Nodular Adenomatosis of Iris Pigment Epithelium

Mark o. M. Tso, M.D., Morton F. Goldberg, M.D., and Joel Sugar, M.D.

A 62-year-old man manifested multiple nodulargrowths in his left iris and unilateral glaucoma.Detailed clinical and pathologic studies showedthat these lesions were adenomas derived from thespurs of Fuchs, Michel, and Grunert in the irispigment epithelium. We suggest terming this newlydescribed entity nodular adenomatosis of the irispigment epithelium and propose a classification ofprimary neoplastic lesions of the iris.

PRIMARY NEOPLASTIC LESIONS of the iris differenti­ate in a variety of ways, depending on their deriva­tion from the neural crest, neural ectoderm, or softtissue stroma.>' From the neural cresr'" develop thenormal iris stromal melanocytes, as well as freckles,nevi, and malignant melanomas. From the neuraltube,1-4·1O the medullary epithelium differentiatesinto the anterior and posterior layers of iris pigmentepithelium, the smooth muscle of the dilato andsphincter muscles, the spurs of Fuchs, Michel, andGrunert, and the clump cells of Koganei (type II) andneoplastic lesions of these structures. 3,11-20 Neo­plasms of neural crest origin are common. Neoplasticlesions derived from the neural tube are infrequentlyseen, but they show a broad spectrum of differentia­tion.

We describe the clinical features of a patient inwhom multiple neoplastic proliferations arose fromthe spurs of Fuchs, Michel, and Grunert in the irispigment epithelium, and the light and electron mi­croscopic features of the lesions. We do not believethat this entity has been described previously in theliterature and propose to term it nodular adenomato­sis of the iris pigment epithelium.

Case Report

A 62-year-old white man complained of blurredvision in his left eye that was of recent onset. His

From the Department of Ophthalmology, University of Il1inoisat Chicago, Eye and Ear Infirmary, Chicago, Illinois. This studywas supported in part by core grant IP30EY01792 from theNational Eye Institute.

Reprint requests to Mark O. M. Tso, M.D., Department ofOphthalmology, University of Il1inois Eye and Ear Infirmary,1855 W. Taylor si.. Chicago, IL 60612.

visual acuity was R.E.: 20/20 and L.E.: 20/30. Multi­ple small, honey-colored, nodular lesions (Fig. 1)were noted on the anterior surface of the iris at the12, 3, and 9 o'clock meridians. One large nodule,located between the 6 and 8 o'clock meridians, mea­sured approximately 3 mm in diameter and infiltrat­ed the anterior chamber angle. Multiple smaller pig­mented lesions also were observed in the inferiorhalf of the chamber angle. A slit-lamp examinationshowed the lesions to be semitransparent with afluffy surface. The base of these tumors seemed tooriginate from the deep stroma of the iris. Fineneovascularization with capillary loops ramified intothe tumor nodules. In the right eye, only small, flat,pigmented iris freckles were observed, and the re­sults of gonioscopic, fundus, and visual field exami­nations were normal.

The intraocular pressure, obtained by applanationtonometry, was R.E.: 13 mm Hg and L.E.: 22 mm Hg.Ophthalmoscopy disclosed a pale and totally cuppedleft optic disk. Goldmann visual fields showed adense inferior centrocecal scotoma on the left with asuperonasal step extending to fixation. The patientwas referred to an internist for systemic examinationfor a possible primary neoplasm with metastasis tothe eye. A chest roentgenogram, upper and lowergastrointestinal tract contrast studies, an intrave­nous pyelogram, bone and thyroid scans, and agallbladder series were normal.

A left-sector iridectomy was performed betweenthe 6 and 8 o'clock meridians to include the large anda smaller lesions. A fluorescein angiogram of the irisperformed after the surgical excision demonstratedlate leakage from the neovascularization of the re­maining nodules. Six years after iridectomy, thelesions remained unchanged and the intraocularpressure of the left eye was controlled medically by aregimen of pilocarpine and timolol maleate.

Light microscopic findings-A large tumor ex­tended from the iris pigment epithelium through thefull-thickness iris stroma to the anterior border ofthe iris (Fig. 2, middle left). In the anterior region ofthe tumor, the cells were arranged as interlacingnests (Fig. 2, middle right), and the connective tis­sue stroma was eosinophilic and fibrillary. Deep inthe iris stroma, the tumor cells were arranged asdiscrete nests of pseudoacini (Fig. 2, bottom left). Afew isolated tumor cells were scattered in the stroma

©AMERICAN JOURNAL OF OPHTHALMOLOGY 100:87-95, JULY, 1985 87

88 AMERICAN JOURNAL OF OPHTHALMOLOGY July, 1985

Fig. 1 (Tso, Goldberg, and Sugar). Top left, Large nodular lesion with fluffy surface is seen between the 6 and 8 o'clockmeridians (black arrows). Note smaller lesions (white arrows) at 12 and 9 o'clock meridians. Top right, Slit-lamp photograph ofthe large lesion (arrows) noted in top left, showing nodular fluffy surface and infiltration into the chamber angle. Bottom left,Iris fluorescein angiogram performed after surgical iridectomy demonstrates neovascularization of small nodules (arrows).Bottom right, Neovascularization of iris nodules (arrow) leaks fluorescein in the late phase of angiogram.

near the iris pigment epithelium (Fig. 2, bottom left).Thin-walled capillaries, which were distinct from thenormal thick-walled iris vasculature, ramified intothe tumor (Fig. 2, bottom right). Away from the maintumor, a small cluster of tumor cells seemed to growfrom the iris pigment epithelium into the iris stromaas a separate focus.

Cytologically, the tumor cells exhibited distinctepithelial characteristics of large ovoid nuclei andprominent nucleoli (Fig. 2, bottom right). Most of

. the cells had abundant eosinophilic cytoplasm withfew melanin granules. There was no nuclear pleo­morphism. Binucleated, multinucleated, and spindlecells were absent. No mitotic activity was noted.

Electron microscopic findings-The tumor cells,which were arranged in nests, had distinct polarity(Fig. 3). The apices of these cells had numerous villi,which interdigitated with those of the adjacent cellsto form a tangle of cell processes in the center of thenest. No definitive lumen formation was noted. Thebase of the cells was lined by a discrete and delicatebasement membrane (Fig. 4). In some places, cellprocesses extended through the basement mem­brane into the iris stroma. The tumor cells werejoined by abundant desmosome-like cell junctions(Figs. 3 and 4). The basal plasmalemma of the tumorcells showed focal densities and caveolae, whichsimulated those of smooth muscle cells (Fig. 4). The

Vol. 100, No. 1 Nodular Adenomatosis 89

,

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,~ .i~. I'.~,h~~

.~ ~ ...:-::~~:~~.},.... ~_. ----Fig. 2 (Tso, Goldberg, and Sugar). Top, Iris tumor extends from iris pigment epithelium to anterior border of the iris,

occupying full-thickness iris stroma (X 45). Middle left, In the anterior region of the tumor, cells are arranged as interlacingnests (x380). Middle right, In the posterior region of the tumor, cells appear as nests of pseudoacini (x380). Bottom left,Thin-walled capillaries (c) ramify in the tumor stroma. The tumor cells have large ovoid nuclei and prominent nucleoli. Somecells have few melanin granules (arrows) (x 400). Bottom right, A separate focus of tumor cells appears as small clustersgrowing from the pigment epithelium into the iris stroma (x 380).

90 AMERICAN JOURNAL OF OPHTHALMOLOGY July, 1985

Fig. 3 (Tso, Goldberg, and Sugar). A nest of tumor cells discloses apical villi that form a tangle of cell processes in nest'scenter. No definitive lumen is seen (X 5,250). Inset shows the circled area under high-power magnification. Adjacent cells arejoined by desmosome-like cell junctions (arrows) (x 12,000).

nuclei of the tumor cells were hyperconvoluted andhad prominent nucleoli. Occasional cells showedvacuolated degeneration within the nucleus (Fig. 5).Abundant smooth- and rough-surfaced endoplasmicreticulum and mitochondria were seen in the cyto­plasm of the tumor cells. Fine interwoven filamentswithout focal density also were noted (Fig. 4). Twotypes of melanin granules were observed: (1) large,ovoid, and frequently homogeneously melanizedmelanosomes closely resembling the melanin gran­ules of the iris pigment epithelium (Fig. 6); and (2)much smaller and irregular clusters of fine granuleswith varying degrees of melanization (Figs. 4 and 6).In most instances the two types of granules werenoted in different cells in each nest; occasionally,both types of melanin granules were found in asingle cell (Fig. 6). Clusters of tumor cells containingthe larger ovoid melanosomes were mostly notedbetween iris pigment epithelium and the dilatormuscles (Fig. 7).

Discussion

Our patient had multiple honey-colored nodularlesions in the iris pigment epithelium that infiltratedthe stroma anteriorly. These lesions were vascular­ized by loops of capillaries that exhibited late fluores­cein leakage on iris angiography and showed someresemblance to the iris angiographic patterns ofgroup III iris melanotic lesions described by Jakobiecand co-workers." The growths infiltrated the cham­ber angle to produce glaucoma. The multiple focalmanifestation of these nodules led us to suspectmetastatic lesions; however, no primary neoplasmwas found. Six years after resection of the largest irisnodule, the glaucoma was controlled medically; neo­plastic infiltration of the chamber angle did notprogress and the remaining smaller nodules did notcontinue to grow. The clinical appearance of theseiris lesions was distinctive.

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Fig. 4 (Tso, Goldberg, and Sugar). Note tumor cells with distinct basement membrane (arrowheads). Multiple poorly formeddesmosomes join adjacent tumor cells (arrows). The tumor cell has prominent nucleoli, abundant mitochondria, and bundles ofinterlacing filaments. Small clusters of irregularly melanized granules (M) are seen scattered in the cytoplasm (X 15,000). Upperinset demonstrates clusters of small granules (arrowheads) with varying degrees of melanization between bundles of finefilaments (arrows) (x 45,000). Lower inset shows cell processes (P) extending through basement membrane (arrowheads) to theiris stroma. Caveolae (arrows) are seen in the basal plasmalemma of the tumor cells (arrows) (x 30,000).

Pathologically, the tumor consisted of nests ofepithelioid "nevoid" cells, which were distinctlypolarized and had a discrete basement membraneand apical villi. Numerous desmosome-like junc­tions joined the adjacent cells. These epithelial char­acteristics suggested that the tumor derived from theiris pigment epithelium. The large, football-shaped,homogeneously melanized melanosomes in thetumor cells further support the pigment epithelialorigin of the tumors. Because of the epithelial charac­teristics of the tumor cells and their multiple focalorigin in the iris, we propose to term this condi-

tion "nodular adenomatosis of the iris pigment epi­thelium."

Other cytologic features of these tumor cells in­cluded abundant intracytoplasmic filaments, plas­malemmal densities, and caveolae. Furthermore, thetumor cells were seen to mingle with the well­differentiated smooth muscle cells of the iris. Thesefeatures suggest that some of the cells were differen­tiating in the direction of the smooth muscles.

Large, oval, homogeneously melanized melan­osomes, which were noted in some of the tumorcells, resemble those of iris pigment epithelium, and

92 AMERICAN JOURNAL OF OPHTHALMOLOGY July, 1985

Fig. 5 (Tso, Goldberg, and Sugar). A tumor cell exhibits vacuolated degeneration (D) within the nucleus (x 17,000).

the clusters of small. irregularly melanized granulesthat are typically seen in iris nevi and malignantmelanomas were also observed in other tumor cells.Occasionally, these two types of melanin granuleswere simultaneously present in a few of the tumorcells. This observation confirms that the tumor cellswere differentiating in multiple directions.

The spurs of Fuchs, Michel, and Grunert have longbeen recognized as normal pigment epithelialgrowths extending from the anterior iris pigmentepithelium into the smooth muscle bundles of theiris,22 with which clump cells of Koganei are asso­elated." Wobmann and Fine10 examined the clumpcells of Koganei by light and electron microscopy andconcluded that two types of pigment cells exist. TypeI cells are pigment-laden macrophages and type IIcells are neuroepithelial cells derived from the spursof the anterior iris pigment epithelium. The conceptthat the spurs are "leftover" pigment epithelial cellsof leiomyogenesis is generally accepted. 10 We suspectthat the tumor reported herein originated from the

spurs of Fuchs, Michel, and Grunert for three rea­sons: (1) the tumor cells showed pigment epithelialand smooth muscle cell characteristics; (2) the tumorcells were found between the anterior pigment epi­thelium and smooth muscle cells of the iris (Fig. 7);and (3) the remarkable multifocal origin of the tumorparalleled the multiple growths of these anatomicspurs.

Nodular adenomatosis may be differentiated fromadenoma of iris pigment epithelium, which frequent­ly occurs as a deeply pigmented lesion bulging to­ward the posterior chamber and pushing the irisanteriorly;" Shields and co-workers" reported anadenoma of the iris pigment epithelium that invadedthe iris stroma anteriorly. Pathologically, adenomaof the iris pigment epithelium consists of deeplypigmented epithelial cells in an acinar or cordiikearrangement that are separated by delicate connec­tive tissue. Offret and Saraux" described the electronmicroscopic features of two types of cells in an irispigment epithelial adenoma: a dark cell with many

Vol. 100, No.1 Nodular Adenomatosis 93

Fig. 6 (Tso, Goldberg, and Sugar). Two distinct types of melanin granules were observed: large and homogeneouslymelanized melanosomes (arrowheads) resembling melanin granules of iris pigment epithelium, and smaller granules ofvarying degrees of melanization (arrows). Both types of granules are seen within the cytoplasm of a cell (x 15,000).

pigment granules and a light cell with intercellularvacuoles. These tumor cells showed polarity withbasement membrane, cell junctions, and villi. Largemelanin granules resembling those of iris pigmentepithelium also were present.

Benign epithelioid cell nevi, as described by [ako­biec, Moorman, and jones," may closely resemblethis entity. However, the epithelioid cell nevi charac­teristically show cellular heterogeneity, consisting ofmononuclear, binuclear, and multinuclear epitheli­oid cells and elongated myoid cells with deeplyeosinophilic cytoplasm. These features were not ob­served in the nodular adenomatosis. Furthermore,

epithelioid cell nevi show poorly developed desmo­somes and an absence of large pigment epithelialmelanin granules, but exhibit well-differentiated cy­toplasmic leptomeres.

Nodular adenomatosis also should be differenti­ated from leiomyoma of the iris;" which classicallydemonstrates smooth muscle differentiation, andmedulloepithelioma of the iris," which may differen­tiate into multiple cell lines including rhabdomyosar­coma. The pigment epithelial characteristics and thesmooth muscle features of the cells of the nodularadenomatosis described herein suggest that this le­sion may be a variant of medulloepithelioma.

94 AMERICAN JOURNAL OF OPHTHALMOLOGY July, 1985

Fig. 7 (Tso, Goldberg, and Sugar). Scattered tumor cells (T) with hyperconvoluted nuclear membrane are noted between irispigment epithelium (PE) and smooth iris musculature (1M) (x 6(000).

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We would like to propose a new classification ofprimary neoplastic lesions of the iris. (1) Melanoticlesions arising from the neural crest include irisfreckles, nevi, melanocytomas, epithelioid cell nevi,and malignant melanomas. These lesions are ob­served in the iris stroma with various degrees ofpigmentation. (2) Tumors derived from the posterioriris epithelium, such as the benign adenomas of theiris pigment epithelium reported by Morris and Hen­kind." mostly extend into the posterior chamber asdeeply pigmented nodular growths. (3) Tumors de­velop from the anterior iris pigment epithelium,including leiomyoma, nodular adenomatosis, andmedulloepithelioma and grow into the iris stroma.They are variably pigmented and show a wide spec­trum of differentiation. (4) Hamartomas and otherproliferative dysgenetic lesions from the iris pigmentepithelium are exemplified by the cases reported byKlein! and Iakobiec and colleagues.! While hamarto­mas are not strictly neoplastic lesions, they are in­cluded in this classification because clinically theymay resemble other neoplasms of the iris. (5) Pri­mary soft tissue tumors include angiomata and neu­rofibromata." This classification has the distinct ad­vantage of grouping lesions embryologically as wellas anatomically in different layers of the iris and maybe helpful in the differential diagnosis of primaryiridic neoplasms.

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