation as a result of mutation in cancer leads to unregulated cell growth and tumor formation. Neurofibromin as a negative RAS regulator functions to maintain RAS in an inactive form and inhibit cell growth. Loss of neurofibromin expression, such as seen in NF1associated OPG tumors, leads to high levels of active GTPbound RAS and increased tumor growth.24–27

RAS imparts its growth signal through the sequential activation of other signaling intermediates, including mitogenactivated protein kinase (MAPK), protein kinase B (Akt), and the mammalian target of rapamycin (mTOR) protein (Figure 53.5). In this regard, loss of neurofibromin in tumor cells leads to high levels of MAPK, Akt, and mTOR activity, which promote cell growth, cell survival, cell motility, and increased protein translation.28–33 Inhibition of RAS or mTOR activity using pharmacologic inhibitors, including farnesyltrans-

412

Figure 53.5  Neurofibromin growth regulation. The NF1 gene is located on chromosome 17q and codes for a large cytoplasmic protein, neurofibromin. A small region of the neurofibromin protein contains the GTPase-activating protein (GAP) domain which serves to inactivate Ras by converting it from its active, guanosine triphosphate (GTP)-bound form to an inactive, guanosine diphosphate (GDP)-bound conformation. Active Ras promotes cell growth by activating its downstream effectors, Akt and mitogenactivated protein kinase (MAPK). Akt, in turn, activates the mammalian target of rapamycin (mTOR) protein. In addition to negative Ras regulation, neurofibromin serves to regulate intracellular cyclic adenosine monophosphate (cAMP) levels positively, likely by stimulating adenylyl cyclase (AC) activity. cAMP inhibits cell growth either by reducing MAPK signaling or through other mechanisms.

ferase inhibitors (RAS) and rapamycin analogs (mTOR), are logical targets for future antineoplastic biologically based drug therapies for NF1-associated OPG.

In addition to its ability to regulate RAS negatively, neurofibromin also functions to generate intracellular cyclic AMP (cAMP) positively.34–36 Although less is known about the role of cAMP in growth control, several studies have shown that increased cAMP levels inhibit cell growth in glioma cells.37,38 In primary mouse astrocytes, loss of Nf1 expression results in decreased levels of intracellular cAMP, likely at the level of adenylyl cyclase,36 and elevated cAMP reduces cell growth by inhibiting MAPK signaling.39 Recent studies on neurofibromin cAMP control in astrocytes have shown that specific cells in the brain (e.g., neurons, microglia, and endothelial cells) produce chemokines (e.g., stromal-derived growth factor-α; CXCL12) that uniquely promote Nf1-deficient astrocyte survival in a cAMPdependent fashion.40

Small-animal models of NF1-associated OPG

As we move into an era of targeted therapeutics, it is important to develop robust and tractable small-animal models of NF1-associated OPG.41 Over the past several years, genetically engineered Nf1 optic glioma mice have been generated

Box 53.2  Use of small-animal models

•Discovery platform to identify new targeted therapies for neurofibromatosis type 1 (NF1)-associated tumors

•Preclinical platform to evaluate new therapies for NF1associated tumors

•Define the cell populations within the tumors sensitive to targeted therapies

•Determine why therapies succeed or fail

•Identify the molecular and cellular pathogenesis of tumor formation and growth

•Pinpoint genetic risk factors for NF1-associated tumors

by inactivation of Nf1 gene expression in glial cells. Interestingly, Nf1 mutant mice lacking neurofibromin expression in glial cells exhibit increased numbers of astrocytes, but do not develop brain tumors.42 Since individuals with NF1 are born with one functional and one nonfunctional copy of the NF1 gene in each cell of their body (NF1+/– cells), two groups developed Nf1+/– mice lacking neurofibromin expression in glial cells to model the human condition more accurately.43,44 Similar to the human tumors, these Nf1 mutant mice developed low-grade astrocytic (glial) tumors affecting the optic nerves and chiasm. Examination of the optic gliomas in these genetically engineered mice demonstrated low proliferative indices, microvascular proliferation, and microglial infiltration. In addition, these tumors demonstrated maximal proliferation between 2 and 4 months, with significantly less proliferation observed thereafter.45 However, unlike their human counterparts, they lack Rosenthal fibers and eosinophilic granular bodies, and cannot be strictly classified as pilocytic astrocytoma. Lastly, small-animal magnetic resonance imaging has been successfully employed to detect these tumors and follow their growth in vivo.46

These small-animal Nf1 optic glioma mouse models have been useful for several purposes (Box 53.2). First, they can be used as platforms for the discovery and evaluation of new therapies against NF1-associated OPG. In this regard, Nf1 mutant mice can be treated with promising therapies as an initial screen prior to evaluation in children with NF1. The availability of such preclinical filters should greatly facilitate the translation of basic science discoveries to clinical practice. Second, these mice can be employed to discover predictive markers of tumor formation, growth, and response to treatment. Researchers have used these mice to identify body fluid proteins whose expression might correlate with disease activity.47 In addition, Nf1 mutant mice have allowed scientists to pinpoint genetic risk factors for brain tumors, which might facilitate the identification of children at greatest risk for developing OPGs. Studies using glioma-prone mice on different genetic backgrounds have identified several genetic regions that harbor genes that strongly influence tumor formation.48 The identification of similar “modifier” genes in humans might lead to the development of predictive genetic tests that allow physicians to counsel patients more accurately about their risk of glioma formation.

Lastly, Nf1 mutant mice are currently being exploited to understand why brain tumors form in children with NF1.

Pathophysiology

Blood vessel

Brain tumor

Figure 53.6  Anatomy of a glioma. Neurofibromatosis type 1-associated optic pathway gliomas are likely composed of a diverse collection of cell types, including microglia, endothelial cells, differentiated glioma cells, and cancer stem cells. Each of these cell types participates in glioma formation and continued growth. Moreover, each cell type represents a logical target for future antiglioma therapy (denoted by the asterisks).

These studies have shown that NF1-associated OPGs are composed of a number of different cell types that each contribute to tumor formation (Figure 53.6). In this respect, immune system cells (microglia) found in NF1-associated OPG produce specific growth signals that promote tumor growth. The microglia in both human and mouse tumors harbor one mutated NF1 gene (Nf1+/– cells) and exhibit functional properties distinct from normal microglia.49 The observation that Nf1+/– microglia increase Nf1–/– astrocyte and glioma growth in vitro and in vivo raises the intriguing possibility that future NF1 optic glioma therapies might target microglia or microglia-produced growth signals.

Finally, within both human pilocytic astrocytomas and Nf1 mouse optic gliomas are rare progenitor (stem) cells.44,45 These cancer stem cells (CSCs) have been proposed to represent cancer-generating cells within the tumor.50,51 In addition, these CSCs have unique cellular and biochemical properties, and therefore respond differently to conventional treatments compared to the more differentiated glioma cells within the tumor.52 Recent studies have shown that neurofibromin plays a critical role in stem cell function relevant to tumorigenesis.53,54 Future studies on these CSCs may lead to the development of future therapies for NF1-associated OPG that target this unique cell type.

As we enter into an age of targeted therapeutics, the development and refinement of robust mouse models of NF1associated OPG provide novel platforms for evaluating new anticancer drugs, assessing therapeutic index, identifying surrogate markers of tumor progression, and defining epigenetic and environmental influences on tumorigenesis. These advances show great promise for more targeted and effective treatments for these tumors.

Conclusion

OPGs in children with NF1 represent both diagnostic and management challenges for clinicians. Whereas considerable progress has been made over the past decade in both our clinical and basic science understanding of these tumors, several key areas deserve future investigation. First, we need to be able to identify efficiently children at greatest risk for developing a symptomatic OPG. Second, these

at-risk children require age-appropriate visual assessment tools to determine when they should be treated. Third, symptomatic children should be treated with agents that have maximal therapeutic efficacy against the tumor with minimal effects on the developing brain. Lastly, improved therapeutic strategies need to be developed for those children who fail initial treatment. With the advent of preclinical and clinical consortia focused on NF1, we are uniquely positioned to improve the future management of these children.

2.Neurofibromatosis. National Institutes of Health Consensus Development Conference Consensus Statement 1987;6:1–7.

4.Listernick R, Ferner RE, Piersall L, et al. Late-onset optic pathway tumors in children with neurofibromatosis 1. Neurology 2004;63:1944–1946.

6.Habiby R, Silverman B, Listernick R, et al. Precocious puberty in children

with neurofibromatosis type 1. J Pediatr 1995;126:364–367.

7.Listernick R, Ferner RE, Liu GT, et al. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 2007;61:189–198.

9.Sharif S, Ferner R, Birch JM, et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol 2006;24:2570–2575.

16.Gutmann DH, Donahoe J, Brown T,

et al. Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas. Neuropathol Appl Neurobiol 2000;26:361–367.

43.Bajenaru ML, Hernandez MR, Perry A,

et al. Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res 2003;63:8573–8577.

45.Bajenaru ML, Garbow JR, Perry A, et al. Natural history of neurofibromatosis

1-associated optic nerve glioma in mice. Ann Neurol 2005;57:119–127.

53.Dasgupta B, Gutmann DH. Neurofibromin regulates neural stem cell proliferation, survival, and astroglial differentiation in vitro and in vivo.

J Neurosci 2005;25:5584–5594.

54.Hegedus B, Dasgupta B, Shin JE, Emnett RJ, et al. Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo

by both cAMPand Ras-dependent mechanisms. Cell Stem Cell 2007;1:443– 457.

S E C T I O N   7

Other

C H A P T E R 54

Phthisis bulbi

Clinical background

Key symptoms and signs

Phthisis bulbi represents an ocular end-stage disease of various causes and is defined by atrophy, shrinkage, and disorganization of the eyeball and intraocular contents (Box 54.1).1,2 Subjective complaints depend on the etiology and severity of phthisis bulbi. Typical clinical symptoms and signs include chronic ocular hypotension (5 mmHg), a shrunken globe, pseudoenophthalmos, intraocular tissue fibrosis and scarring, vision loss, and recurrent episodes of intraocular irritation and pain.3

Historical development

The term phthisis bulbi derives from the Greek word phthiein or phthinein, meaning shrinkage or consuming, and was first used by Galen.3 Over the last 200 years, the clinical interpretation of phthisis bulbi has often been modified according to the underlying disease and structural changes; a clear distinction from ocular atrophy was often difficult and controversial.4 Hogan and Zimmerman1 were the first ones who stated that both terms – atrophy and phthisis bulbi – refer to consecutive stages in the degeneration process of a severely damaged eye. Their descriptive classification system including three different stages – (1) ocular atrophy without shrinkage; (2) with shrinkage; and (3) with shrinkage and disorganization – has been further modified by Yanoff and Fine2 (Table 54.1).

Epidemiology

Epidemiological data on phthisis bulbi are mainly based on retrospective clinicopathological studies on enucleated eyes.5–10 Enucleations are usually the result of failed ocular treatment or end-stage diseases (i.e., phthisis bulbi) associated with blind, painful, or cosmetically unacceptable eyes. The incidence of enucleation in general has slightly decreased during the last decades because of improved diagnostic and therapeutic approaches, and the trend towards globepreserving procedures; however, information on the incidence of phthisis bulbi is limited.10,11 In contrast, the

prevalence of phthisis bulbi in enucleated eyes is well documented, ranging from 11.2% to 18.7% with an average of 13.7%, and has remained fairly stable over the last 60 years (Table 54.2).5–9 However, statistical evaluations indicate a slight increase in the number of enucleations for phthisis bulbi during the last two decades.9,10,12

In general, phthisis bulbi involves elderly patients, usually 65–85 years of age.9,12 Children and adolescents (≤20 years of age) are only rarely affected (3.7–6.4%), mainly due to ocular trauma and congenital malformations. Right and left eyes are almost equally affected. The initial insult usually takes place 20–30 years prior to enucleation. Two age peaks at 35 and 75 years of age were found in 69 phthisical eyes with previous trauma.3 Overall, phthisis bulbi occurs more often in males than in females.3,5,6,8,9 The imbalance in sex distribution, at least in part, can be explained by predominance of ocular trauma (i.e., concussion, perforation) in the past ocular history of patients with phthisis bulbi, which occurs more often in men than women.6,9,13

Genetics

A possible relationship between myotonic dystrophy and ocular hypotony has been described by Kuechle and coworkers.14 The examined eyes displayed a diminished blood– aqueous barrier (BAB) function and diffuse choroidal edema, presumably due to elevated follicle-stimulating hormone and luteal hormone serum levels.

Diagnostic workup

Phthisical eyes are usually easily accessible for slit-lamp examination, which allows evaluation of the periocular region and structures of the anterior segment. In less advanced stages of the disease with a lack of significant corneal opacification, intraocular fibrosis (i.e., cyclitic membranes) or cataractous changes of crystalline lens, gonioscopy, direct and indirect ophthalmoscopy, fluorescein angiography, and optical coherence tomography may be useful for evaluation of the anterior-chamber angle, choroid, and retina.15 Once optical visualization of the intraocular structures is obscured, ultrasound biomicroscopy and other noninvasive diagnostic imaging techniques such as com-

puted tomography (CT) and magnetic resonance imaging (MRI) may be applied to validate morphologic abnormalities of the anterior chamber and ciliary body as well as to exclude intraocular ossification, or possibly foreign bodies (Box 54.2).16,17 However, the differential diagnostic utility of these imaging techniques is often limited based on the severe structural changes seen in phthisical eyes.

Although phthisis bulbi is defined as ocular shrinkage and ocular hypotony, intraocular pressure (IOP) readings using applanation or impression tonometry devices (i.e., Goldmann, Schiotz), may be inaccurate because of the anatomical changes of the anterior segment (i.e., corneal edema, scarring, shrinkage) and the sunken location of the eyes in the orbit.

Differential diagnosis

Although the underlying diseases and the clinical course of phthisis bulbi are quite variable, the end-stage disease is rarely missed because of characteristic clinical features (i.e., small, soft, atrophic eyes), which are often associated with

Box 54.1  Definition–phthisis bulbi

Phthisis bulbi represents an ocular end-stage disease characterized by:

•Atrophy

•Shrinkage

•Disorganization of the eyeball and its intraocular contents

Box 54.2  Diagnostic workup of phthisical eyes

Useful diagnostic tools in the evaluation of phthisis bulbi include:

•Indirect/direct ophthalmoscopy

•Gonioscopy

•Fluorescein angiography

•Optical coherence tomography

•Ultrasound (A- and B-scan)

•Computed tomography (CT) and magnetic resonance imaging (MRI)

decreased or lost vision. However, clinicians should be aware of any potential disease entity which, if not treated properly, may result in a blind, often painful phthisical eye. Intraocular malignancies (i.e., retinoblastoma, malignant uveal melanoma) should be taken into consideration if the ocular history is limited and an obvious cause for phthisis is missing.6 In addition, congenital abnormalities like microphthalmos and microcornea should be kept in the differential diagnosis of phthisis bulbi.18

Treatment

Therapeutic approaches are very limited in phthisical eyes; symptomatic treatment (i.e., artificial tears, ointments, topical corticosteroids, nonsteroidal eye drops, antiinfectious agents) may be recommended in patients with mild ocular symptoms (i.e., irritation, pain). Contact lenses or scleral shells can be used for cosmetic purposes. Once phthisical eyes become chronically irritated and painful, enucleation or evisceration with implantation of an intraocular or orbital implant should be performed, especially with regard to potential long-term complications (i.e., sympathetic ophthalmia, ulceration, perforation) and to exclude intraocular malignancies.19,20

Prognosis and complications

The diagnosis of phthisical eyes implies a frustrating clinical situation demonstrating the result of failed previous ocular therapy in which restoration of the morphologic and func-

Table 54.1  Grading system of atrophia and phthisis bulbi

Modified from Yanoff M, Fine BS. Nongranulomatous inflammation: uveitis, endophthalmitis, panophthalmitis, and sequelae. In: Yanoff M, Fine BS (eds) Ocular Pathology, 5th edn. St. Louis, MO: Mosby, 2002:72–73.