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

mimicry in human liver specimens. Although vasculogenic mimicry patterns may be identified in nearly every location to which uveal melanoma disseminates, including the liver,13 their presence in advanced human hepatic metastases is variable.

Thus, vasculogenic mimicry may help to keep hepatic uveal melanoma micrometastases biologically “in check,” at least for a period of time, and when the dampening effect of vasculogenic mimicry on aggressive tumor cell behavior is overridden, clinically significant and lethal hepatic metastases emerge. Additional investigations into the mechanisms by which vasculogenic mimicry dampens tumor cell behavior in the liver and identification of those events that suppress the microenvironmental dampening of aggressive tumor cell behavior are indicated. If ophthalmic oncologists can identify patients at high risk for metastasis when the primary tumor is first diagnosed and treated, these patients

Conclusion

can be assumed already to have subclinical micrometastatic disease and therapeutic intervention targeted to maintaining the dampening effects of vasculogenic mimicry on aggressive tumor cell behavior can be implemented. A therapeutic strategy of maintaining patients on chronic therapy to suppress the emergence of clinically significant and lethal metastatic disease from subclinical micrometastases – the chemoprevention of clinically overt metastases – may be a viable clinical approach to achieving long-term survival in uveal melanoma patients now without hope of cure.

Vasculogenic mimicry may, by analogy, play a key role in the well-known resistance of uveal melanoma to most forms of conventional chemotherapy. If the most malignant cells in a tumor can generate a tumor biofilm, then cells entrapped within the biofilm may evade targeting by drugs, and the chromatin sequestration induced by contact with the biofilm may also contribute to a novel form of drug resistance. It is of interest that the malignancies most susceptible to chemotherapy are the leukemias, planktonic malignancies lacking a stroma and the opportunity to develop a tumor biofilm. Molecular targeting of the tumor cell-generated microenvironment – the tumor biofilm known as vasculogenic mimicry

– may therefore provide a novel approach to the treatment of metastatic uveal melanoma, a condition for which no effective therapy currently exists (Box 50.1).

Conclusion

Highly invasive melanoma cells generate a patterned extracellular matrix around packets of these cells. The histologic

Figure 50.1  (A) Vasculogenic mimicry patterns stained with an antibody to fibronectin. The looping patterns surround packets of uveal melanoma cells. The patterns connect to blood vessels (arrow). The patterns have been shown to contain laminin, collagens IV and VI, fibronectin, and heparan sulfate proteoglycan. (B) Kaplan–Meier survival curve showing that patients whose tumors contain vasculogenic mimicry patterns have a significantly worse prognosis than patients whose tumors lack these patterns. (Redrawn with permission from Folberg R, Rummelt V, Parys-Van Ginderdeuren R, et al. The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology 1993;100:1389–1398.)

detection of these vasculogenic mimicry patterns is associated with an aggressive clinical course. Pattern generation is also very strongly associated with other markers of tumor progression, such as monosomy 3 and gene expression signatures. Therefore, the detection of these patterns clinically by noninvasive means such as indocyanine green angiography or specialized ultrasonography may serve as a noninvasive substitute for biopsy. The patterns have been shown to conduct fluid in vitro, in animal models, and in patients and may contribute to the tumor microcirculation independent of angiogenesis. Angiogenesis inhibitors are not effective in preventing the formation of vasculogenic mimicry patterns. However, vasculogenic mimicry provides novel targets for therapy because after the tumor cells generate these patterns,

the invasive behavior of these cells is diminished and chromatin is sequestered. The generation of this “tumor biofilm” may provide a new explanation for drug resistance in uveal melanoma, and the molecular interactions between the extracellular matrix and the tumor cells may constitute novel approaches to nontoxic therapies for the chemoprevention of hepatic metastases and the treatment of established clinical metastatic disease (Figures 50.1 and 50.2).

Acknowledgment

This work was supported by grant R01 EY10457, National Institutes of Health, Bethesda, Maryland, USA.

1.The COMS randomized trial of iodine

125brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report no.

28.Arch Ophthalmol 2006;124:1684– 1693.

2.McLean IW, Foster WD, Zimmerman LE, et al. Modifications of Callender’s classification of uveal melanoma at the Armed Forces Institute of Pathology. Am J Ophthalmol 1983;96:502–509.

3.Augsburger JJ, Shields JA, Folberg R, et al. Fine needle aspiration biopsy in the diagnosis of intraocular cancer cytologic– histologic correlations. Ophthalmology 1985;92:39–49.

4.Folberg R, Augsburger JJ, Gamel JW, et al. Fine-needle aspirates of uveal melanomas and prognosis. Am J Ophthalmol 1985;100:654–657.

5.Damato B. Current management of uveal melanoma. Ejc Suppl 2005;3:433–435.

6.Folberg R, Pe’er J, Gruman LM, et al. The morphologic characteristics of tumor blood vessels as a marker of tumor progression in primary human uveal

melanoma: a matched case-control study. Hum Pathol 1992;23:1298–1305.

7.Folberg R, Rummelt V, Parys-Van Ginderdeuren R, et al. The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology 1993;100:1389–1398.

8.Sakamoto T, Sakamoto M, Yoshikawa H, et al. Histologic findings and prognosis of uveal malignant melanoma in Japanese patients. Am J Ophthalmol 1996;121:276–283.

9.McLean IW, Keefe KS, Burnier MN. Uveal melanoma: comparison of the prognostic value of fibrovascular loops, mean of the ten largest nucleoli, cell type and tumor size. Ophthalmology 1997;104:777– 780.

10.Makitie T, Summanen P, Tarkannen A, et al. Microvascular loops and networks as prognostic indicators in choroidal and ciliary body melanomas. J Natl Cancer Inst 1999;91:359–367.

11.Thies A, Mangold U, Moll I, et al. PAS-positive loops and networks as a prognostic indicator in cutaneous

malignant melanoma. J Pathol 2001;195:537–542.

12.Folberg R, Maniotis AJ. Vasculogenic mimicry. APMIS 2004;112:508–525.

13.Rummelt V, Folberg R, Rummelt C, et al. Microcirculation architecture of melanocytic nevi and malignant melanomas of the ciliary body and choroid. A comparative histopathologic and ultrastructural study. Ophthalmology 1994;101:718–727.

14.Scholes AGM, Damato BE, Nunn J, et al. Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival. Invest Ophthalmol Vis Sci 2003;44:1008–1011.

15.Onken MD, Lin AY, Worley LA, et al. Association between microarray gene expression signature and extravascular matrix patterns in primary uveal melanomas. Am J Ophthalmol 2005;140:748–749.

Overview

Choroidal melanoma is the most common primary malignant intraocular tumor with an annual incidence in the USA of 0.8 cases per 100 000 population.1 Once metastasis becomes clinically apparent, the 1-year mortality rate approaches 80%.2 Given this poor prognosis, enucleation was historically considered the only appropriate management for choroidal melanoma. However, in recent decades there have been many new developments in management, with a trend toward more conservative therapeutic methods. The impetus for this shift in paradigm was the proposition by Zimmerman et al3 that enucleation may in fact promote metastasis by intraoperative dissemination of tumor emboli. The transient rise in post-therapeutic mortality that prompted this theory has been validated over the ensuing 25 years, but is now believed to be attributable to prediagnosis and treatment micrometastasis in uveal melanoma. Therapeutic options have since expanded to include transpupillary thermotherapy (TTT), plaque radiotherapy, charged-particle irradiation, local resection, and observation.

The Collaborative Ocular Melanoma Study (COMS)4 is the first set of randomized clinical trials designed with sufficient power to detect a difference in survival outcomes between treatment modalities. Between 1986 and 1994, investigators screened 6078 patients at 43 clinical centers, placing each eligible subject into one of three categories: small, medium, or large choroidal melanoma (Figure 51.1). Specifically, small tumors were defined as less than 2.5 mm in apical height. Tumors between 2.5 and 10 mm in apical height and no more than 16 mm in basal diameter were classified as medium, and those greater than 16 mm in basal diameter were classified as large. Herein, we review management options for each of these size classifications, as evaluated by the COMS and other clinical studies.

Small choroidal melanoma

Of the three sizes of choroidal melanoma, treatment of small-sized tumors is most controversial. This is due in large part to the inability to differentiate reliably suspicious nevi from true cancers, with consequential limited understanding of the natural history and metastatic potential of such tumors.

Natural history

Five risk factors for growth were identified in a retrospective review of 1329 patients with choroidal tumors less than 3 mm in thickness.5 By multivariate analysis each of these clinical features (greater tumor thickness, orange pigment, symptoms of blurred vision or flashes/floaters, subretinal fluid, posterior margin touching the optic disc) was found independently to increase the relative risk of growth (Box 51.2). Further, documented growth was predictive of metastasis. Another retrospective series found not only tumor thickness, orange pigment, and presence of symptoms but also hot spots on fluorescein angiogram and internal quiet zone on B-scan to be significant predictors of growth.6 Stratification of treatment based upon risk factors has been suggested to optimize management, but studies have failed to show a treatment benefit with respect to mortality.

Small choroidal melanocytic lesions will exhibit growth in 18–36% of cases and metastasis in 2–5% of cases when followed for at least 5 years.5,6 Given a lack of tumor-related mortality in cases that failed to exhibit growth,5,6 it has been argued that indeterminate lesions may be observed and treated only if growth is documented.

Transpupillary thermotherapy (TTT)

TTT is a technique by which a 3 mm diode laser beam introduced through the pupil heats the tumor to 60–65°F for 1 minute. In contrast to photocoagulation, which has been abandoned due to inadequate tumor control, TTT raises the tumor to a lower temperature but achieves a greater depth of tumor necrosis. Tumor necrosis is due primarily to the direct thermal effect of the laser, with secondary effect from ischemia due to vascular occlusion. TTT is contraindicated in patients with media opacity, peripheral tumor, significant subretinal fluid, and small pupil.

Originally introduced as monotherapy for choroidal melanoma in 1994,7 TTT was designed to spare patients the visual morbidity that plaque brachytherapy was known to impart. Early results were encouraging, with tumor control achieved in 91% of cases after a mean of three treatment sessions.8 However, Kaplan–Meier estimates revealed recurrence rates of 4% at 1 year, 12% at 2 years, and 22% at 3 years of follow-up. Further, a lack of benefit with respect to visual outcomes was demonstrated in a case-matched retrospective comparison of TTT monotherapy with plaque

Figure 51.1  Collaborative Ocular Melanoma Study (COMS) design and randomization scheme.

brachytherapy, which has more reliable tumor control rates.9 Clinicopathologic examination of eyes enucleated after failed TTT suggests high rates of extrascleral extension, in most cases undetectable on ultrasonography.10 Minor degrees of extraocular extension are expected to be locally controlled by brachytherapy. TTT is thus best employed as an adjunct to plaque brachytherapy, with TTT necrosing superficial tumor and plaque radiation necrosing tumor adjacent to and invading sclera. One study reported 93.8% local tumor control rate with combination therapy with brachytherapy and adjunctive TTT over a mean follow-up period of 5 years.11

COMS small tumor trial

Proportion that grew

A

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 1 2 3 4 5 6 7 8 Time since enrollment (years)

As part of the COMS, an observational study of small choroidal melanomas was undertaken with the goal of assessing tumor growth (defined as increase from small to either medium or large) and its impact on survival. Probability of growth by Kaplan–Meier analysis was 11%, 21%, and 31% at 1, 2, and 5 years following enrollment (Figure 51.2A; Box 51.1).12 Clinical features associated with tumor growth included prominent orange pigment, absence of drusen, absence of retinal pigment epithelium changes adjacent to the tumor, tumor thickness of at least 2 mm, and largest basal diameter of 12 mm or more (Box 51.2). Though only 16 of the 204 patients received treatment, the risk of death was low, with the authors reporting a Kaplan–Meier melanoma-related mortality of 1% at 5 years (Figure 51.2B).13 All-cause mortality was higher, with patients are three to four times more likely to die of some competing cause than of their melanoma.

Medium choroidal melanoma

A large body of literature attests to the efficacy of radiotherapy (either external-beam radiation therapy (EBRT) or episcleral plaque therapy) in the treatment of medium-sized choroidal melanoma. The COMS trial for medium-sized melanomas (discussed in detail below) concluded that sightconserving brachytherapy does not adversely affect survival outcomes when compared with enucleation. Since the globe and some vision can usually be maintained, radiotherapy has become the mainstay for sight-preserving treatment of mediumand large-sized choroidal melanoma.

Plaque brachytherapy

Brachytherapy is the most commonly used radiation modality for the treatment of choroidal melanoma. A bowl-shaped heavy-metal plaque implanted with a radioactive isotope (Figure 51.3), sized to exceed tumor margins by 2 mm, is

0.1

Figure 51.2  Collaborative Ocular Melanoma Study small melanoma observational study. (A) Kaplan–Meier plot of growth of small tumors.

(B) All-cause (solid line) and small melanoma-related (dashed line) mortality. (Reproduced with permission from Singh AD, Kivela T. The Collaborative Ocular Melanoma Study. Ophthalmol Clin North Am 2005;18:129–142.)

Box 51.1  Small choroidal melanoma (Collaborative

Ocular Melanoma Study definition)

•  < 2.5 mm in apical height

Figure 51.3  Episcleral brachytherapy plaque with radioisotope seeds.

Box 51.2  Risk factors for growth of small choroidal

melanoma

sutured to episclera for a period of up to 1 week with the goal of delivering 80–100 Gy to the tumor apex. Plaques implanted with cobalt-60 were introduced in the 1960s; however, visual morbidity was high due to substantial radiation dosage to surrounding ocular structures by virtue of the high-energy emission properties of Co-60 which do not permit adequate shielding. Favorable long-term tumor control rates and improved visual outcomes have since been demonstrated with several other isotopes. Iodine-125 brachytherapy­ was evaluated by the COMS (discussed below) and as a result has become the most common isotope used in North America. One-half millimeter of gold can shield the I-125 source whereas equivalent shielding of Co-60 requires 2 meters or 6 foot of lead. Ruthenium-106, a beta-emitter, was concurrently popularized in Europe during the Cold War, and has since been adopted by some centers in the USA due to the theoretical decreased risk in visual morbidity suggested by dosimetry studies. A total of 579 patients in Sweden treated with ruthenium-106 for choroidal melanoma less than 7 mm in diameter (9.2% classified as “large” by COMS standard) enjoyed a 5-year tumor-specific survival rate of 94.9%.14 Other large studies

Medium choroidal melanoma

Box 51.3  Medium choroidal melanoma (Collaborative Ocular Melanoma Study (COMS) definition)

have noted 82–84% overall (all-cause) 5-year survival rates with ruthenium-106.15,16 Strontium-9017 and palla- dium-10318 have been shown to produce local tumor control rates of 92% and 96% at 5-year follow-up. Due to the large sample size required to detect a difference between treatment outcomes with different isotopes, no randomized trials have been undertaken. Figure 51.4 shows a medium melanoma before and 1 year after treatment with iodine brachytherapy.

Brachytherapy versus enucleation

The COMS randomized 1317 patients with choroidal melanoma classified as medium-sized to receive either I-125 brachytherapy or enucleation (Figure 51.1 and Box 51.3). Eligible patients were free of metastasis at enrollment. Follow-up is ongoing via periodic queries to the National Death Index, though formal clinical follow-up has ended. The 5-, 10-, and 12-year rates of death with histopathologically confirmed melanoma metastasis were similar for I-125 brachytherapy (10%, 18%, and 21%) and enucleation (11%, 17%, and 17%) (Figure 51.5).19 Further, a trend towards increased 5-year risk of death for patients who were eligible for the COMS but deferred treatment when compared with COMS trial patients suggested a life-extending effect of treatment of mediumand large-sized melanomas.20

When a subset of patients in each treatment group were questioned regarding difficulty driving, anxiety, near vision, and other quality of life measures, patients treated with brachytherapy were more likely to have symptoms of anxiety and those treated with enucleation reported poorer visual function.21 However, difference in visual function between treatment groups declined by 3–5 years following treatment, in accordance with decrease in visual acuity due to radiationinduced side-effects. Given no significant difference in survival between brachytherapy and enucleation, treatment choice should be made on an individual basis based upon patient preference.

The vast majority of patients with medium-sized melanoma will not have detectable metastasis at the time of diagnosis; nonetheless, a preoperative systemic evaluation should be undertaken. The presence of clinically detectable metastasis could shorten life expectancy and deem local treatment inappropriate; further, treatment for metastatic disease may be indicated depending on location and extent. In all, 60–89% of patients with metastatic choroidal melanoma will have hepatic involvement.2,22 Other common sites of metastasis include lung, bone, subcutaneous tissues,

Years since enrollment

Figure 51.5  Collaborative Ocular Melanoma Study medium melanoma randomized trial. Kaplan–Meier plot of all-cause mortality following brachytherapy (solid line) or enucleation (dashed line). Note similar outcomes.

lymph node, and brain. Thus, evaluation should include a complete physical exam, a complete blood count, serum liver function studies, and a chest X-ray or computed tomography. Therapeutic regimens administered to patients enrolled in COMS who developed metastasis included chemotherapy (23%), radiation (4%), immunotherapy (2%), and a combination of these (5%).2 Of the 793 patients who developed metastatic disease, only 8 survived 5 years or longer.

Large choroidal melanoma

Choroidal melanomas classified as large by the COMS standard are most commonly managed by enucleation. However, radiation therapy (either as monotherapy or adjunct therapy) and local resection may be viable treatment options in some cases.

Box 51.4  Large choroidal melanoma (Collaborative

Ocular Melanoma Study (COMS) definition)

•  >16 mm in basal diameter

External-beam radiation therapy (EBRT)

EBRT (charged-particle beams of proton or helium ions) allows for a high dosage of radiation to be delivered to a tumor, regardless of size or proximity to fovea or optic nerve (Box 51.4). At most centers, patients undergo preradiation surgery during which tumor borders are delineated by transillumination and tantalum rings subsequently sutured to the sclera at the tumor borders. EBRT is then administered with the assistance of a sophisticated treat­ ment planning program that utilizes a three-dimensional model of the tumor based on fundus photographs, ultrasound measurements, and location of tantalum rings on roentgenogram.

Though its use is limited by the cost and limited availability of proton facilities, with less than 50 worldwide, outcomes with respect to local control, eye loss, and vision loss have been favorable for EBRT. Of 1922 patients with choroidal melanoma treated with proton therapy at the Harvard Cyclotron over the course of 20 years, local recurrence was documented in only 45 (3.2%) at mean follow-up of 5.2 years.23 Of note, large tumor size (>15 mm in diameter and >5 mm in height) imparted more than double the risk of recurrence in multivariate analysis. Another series of patients treated at the Biomedical Cyclotron Centre (Nice, France) reported a 4.5% rate of local recurrence at 5 years.23 Helium

ion irradiation has been shown to produce similar local tumor control (4.6% at 10 years).24

As with brachytherapy, adverse effects of EBRT are substantial and include radiation retinopathy (Figure 51.6) and optic neuropathy, neovascular glaucoma, and posterior subcapsular cataract. One series reported at least one ocular complication (maculopathy, optic neuropathy, vascular occlusion, retinal detachment, or neovascular glaucoma) in 57% of patients treated with proton therapy at 5-year followup.25 Neovascular glaucoma has been reported in 35% of patients treated with helium ion therapy, with 49% of these patients eventually requiring enucleation.24 The 5-year rate of vision loss at 5 years is 52–68%,26,27 with tumor location within 2 disc diameters of the optic nerve and macula being the strongest predictor of poor visual outcome.26 A randomized controlled trial has established a dose of 50 GyE (Gray equivalents) as providing comparable local tumor control (versus 70 GyE), while imparting a lesser degree of visual loss.28

Enucleation after EBRT may be indicated if the patient experiences tumor recurrence or radiation-related complications. Neovascular glaucoma is the most common complication leading to enucleation after EBRT. The probability of enucleation 2 years after proton beam radiation is 5%, and increases to 9% and 12% by 5 years and 10 years after irradiation, respectively.29

Kaplan–Meier estimates of 5-year all-cause mortality were also similar for enucleation and pre-enucleation arms (57% and 62%, respectively; P = 0.32) (Figure 51.7). The hazard ratio for death for patients enrolled in the COMS PERT trial (versus eligible but not enrolled) was 1.12, after adjusting for prognostic covariates and stratifying by clinical center.32 This finding suggests that, while treatment for large choroidal melanoma may not be beneficial with respect to mortality outcomes, it does not appear to accelerate metastasis and death, as suggested by Zimmerman et al.3

Local resection

Foulds33 pioneered transscleral local resection as a method for conservation of the eye and vision in patients with choroidal melanoma deemed too large for radiotherapy. It has been argued that the procedure is time-consuming and requires more complicated postoperative care. It is a technically difficult procedure and is performed by only a few skilled surgeons; however, in experienced hands outcomes are favorable. Of 310 tumors with mean diameter of 13 mm and thickness of 7 mm resected by either Foulds33 or Damato et al34 between 1970 and 1994, 24 had residual tumor postoperatively and 57 developed delayed local recurrence over a median follow-up of 36 months. Further, 39% retained vision between 6/6 and 6/36 at the time of final visit.34

Enucleation versus pre-enucleation radiation treatment (PERT)

In the third part of the COMS, 1003 patients with a large choroidal melanoma were randomly assigned to enucleation with and without prior radiation (Figure 51.1), based on the finding that preoperative radiation reduces metastasis in other malignancies. The study found no difference between the two treatment arms with respect to mortality30 and local complications.31 Specifically, the death rate at 10 years due to histopathologically confirmed metastases was 40% for enucleation alone and 45% for pre-enucleation radiation.30

Future directions

Stereotactic radiotherapy

Stereotactic radiotherapy involves using gadoliniumenhanced magnetic resonance imaging scans to aid in the precise delivery of high-energy X-ray or gamma-ray radiation to the tumor from multiple directions either concurrently or sequentially. During the treatment, the patient lies supine and the head and eye are immobilized. Radiation is delivered with a safety margin of approximately 2 mm in all

directions, and a dose–volume histogram analysis is performed to determine probability of complications. Local tumor control rates ranging between 84 and 98% have been reported.35–37 However, radiation-induced side-effects, including retinopathy, cataract, and optic neuropathy are problematic, with 44%, 23%, and 41% prevalence at 33-month follow-up in one series.35

Adjuvant/targeted therapy

At this time, there is no chemotherapy with proven efficacy against choroidal melanoma. Recent meta-analysis of several randomized trials has shown a significant survival benefit of adjuvant treatment with interferon-α for cutaneous melanoma.38 Ocular melanoma behaves differently and has different cell surface markers than cutaneous melanoma; thus such studies need to be repeated for the eye tumor. However, given a significantly lower incidence of choroidal (versus cutaneous) melanoma, randomized prospective trials with sufficient power to detect a difference between two treatment groups are not feasible. Regardless, systemic chemotherapy offers perhaps the greatest hope for improvement in survival outcomes in a disease entity in which hematologic micrometastases are often detectable at presentation.39

Cytogenetic studies of choroidal melanomas have revealed common nonrandom cytogenetic aberrations affecting chromosomes 3, 6, and 8. Monosomy 3, the most common chromosomal abnormality found in choroidal melanoma, has been implicated as a significant predictor of poor prognosis and metastatic disease40 (Figure 51.8). Other abnormalities observed more often in metastasizing tumors include loss of 6q and gain of 8q.41 Extra copies of 6p have been correlated with better prognosis.42 It has also been reported that certain chromosomal aberrations become more frequent as the tumor progresses.43 Further investigation into the exact contributions of various chromosomal abnormalities to the pathogenesis and progression of choroidal melanoma may provide opportunity for customized therapy for different chromosomal subtypes.

An important current opportunity for research involves the management of small ocular melanoma. Most patients do not die of their tumor and treatment damages vision, so deferral of treatment is common. Yet, if the tumor grows to medium tumor size, the mortality rate increases significantly. Randomized trials comparing prompt treatment versus treat-

Relapse-free survival (years)

Figure 51.8  Monosomy 3 as a poor prognostic factor. Kaplan–Meier relapse-free survival of patients with and without monosomy 3. Note decrease in survival in patients with tumors exhibiting monosomy 3.

(Reproduced with permission from Prescher G, Bornfeld N, Hirche H, et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996;347:1222–1225.)

ment if growth is detected should be undertaken if an adequate sample size of eligible subjects becomes available.

Conclusion

A shift in paradigm towards more conservative treatment of choroidal melanoma in recent decades was initially spurred by the Zimmerman hypothesis and later substantiated by the COMS. Whereas medium-sized melanomas were once treated by enucleation, in the post-COMS era patients enjoy similar all-cause mortality and perhaps improved quality of life with sight-conserving brachytherapy. Large choroidal melanomas are still largely managed by enucleation; however, EBRT (either as primary or adjunct therapy) and local resection may be effective alternative treatment options. Whether small melanomas should be observed or treated with brachytherapy (with or without adjunctive TTT) remains controversial. Future development of targeted adjuvant chemotherapy guided by tumor cytogenetic studies holds promise for improvement in mortality rates, which have remained unchanged for decades despite improvement in local recurrence rates.

1.Singh AD, Topham A. Incidence of uveal melanoma in the United States: 1973–1997. Ophthalmology 2003;110: 956–961.

2.Diener-West M, Reynolds SM, Agugliaro DJ, et al. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study group report no. 26.

Arch Ophthalmol 2005;123:1639– 1643.

3.Zimmerman LE, McLean IW, Foster WD. Does enucleation of the eye containing a malignant melanoma prevent or accelerate the dissemination of tumour cells? Br J Ophthalmol 1978;62:420–425.

4.Design and methods of a clinical trial for a rare condition: the Collaborative Ocular Melanoma Study. COMS report

no. 3. Control Clin Trials 1993;14:362– 391.

12.Factors predictive of growth and treatment of small choroidal melanoma: COMS report no. 5. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol 1997;115:1537–1544.

13.Mortality in patients with small choroidal melanoma. COMS report no. 4. The Collaborative Ocular Melanoma

Study Group. Arch Ophthalmol 1997; 115:886–893.

19.The COMS randomized trial of iodine

125brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report no.

28.Arch Ophthalmol 2006;124:1684– 1693.

20.Straatsma BR, Diener-West M, Caldwell R, et al. Mortality after deferral of treatment or no treatment for choroidal melanoma. Am J Ophthalmol 2003;136:47–54.

21.Melia M, Moy CS, Reynolds SM, et al. Quality of life after iodine 125

brachytherapy vs enucleation for choroidal melanoma: 5-year results from the Collaborative Ocular Melanoma Study: COMS QOLS report no. 3. Arch Ophthalmol 2006;124:226–238.

30.The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma II: initial mortality findings. COMS report no. 10. Am J Ophthalmol 1998;125:779–796.

31.The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma III: local

Key references

complications and observations following enucleation COMS report no. 11. Am J Ophthalmol 1998;126:362– 372.

32.Gilson MM, Diener-West M, Hawkins BS. Comparison of survival among eligible patients not enrolled versus enrolled in the Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma. Ophthalm Epidemiol 2007;14:251–257.

Overview

Sebaceous cell carcinomas account for 1–5% of all eyelid malignancies and primarily affect older adults with a slight female gender bias.1 Despite representing a small fraction of all eyelid tumors, 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% (Box 52.1). Sebaceous cell carcinomas typically arise from the meibomian glands, but can also develop within the pilosebaceous glands of the eyelid cilia (glands of Zeis) and the caruncle.2,3 Although the clinical science of diagnosing and treating sebaceous cell carcinomas of the eyelid has advanced significantly in the past two decades, treatment is still surgical and hampered by poor understanding of the biology of these tumors. Given that cell biology and molecular signaling are intimately related to the function and development of these glands, this chapter will: (1) review the functional role of the sebaceous glands on the eyelid and normal sebaceous gland biology; (2) discuss the clinical and pathologic features of sebaceous cell carcinoma; and (3) summarize the important genetic, molecular, and cellular regulators of sebaceous cell carcinoma and demonstrate how these might shed light on the clinical behavior of these tumors.

Sebaceous gland physiology

Sebaceous glands can be grouped based on their location, association with hair follicles, and function. Although sebaceous glands are found throughout the body, certain areas are particularly rich in sebaceous gland content. While most sebaceous glands are associated with hair follicles (i.e., pilosebaceous glands), free glands can be found throughout the body, and some of them have evolved to perform specialized functions such as hormone signaling and odor production.4 The meibomian glands of the eyelids are one type of specialized sebaceous gland. While this chapter will focus on the biology of sebaceous cancer of the eyelids, much of the science of sebaceous glands and sebaceous cell carcinoma is based on studies of the common pilosebaceous glands.

The evolutionary origins of pilosebaceous glands are not clear, and their function in humans is controversial. Seba-

ceous glands are holocrine glands which release sebum via the disintegration of mature, lipid-laden cells and, as a result, require continual cellular proliferation, differentiation, and maturation. These processes and, hence, the kinetics of sebum secretion, are regulated by a complex set of signals under both endocrine and neuroregulatory control.

The function of human sebum is controversial. One interesting hypothesis suggests that sebum assumes unique functions at different temperatures. At temperatures below 30°C, the sebum of pilosebaceous glands serves to create a waterrepellent skin cover. At temperatures above 30°C, human sebum assumes the characteristics of a surfactant. Sweat with high surface tension that drips off skin will cause dehydration without contributing to evaporative cooling.5 By acting as a surfactant for eccrine secretions, sebum lowers the surface tension of sweat and allows the sweat to be retained on the skin to achieve its thermoregulatory function. The meibomian glands of the eyelid have a similar function, namely to stabilize the tear film. The normal evaporation rate of the tear film is 25 g/cm2/min. This increases 4–20- fold in the absence of the lipid layer.6 However, the makeup of sebum is quite different from that of meibomian secretions. The main lipids in human sebum are triglycerides, wax esters, and squalene.4 In contrast, meibomian lipids are composed of sterols and wax esters, with only minor amounts of triglycerides, hydrocarbons, polar lipids, and free fatty acids. In addition, the chains of meibomian lipids are longer and contain unique fatty acids and alcohols. Cutaneous sebum was shown to disrupt the tear film, suggesting that the unique composition of meibomian gland lipids is important to the maintenance of the tear film and likely prevents the spread of cutaneous sebum on to the ocular surface.7

Clinical background

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.8,9 Therefore, understanding the demographics and risk factors as well as recognizing the key clinical features of sebaceous cell carcinoma may allow prompt diagnosis and therapy, to reduce mortality and ocular morbidity.