PRIMARY AND METASTATIC UVEAL MELANOMA 1.1 Clinical aspects of uveal melanoma 1.1.1 Inlroduclioll 10

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Transcript of PRIMARY AND METASTATIC UVEAL MELANOMA 1.1 Clinical aspects of uveal melanoma 1.1.1 Inlroduclioll 10


    towards a therapeutic approach

  • Tekening omslag: Yolanda Eijgenstein

    Druk & vormgeving: Vormgeving Rotterdam

    ISBN 90 72206 09 6


    towards a therapeutic approach

    (Primair en gemetastaseerd oogmelanoom:

    naar een therapeutische benadering)


    Ter verkrijging van de graad doctor

    aan de Erasmus Universiteit Rottenhun

    op gezag van de rector Illagnifïcus

    Prof. Dr. P. W.C. Akkermans M.A.

    en volgens besluit van het college voor promoties.

    De openbare verdediging zal plaatsvinden op

    woensdag 15 mei 1996 011113.45 uur


    Gregorius Petrus Maria Luyten geboren te Etten-Leur

  • Pro 111 0 ti eco Illllliss i e



    Overige leden:

    Prof'. Dr. P.T.V.M. de Jong

    Dr. C.M. Mooy

    Prof. Dr. D. Bootsm3

    Prof. Dr. G. Stoter

    Prof. Dr. W . .J. l'vIooi

  • To m)' dearcsl Yolanda


    CHAPTER 1 Introduction 8

    1.1 Clinical aspects of uveallllelallollla 8

    1.1.1 Introduction to the subject 8

    1.1.2 Treatment of the primary tumor 10

    1.1.3 Metastatic disease and sllI'vival 12

    1.2 AilllS aJul scope of the thesis 15

    1.3 Illtroductioll to the studies 17

    1.3.1 Chapter 2: Thc origins of metastases 17

    1.3.2 Chapter 3,4 and 5: Clinical and histopathological factors 18

    1.3.3 Chapter 6 to 9: Experimcntal studies 20 Chapter 6: Uvealmclanoma cclllines 20 Chapter 7: Tumor genetics and inullunology 21 Chapter 8 and9: Animalmodels 29

    Relerences 32



    No delllonstnlted effect of pre-ellucleation irradiation of

    uveallllelallollla patiellts

    Metastatic uveallllelanollla:


    A lllol'phologÏcal and illllllunohistochelllical allalysis 56







    CHAPTER 10


    Neuml eeIl a(I11esion molecule distribution in primary

    and llletastatic llveallllelanOlna

    The expression NM23 gene in uveal melanoma

    Establishment mul eharaeterization of primary mul

    metastatic uveal melanoma eelllines

    Expression of MAGE, GP100 and tyrosillase in uveal

    melanoma eelllines

    Relationship between natural killer eeIl susceptibility and

    metastasis of hmlUm uveal melanoma eeIls in

    a lllurine lllodel

    A chicken embryo model to study growth of


    Discussion and future perspectives

    Samenvatting in het Nederlands

    List of abbreviations

    Curriculum vitae

    List of publications

















    1.1 Clinical aspects of uveal melanoma

    1.1.1 Inlroduclioll 10 Ihe subject

    Uveal melanoma is a unCOll111lon discase with on estimation 80-100, yeurly incident

    cases in The Netherlands (6 per million) (De Jong, 1987). Neverlhe1ess, uvea1

    melanoma is the most coml11on primary malignant intraocular tumors in adults (Egan,

    1988). Morcover, this type of cancel' orten proves fatal to the patient. Although 50 % of

    the patients treated for their primary lIveal tumor recovers eompletely, the other

    50 % eventually dies of metastatic diseuse (Gamel,1993; MeLean, 1993; Diener-West,

    1992; Jensen, 1982). Tn other 1V0rds, half of the patients suffering from a primary uvea1

    melanoma c1evelops metastatie discase at a distant site, whieh is then lethal in all cases.

    Tn contrast ta cutaneous melanoma, uvealmclanoma disseminates primarily

    hacmatogenously anel with a slrong preferenee for the Iiver; once metastases have been

    diagnosed, the patient's life expeetancy is only 2 to 9 months (Kath, 1993; Alberl,

    1992; Gragouclas, 1991; Rajpal, 1983; Bedikian, 1981; ehar, 1978). These metastases

    offen becoll1c c1inically manifest years after initial trealment, that is, llveal melanomas

    metastasize relatively late. The patient's median survival time aftel' discovery of the

    primary tumor is 6.5 years (McLean, 1993), with a peak of elanomH-related deaths

    between the secOIld ano fourth year following initial treatment (Zimmerman, 1978).

    Tn brief, the studies presented in this thesis basically aim at prevention of (death by)

    metastatic uvea1melanoma. Before we continue, it should be noted that wherever the

    term uvea1melanoma is used in this baak, it relers only to melanoma of the choroid

    and the ci1iary body. Melanomas 10cated in the iris, the third part of the uvea, are

    re1atively benign with a low incidence of developing metastases at distant sites and are

    therefore left out of the study here. The reader interested in iris melanoma is referred to

    other reports (Grossniklaus, 1995; Jensen, 1993; Brown, 1990).


  • INTRODtJCTION ____ _

    Tu date, studies on uveal melanoma mainly focused on the rcfinement of

    clinical eliagnosis anel treatmcnt of the primary tumor. This has resulteel in a dccrease

    in the c1inicalmisdiagnosis ratc from 3.5 up to 20 % (COMS, 1990; Jensen, 1963) to

    less than 1 % at present (Davidorf, 1983; COMS, 1990; pers on al data). The fact th at

    tocltty, in specialized centers, the correct diagnosis of primary uvcal melanoma can be

    made in 1110re than 99 % of the cases is mainly owed to the application of indirect

    ophthalmoscopy in experienced hands together with the use of ultrasonography.

    Fluorescenee angiography has made the diagnosis also more reliablc. These devices

    are hclpful in diseriminating uvealmelanoma from other types of ocular tumors and

    disorelers, sueh as choruidal nevi, haemangiomas and metastases, granulomas and

    macular c1egeneration, For instanee, a tumor or biconvex or lllUshroom-like shape lhat shows choroidal excavation on the B-mode and a low to moderate high intern al

    rellectivity on the A-mode in an examination by ultrasonography will, when combined

    with indirect ophthalmoscopy, certainly be recognized as a choroidalmelanoma.

    However, metastatic choroidallesions, that usually show a high internal rellectivity on

    the A-mode, can be highly variabie in their ultrasound pa((ern. In sueh cases

    examination of fine-needle aspiration biopsies (FNAB) can be useful (Shields, 1993),

    but then again, in the cytological evaluation ofFNAB, differentiating melanomas and

    other intraocular tumors ean be hard too. Next, in cases in which it is difficult to

    discriminate a small dormant melanoma from a choroidal nevus, tumor growth can be

    followed by B-mode ultrasonography to evaluate the tumor height, and by serial

    Iluorescence angiography to cvaluate thc tumor diameter. Finally, in diagnosing

    primary uvea( melanomas, magnetic resonance imaging with contrast (gadolinium)

    may be used. The problem with applying this techniqlle, however, is that the

    characteristical image of thc paramagnctic melanin is not present in all cases (Fen'is,

    1995; De Potter, 1994; Bioom, 1992).

    When a primary uvealmelanoma has been diagnosed, the patient is usually

    screcned for the presence of extraocwar malignancies anel distant metastases of the

    uvealmelanoma by a complete physical examination, an X-ray of the chest, liver

    funetion tests, and liver lIltrasonography. In about 8% of the cases another seeOlld

    primary tumor can be found (l

  • CHAPTEI~ .~I ___ _

    light in approximately 2 % of the cases (Paeh, 1986; pers(lJlal data). Furthennore,

    before the decision of treatment can be made, aU factors that may be of importanee to

    the therapeutic choke have to be evaluated for each patient individually, sueh as visu,,1

    aeuity, intraoclliar pressure and other concomitant disorders or the affected anel the

    non-affeeteel eye; size, location anel episcleral extension of the tumor, and age anel

    general health of the patient (Shields, 1993; id. 1991).

    1.1.2 Treatmellt of the primary tumor

    Ollee thc diagnusis of primary llvealmelanoma has been made) the choicc of

    treatment is controversial (Shields, 1993; id. 1991).ln the past, thc only available

    treatment was enueleation of the tumor-eontaining eye. Tt is generaUy agreed up on that

    this therapy is still preferabie in cases of large melanomas (largest tumor diameter (LTO)

    > 15 mm and/or tumor height > 5 mm) (De Jong, 19X7; Manschot 1980). However,

    mainly with regm'd to small (LTD

  • _---'I"N-'T R 0 D U CT JON --- -_._- --_.

    llltrasonography and fluorescence ungiography, - some tlLllhors advocate mere

    observation untillumor enlargemenl has been demonstrateu (Butler, 1994;

    Augsburger, 1993). However, a recenl clinical study reports thai 3 % of lhe palients wilh

    lumors less lhan 3 mm in height and up to 19% of them in case ol' proven tumor groWlh

    will develop distant metastases af ter all (Shields, 1