Ординатура / Офтальмология / Английские материалы / Orbital Tumors Diagnosis and Treatment_Karcioglu_2005

the invasive front, 5 or more mitotic tumor cells per 10 high-power fields (HPF), involvement of caruncle and orbital soft tissues with melanoma, and involvement of lateral and deep margins (of the excisional biopsy) with melanoma. If the margins are positive for tumor, the patient should receive additional treatment with wider excision, cryotherapy, brachytherapy, or local antimetabolites. For one or more other findings, the patient should be followed clinically every 3 months for 1 to 2 years to detect early recurrence.65

Although radiotherapy has been tried on conjunctival melanomas, these tumors are not very responsive to radiation, and the EBRT may lead to several complications.66 Recent work suggests that brachytherapy may offer better therapeutic outcomes for conjunctival melanoma.67,68

Topical chemotherapy with antimetabolites is another type of treatment under current investigation. Data are limited but promising; in particular, mitomycin C may be beneficial in treatment of superficial conjunctival melanomas.69

Conjunctival melanomas should be closely followed after treatment because approximately half these patients develop recurrences within the first 5 years after primary treatment and one third eventually develop disseminated disease. In many cases of recurrence, there is orbital invasion and development of the signs and symptoms of rapidly developing spaceoccupying lesions. These patients should be evaluated for regional lymph node involvement and dissemi-

nated disease to distant organs. CT and MRI can be invaluable to determine the extent of secondary orbital invasion, and the systemic workup should be done in consultation with an ocular oncologist. Although it is believed that regional lymph nodes are the initial site of metastasis, the pathways of dissemination are not well established.70

For a tumor that extends into the orbit, local resection of the lesion is no longer feasible and exenteration may be indicated. In a recent study of over 150 patients, 65% had no tumor recurrence after treatment and 35% experienced at least one recurrence; 5 or more recurrences were seen in 3% of the cases.71,72 Twenty out of 150 patients (13%) developed orbital extension to different degrees and were treated with exenteration. Of the 20 exenterations, 7 were performed as initial procedures, 6 were done after the first recurrence, and 7 after multiple recurrences. The investigators concluded that exenteration became indicated in 8% of their patients by the 5-year follow-up and 32% of their patients by the 15-year follow-up.

Although the orbital exenteration has been a time-honored treatment for advanced cases of conjunctival melanoma, there is still no consensus on its indications and surgical technique. In the 1950s, early exenteration with complete removal of the globe and orbital soft tissues was advocated as the preferred treatment.73,74 The idea of performing extensive, mutilating surgery was later challenged, and

the exenteration was performed only for tumors involving the fornices or extending to the eyelid skin and tumors that did not respond to EBRT.75,76 Others suggested that in cases of diffuse melanoma involving the caruncle, the exenteration should be combined with radical neck dissection.77 Later it was realized that prophylactic lymph node dissection did not help to improve the incidence of disseminated disease. The technique was thus abandoned.78 Today lymph node dissection is performed only for staging purposes when evidence exists of metastatic disease.79 Recent investigation of regional lymph node metastasis in conjunctival melanoma performed with sentinel lymph node mapping and biopsy indicated that preauricular lymph nodes were most commonly involved (see Chapter 12). A recent clinical study by Esmaeli and coworkers found approximately 40% involvement of regional lymph nodes within about 3 years of initial diagnosis.70 The most commonly involved lymph nodes were preauricular nodes in approximately 75% of the 11 patients with lymph node disease. It was concluded that sentinel lymph node biopsy may develop as a potential test for early detection of microscopic nodal metastasis, and therefore, these results may be used as another piece of information in decision making for exenteration. Other clinical features predictive of orbital extension of conjunctival melanoma were reported as follows: visual acuity of 20/200 or worse, extralimbal location, amelanotic tumors, caruncular lesions, and tumors that present with the histopathologic invasion deeper than 1 mm.72 It has been noted that lesions with invasion deeper than 2 mm do not respond well even to orbital exenteration in terms of avoiding dissemination of the tumor. Paridaens and coworkers reported that mortality ranges between 33 and 50% for melanomas thicker than 1 mm invasion despite exenteration.79 The same authors indicated that invasion of the lymphatics, blood vessels, and sclera as well as the incomplete excision at the time of initial treatment indicated very poor outcomes.

References

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conjunctival tumors and squamous cell carcinoma. Am J Ophthalmol 1983;95:359–363.

33.Frucht-Pery J, Rozenman Y. Mitomycin C therapy for corneal intraepithelial neoplasia. Am J Ophthalmol 1994;117:164– 168.

34.Shields CL, Naseripour M, Shields JA. Topical mitomycin C for extensive, recurrent conjunctival–corneal squamous cell carcinoma. Am J Ophthalmol 2002;133:601–606.

35.Buus DR, Tse DT, Folberg R. Microscopically controlled excision of conjunctival squamous cell carcinoma. Am J Ophthalmol 1994;117:97–102.

36.Karcioglu ZA, Caldwell DR. Frozen section diagnosis in ophthalmic surgery. Surv Ophthalmol 1984;28:323–332.

37.Broders AC. Practical points on microscopic grading of carcinoma. N Y J Med 1932;32:667–671.

38.Friedman HI, Cooper PH, Wanebo JH. Prognostic and therapeutic use of microstaging of cutaneous squamous cell carcinoma of the trunk and extremities. Cancer 1985;56:1099– 1105.

39.Lund HC. How often does squamous cell carcinoma of the skin metastasize? Arch Dermatol 1965;92:635–637.

40.Martin H, Strong E, Shapiro RH. Radiation induced skin cancer of the head and neck. Cancer 1970;25:61–71.

41.Brennan JA, Mao L, Hruban RH, et al. Molecular assessment of histopathological staging in squamous cell carcinoma of the head and neck. N Engl J Med 1995;332:429–435.

42.Sun EC, Fears TR, Goerdert JJ. Epidemiology of squamous cell conjunctival cancer. Cancer Epidemiol Biomarkers Prev

1997;6:73–77.

43.Newton R, Ferlay J, Reeves G, et al. Effect of ambient ultraviolet radiation on incidence of squamous cell carcinoma of the eye. Lancet 1996;347:1450–1451.

44.Lane DP. p53 and human cancers. Br Med Bull 1994;50: 582–599.

45.Toth J, Karcioglu ZA, Moshfeghi AA, et al. The relationship between human papillomavirus and p53 gene in conjunctival squamous cell carcinoma. Cornea 2000;19:59–62.

46.Karcioglu ZA, Toth J. Relation between p53 over-expression and clinical behavior of ocular/orbital invasion of conjunctival squamous cell carcinoma. Ophthalmic Plast Reconstr Surg

2000;16:443–449.

47.Karcioglu ZA, Issa TM. HPV in neoplastic and non-neoplastic conditions of the external eye. Br J Ophthalmol 1997;81: 595–598.

48.McDonnell JM, McDonnell PJ, Mounts P, et al. Demonstration of papillomavirus capsid antigen in human conjunctival neoplasia. Arch Ophthalmol 1986;104:1801–1805.

49.Maclean H, Dhillon B, Ironside J. Squamous cell carcinoma of the eyelid and the acquired immunodeficiency syndrome. Am J Ophthalmol 1996;121:219–221.

50.Lewallen S, Shroyer KR, Keyser RB, Liomba G. Aggressive conjunctival squamous cell carcinoma in three young Africans. Arch Ophthalmol 1996;114:215–218.

51.Campbell RJ. Tissue diagnosis: eyelid and conjunctiva. In: Karcioglu ZA, ed. Laboratory Diagnosis in Ophthalmology. New York: Macmillan; 1987:1–23.

52.Seregard S. Conjunctival melanoma. Surv Ophthalmol 1998; 42:21–50.

53.Folberg R, McLean IW, Zimmerman LE. Malignant melanoma of the conjunctiva. Hum Pathol 1985;16:136–143.

54.Liesegang TJ,Campbell RJ. Mayo Clinic experience with conjunctival melanoma. Arch Ophthalmol 1980;98:1385.

55.McDonnell JM, Carpenter JD, Jacobs P, et al. Conjunctival melanocytic lesions in children. Ophthalmology 1989;96: 986–993.

56.Folberg R, McLean W, Zimmerman LE. Conjunctival melanosis and melanoma. Ophthalmology 1984;91:673–678.

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58.Grossniklaus HE, Green WR, Luckenbach M, Chan CC. Conjunctival lesions in adults. A clinical and histopathologic review. Cornea 1987;6:78–116.

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64.Esmaeli B. Sentinal node biopsy as a tool for accurate staging of eyelid and conjunctival malignancies. Curr Opin Ophthalmol 2002;13:317–323.

65.Folberg R, McLean IW, Zimmerman LE. Conjunctival melanosis and melanoma. Ophthalmology 1984;91:673–678.

66.Lederman M, Wybar K, Busby. Malignant epibulbar melanoma. Natural history and treatment by radiotherapy. Br J Ophthalmol 1984;68:605–617.

67.Lommatzsch PK, Lommatzsch RE, Kirsch I, Furmann P. Therapeutic outcome of patients suffering from malignant melanoma of the conjunctiva. Br J Ophthalmol 1990;74: 615–619.

68.Shields JA, Shields CL, Freire JE, et al. Plaque radiotherapy for selected orbital malignancies: preliminary observations: the 2002 Montgomery Lecture, part 2. Ophthalmic Plast Reconstr Surg 2003;19:91–95.

69.Finger PT, Milner MS, McCormick SA. Topical chemotherapy for conjunctival melanoma. Br J Ophthalmol 1993;77: 751–753.

70.Esmaeli B, Wang X, Youssef A, Gershenwald JE. Patterns of regional and distant metastasis in patients with conjunctival melanoma. Experience at a cancer center over 4 decades. Ophthalmology 2001;108:2101–2105.

71.Shields CL, Shields JA, Gündüz K, et al. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis and death in 150 consecutive patients. Arch Ophthalmol 2000; 118:1497–1507.

72.Shields JA, Shields CL, Gündüz K, et al. Clinical features predictive of orbital exenteration for conjunctival melanoma.

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75.Zimmerman LE. Discussion of pigmented tumors of the conjunctiva. In: Boniuk M, ed. Ocular and Adnexal Tumors. St Louis: CV Mosby; 1964:24–48.

76.Jay B. Nevi and melanomata of conjunctiva. Br J Ophthalmol 1965;49:169–204.

77.Tucker MA, Shields JA, Hartge P, et al. Sunlight exposure as risk factor for intraocular malignant melanoma. N Engl J Med 1985;313:789–792.

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Rarely, intraocular tumors extend transclerally and invade the periocular tissues and the or- bit.1–5 These tumors include retinoblastoma, uveal melanoma, malignant medulloepithelioma,

retinal pigment epithelium carcinoma, and optic disk melanocytoma. The secondary involvement of orbital soft tissues with extraocular tumors is a rare condition, and the only clinically significant lesions in this group are retinoblastoma and choroidal melanoma; therefore, only these two tumors are discussed in this chapter.

RETINOBLASTOMA

Retinoblastoma (Rb) is the most common intraocular malignant tumor in childhood, with an incidence of 1 in 15,000 live births. Early diagnosis and treatment have significantly increased survival rate and organ preservation in recent years.6 With advances in therapy, survival has risen from 30% in the 1930s to nearly 95% in the 1990s.7

Primary enucleation continues to be a common choice of treatment of Rb. External beam radiation therapy (EBRT) is an effective therapeutic option but unfortunately is associated with second nonocular malignancies. Historically, the use of chemotherapy has been limited to retinoblastoma with local invasion of the orbit and optic nerve in metastatic disease. Chemotherapy is now used as a conservative treatment in an effort to avoid EBRT and/or enucleation and obtain better functional results.8,9

Extraocular Rb is a common problem of pediatric oncology in developing countries and is almost always due to delay in diagnosis of the intraocular disease (Figure 22.1).10,11 Extraocular extension is the most significant risk factor associated with very poor prognosis. In medically advanced countries, most cases of orbital Rb present as a recurrence following primary enucleation for intraocular tumor.12 Orbital extension of intraocular Rb or orbital recurrence after enucleation has been reported to comprise 12% of all cases.12,13 Orbital involvement of Rb carries a poor prognosis and is associated with a high risk of metastasis to the central nervous system (CNS), lymph nodes, bone marrow, and bones.14 Statistically signif-

icant risk factors for orbital involvement include massive choroidal involvement, microscopic extrascleral invasion, optic nerve involvement beyond the resection margin, late enucleation, and delay in diagnosis.

Orbital invasion from advanced intraocular Rb may follow several anatomical pathways, including Schlemm canal, posterior ciliary vessels and nerves, and anterior and posterior emissary channels; it may happen, as well, by direct scleral erosion (Figure 22.2).15

However, surgical procedures can also allow access into the orbit for tumor cells.16 Karcioglu et al. reported that a 25-gauge needle can seed tumor into the sclera and facilitate access into the orbit.17 Pars plana vitrectomy in an eye with suspected retinoblastoma should be avoided. Openings in the limbus and sclera may create tissue tracts for the Rb cells to invade the orbit (Figure 22.3). Stevenson et al. reported three patients who developed recurrence in the orbit and lymph nodes after vitrectomy for unsuspected Rb.18 Fine-needle aspiration biopsy (FNAB) is advised only in extraordinarily unusual clinical presentations.19

If the diagnosis of Rb is done from biopsy or vitrectomy results, efforts should be made to prevent orbital recurrence. Prophylactic chemotherapy and EBRT should be delivered in addition to enucleation to prevent systemic tumor dissemination.20 Orbital symptoms are usually absent when extraocular extension is only microscopic. A significant orbital extension, on the other hand, produces symptoms of a retrobulbar space-occupying mass, including rapidly progressing proptosis, chemosis, and extraocular motility disturbance. Recurrent Rb following enucleation presents with displacement of the implant, difficulty in wearing an ocular prosthesis, chemosis, and cellulitis (Figures 22.4 and 22.5).18,21

For a correct staging of orbital involvement, all patients should undergo a careful diagnostic workup before excisional biopsy. Procedures include computed tomography (CT) and magnetic resonance imaging (MRI) of the head and orbit, bone scintigraphy, lumbar puncture with cell count and examination of the cytocentrifugate, bone marrow aspiration, and biopsy and ocular examination under anesthesia. Usually Rb extending to the orbit is less differentiated than the primary tumor, and sometimes it is difficult to dis-

FIGURE 22.1. Axial CT scan showing a retinoblastoma of the left globe extending into the optic nerve, meninges, and orbital soft tissues (arrowhead). Note the multiple calcifications within the intraocular tumor. The secondary orbital extensions and metastatic foci of retinoblastomas very rarely show calcification.

tinguish between recurrency and second tumors (Figure 22.2).22

CT and MRI to document the extension of the orbital involvement are mandatory (Figures 22.1 and 22.4). At CT, large enough orbital extension appears as an intraconal mass with moderate enhancement after administration of contrast medium. On T1weighted MRI studies, Rb produces a homogeneous to heterogeneous signal that is hyperintense to the vitreous body and to muscle and hypointense to fat, while in T2-weighted images, it appears hypointense to the vitreous and isointense to fat with variable degree of enhancement after gadolinium administration (Figure 22.6). In an attempt to improve the poor outcome of Rb cases with orbital involvement, different therapeutic protocols have been applied. Reese in the

FIGURE 22.2. Histopathologic appearance of the intraocular retinoblastoma (iRb) composed of poorly differentiated small rounded cells with areas of necrosis and calcification. The tumor infiltrates (arrowhead) the sclera (S) to extend into orbital tissues. The orbital retinoblastoma (oRb) has a similar histology to its intraocular counterpart.

FIGURE 22.3. Retinoblastoma cells leaving the globe through the opening of vitrectomy (white arrowhead). Inset: Cluster of retinoblastoma cells.

1950s proposed orbital exenteration followed by EBRT, but there were no survivors among 25 children treated.23 Orbital extension of Rb was associated with high mortality rates ranging from 94 to 100% with a mean survival of 14 months. In 1984 Mackay et al. reported that regardless of what therapy was given, affected patients died within approximately 6 months.24 Over the past 15 years, a multidisciplinary treatment approach has improved prognosis. Different chemotherapy regimens are used for orbital Rb (Table 22.1).

Cyclophosphamide, platinum derivatives, Adriamycin, vincristine, and epipodophyllotoxins are the drugs most often used because their efficacy has been established in the treatment of other neuroectodermal tumors (neuroblastoma). Chemotherapy combined with EBRT improves survival in orbital disease.25 Complete remission for 8 to 84 months was achieved in 5 patients with orbital recurrence after enucleation by combining excisional biopsy of the tumor with EBRT and systemic chemotherapy (cyclophosphamide, cisplatin, vincristine, methotrexate, and etoposide) and intrathecal (methotrexate) chemotherapy.26 The use of high-dose chemotherapy regimens with autologous bone marrow transplantation has been used in patients with metastases.

Good results in terms of survival have been reported with chemotherapy and orbital EBRT. Doz et al. reported their experience in 33 patients (20 with orbital Rb and 13 with orbital Rb with metastases) who received systemic and intrathecal chemotherapy and orbital and cranial EBRT. The authors concluded that associated CNS disease still carries a bad prognosis and confirmed that intensive chemotherapy using cyclophosphamide, platinum compounds, epipodophyllotoxins, doxorubicin, and vincristine was effective in orbital Rb. In this series, the disease-free interval was longer when patients had no CNS disease.12

Aggressive treatment by combining radical surgery, chemotherapy, and EBRT may allow survival and complete tumor regression. In a retrospective study of 16 patients with orbital involvement of intraocular Rb, Kiratli et al. and others documented a satisfactory local and systemic tumor regression combining exenteration, EBRT, and chemotherapy.27,28 However, prognosis depends on the extent of orbital involvement. In cases with massive orbital involvement, the probability of systemic metastases increases severely, and mortality is 90% at 10 years. Microscopic extraocular extension, on the other hand, offers excellent survival.29 Two different categories of patients with overt extraocular disease have been identified: those with extraocular disease limited to the orbit (isolated or with lymph node involvement) and those with

systemic disease and/or CNS dissemination in addition to orbital disease.

Orbital involvement associated with CNS disease carries a bad prognosis, and in such cases CNS irradiation is mandatory. With the use of high-dose chemotherapy followed by autologous bone marrow transplantation, the results may be quite promising. Grabowski and Abramson were able to induce a disease-free state in 10 of 12 children after a mean follow-up of 44 months by using chemotherapy and whole-brain irradiation and intrathecal chemotherapy when CNS metastases were present.13

The fundamental question of which treatment combination should be the optimum is still unanswered. This is because of the extreme rarity of advanced cases with orbital involvement and the dif-

FIGURE 22.5. Recurrent retinoblastoma in a 3-year-old child after enucleation. Lower frame depicts the intraoperative appearance of the right orbit after the removal of the recurrent tumor mass (inset).

ficulty of conducting large randomized trials because of the nature of the disease. The trend, however, is to adopt an individualized and aggressive approach (surgery, EBRT, and chemotherapy) to obtain longer survival and a better chance of tumor control.

FIGURE 22.6. T1-weighted, fat suppressed axial MR image showing recurrent intraorbital Rb with markedly high signal after gadolinium enhancement.

TABLE 22.1. Chemotherapy Regimens Used for the Treatment of Orbital Rb.

aN-(2-chloroethyl)-N -cyclohexyl-N-nitrosourea.

CHOROIDAL MELANOMA

The uveal melanoma, the most common primary malignant neoplasm of the adult eye, originates from the monocytes of the uvea and has the capacity to invade the adjacent tissue structures aggressively and metastasize systemically. The current WHO classification of uveal melanoma histology discerns three major histopathologic types: spindle cell, epithelioid cell, and mixed.30–33 Extraocular extension of uveal melanoma in periocular and orbital soft tissues is the most common type of orbital melanoma.34–38 Transcleral extension and invasion of the adjacent soft tissues usually occurs with large choroidal melanomas, but occasionally medium-sized tumors may develop a limited degree of extraocular extension. Neglected tumors, particularly with corneal opacification with or without phthisis and flat diffuse melanomas, are at greater risk to invade the orbital soft tissues.39,40 It has been reported by Shields that approximately 10% of patients with ciliochoroidal melanomas have extrascleral extension at the time of enucleation.41 It has also been reported that uveal melanoma extensions into the orbit account for approximately one fourth of secondary orbital tumors. The orbital lesions compiled in this study, however, primarily belong to the preimaging era. The current incidence of this occurrence is probably far less than what was reported by Shields and coworkers. In another series from the 1960s and 1970s, the extension of choroidal melanoma was reported to be approximately 2% of all orbital tumors.42

Intraocular melanoma is known to leave the eye through emissarial channels, extend onto the scleral

surface, and disseminate into the orbital soft tissues (Figure 22.7). In the early stages of the extrascleral extension, the sclera is relatively intact and is often of normal thickness.43 When the tumor reaches a certain volume, the sclera is invaded beyond the margins of the emissarial channel, and the tumor forms a nodule within the retrobulbar fibroadipose tissues of the orbit. Initially this presents as a nodular formation, but as the tumor grows it may be widespread and extend into the meninges and the optic nerve, and to the lumina of the orbital vasculature (Figures 22.8 and 22.9). Most of the aggressively extending tumors are proven to be of epithelioid cell type, but spindle cell and mixed-cell tumors may also extend into the orbit.

When the volume of the retrobulbar melanoma is sufficient, the results are proptosis, extraocular motility disturbance, congestion of the conjunctival blood vessels, and chemosis, depending on the location and the rapidity of the growth. The eye and the periorbita may be painful and tender to palpation, masquerading as an inflammatory pathology such as endophthalmitis.44

Secondary involvement of the orbit with uveal melanoma may also develop as a recurrence of an unnoticed extraocular tumor months or years after enucleation.45,46

As soon as extraocular extension is clinically suspected, the patient should be investigated with ultrasonography, CT scan, and/or MRI (Figure 22.10). B- scan ultrasonography may be helpful to demonstrate the extraocular component of the tumor, which typically appears as a nodular, solid mass adjacent to the base of the intraocular tumor.47 Once the extrascleral component has reached a certain size, standardized A- scan ultrasonography and color Doppler echography may be useful to assess the internal reflectivity of the blood flow of the tumor nodule.48 The presence of a small intraocular tumor in a suspected case of scleral extension should not rule out the possibility of extension, since it is well known that small or flat choroidal melanomas may also be associated with large intraorbital nodules. Differential diagnosis of extraocular extension of a choroidal melanoma includes

localized inflammatory processes of extraocular muscles and Tenon’s capsule with edema, congested retrobulbar blood vessels, and phthisis with or without hemorrhage (Figure 22.10B).

Diagnosis of uveal melanoma is usually made by indirect ophthalmoscopy, intravenous fluorescein angiography, and ultrasonography. In cases of suspected orbital extension, imaging with CT scan and/or MRI is more helpful than B-scan ultrasonography. Although most choroidal melanomas bigger than 3 to 4 mm in diameter are seen as hyperdense, circumscribed, markedly enhancing tumors with CT, high-resolution MRI is the choice of imaging technique to rule out small intraocular tumors and

retrobulbar extension of the tumor into orbital soft tissues.

A very helpful feature of melanoma in MRI is based on the signal characteristics of the melanin. Melanin produces stable free radicals that create a paramagnetic proton relaxation enhancement that, in turn, leads to shortening of T1 and T2 relaxation times. This allows the melanoma to present with a moderately high signal on T1-weighted and a moderately low signal on T2-weighted images.49–51 Gadoliniumenhanced T1-weighted images are superior to ordinary T1-weighted images to detect and delineate intraocular and extraocular components of a melanoma. A great majority of melanomas change their histopath-

ologic characteristics when they leave the globe to invade the orbital soft tissues. For example, pigmented tumors are known to become amelanotic, and necrotic tumors develop a solid structure (Figure 22.9). This point should be kept in mind; since if a tumor happens to differentiate into an amelanotic lesion, signal

characteristics of melanin will not be helpful in MRI differential diagnosis.

Extraocular extension of ciliary body melanomas, which can be seen subconjunctivally, has been described in approximately 10% of these tumors.52,53

It has been reported that secondary orbital mela-