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Figure 1.
Case 1. Combined nevus located at the limbus. Note the corneal involvement.

Case 1. Combined nevus located at the limbus. Note the corneal involvement.

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).

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).

Figure 3.
Case 30. A, Combined nevus. B, 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).

Case 30. A, Combined nevus. B, 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).

Figure 4.
Case 29. A, Combined nevus at the limbus. B, Pigmented spindle-shaped and dendritic blue nevus cells superficial to nevocytic nevus cells and epithelial cysts (hematoxylin-eosin, original magnification ×50).

Case 29. A, Combined nevus at the limbus. B, Pigmented spindle-shaped and dendritic blue nevus cells superficial to nevocytic nevus cells and epithelial cysts (hematoxylin-eosin, original magnification ×50).

Figure 5.
Case 6. Combined nevus with satellite lesions. Note the slate-gray color of one of the satellite lesions.

Case 6. Combined nevus with satellite lesions. Note the slate-gray color of one of the satellite lesions.

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.

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).

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).

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). B, Deeper biopsy specimens showing spindle-shaped, pigmented blue nevus cells (arrow) in superficial layers of sclera (hematoxylin-eosin, original magnification ×50).

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). B, Deeper biopsy specimens showing spindle-shaped, pigmented blue nevus cells (arrow) in superficial layers of sclera (hematoxylin-eosin, original magnification ×50).

Figure 9.
Case 6. A, Pigmented spindle-shaped and dendritic blue nevus cells (arrow) (hematoxylin-eosin, original magnification ×50). B, Nest of nevocytic cells (arrows) (hematoxylin-eosin, original magnification ×100).

Case 6. A, Pigmented spindle-shaped and dendritic blue nevus cells (arrow) (hematoxylin-eosin, original magnification ×50). B, Nest of nevocytic cells (arrows) (hematoxylin-eosin, original magnification ×100).

Figure 10.
Case 31. A, Epithelial cysts; some contain calcified concretions (hematoxylin-eosin, original magnification ×30). B, 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).

Case 31. A, Epithelial cysts; some contain calcified concretions (hematoxylin-eosin, original magnification ×30). B, 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).

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).

Case 14. Pigmented spindle-shaped and dendritic blue nevus cells (arrow) under and beside junctional and subepithelial nevocytic cells (hematoxylin-eosin, original magnification ×50).

Table 1. 
Demographic and Tumor Characteristics*
Demographic and Tumor Characteristics*
Table 2. 
History and Characteristics of Nevi*
History and Characteristics of Nevi*
1.
Tieche  M Über benigne Melanome (Chromatophorome) der haut-blaue Naevi. Virchows Arch Pathol Anat. 1906;186212- 229Article
2.
Dubreuilh  WPetges  G Le naevus bleu. Ann Dermatol. 1911;2552- 556
3.
Lund  HZKraus  JM Melanotic tumors of the skin. Atlas of Tumor Pathology Washington, DC Armed Forces Institute of Pathology1962;1 ((pt 3)) 108
4.
Jakobiec  FAZuckerman  BDBerlin  AJOdell  PMacRae  DWTuthill  RJ Unusual melanocytic nevi of the conjunctiva. Am J Ophthalmol. 1985;100100- 113
5.
Johnson  BL Ocular combined nevus: report of a case of scleral blue nevus associated with a choroidal nevus. Arch Ophthalmol. 1970;83594- 597Article
6.
Teekhasaenee  CRitch  R Glaucoma in phakomatosis pigmentovascularis. Ophthalmology. 1997;104150- 157Article
7.
Boyd  ASRapini  RP Cutaneous collision tumors: an analysis of 69 cases and review of the literature. Am J Dermatopathol. 1994;16252- 257Article
8.
Gartmann  HMüller  H Über das gemeinsame Vorkommen von blauem Naevus und Naevuszell-Naevus in ein und derselben Geschwulst ("combined nevus"). Z Hautkr. 1997;52389- 398
9.
Fletcher  VSagebiel  RW The combined nevus: mixed patterns of benign melanocytic lesions must be differentiated from malignant melanoma. Ackerman  ABed.Pathology of Malignant Melanoma New York, NY Masson Publishing1981;273- 284
10.
Pulitzer  DRMartin  PCCohen  APReed  RJ Histologic classification of the combined nevus: analysis of the variable expression of melanocytic nevi. Am J Surg Pathol. 1991;151111- 1122Article
11.
Requena  LBarat  AHasson  A  et al.  Malignant combined nevus. Am J Dematopathol. 1991;13167- 173
12.
Jakobiec  FAFolberg  RIwamoto  T Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology. 1989;96147- 166Article
13.
Folberg  RJakobiec  FABernardino  VBIwamoto  T Benign conjunctival melanocytic lesions: clinicopathologic features. Ophthalmology. 1989;96436- 461Article
Clinical Sciences
September 1999

Combined Nevi of the Conjunctiva

Author Affiliations

From the Department of Ophthalmology, University of California, San Francisco.

Arch Ophthalmol. 1999;117(9):1121-1127. doi:10.1001/archopht.117.9.1121
Abstract

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 1999. 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.

COMBINED 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, Teiche1 predicted that such a combination could occur; in 1912, Dubreuilh and Petges2 described it in the skin. Lund and Kraus3 called these nevi the True and the Blue. Many combined nevi of the 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.

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.B.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. Before 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.

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 had a few cysts and variable pigment. The clinical diagnosis was primary acquired melanosis. The lesion was excised.

CASE 29

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.

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 (Figure 1, Figure 3, and Figure 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 (Figure 3 and Figure 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 (Figure 2, Figure 6, Figure 7, and Figure 8). Sometimes the two components were located adjacent to each other at the same depth (Figure 3 and Figure 9) and sometimes the blue nevus was superficial to the nevocytic nevus (Figure 4 and Figure 10, B); occasionally the two components were mixed together (Figure 11). In some cases the blue nevus component was very limited (Figure 10, B). 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.

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. Blue 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 Johnson5 (a scleral blue nevus and a choroidal nevus), phakomatosis pigmentovascularis6 (a nevus flammeus combined with a nevus of Ota), or collision tumors7 (the association of two different tumors, such as a nevocytic nevus and a basal cell carcinoma).

Large series of combined nevi of the skin have been reported. Gartman and Müller8 found 79 cases in a series of 7733 pigmented skin lesions over a 30-year period. Fletcher and Sagebiel9 reported 50 cases from the Dermatopathology Department, University of California at San Francisco, over a period of 4 years. Pulitzer and his colleagues10 described 95 cases in patients aged from 3 to 74 years. Although the clinical diagnosis in many of these cases was often malignant melanoma, most but not all11 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 reported4; 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 al4) have been benign, although 11 had a potentially malignant clinical diagnosis (8 were suspected to 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.

Blue 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 lesion 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 lesions, 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.

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Article Information

Accepted for publication June 23, 1999.

Presented at the 135th annual meeting of the American Ophthalmological Society, Santa Barbara, Calif, May 24, 1999.

Reprints: J. Brooks Crawford, MD, Hogan Eye Pathology Laboratory, Box 0730, K-219, 10 Kirkham St, San Francisco, CA 94143.

References
1.
Tieche  M Über benigne Melanome (Chromatophorome) der haut-blaue Naevi. Virchows Arch Pathol Anat. 1906;186212- 229Article
2.
Dubreuilh  WPetges  G Le naevus bleu. Ann Dermatol. 1911;2552- 556
3.
Lund  HZKraus  JM Melanotic tumors of the skin. Atlas of Tumor Pathology Washington, DC Armed Forces Institute of Pathology1962;1 ((pt 3)) 108
4.
Jakobiec  FAZuckerman  BDBerlin  AJOdell  PMacRae  DWTuthill  RJ Unusual melanocytic nevi of the conjunctiva. Am J Ophthalmol. 1985;100100- 113
5.
Johnson  BL Ocular combined nevus: report of a case of scleral blue nevus associated with a choroidal nevus. Arch Ophthalmol. 1970;83594- 597Article
6.
Teekhasaenee  CRitch  R Glaucoma in phakomatosis pigmentovascularis. Ophthalmology. 1997;104150- 157Article
7.
Boyd  ASRapini  RP Cutaneous collision tumors: an analysis of 69 cases and review of the literature. Am J Dermatopathol. 1994;16252- 257Article
8.
Gartmann  HMüller  H Über das gemeinsame Vorkommen von blauem Naevus und Naevuszell-Naevus in ein und derselben Geschwulst ("combined nevus"). Z Hautkr. 1997;52389- 398
9.
Fletcher  VSagebiel  RW The combined nevus: mixed patterns of benign melanocytic lesions must be differentiated from malignant melanoma. Ackerman  ABed.Pathology of Malignant Melanoma New York, NY Masson Publishing1981;273- 284
10.
Pulitzer  DRMartin  PCCohen  APReed  RJ Histologic classification of the combined nevus: analysis of the variable expression of melanocytic nevi. Am J Surg Pathol. 1991;151111- 1122Article
11.
Requena  LBarat  AHasson  A  et al.  Malignant combined nevus. Am J Dematopathol. 1991;13167- 173
12.
Jakobiec  FAFolberg  RIwamoto  T Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology. 1989;96147- 166Article
13.
Folberg  RJakobiec  FABernardino  VBIwamoto  T Benign conjunctival melanocytic lesions: clinicopathologic features. Ophthalmology. 1989;96436- 461Article
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