144 ORBITAL RHABDOMYOSARCOMA

DIAGNOSIS

Clinical features

Clinical features include: proptosis, ptosis, ocular congestion, decreased extraocular motility.

Laboratory tests

●Blood tests:

●Complete blood count to rule out pancytopenia from bone marrow infiltration;

●Liver function tests to rule out liver metastases;

●Renal function tests.

●Imaging tests:

●Chest x-ray or computed tomography (CT) of the lung to rule out metastases;

●Computed tomography or magnetic resonance imaging (MRI) of the orbit to assess the location and configuration of the tumor and plan the surgical approach. Both CT and MRI demonstrate an orbital mass that shows enhancement with contrast dye. It is uncommon to find bone erosion from this tumor.

●Pathology:

●Gross features — firm yellow white tumor, often with hemorrhage;

●Microscopic features — orbital rhabdomyosarcoma demonstrates tumor cells with cross striations within their cytoplasm. These striations are best appreciated with the Masson trichrome stain or the phosphotungstic acidhematoxylin (PTAH) stain. Immunoperoxidase techniques assist in diagnosis by identifying desmin, myoglobulin, and actin. On electron microscopy the tumor cells can demonstrate thin (actin) myofilaments and thick (myosin) filaments. Characteristic muscle banding of A, I, and Z lines may be found.

Orbital rhabdomyosarcoma is classified into three histopathologic types as listed below, but often there is overlap of these types:

●Embryonal — found in nearly 70% cases and consists of loose and compact spindle cells; botryoid is a variant of embryonal pattern but located near the expandable conjunctival mucosa leading to a polypoid tumor;

●Alveolar — carries the worst prognosis and consists of loosely cohesive, poorly differentiated oval to round tumor cells arranged in a trabecular pattern resembling the alveoli of the lung;

●Pleomorphic — least common variant, consisting of variably sized, loosely arranged pleomorphic cells, often in association with muscles.

Clinical differential diagnosis

●Dermoid cyst.

●Orbital cellulites.

●Idiopathic orbital inflammation (pseudotumor).

●Capillary hemangioma.

●Lymphangioma.

●Orbital subperiosteal hematoma.

Pathologic differential diagnosis

●Fibrous histiocytoma.

●Fibrosarcoma.

●Nodular fasciitis.

●Malignant schwannoma.

●Leiomyosarcoma.

●Ewing’s sarcoma.

●Metastatic neuroblastoma.

●Alveolar soft part sarcoma.

●Hemangiopericytoma.

●Granulocytic sarcoma.

●Lymphoma.

●Osteogenic sarcoma.

●Primitive neuroectodermal tumor (PNET).

●Other rare conditions.

PROPHYLAXIS

There is no known prevention of this disease. Rhabdomyosarcoma can occur as a second tumor in children with germinal mutation retinoblastoma.

TREATMENT

The treatment consists of local debulking of the orbital mass and adjuvant radiotherapy and chemotherapy. The combinations of various modalities must be individualized and depends on the specific extent of the disease. The disease progresses rapidly and treatment should be urgent. It is emphasized that the management of a child with rhabdomyosarcoma should be performed at a major oncology center with ocular oncologist and pediatric oncologist working in collaboration.

Local

Excisional biopsy — Orbital biopsy is performed with the intent to gently debulk as much tissue as possible for diagnostic and therapeutic purposes. The approach to the biopsy is dictated by the extent and accessibility of the tumor both clinically and on imaging studies.

Radiotherapy

●External beam radiotherapy — this is delivered to the orbit

over 4 to 6 weeks for a total dose of 4000 cGy to 6000 cGy.

●Gamma knife radiotherapy — this new technique may have potential for orbital rhabdomyosarcoma but has not yet been reported.

●Orbital exenteration — This is reserved for aggressive recurrent disease. An eyelid sparing technique provides the most acceptable cosmetic appearance.

Systemic

Chemotherapy

●The most frequently used chemotherapy regimen is the VAC protocol:

● Vincristine;

●Dactinomycin (Actinomycin-D);

●Cyclophosphamide.

COMPLICATIONS

The complications of uncontrolled rhabdomyosarcoma could cost the patient his or her life. However, the complications of treatment of this malignancy can be very destructive to the eye and orbit as well as the surrounding tissue. Excisional biopsy of the mass can lead to ptosis, diplopia, strabismus, and vision loss. Radiotherapy has side effects of cilia loss, cutaneous erythema, dry eye symptoms, cataract, retinopathy, papillopathy, neovascular glaucoma, orbital volume loss and visual loss. The orbital bones may be slowed in their growth due to radiotherapy. The systemic side effects of chemotherapy with bone marrow suppression, risk for infection and other short and long term effects should be realized.

COMMENTS

Orbital rhabdomyosarcoma is the most common primary orbital malignancy of childhood. It is characterized by rapid proptosis in an otherwise healthy child. Early diagnosis of the tumor is important to facilitate proper treatment and provide the best life prognosis. Management decisions are best approached by a coordination of multispecialists at major oncology centers.

REFERENCES

Abramson DH, Ellsworth RM, Tretter P, et al: The treatment of orbital rhabdomyosarcoma with irradiation and chemotherapy. Ophthalmology 86:1330–1335, 1979.

Fiorillo A, Migliorati R, Grimaldi M, et al: Multidisciplinary treatment of primary orbital rhabdomyosarcoma. Cancer 67:560–563, 1991.

Jones IS, Reese AB, Kraut J: Orbital rhabdomyosarcoma. An analysis of 62 cases. Am J Ophthalmol 61:721–736, 1966.

Shields CL, Shields JA, Honavar SG, Demirci H: The clinical spectrum of primary ophthalmic rhabdomyosarcoma. Ophthalmology 108:2284– 2292, 2001.

Shields JA, Shields CL: Rhabdomyosarcoma: review for the ophthalmologist. Surv Ophthalmol 48:39–57, 2003.

Wharam M, Beltangady M, Hays D, et al: Localized orbital rhabdomyosarcoma. An interim report of the Intergroup Rhabdomyosarcoma Study Committee. Ophthalmology 94:251–254, 1987.

least as an important cofactor in the genesis of benign and malignant epithelial neoplasm in humans, including the papilloma.

In the eye, HPV has been considereded as an important factor for the development of the conjunctival papilloma. Some oncogenic HPV types have been detected in carcinomas of the conjunctiva and lacrimal sac and in some sporadic retinoblastoma.

HPV is normally spread by contact, however, the transmission route of HPV to the conjunctiva is still object of investigation. Fetal contact with infected maternal tissue or fluids might be a way of direct transmission. Autoinoculation is another probable transmission mode and may result in multicentric infection.

There is no predilection for race, but a male preponderance has been found among patients with conjunctival papilloma.

The reported frequency of HPV DNA in conjunctival papilloma varies from 50% to 100%.

The HPV types found in papillomas of the conjunctiva are mainly HPV-6, 11, and less frequently HPVs 18, 33 and 16, considered a potent human carcinogen.

The lesions identified in children and young adults are always benign and often associated to HPV infection caused by HPV types 6 and 11. Papillomas seen in adults and older patients may also harbour HPV-16 or may not have a viral origin according to some authors.

PRESENTATION

Papillomas may affect one or both eyes and appear as isolated or multiple lesions of variable sizes. The main sites of involvement are the fornices (especially the inferior ones) followed by:

●Bulbar conjunctiva;

●Lacrimal caruncle;

●Lacrimal sac, puncta or canaliculus;

●Lid skin margin.

Lesions are redish (conjunctiva) or grayish (skin) and can be sessile or pedunculated with multiple tiny ‘finger-like’ projections (raspberry like).

Conjunctival papillomas tend to be sessile in adults and pedunculated in children. Although pedunculated papillomas most frequently are located in the fornix and sessile papillomas in the bulbar conjunctiva, both types may develop anywhere in the conjunctiva.

145 PAPILLOMA 078.1

(Wart, Verrucous Lesion)

Maristela Amaral Palazzi, MD, PhD

São Paulo, Brazil

ETIOLOGY/INCIDENCE

Papilloma is an acquired benign lesion that may affect the skin and mucous membranes especially those of genitourinary and respiratory tract, oral cavity and ocular surface.

Human papillomaviruses (HPVs) are a wide group of DNA viruses that have been recognized as the main cause or at

COURSE/PROGNOSIS

Some lesions may regress spontaneously without treatment, especially in children, while recurrences are often noted in many patients.

Papilloma should not be left untreated for many years in older patients once some lesions have shown malignant transformation.

DIAGNOSIS

The clinical appearence of a papilloma is very characteristic, however, the histologic evaluation is necessary to avoid misdiagnosis, especially in older patients.

Histopathological analysis of lesions is always advisable in adults to avoid misdiagnosis with malignant tumors.

FUTURE PERSPECTIVES

HPV vaccines with both prophylatic and therapeutic potential are being developed and some are already being tested in gynecologic patients. This has been considered a promising perspective in the management of HPV associated tumors.

REFERENCES

Basti S, Macsai MS: Ocular surface squamous neoplasia — a review. Cornea 22(7):687–704, 2003.

Burnier MN, Jr, Correia CP, Mc Cartney ACE: Tumors of the eye and ocular adnexae, In: Fletcher CDM, ed: Diagnostic histopathology of tumors. London, Churchill Livingstone, 2001.

de Keizer RJW, de Wolff-Rouendaal D: Topical α-interferon in recurrent conjunctival papilloma. Acta Ophthalmologica Scandinavica 81:193– 196, 2003.

IARC monographs on the evaluation of carcinogenic risks to human. Human papillomaviruses. Lyon, France: International Agency for Research on Cancer, 1995:64.

Koutsky LA, Ault KA, Wheeler CM, et al: A Controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 347(21):1645–1651, 2002.

Nakamura Y, Mashima Y, Kameyama K, et al: Detection of human papillomavirus infection in squamous tumours of the conjunctiva and lacrimal sac by immunohistochemistry, in situ hybridization, and polymerase chain reaction.Br J Ophthalmol 81:308–313, 1997.

Palazzi MA, Yunes JA, Cardinalli IA, et al: Detection of oncogenic human papillomavirus in sporadic retinoblastoma. Acta Ophthalmol Scand 81:396–398, 2003.

Parkarian F, Kaye J, Cason J, et al: Cancer associated human papillomaviruses: perinatal transmission and persistence. Br J Obst Gynecol 101:514–517, 1994.

Shields CL, Shields JA: Tumors of the conjunctiva and cornea. Surv Ophthalmol 49(1):3–24, 2004.

Sjö NC, Heegaard S, Prause JU, et al: Human papillomavirus in conjunctival papilloma. Br J Ophthalmol 85:785–787, 2001.

Wilson FM, Ostler HB: Conjunctival papilloma in siblings. Am J Ophthalmol 77:103–107, 1994.

Yuen HKL, Yeung EFY, Chan NR, et al: The use of postoperative topical Mitomycin C in the treatment of recurrent conjunctival papilloma. Cornea 21(8):838–839, 2002.

146 PERIOCULAR MERKEL CELL CARCINOMA 173.9

(Cutaneous Neuroendocrine

Carcinoma, Endocrine Carcinoma of

the Skin, Small Cell Skin Carcinoma,

Trabecular Carcinoma)

Tero Kivelä, MD, FEBO

Helsinki, Finland

tumors in these locations account for 10% of all cases. Since 1990, about 175 periocular Merkel cell carcinomas have been reported; however, this tumor is now well known and not all cases enter the literature.

Most periocular Merkel cell carcinomas develop in the eyelids and canthal region, preferentially in the upper eyelid; the remainder occur in the eyebrows. Merkel cell carcinoma metastatic to the eyelid, orbit, choroid and ciliary body has been described.

The median age of patients with eyelid tumors is 76 years, with an age range from 14 to 102 years, and two thirds are women. The tumor is extremely rare in Africans and Asians.

Human immunodeficiency virus infection, therapeutic immunosuppression (e.g. after renal and cardiac transplantation, in rheumatoid arthritis), chronic lymphocytic leukemia and chronic sunlight and arsenic exposure predispose also younger individuals and non-Caucasians to develop Merkel cell carcinoma.

Merkel cell carcinomas are ascribed to an epidermal stem cell common to keratocytes and Merkel’s cells, specialized epidermal cells with neuroendocrine features associated with nerve endings in touch receptors.

●In the eyelids, single Merkel’s cells occur in the epidermis, the outer root sheaths of hairs and eyelashes and the dermis.

●Aggregates of Merkel’s cells, called touch spots, occur regularly at the palpebral margin between successive eyelashes.

COURSE/PROGNOSIS

A meta-analysis was performed of 112 patients with a Merkel cell carcinoma of the eyelid.

●The primary tumors grew rapidly, with a median history of 3 months; the range was from a few weeks to 3 years.

●Based on life-table analysis, a local recurrence in the eyelid or orbit developed in 30% of patients in 2 years; repeated recurrences were common.

●Regional metastases to ipsilateral preauricular, submandibular, cervical and jugulodigastric lymph nodes developed in 38% and 47% of patients in 2 and 5 years, respectively; systemic metastasis was often heralded by regional lymph node involvement.

●Systemic metastases most commonly affect the liver, bone, lungs, skin, and brain but may occur in any location.

●The cumulative 2- and 5-year survival rate was 81% and 68%, respectively. Survival was worse for patients who experienced a local relapse; mortality rates are decreasing with better recognition and more radical treatment of primary Merkel cell carcinoma.

These figures correlate closely both with those reported for Merkel cell carcinoma in general and with those of 28 patients who had eyebrow lesions. There is no firm evidence that periocular Merkel cell carcinoma has a better-than-average prognosis.

protuberant but may be pedunculated; it typically spares the eyelashes; and it rarely ulcerates the skin.

●Reddish or purplish erythematous skin and telangiectatic vessels from associated inflammation and possible invasion of local lymphatic vessels are highly characteristic and often imitate chalazion.

●Because of frequent lymph node metastasis, palpation and imaging of regional lymph nodes is mandatory; consideration should be given to sentinel node biopsy undertaken by an oculoplastic surgeon, plastic surgeon and pathologist familiar with this procedure.

Laboratory findings

●Histopathologic diagnosis is based on the presence of neuroendocrine granules and whorls of intermediate filaments by electron microscopy and on coexpression of cytokeratins, neurofilaments, and neuroendocrine markers by immunohistochemistry.

Differential diagnosis

Most periocular Merkel cell carcinomas are unidentified or misdiagnosed clinically.

●Chalazion is a frequent misdiagnosis.

●Other repeated clinical misdiagnoses include papilloma, hemangioma and basal cell carcinoma.

Surgical

●Full-thickness resection of eyelid tumors and wide resection of other periocular tumors with a 5-mm margin, followed by appropriate plastic surgical reconstruction, is recommended.

●Frozen section control is useful to ensure the deep margin of excision, but it does not guard against early lateral spread through lymphatic vessels.

●Because of very frequent lymphatic infiltration, prophylactic irradiation with 50 Gy in 20 to 25 fractions to the tissues between the tumor bed and local lymph nodes is recommended.

●Routine prophylactic lymph node dissection without sentinel node biopsy is not recommended.

●Radical neck dissection for proved regional lymph node metastases, with or without irradiation and chemotherapy, is recommended because it may result in a permanent cure.

●Consider exenteration for orbital recurrence in the absence of systemic metastases.

COMPLICATIONS

Some patients have died as a result of the chemotherapy regi-

●Protection of skin from excessive sunlight and burning; this will also reduce the incidence of other, more common skin cancers.

●Immunosuppressed patients can be cautioned about higher than average risk of skin cancer, including Merkel cell carcinoma, to expedite diagnosis.

TREATMENT

Prompt initial therapy is a prerequisite for a favorable outcome.

Systemic

●Chemotherapy is an effective treatment for extensive local or recurrent, as well as metastatic, Merkel cell carcinoma, but progressive disease after cessation of therapy is common.

●Chemotherapy regimens are continuously evolving, and the choice of treatment should be delegated to experts in cancer chemotherapy.

●Irradiation with or without chemotherapy is an effective palliative treatment for systemic metastases. It has fewer complications than chemotherapy and is likewise associated with risk of recurrence.

Ocular

●Uveal metastases respond well to radiation.

Medical

●In selected cases, irradiation may be successfully used as primary therapy to avoid extensive plastic surgery and chemotherapy in elderly or debilitated persons.

●Chalazia are rare in elderly people and should always undergo a biopsy to exclude Merkel cell or sebaceous carcinoma.

●A systemic workup is mandatory to exclude the possibility of a primary cancer elsewhere, especially to rule out metastatic Merkel cell or small cell lung carcinoma to the eyelid.

●Patients must be followed carefully for evidence of recurrent disease and regional or systemic metastases.

SUPPORT GROUPS

None identified. A general resource for skin cancer is provided by The Skin Cancer Foundation, New York, NY, URL www.skincancer.org

REFERENCES

Alexander E, 3rd, Rossitch E, Jr, Small K, et al: Merkel cell carcinoma. Long term survival in a patient with proven brain metastasis and presumed choroid metastasis. Clin Neurol Neurosurg 91:317–320, 1989.

Kivelä T, Tarkkanen A: The Merkel cell and associated neoplasms in the eyelids and periocular region. Surv Ophthalmol 35:171–187, 1990.

Mehrany K, Otley CC, Weenig RH, et al: A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma. Dermatol Surg 28:113–117, 2002.

Miller RW, Rabkin CS: Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 8:153– 158, 1999.

Mortier L, Mirabel X, Fournier C, et al: Radiotherapy alone for primary Merkel cell carcinoma. Arch Dermatol 139:1587–1590, 2003.

Poulsen M: Merkel-cell carcinoma of the skin. Lancet Oncol 5:593–599, 2004.

A complete and detailed pedigree should be obtained to include a family history of eye disease and ocular and systemic cancer. Dysfunction of the RB gene has been noted to correlate with the development of other cancers, including osteosarcoma. Both parents should undergo dilated fundus examinations. Spontaneous regression is rare but does occur; therefore, an ‘asymptomatic’ parent may harbor signs of this spontaneously regressed disease. Siblings of an affected child should be examined. The frequency of these examinations depend on the statistical likelihood that a germinal mutation is present in the family.

Differential diagnosis

●Coats’ disease.

●Toxocara.

●Toxoplasmosis.

●Norrie’s disease.

●Medulloepithelioma.

●Leukemia.

●Malignant melanoma.

●Enucleation.

●External-beam irradiation (4000 cGy); this is very effective for posterior tumors; increases the risk for second nonocular tumors.

●125I radioactive plaque.

●Locally directed; minimizes radiation to normal tissue; useful for small nondisseminated tumors.

●Cryotherapy.

●Especially effective for small anterior tumors.

●Laser photocoagulation.

●Directly over tumor.

●Ablative.

●Gentle heating (facilitates effect of chemotherapy).

●Hyperthermia.

COMPLICATIONS

Complications include secondary nonocular cancer, cataract (radiation), radiation retinopathy, radiation optic neuropathy,

TREATMENT

Medical therapy should be directed toward complete control of the tumor and the preservation of as much useful vision as possible. Treatment usually is individualized to the specific patient.

Unilateral retinoblastoma with a poor prognosis for vision usually is treated with enucleation. If the tumor has not invaded the optic nerve and there is no evidence of extraocular disease, then usually no further treatment is given (survival rate of greater than 90%). However, there is debate over the prognostic significance of histopathologic choroidal invasion. The patient with optic nerve invasion past the lamina cribrosa usually is treated with systemic chemotherapy after surgery; if the tumor is evident past the surgical line of transection, then orbital radiation is added to the regimen. Optic nerve involvement decreases the prognosis for survival to 60%, and disease past the line of transection decreases the survival rate to less than 20% even with additional treatments. Great care should be taken to avoid perforation of an eye harboring a retinoblastoma during enucleation (thus converting an intraocular retinoblastoma to extraocular disease). Efforts should be made to obtain the longest possible section of optic nerve at the time of enucleation.

Bilateral disease often presents a greater challenge in terms of preserving life and vision. These patients are genetically prone to second primary carcinomas; therefore, there is a great emphasis on treatment methods that will not enhance the lifelong risk of secondary carcinomas. Retinoblastomas are extremely sensitive to external beam radiation, but that treatment is associated with a lifelong increased risk of second primary carcinomas. For this reason, external beam radiation is no longer the initial treatment of choice of retinoblastoma.

Primary systemic chemotherapy (carboplatin, etoposide, and vincristine) to reduce tumor volume followed by local methods such as cryotherapy and laser photocoagulation, both hyperthermia and ablation, has been shown to be very effective in eradicating nondisseminated intraocular disease. The longterm effect of this regimen on the incidence of secondary carcinomas is unknown.

●Systemic chemotherapy plus local therapy (cryotherapy, laser, plaque).

COMMENTS

Strategies for the treatment of bilateral disease are often complex and depend on the patient’s age, tumor size and location, and vitreous involvement. Children with retinoblastomas should be managed by a team that includes an ophthalmologist, a pediatric oncologist, a radiation oncologist, a social worker, and a genetic counselor. This team should be composed of professionals who are familiar with this disease.

REFERENCES

Abramson DH, Greenfield DS, Ellsworth RM: Bilateral retinoblastoma: correlation between age at diagnosis and time course for new intraocular tumors. Ophthalmol Pediatr Genet 1:7, 1992.

Beck MN, Balmer A, Dessing C, et al: First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol Aug 18(15):2881– 2887, 2000.

DiCiommo D, Gallie BL, Bremner R: Retinoblastoma: the disease, gene and protein provide critical leads to understand cancer. Semin Cancer Biol 10(4):255–269, 2000.

Friedman DL, Himelstein B, Shields CL, et al: Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 18(1):12–17, 2000.

Gallie BL, Budning A, Deboer G, et al: Chemotherapy with focal therapy can cure intraocular retinoblastomas without radiotherapy. Arch Ophthalmol 114:1321–1328, 1996.

Kingston JE, Hungerford JL, Madreperla SA, Plowman PN: Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol 114:1339–1343, 1996.

MacDonald DJ, Lessick M: Hereditary cancers in children and ethical and psychosocial implications. J Pediatr Nurs 15(4):217–225, 2000.

Murphree AL, Villablanca JG, Deegan WF, et al: Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 114:1348–1356, 1996.

Noorani HZ, Khan HN, Gallie BL, Detsky AS: Cost comparison of molecular versus conventional screening of relatives at risk for retinoblastoma. Am J Hum Genet 59:301–307, 1996.

Shields CL, Shields JA, Meadows AT: Chemoreduction for retinoblastoma may prevent trilateral retinoblastoma. J Clin Oncol 18(1):236–237, 2000.