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1 CLINICAL SCIENCES Combined Nevi of the Conjunctiva J. rooks Crawford, MD; Edward L. Howes, Jr, MD; Devron H. Char, MD Objective: To report the clinical and histologic features of combined nevi of the conjunctiva, a type of nevus that is not uncommon in the skin but rarely has been reported in the conjunctiva. Methods: Conjunctival nevi and melanomas in the files of the University of California at San Francisco Eye Pathology Laboratory from 1984 to 1999 were reviewed for the presence of features of both standard nevocytic nevi and blue nevi. Clinical histories and, when available, clinical photographs were obtained. Results: Thirty combined nevi were discovered between 1984 and One case before 1984 had been incorrectly diagnosed as a junctional nevus. The dendritic and spindle-shaped blue nevus cells had been overlooked because they were not recognized as distinct from the standard nevocytic nevus cells. The recognition of blue as well as a brown color, a deep as well as a superficial component in the lesion, or a history of pigmentation since birth may help to establish the correct clinical diagnosis and prevent an unnecessarily deep surgical resection. Although growth of the lesion or satellites in some may favor a clinical diagnosis of melanoma, no lesions in this series were malignant. Conclusion: Despite a paucity of reports of combined nevi of the conjunctiva in the medical literature, this type of nevus, a combination of a nevocytic and a blue nevus, is common and has been overlooked in the past. Arch Ophthalmol. 1999;117: From the Department of Ophthalmology, University of California, San Francisco. COMINED NEVI are composed of both nevocellular cells and blue nevus cells. The former may be pigmented or nonpigmented and have a junctional, compound, or subepithelial distribution; the latter are spindle-shaped or multipolar dendritic cells, usually laden with fine melanin granules. In 1906, Teiche 1 predicted that such a combination could occur; in 1912, Dubreuilh and Petges 2 described it in the skin. Lund and Kraus 3 called these nevi the True and the lue. Many combined nevi of the See also page 1131 skin have since been described, but rarely has such a lesion been described in the conjunctiva. In 1985, Jakobiec and his colleagues reported a single case in the conjunctiva and stated: A mixed nevus of the conjunctiva has never been reported before. 4(p112) They believed that these lesions probably occurred more frequently in the conjunctiva than the literature would suggest. However, since their report, no additional cases have been reported. We agree that these lesions are relatively common in the conjunctiva, but have been overlooked in the past for various reasons. REPORT OF CASES CASE 7 A 67-year-old white man had a pigmented lesion of the conjunctiva of the right eye at the limbus for at least 20 to 30 years. Recently, it had become darker and more vascular, but did not seem to grow. It had intrisic vascularity, cysts within the 2-mm thick lesion, and a few satellite lesions. The clinical diagnosis was conjunctival melanoma. It was excised and the base was treated with cryotherapy. CASE 8 An 18-year-old white woman had a pigmented lesion on the temporal bulbar conjunctiva of the left eye since birth, but it had grown to 3 times its original size. It was gelatinous, was movable over the sclera, and 1121

2 MATERIALS AND METHODS We reviewed all of the cases on file for 1984 to 1999 in the Eye Pathology Laboratory, University of California at San Francisco, that were coded as either a nevus or a melanoma of the conjunctiva. An ophthalmic pathologist (J..C.) and a general pathologist with a special interest and expertise in ophthalmic pathology (E.L.H.) independently reviewed all the glass slides prepared from each case. Only cases in which both the reviewers agreed with the diagnosis of a combined nevus are included in this series. efore 1984, no lesion was correctly diagnosed as a combined nevus (case 1, Figure 1 and Figure 2). We attempted to obtain clinical histories for all the patients and, when they were available, clinical photographs. We also attempted to gather follow-up information on all the cases, but since many of these cases were referred from outside sources, this information was often impossible to obtain. Table 1. Demographic and Tumor Characteristics* Figure 1. Case 1. Combined nevus located at the limbus. Note the corneal involvement. Case No./ Age, y/sex Location of Lesion Clinical Diagnosis 1/NA/F Limbus Nevus 2/28/M Limbus Rule out melanoma 3/27/F ulbar conjunctiva Pigmented tumor 4/13/M Limbus Rule out melanoma 5/9/M Caruncle Nevus 6/14/F Limbus Nevus 7/67/M Limbus Melanoma 8/18/F ulbar conjunctiva Primary acquired melanoma 9/26/F Conjunctiva Nevus 10/41/M Plica Pigmented tumor 11/46/F Conjunctiva Nevus 12/45/F ulbar conjunctiva Nevus 13/73/M Conjunctiva Pigmented tumor 14/15/F Conjunctiva Primary acquired melanoma 15/38/F Conjunctiva Melanoma 16/26/M Limbus Foreign body 17/72/F Lower eyelid margin Nevus 18/37/M Conjunctiva Rule out melanoma 19/27/M Lower eyelid margin Pigmented tumor 20/14/F Conjunctiva Nevus 21/37/F Caruncle Pigmented tumor 22/29/M Plica Pigmented tumor 23/52/F Upper eyelid margin Rule out melanoma and basal cell carcinoma 24/69/M Conjunctiva Neoplasm 25/24/F Limbus Tumor 26/34/F ulbar conjunctiva Primary acquired melanoma 27/70/F Eyelid margin Pigmented tumor 28/27/M Caruncle Pigmented tumor 29/33/M Limbus Melanoma 30/37/M Limbus Rule out melanoma 31/48/M Conjunctiva Nevus and sector melanosis *NA indicates not available. had a few cysts and variable pigment. The clinical diagnosis was primary acquired melanosis. The lesion was excised. CASE 29 Figure 2. Case 1. Original pathologic diagnosis was junctional nevus. Note heavily pigmented, dendritic, and spindle-shaped nevus cells (arrow) at the deep edge of the specimen beneath the junctional and subepithelial nevocytic nevus cells (hematoxylin-eosin, original magnification 100). A 33-year-old Hispanic man had a pigmented lesion in the conjunctiva of the right eye for as long as he could remember. Recently, it had enlarged and grown closer to the limbus. It was 1.5 mm thick, with vessels on its surface and some microcysts in its center. The clinical diagnosis was melanoma. A superficial corneal and conjunctival resection was done. 1122

3 Table 2. History and Characteristics of Nevi* Case No. History of Growth? Presence of Clinical Cyst? Cysts on Pathological Examination? Comments 1 NA NA No 2 Yes, for 3 months NA No Separate sclera 3 Yes NA Yes 4 Yes, recurrent NA Yes 5 No No NA 6 Yes, recurrent NA No Satellite lesions 7 No, increased pigment Yes Yes and vessels 8 Yes, tripled in size Yes Yes 9 NA NA No 10 No Yes No 11 NA NA No 12 No No No Patient thought it was a foreign body 13 NA NA No 14 NA NA No 15 No NA Yes Diagnosis by general pathologist as melanoma 16 NA NA No 17 NA NA No 18 Yes, for 1 year NA No 19 NA NA No 20 NA NA No Diagnosis by pathologist as nevus 21 NA NA No 22 Yes NA Yes Satellite lesions 23 No, discovered by patient 3 weeks before NA No Patient concerned because sister died of melanoma 24 NA NA Yes 25 NA NA No 26 No NA No Inflamed for 1 wk 27 NA NA No 28 Yes NA No 29 Yes Yes Yes 30 Yes Yes Yes Inflamed for 3 wk 31 Yes Yes Yes Calcified concretions in cysts *NA indicates not available. Cases 6, 7, 8, 15, 25, 26, 29, 30, and 31 had had lesions since childhood. CASE 30 A 37-year-old Hispanic man had a pigmented lesion in the conjunctiva of his right eye since childhood (possibly a birthmark). It suddenly became irritated, painful, and inflamed, with involvement of 180 of conjunctiva and episclera. The redness subsided after the use of topical steroids. The presence of microcysts suggested a nevus that had undergone malignant transformation to a melanoma. RESULTS Combined nevi account for 20% to 40% of the conjunctival nevi that we receive in our laboratory for diagnosis each year. Twenty-eight (33%) of the 85 conjunctival nevi that we reviewed for the 10-year period from 1989 to 1999 were combined nevi. Thirty-one combined nevi of the conjunctiva have been documented (Table 1 and Table 2). The patient s age at the time of excision varied from 9 to 72 years. At least 9 patients had a history of conjunctival pigmentation since early childhood; at least 11 of the lesions were growing. Nine involved the limbus (Figures 1, 3, and 4), 4 were located at the eyelid margin, and 5 involved the caruncle or plica semilunaris. The clinical diagnoses were melanoma or rule out melanoma in 8 cases and primary acquired melanosis (potentially malignant neoplasms) in 3 cases. Two had the appearance of a foreign body. At least 6 had clinically visible cysts (Figures 3 and 4), and 10 were observed on pathologic examination. Two had satellite lesions that made them look like malignant neoplasms (Figure 5). Most often the blue nevus component was smaller and deeper than the nevocytic nevus (Figures 2, 6, 7, and 8). Sometimes the two components were located adjacent to each other at the same depth (Figures 3 and 9) and sometimes the blue nevus was superficial to the nevocytic nevus (Figures 4 and 10, ); occasionally the two components were mixed together (Figure 11). In some cases the blue nevus component was very limited (Figure 10, ). The nevocytic components varied greatly in their degree of pigmentation, but the blue nevus component was moderately to heavily pigmented. In one case, the surgical resection included a separate piece of superficial scleral tissue (Figure 8). None of the lesions had a malignant component or recurred. 1123

4 A C Figure 3. Case 30. A, Combined nevus., Epithelial cysts, nests of nevocytic nevus cells, and a few heavily pigmented, spindle-shaped blue nevus cells (hematoxylin-eosin, original magnification 50). C, Pigmented dendritic and spindle-shaped blue nevus cells in an area adjacent to the nevocytic component of the combined nevus (hematoxylin-eosin, original magnification 100). A Figure 4. Case 29. A, Combined nevus at the limbus., Pigmented spindle-shaped and dendritic blue nevus cells superficial to nevocytic nevus cells and epithelial cysts (hematoxylin-eosin, original magnification 50). COMMENT Some neural crest cells migrate to the surface epithelium and become dendritic melanocytes or nevocytes; these nevocytes become junctional nevi, compound nevi, or subepithelial nevi. Other neural crest cells do not complete the migration to the epithelium and are left behind in the subepithelial tissue to form neurocristic hamartomas, such as ocular melanosis, oculodermal melanosis, and blue nevi. lue nevi differ from ocular and oculodermal melanoses in that they are more localized, have palpable thickness, and are more cellular. The combined nevi included in this series are composed of at least a few nevocellular nevus cells with or without pigmentation, often forming nests, and a few blue nevus type cells, usually more heavily pigmented, consisting of dendritic spindle-shaped cells with long axes parallel to the conjunctival surface. We did not include the type of ocular combined nevus described by Johnson 5 (a scleral blue nevus and a choroidal nevus), phakomatosis pigmentovascularis 6 (a nevus flammeus combined with a nevus of Ota), or collision tumors 7 (the association of two different tumors, such as a nevocytic nevus and a basal cell carcinoma). 1124

5 Figure 5. Case 6. Combined nevus with satellite lesions. Note the slate-gray color of one of the satellite lesions. Large series of combined nevi of the skin have been reported. Gartman and Müller 8 found 79 cases in a series of 7733pigmentedskinlesionsovera30-yearperiod.Fletcher and Sagebiel 9 reported 50 cases from the Dermatopathology Department, University of California at San Francisco, over a period of 4 years. Pulitzer and his colleagues 10 described95casesinpatientsagedfrom3to74years.although the clinical diagnosis in many of these cases was often malignant melanoma, most but not all 11 of the reported combined nevi of the skin have been benign. Although this type of nevus is common, only a single case of a combined nevus of the conjunctiva has previously been reported 4 ; recent comprehensive articles on pigmented conjunctival lesions do not mention them. 12,13 They have been overlooked in the past because the blue nevus cells were few, not in every histologic section, or not recognized as distinct from the standard nevocytic nevus cells. All the reported conjunctival combined nevi (the 31 cases in this series and the first one reported by Jakobiec et al 4 ) have been benign, although 11 had a potentially malignant clinical diagnosis (8 were suspected to Figure 6. Case 15. Note dendritic and spindle-shaped blue nevus cells beneath nests and sheets of less pigmented nevocytic cells and epithelial cysts. A general pathologist diagnosed this as a melanoma. Figure 7. Case 8. Pigmented, spindle-shaped, and dendritic blue nevus cells (arrow) beneath nests of amelanotic nevocytic cells and epithelial cysts (hematoxylin-eosin, original magnification 50). A Figure 8. Case 2. A, Superficial biopsy specimen, showing epithelial inclusions and sheets of nevocytic cells beneath the surface epithelium; more pigmented spindle-shaped blue nevus cells (arrow) appear at the deep margin of the biopsy specimen (hematoxylin-eosin, original magnification 50)., Deeper biopsy specimens showing spindle-shaped, pigmented blue nevus cells (arrow) in superficial layers of sclera (hematoxylin-eosin, original magnification 50). 1125

6 A Figure 9. Case 6. A, Pigmented spindle-shaped and dendritic blue nevus cells (arrow) (hematoxylin-eosin, original magnification 50)., Nest of nevocytic cells (arrows) (hematoxylin-eosin, original magnification 100). A Figure 10. Case 31. A, Epithelial cysts; some contain calcified concretions (hematoxylin-eosin, original magnification 30)., A small group of spindle-shaped blue nevus cells (arrow) over and adjacent to nests and sheets of nevocytic cells and epithelial cysts (hematoxylin-eosin, original magnification 50). be melanomas and 3 to be primary acquired melanosis). A history of growth in the lesion or the presence of satellite lesions may have favored a clinical diagnosis of melanoma in some of the cases. lue nevus cells, like the cells in ocular and oculodermal melanosis, are usually located deeper than most nevocytic nevus cells, may be bluer or grayer than usual nevi, and have usually been pigmented since early in childhood. These features, if recognized, may help provide the correct clinical diagnosis. A correct diagnosis may make surgical excision unnecessary; if an excision is necessary, the surgeon can avoid doing a deep excision that would involve the sclera. If excision is necessary because of the cosmetic defect, the superficial component could be excised and examined while the deeper pigment could presumably be eliminated with cryotherapy. One criticism of this series is the lack of a specific definition of the percentage of each type of cell in an individual lesion that is required to qualify it as a true combined nevus. Usually one cell type predominated, such as the blue nevus component in case 6 or the nevocytic component in most cases. We chose to include every le- 1126

7 sions, the nature of these tumors can often be suspected because of a history of a pigmented spot since birth or early childhood, the presence of microcysts within the lesion, or the presence of areas of blue or gray, perhaps in the deeper or even episcleral layers, along with areas of a more brownish color nearer the surface. The correct clinical diagnosis of these tumors may eliminate the need for an unnecessarily deep resection that involves the sclera. Figure 11. Case 14. Pigmented spindle-shaped and dendritic blue nevus cells (arrow) under and beside junctional and subepithelial nevocytic cells (hematoxylin-eosin, original magnification 50). sion in which at least one small group of cells of the smaller component (either nevocytic or blue) could be clearly identified. Also, the clinical histories are often sparse and lack detail. Therefore, the number of cases with a history of pigmentation since childhood, clinically visible cysts, or growth reflects the minimum incidence of these features. A third criticism is that we lack a follow-up history for many of the patients. This problem occurred in many of the reports of combined nevi of the skin and is the result of the referral nature of the series. Many of the cases were referred to our department from distant sources and we have been unable to obtain further information about the outcome of the patients. Questionnaires were sent to all of the referring physicians, but many were not completed because the patients had not been seen after an initial postoperative interval. We would like to assume that this is because the patients had no further trouble or recurrences. If they had a recurrence and saw a different physician, we believe our laboratory probably would have been contacted to ascertain the nature of the original lesion. However, we cannot be certain of this. CONCLUSION Combined nevi of the conjunctiva are not rare. They have been overlooked in the past because the blue nevus component of the lesion has not been recognized. Despite a clinical history of growth or the presence of satellite le- Accepted for publication June 23, Presented at the 135th annual meeting of the American Ophthalmological Society, Santa arbara, Calif, May 24, Reprints: J. rooks Crawford, MD, Hogan Eye Pathology Laboratory, ox 0730, K-219, 10 Kirkham St, San Francisco, CA REFERENCES 1. Tieche M. Über benigne Melanome (Chromatophorome) der haut-blaue Naevi. Virchows Arch Pathol Anat. 1906;186: Dubreuilh W, Petges G. Le naevus bleu. Ann Dermatol. 1911;2: Lund HZ, Kraus JM. Melanotic tumors of the skin. In: Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 1962;1(pt 3): Jakobiec FA, Zuckerman D, erlin AJ, Odell P, MacRae DW, Tuthill RJ. Unusual melanocytic nevi of the conjunctiva. Am J Ophthalmol. 1985;100: Johnson L. Ocular combined nevus: report of a case of scleral blue nevus associated with a choroidal nevus. Arch Ophthalmol. 1970;83: Teekhasaenee C, Ritch R. Glaucoma in phakomatosis pigmentovascularis. Ophthalmology. 1997;104: oyd AS, Rapini RP. Cutaneous collision tumors: an analysis of 69 cases and review of the literature. Am J Dermatopathol. 1994;16: Gartmann H, Müller H. Über das gemeinsame Vorkommen von blauem Naevus und Naevuszell-Naevus in ein und derselben Geschwulst ( combined nevus ). Z Hautkr. 1997;52: Fletcher V, Sagebiel RW. The combined nevus: mixed patterns of benign melanocytic lesions must be differentiated from malignant melanoma. In: Ackerman A, ed. Pathology of Malignant Melanoma. New York, NY: Masson Publishing; 1981: Pulitzer DR, Martin PC, Cohen AP, Reed RJ. Histologic classification of the combined nevus: analysis of the variable expression of melanocytic nevi. Am J Surg Pathol. 1991;15: Requena L, arat A, Hasson A, et al. Malignant combined nevus. Am J Dematopathol. 1991;13: Jakobiec FA, Folberg R, Iwamoto T. Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology. 1989;96: Folberg R, Jakobiec FA, ernardino V, Iwamoto T. enign conjunctival melanocytic lesions: clinicopathologic features. Ophthalmology. 1989;96: