Frederick A. Jakobiec

INTRAVITREOUS INJECTIONS OF VASCULAR ENDOTHELIAL GROWTH FACTOR PRODUCE RETINAL ISCHEMIA AND MICROANGIOPATHY IN AN ADULT PRIMATE

PURPOSE The purpose of the study is to determine the effect of exogenous vascular endothelial growth factor (VEGF) on the primate retina and its vasculature. METHODS Ten eyes of five animals were studied. Physiologically relevant amounts of the 165 amino acid isoform of human recombinant VEGF were injected into the vitreous of six healthy cynomolgus monkey eyes. Inactivated human recombinant VEGF or vehicle was injected into four contralateral control subject eyes. Eyes were assessed by slit-lamp biomicroscopy, tonometry, fundus color photography, fundus fluorescein angiography, light microscopy, and immunostaining with antibodies against proliferating cell nuclear antigen and factor VIII antigen. RESULTS All six bioactive VEGF-injected eyes developed dilated, tortuous retinal vessels that leaked fluorescein. Eyes receiving multiple injections of VEGF developed progressively dilated and tortuous vessels, venous beading, edema, microaneurysms, intraretinal hemorrhages and capillary closure with ischemia. The severity of the retinopathy correlated with the number of VEGF injections. None of the four control eyes exhibited any abnormal retinal vascular changes. The endothelial cells of retinal blood vessels were proliferating cell nuclear antigen positive only in the bioactive VEGF-injected eyes. CONCLUSION Vascular endothelial growth factor is sufficient to produce many of the vascular abnormalities common to diabetic retinopathy and other ischemic retinopathies, such as hemorrhage, edema, venous beading, capillary occlusion with ischemia, microaneurysm formation, and intraretinal vascular proliferation.

Lymphoid hyperplasia and malignant lymphoma occurring in the ocular adnexa orbit conjunctiva and eyelids a prospective multiparametric analysis of 108 cases during 1977 to 1987

We performed a prospective multiparametric correlative clinical, histopathologic, and immunologic analysis of 117 ocular adnexal lymphoid proliferations developing in 108 patients between October 1977 and July 1987. The ocular adnexal lymphoid proliferations were distributed among the 108 patients as follows: orbit 69 (64%), conjunctiva 30 (28%), and eyelids nine (8%). The 117 ocular adnexal lymphoid proliferations were classified as follows: polyclonal lymphoid hyperplasia, 32 (22 orbit, nine conjunctiva, one eyelid) (27%); monoclonal B cell lymphoma, 81 (48 orbit, 25 conjunctiva, eight eyelid) (69%); null cell lymphoma, one (orbit) (1%); and histologically indeterminate, three (one each: orbit, conjunctiva, eyelid) (3%). Patients presenting with ocular adnexal polyclonal lymphoid hyperplasia and monoclonal B cell lymphoma, and patients developing unilateral and bilateral ocular adnexal lymphoid proliferations did not differ significantly with respect to age, sex, presenting complaints, duration of symptoms, or ophthalmic findings. Classifying ocular adnexal lymphoid proliferations into benign and malignant categories by histopathologic criteria and into polyclonal and monoclonal B cell categories by immunophenotypic criteria was not useful in predicting eventual outcome, including the occurrence of extraocular lymphoma. However, the clinicopathologic characteristics did differ according to the anatomic site of involvement and histopathology of the ocular adnexal lymphoid proliferations. Lymphoid infiltrates of the conjunctiva were associated with a lower incidence of extra-ocular lymphoma (20%) than were those of the orbit and eyelid, 35% and 67%, respectively (statistically significant, P less than .03). Ocular adnexal small lymphocytic and intermediate lymphocytic lymphomas were less often associated with extra-ocular lymphoma than were ocular adnexal lymphomas of all other histologic types, 27% and 46%, respectively (P less than .09). However, the single most important and statistically significant prognostic factor in these patients was the extent of disease at the time of presentation with an ocular adnexal lymphoid proliferation (P less than .001). Eighty-six percent of patients presenting with a unilateral or bilateral clinical stage lE ocular adnexal lymphoid proliferation, regardless of the histopathology or the immunophenotype, had a benign indolent clinical course and failed to develop ocular or extra-ocular lymphoma during a median follow-up period of 51 months. The results of this study substantially improve our understanding of extranodal small lymphocytic proliferations in general, and those of the ocular adnexa in particular.

Immunohistochemical and ultrastructural studies on the exenterated orbital tissues of a patient with graves' disease

The exenterated orbital contents obtained post mortem from a 47-year-old man who had an eight-month history of treated hyperthyroidism and a two-month history of visual complaints were examined histopathologically, immunohistochemically, and by electron microscopy. All of the extraocular muscles were massively enlarged, due to early diffuse endomysial fibrosis, mucopolysaccharide deposition, and a predominantly perivascular lymphocytic and plasmacytic infiltration. Histochemical stains revealed that the intramuscular mucopolysaccharides were weakly sulfated and polycarboxylated, establishing that they were products of fibroblastic activation rather than derived from mast cells. Subsarcolemmal deposits in the myofibers were shown by electron microscopy to be collections of glycogen rosettes with intermixed lipid deposits. These inclusions were interpreted as secondary phenomena due to abnormal muscle energetics from restrictions in contractility, and not as evidence of a primary degeneration of the extraocular muscle fibers themselves. The sarcomeric organization of the striated muscle cells was undisturbed, and therefore the pathologic changes occurred int he interstitial space of the endomysium. A monoclonal antibody specific for neurofilaments (antibody 4.3 F9) revealed, in comparison with normal controls, a preferential loss of large-type axons of the proximal segment of the orbital portion of the optic nerve as well as in the intracanalicular portion. The axonal loss was associated with a mildly increased number of astrocytes as demonstrated by an antibody against glial fibrillary acidic protein. The meninges of the optic nerve, the orbital fat, and the tendons of the extraocular muscles were uninflamed. The foregoing findings are compatible with a compressive optic neuropathy mediated by the massively swollen extraocular muscles impinging upon the optic nerve at the orbital apex.

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.

Orbital lymphoid neoplasms. A clinicopathologic study of 60 patients

Sixty cases of orbital lymphoid neoplasms originally accessioned as malignant lymphomas were analyzed histopathologically and the follow‐up data evaluated separately for each category as follows: inflammatory pseudo‐tumor, 5; reactive lymphoid hyperplasia, 8; atypical lymphoid hyperplasia, 7; and malignant lymphocytic lymphoma (classified according to Rappaport), 40. Significant clinical differences were not observed among these patients, suggesting that the lesions must be distinguished by histologic rather than clinical criteria. Systematic application of the histologic criteria discussed here improved diagnostic accuracy and our ability to predict clinical outcome as substantiated by follow‐up data. Two of 13 patients (15%) with benign pseudo‐lymphomas, 2 of 7 patients (29%) with atypical lymphoid hyperplasia, 2 of 8 patients (25%) with well differentiated lymphocytic lymphomas, and 22 of 32 patients (68%) with less well differentiated lymphocytic lymphomas either had or later developed systemic lymphomas. Thus, the degree of cytologic differentiation appears to be the single most important factor for determining the prognosis of patients with orbital lymphoid neoplasms. Cancer 46:576–589, 1980.

Benign conjunctival melanocytic lesions. Clinicopathologic features.

The common acquired conjunctival nevus usually undergoes progressive maturation and only exceptionally gives rise to conjunctival melanoma. Pure junctional nevi are rare except in childhood. Histologically, however, a junctional nevus may be indistinguishable from primary acquired melanosis (PAM) with atypia, a condition of middle-aged and elderly individuals that has a tendency to evolve into melanoma. Nevi in adolescents may attract a vigorous lymphocytic response and may cause clinical and histologic confusion with other entities, particularly a regressing nodule of melanoma that occurs predominantly in adults. Rarely, congenital conjunctival nevi are identified, sometimes in patients with adjacent congenital nevi of the eyelid. A variety of unusual nevi, including balloon-cell nevi, Spitz nevi, epithelioid cell nevi, dysplastic nevi, recurrent nevi, episcleral melanosis and the nevus of Ota, blue and cellular blue nevi, melanocytoma, and composite or mixed nevi all may be identified in the conjunctiva. Concepts of histogenesis as well as the clinical, light microscopic, and ultrastructural features of these and other benign pigmentary conditions of the conjunctiva are described.

Elastodysplasia and elastodystrophy as the pathologic bases of ocular pterygia and pinguecula

Specimens of normal conjunctiva from three adult patients were examined by electron microscopy, which revealed normal elastogenesis in the substantia propria, but more prominently, in the episcleral tissues. Ultrastructural examination of eight pterygia and three pinguecula also disclosed evidence of elastogenesis, but in these lesions the morphogenetic sequence of fiber formation was distorted, and the elastic fibers were abnormal. The zone of hyalinization of the substantia propria immediately beneath the epithelium was the only site that manifested clear-cut evidence of collagen degeneration, which assumed the forms of effacement of the longitudinal periodicity of the collagen fibers, and of microfibrillar unfurling of the ends of the collagen fibers. Fibroblastic activity and elastic fiber formation were inconspicuous in this region. Beneath the hyalinized zone were collections of eosinophilic granular material. This material was shown ultrastructurally to be composed of excessive numbers of hollow-centered microfibrils (an elastic fiber precursor), with a tendency to clump centrally in the larger aggregated sheets and to acquire electron-dense inclusions. Numerous fibroblasts were found within this material. Finally, the elastotic fibers of light microscopy represented an abnormal maturational phase of elastic fiber production. These abnormal elastic fibers had microfibrils at their peripheries, but numerous electron-dense inclusions were associated with focal zones of amorphous elastin deposition. Occasionally histiocytes appeared to be engulfing these abnormal fibers. We have concluded that a large component of pinguecula and pterygia is the result of newly synthesized elastic fiber precursors and abnormal maturational forms of elastic fibers (elastodysplasia) that undergo secondary degeneration (elastodystrophy). These structures are presumed to be elaborated by actinically damaged fibroblasts of the substantia propria.

Retinoblastoma and intracranial malignancy

The occurrence of independent brain tumors in two patients with retinoblastoma is described. One patient with well‐differentiated biliteral retinoblastomas developed, over two years later, a pineal tumor but no other metastatic lesions. The pineal tumor was composed of small neuroblastic cells and a second population of larger cells with vesicular nuclei and more abundant cytoplasm. This feature is not characteristic of either primary or metastatic retinoblastoma. In the second patient the symptoms of a brain tumor led to the discovery of a small uniocular, well‐differentiated retinoblastoma. The brain tumor was retrochiasmal, highly differentiated (showing areas of photoreceptor differentiation), and interpreted as an ectopic nonmetastatic retinoblastoma. The possible histogenetic origins of the brain tumors are discussed. Patients who develop symptoms of a brain tumor after a prolonged interval since the treatment of their ocular tumors should be suspected of harboring a second intracranial primary.

IgG4-Related Systemic Disease as a Cause of “Idiopathic” Orbital Inflammation, Including Orbital Myositis, and Trigeminal Nerve Involvement

IgG4-related systemic disease (IgG4-RD) is an inflammatory condition of unknown etiology that has been identified as the cause of tumefactive lesions in a number of tissues and organs. The role of the IgG4 remains to be clarified fully, but the histopathologic diagnosis hinges upon the finding of IgG4-bearing plasma cells in addition to characteristic morphologic features, with or without elevated seum IgG4. We present a 56-year-old man with orbital pseudotumor in whom, after 30 years of intractable disease, biopsy showed IgG4-RD involving the lacrimal gland, extraocular muscles, intraconal fat, and trigeminal nerve. Six months after initiating treatment with rituximab, his disease remained dormant, with improvement in his proptosis and normalization of serum IgG4 levels. We review the differential of idiopathic orbital inflammatory disease, including IgG4-RD, and emphasize the need for biopsy for accurate diagnosis and to guide appropriate treatment.

Combined Clinical and Computed Tomographic Diagnosis of Primary Lacrimal Fossa Lesions

We studied 39 patients who had solid mass-lesions primary in the lacrimal gland by computed tomography and reviewed their clinical histories. Twenty-three patients had either inflammatory conditions (16 cases) or lymphoid tumors (seven cases), with average symptomatic periods of less than a year. In this group, soft-tissue contour analysis in the axial and corneal projections demonstrated diffuse, compressed, and molded enlargements of the lacrimal gland in an oblong fashion, and there were no associated bone defects. Sixteen parenchymal benign or malignant tumors (six benign mixed tumors, one schwannoma, and nine malignant epithelial tumors) exhibited rounded or globular soft-tissue outlines and were frequently associated with contiguous bone changes. The benign tumors had smooth encapsulated outlines at their margins, whereas the malignant tumors displayed microserrations indicative of infiltration. The patients with the benign mixed tumors had had symptoms, on the average, for more than a year, whereas those with epithelial malignancies became symptomatic or had a preexisting benign mixed tumor that became exacerbated in periods of less than six months. Contour analysis of the soft-tissue mass depicted in coronal and axial tomograms is a valuable adjunct that leads to more accurate preoperative diagnosis when combined with a radiographic search for bone changes and the clinical history. Once a diagnosis regarding the presumptive lesional family has been made preoperatively, corticosteroid therapy may be instituted for acute inflammation and biopsies through the eyelid should be performed for suspected chronic inflammations, lymphoid lesions, or epithelial malignancies. A lateral orbitotomy without prior biopsy should be performed for rounded, well-encapsulated masses of long duration that are likely to be benign mixed tumors.