Lorenz E. Zimmerman

Does enucleation of the eye containing a malignant melanoma prevent or accelerate the dissemination of tumour cells.

A reappraisal of survival data on patients with uveal melanomas has led us to these impressions: (a) that the mortality rate before enucleation is low, estimated at 1% per year; (b) that the mortality rate rises abruptly following enucleation, reaching a peak of about 8% during the second year after enucleation; and (c) that approximately two-thirds of the fatalities could be attributed to the dissemination of tumour emboli at the time of enucleation. From these impressions we believe the following conclusions are warranted: (a) enucleation as it has been performed in the past may have for many patients an adverse rather than a beneficial effect with respect to the development of metastatic disease from malignant melanoma of the choroid and ciliary body. (b) A long-term follow-up study of untreated patients with melanomas of the choroid and ciliary body is indicated. (c) New techniques for enucleation designed to prevent the dissemination of tumour cells must be developed and tested to enable the ophthalmic surgeon to remove safely the tumour-containing eye that has developed such complications as uncontrollable glaucoma, panophthalmitis, or proptosis from extraocular extension.

Modifications of Callender's Classification of Uveal Melanoma at the Armed Forces Institute of Pathology

One hundred well-documented cases of uveal melanoma accessioned at the Armed Forces Institute of Pathology before 1970 were reviewed and reclassified to identify changes made in the Callender classification. We compared the new classification with the original classification to determine the effect of the changes on the prediction of outcome for the patient after enucleation. Staff pathologists had originally classified 52 of the 100 cases as spindle-cell type melanoma. Only 31 of the 100 cases were reclassified as spindle-cell types (two spindle-cell nevi and 29 spindle-cell melanomas). Tumors classified as mixed-cell type were further subdivided into groups based on the percentage and size of the epithelioid cells. Tumors formerly classified as spindle-cell type that contained small or rare epithelioid cells were reclassified as mixed-cell type. This improved the prediction of outcome for the patient. We found that nucleolar size and pleomorphism are important variables that should be considered in the classification of uveal melanomas.

Blindness caused by photoreceptor degeneration as a remote effect of cancer.

Three postmenopausal women developed photoreceptor degeneration one to four months preceding or following discovery of an anaplastic tumor. Two patients had transitory visual obscurations and bizarre visual sensations. Ring scotomas progressed to severe visual field loss. Retinal arteries were markedly narrowed. Electroretinograms revealed almost total absence of response in one patient, and another complained of the recent onset of night blindness. In all three patients severe degeneration of the photoreceptor cells associated with melanophagic activity was shown histologically. In two patients neuropathologic examination from the retinal bipolar cells to the occipital cortex revealed no significant alterations.

Uveal melanoma: Location, size, cell type, and enucleation as risk factors in metastasis

In this series of 3,432 cases of malignant melanoma of the choroid and ciliary body, mortality from metastasis 15 years after enucleation was 46 per cent. This mortality was at least ten times greater than has been observed with tumors of the iris, probably owing to the greater size and more malignant cytology of choroidal and ciliary body tumors. In 56 per cent of the 3,432 cases, the melanomas were composed of a mixture of spindle and epithelioid cells. The 15-year mortality of patients with melanomas of mixed cell type was three times that of patients with tumors of pure spindle cell type. In 30 per cent of the cases in this series, the melanomas of the choroid and ciliary body were larger than 15 mm in diameter. Size was highly correlated with mortality. The distribution of deaths following enucleation in the 3,432 cases was a log-normal function of time from enucleation. This indicated that metastasis occurred in these fatal cases close to the time of enucleation. The authors were also able to infer that many years were usually required for these uveal melanomas to grow from small (7 to 10 mm in diameter) to large (greater than 15 mm in diameter). These observations are consistent with the hypothesis that dissemination of tumor cells at the time of enucleation has been a major cause of metastasis with small and medium-sized uveal melanomas.

Incidence of Second Neoplasms in Patients with Bilateral Retinoblastoma

The cumulative incidence of second neoplasms in 215 patients with bilateral retinoblastoma was calculated using the life-table method. Second tumors developed in 4.4% of the patients during the first 10 years of follow-up, in 18.3% after 20 years, and in 26.1% after 30 years. The 30-year cumulative incidence was 35.1% for the 137 patients who received radiation therapy compared with an incidence rate of 5.8% for the 78 patients who did not receive radiation. In the 137 patients who received radiation, second tumors developed both inside and outside the field of therapy. There was a 30-year incidence rate of second tumors of 29.3% within the field of irradiation and 8.1% outside the field. The rate outside the field of irradiation (8.1%) was similar to that observed in nonirradiated patients (5.8%). Our findings indicate that carriers of the retinoblastoma gene have an increased incidence of second tumors, and that the incidence rate is further increased in patients who receive radiation therapy.

An Evaluation of Enucleation in the Management of Uveal Melanomas

Uveal melanomas are slow growing tumors that may infiltrate out of the eye, mainly following ciliary vessels or nerves, or invade blood vessels, but only rarely do they produce metastatic disease before discovery and treatment. There are, however, large gaps in our knowledge of the frequency and rate of growth of small tumors to those of moderate or large size. We have estimated the mortality from untreated uveal melanomas to be 1% per year or less. Almost all information concerning prognostic factors has been gained from studies based on cases treated by enucleation. The same information is not necessarily applicable to untreated tumors. A study of deaths from metastatic uveal melanomas reveals a striking relationship to enucleation, regardless of whether one deals with cases in which the eye had been symptomatic for a long or short time. Following a low preoperative mortality of 1% or less, the annual mortality rises to about 4% during the first year and then peaks at 8 to 12% during the second year, tapering off during the next three to five years to return to a remarkably constant level of 1 to 2% thereafter. We postulated that this relationship of peak mortality to enucleation is attributable mainly to an often overwhelming dissemination of tumor cells taking place during surgery or to a lowering of the hosts immunologic defense mechanisms as a consequence of the operation, or both. We urge the pooling of all available information gained from clinical studies made on untreated tumors and recommend prospective studies of a variety of other methods of treating uveal melanomas in addition to the standard enucleation.

A Clinicopathologic Study of 56 Cases of Intraocular Medulloepitheliomas

A clinicopathologic and follow-up study of 56 intraocular medulloepitheliomas in the Registry of Ophthalmic Pathology revealed a mean age of five years at the time of definitive diagnosis, most patients having had a delay in surgical therapy of more than one year after onset of signs or symptoms. Histologic evidence of malignancy was observed in 37 tumors, and follow-up studies revealed four patients to have died of metastatic disease. Heteroplastic elements (brain tissue, cartilage, or rhabdomyoblasts) were observed in four benign and 17 malignant tumors; these 21 were designated teratoid medulloepitheliomas. The most important prognostic feature was extraocular extension, observed in ten cases. All four of the known tumor deaths were preceded by clinically obvious orbital spread. In four additional cases with orbital involvement the patients were lost to follow-up. We concluded, therefore, that the prognosis is worse than the results of this study would indicate, especially among those cases observed to habe extraocular extension.

Malignant melanoma of the conjunctiva

One hundred thirty-one cases of conjunctival melanoma in which biopsies had been performed were studied to determine potential factors that might affect outcome in patients with these lesions. Two groups of lesions were identified: those associated with primary acquired melanosis (melanoma with PAM, 98 cases, 74.8 per cent) and those without primary acquired melanosis (melanoma without PAM, 33 cases, 25.2 per cent). The overall mortality rate in the 131 cases was 26 per cent (34 of 131); the mortality rate due to melanoma with PAM was 25.5 per cent (25 of 98), and that due to melanoma without PAM was 27.3 per cent (9 of 33). If PAM was associated with the lesion, the presence of atypical melanocytes within the epithelium (pagetoid invasion) was a sensitive indicator of subsequent metastasis. Tumor thickness may also be useful for predicting subsequent metastases. None of the histologic parameters studied proved useful for predicting outcome in patients who had melanomas without PAM. The presence or absence of nevi had no effect on prognosis.

Fibrous histiocytoma of the orbit. A clinicopathologic study of 150 cases.

This is a clinicopathologic study of 150 cases of fibrous histiocytoma of the orbit. The tumors occurred in adults (median age, 43 years). The upper and nasal portions of the orbit were the most common sites of involvement. The most common signs and symptoms were proptosis (60 per cent), mass (46 per cent), and decreased vision (25 per cent). Based on the histopathologic features, the tumors were classified in three groups: benign (94 cases), locally aggressive (39 cases), and malignant (17 cases). The biological behavior correlated well with the duration of symptoms, the size and margins of the mass, and the histologic classification. The rate of recurrence was 31 per cent for the benign tumors, 57 per cent for the locally aggressive tumors, and 64 per cent for the malignant tumors. Follow-up data were obtained for 123 patients, with a mean duration of seven years. The ten-year survival of patients with benign, locally aggressive, and malignant fibrous histiocytoma was 100 per cent, 92 per cent, and 23 per cent, respectively. Nine patients died as a result of the tumor, six from local invasion of adjacent structures and three from metastatic disease. Fibrous histiocytoma is the most common primary mesenchymal orbital tumor of adults. The origin of the neoplasm is probably a primitive mesenchymal cell. Complete surgical excision appears to be the treatment of choice.

A Light Microscopic, Autoradiographic Study of Axoplasmic Transport in the Optic Nerve Head During Ocular Hypotony, Increased Intraocular Pressure, and Papilledema

Cyclocryotherapy of the monkey eye reliably produces transient increased intraocular pressure followed by prolonged hypotony, during which papilledema occurs. Axoplasmic transport was studied while the intraocular pressure was both increased and decreased after cyclocryotherapy by autoradiography following the intravitreal injection of tritiated leucine and proline. Surgical fistulization of the anterior chamber was also used to produce hypotony and papilledema. Significant alterations of both the rapid and the slow components of axoplasmic transport were demonstrated in the nerve head during increased intraocular pressure, and in ocular hypotony with papilledema.