Cellular Blue Nevus of the Conjunctiva Jeffrey A. Blicker, MD, CM,1 Jack Rootman, MD, FRCS(C),1 ,2 Valerie A. White, MD, FRCP(C)1 ,2
Background: Cellular blue nevi of the conjunctiva are extremely rare, and their natural history and malignant potential have not been fully ascertained. Methods: A report of an unusually well-documented case of growth of a cellular blue nevus is presented, along with a review of current knowledge of this lesion. Results: A 71-year-old woman presented with a darkly pigmented raised lesion of the conjunctiva, which had slowly enlarged over 47 years. There were nonconfluent areas of involvement of the upper and lower lids. Results of biopsy showed the lesion to be a cellular blue nevus, with no evidence of malignancy. Conclusion: This well-documented case of slow growth and spread without malignant transformation adds to the knowledge of this rare lesion. Ophthalmology 1992;99:1714-1717
Blue nevi of the conjunctiva are rare, and cellular blue nevi extremely rare. In a series of2455 conjunctival lesions in adults, 317 were pigmented and only 5 were blue nevi. J In Jay's2 series of nevi and melanomas of the conjunctiva, 5 of 282 nevi were totally or partially common blue nevi; of 104 melanomas, 2 arose in common blue nevi and I in a cellular blue nevus. Very few complete clinical and histologic descriptions and illustrations of cellular blue nevi of the conjunctiva are present in the English-language literature. 2.3 Therefore, we present the clinicopathologic description and illustration of a cellular blue nevus of the conjunctiva, which has a documented 47-year history.
Originally received: March 3, 1992. Revision accepted: May 26, 1992. I Department of Ophthalmology, Vancouver General Hospital and University of British Columbia, Vancou ver, British Columbia. 2 Department of Pathology, Vancou ver General Hospital and University of British Columbia, Vancouver, British Columbia. Presented at the Michael Hogan Eye Pathology Society meeting, Stanford, October 1990.
The authors received no specific financial support for this study, and have no financial interest in any company or product discussed in it. Reprint requests to Valerie A. White, MD, Department of Pathology, Vancouver General Hospital, 855 W 12th Ave, Vancouver, British Columbia, Canada, V5Z IM9.
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Case Report A 71-year-old woman presented with a pigmented conjunctival lesion. The patient was apparently born with a pigmented birthmark involving the skin of the right side of the face that had completely disappeared by adolescence. In 1942, at age 25 , a brown pigmented lesion of the right lower lid and inferior forn ix was noted. In 1959, at age 42, the patient was seen at Moorfield's Eye Hospital in London, England, where nonconfluent pigmented lesions involving the right inferior fornix, caruncle, and lateral canthal area were seen. No biopsies or active treatment were undertaken at that time. Photographs were taken and were provided to us by the patient (Fig I). In October 1989, at age 71 , the patient presented to the Ocular Oncology Clinic at Vancouver General Hospital with a raised and heavily pigmented black nodular lesion involving the entire right inferior fornix and medial canthal region extending to the lid margin and punctum (Fig 2). Eversion ofthe upper lid showed involvement of the temporal third of the lid margin associated with a nodular mass of the palpebral conjunctiva, as well as a lacrimal cyst (Fig 3). There was a nodule and marginal pigmentation of the lid medially. In addition, there was perilimbal pigmentation, which is in fact evident in the 1959 photographs. The remainder of the ocular examination was unremarkable, as were the fundus and periocular skin. Because of the extent and confluence of the lesions, the patient was taken to the operating room. An excision of the right lower lid forniceal lesion and multiple conjunctival and lid margin biopsies were performed.
Blicker et al . Cellular Blue Nevus
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Ophthalmology
Volume 99, Number 11, November 1992
Top left, Figure 1. Photograph of the patient taken in 1959. Notice the lower forniceal and lid margin involvement, as well as the perilimbal pigmentation. Top right, Figure 2. Photograph of the patient taken in 1989. Notice the growth of the lesions over the 30-year period and the new areas of noncontiguous involvement. Second row left, Figure 3. Photograph of the upper fornix taken in 1989. Notice the palpebral conjunctival and lid margin involvement. Second row right, Figure 4. Low-power photomicrograph of conjunctival excision ftom the lower fornix shows lightly pigmented, irregularly shaped lobules of cellular blue nevus in the substantia propria. Notice the lack of involvement of the overlying epithelium (hematoxylin-eosin; original magnification, X5). Third row left, Figure 5. High-power photomicrograph shows that the cells comprising the cellular blue nevus have minimal nuclear pleomorphism, inconspicuous nucleoli, and no mitotic figures (hematoxylin-eosin; original magnification, X80). Third row right, Figure 6. Photomicrograph taken near the margin of the nevus shows central cellular lightly pigmented area and peripheral area containing dendritic heavily pigmented nevus cells (hematoxylin-eosin; original magnification, X50). Bottom left, Figure 7. At the margins of the lesion, dendritic melanocytes surround adipocytes and blood vessels without destruction (hematoxylineosin; original magnification, X50). Bottom right, Figure 8. Biopsy from the eyelid margin shows common blue nevus (hematoxylin-eosin; original magnification, X50). (
Pathology Histologically, the sections from the lower forniceallesion showed the presence of a melanocytic proliferation situated entirely within the substantia propria, without involvement of the epithelium. The tumor was disposed within irregularly shaped nodules, some of which were contiguous with each other (Fig 4). The proliferation was composed of minimally pleomorphic, small, plump, spindle-shaped cells with small nucleoli (Fig 5). The main body of this portion of the lesion showed minimal pigmentation centrally within more plump cells, as well as a network of collagen fibers that surrounded single cells and collections of cells. The melanocytes at the margins of nodules assumed a more elongated, dendritic appearance, and were more heavily pigmented (Fig 6). These cells surrounded individual adipocytes, as well as normal appearing blood vessels and nerves without causing destruction (Fig 7). A chronic focal inflammatory infiltrate was present in the epithelium. No mitotic figures were present. The lesion stained moderately strongly with HMB-45 (Enw Diagnostics, New York, NY, monoclonal) and focally for S I ()() protein (Research Development Corporation, Toronto, Ontario, Canada, polyclonal). Results of the biopsy of the caruncle showed similar features. The biopsies of the inferomedial bulbar conjunctiva and eyelid margins showed elongated, heavily pigmented, spindle-shaped cells consistent with common blue nevus (Fig 8).
Discussion Cellular blue nevi are most commonly located in the buttock, sacrococcygeal region, scalp, face, and back of the hands and feet, and also have been described in the chest, breast, cervix, spermatic cord, and lung. 4 - 6 In contrast to common blue nevi, cellular blue nevi appear histologically to have biphasic pattern. There are
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highly cellular, lightly pigmented nodules consisting of uniform appearing spindle-shaped cells with small nuclei with little mitotic activity. These nodules are surrounded by sclerotic lesions containing more elongated, dendritic, heavily pigmented cells that are characteristic of common blue nevi. The described lesion was believed to be a cellular rather than a common blue nevus because of its large size, lack of pigmentation centrally within the larger nodules, and presence of plump rather than dendritic-shaped cells. Due to the rarity of cellular blue nevi of the conjunctiva and to the paucity of descriptions available, this distinction can be difficult to make. Staining with HMB-45 has been described as occurring in most common blue nevi and cellular blue nevi of the skin, and is therefore not unexpected in the conjunctiva.7 Because of their position in the subepithelial tissues of both skin and conjunctiva, blue nevi tend to have an appearance that may be distinct from other nevi and from malignant melanomas. Blue nevi can appear to be blue due to the Tyndall effect. That is, the shorter wavelengths of light are scattered while the longer wavelengths (blue) are reflected, giving an overall blue appearance. In fact, blue nevi may appear blue, slate gray, brown, or black in color, depending on both the thickness and the depth of location. This variability is particularly true in the conjunctiva, where the epithelium is thin.I,B Our patient's lesion was black. It is generally reported that common blue nevi have little or no malignant potential, and that cellular blue nevi may have a low malignant potentia1. 5,6 Malignant blue nevus has been defined as a malignant melanoma arising from a pre-existing cellular blue nevus, 6 or alternately as a malignant variant of blue nevus. 9 Whether the latter in fact exists as a separate clinical entity is not certain. In one study, 11 of 12 malignant blue nevi of the skin arose in a background of cellular blue nevus. lO Histologically, these lesions demonstrate marked cellular pleomorphism, nuclear atypia, normal and atypical mitotic figures, and areas of necrosis. 9 ,l0 The outcome is usually poor with
Blicker et al . Cellular Blue Nevus metastases to lymph nodes and viscera, as well as local recurrences. 9 ,IO The term malignant blue nevus also has been used in the dermatologic literature to describe well-differentiated cellular blue nevi with the presence of blue nevus cells in regional lymph nodes. It has been postulated that these cells may be passively squeezed into lymphatic channels from where they lodge in the lymph nodes. 6 There does not seem to be more malignant potential or a worse prognosis in these patients. The term benign metastasizing cellular blue nevus has been proposed to describe these lesions. s The case described here gives an unusual history of a pigmented birthmark of the face that subsequently completely disappeared over a number of years. It was not clinically apparent at the time of examination, which suggests deep dermal involvement. The relationship of the cellular blue nevus to the facial pigmentation or the possible existence of oculodermal melanocytosis (Nevus of Ota) is unclear. This case also provides a documented history of at least 47 years of slowly progressive growth of a cellular blue nevus, with possibly new foci arising, or local contiguous and noncontiguous spread. It cannot be ruled out that the lesion may in fact have been present since birth. This would give a history of71 years of growth. No malignant transformation was noted in any of the excised tumor. There still remains much to be elucidated about the natural history and possible malignant potential of cellular blue nevus of the conjunctiva. This case oflong-term slow
growth without signs of malignant transformation or metastases adds to the accumulated knowledge.
References 1. Grossniklaus HE, Green WR, Luckenbach M, Chan Cc. Conjunctival lesions in adults. A clinical and histopathologic review. Cornea 1987;6:78-116. 2. Jay B. Naevi and melanomata of the conjunctiva. Br J Ophthalmol 1965;49: 169-204. 3. Spencer WH, Zimmerman LE. Conjunctiva. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook, 3rd ed. Vol. 1. Philadelphia: WB Saunders, 1985; chap. 2. 4. Lever WF, Schaumberg-Lever G. Histopathology of the Skin, 7th ed. Philadelphia: JB Lippincott, 1990;777-80. 5. Temple-Camp CRE, Saxe N, King H. Benign and malignant cellular blue nevus. A clinincopathological study of 30 cases. Am J Dermatopathol 1988;10:289-96. 6. Rodriguez HA, Ackerman LV. Cellular blue nevus. Clinicopathologic study offorty-five cases. Cancer 1968;21 :393405. 7. Wood WS, Tron VA. Analysis ofHMB-45 immunoreactivity in common and cellular blue nevi. J Cutan Pathol 1991;18:261-3. 8. Eller AW, Bernardino VB Jf. Blue nevi of the conjunctiva. Ophthalmology 1983;90: 1469-71. 9. Speakman JS, Phillips MJ. Cellular and malignant blue nevus complicating oculodermal melanosis (nevus ofOta syndrome). Can J Ophthalmol 1973;8:539-47. 10. Connelly J, Smith JL Jf. Malignant blue nevus. Cancer 1991;67:2653-7.
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Background: Cellular blue nevi of the conjunctiva are extremely rare, and their natural history and malignant potential have not been fully ascertained. Methods: A report of an unusually well-documented case of growth of a cellular blue nevus is presented, along with a review of current knowledge of this lesion. Results: A 71-year-old woman presented with a darkly pigmented raised lesion of the conjunctiva, which had slowly enlarged over 47 years. There were nonconfluent areas of involvement of the upper and lower lids. Results of biopsy showed the lesion to be a cellular blue nevus, with no evidence of malignancy. Conclusion: This well-documented case of slow growth and spread without malignant transformation adds to the knowledge of this rare lesion. Ophthalmology 1992;99:1714-1717
Blue nevi of the conjunctiva are rare, and cellular blue nevi extremely rare. In a series of2455 conjunctival lesions in adults, 317 were pigmented and only 5 were blue nevi. J In Jay's2 series of nevi and melanomas of the conjunctiva, 5 of 282 nevi were totally or partially common blue nevi; of 104 melanomas, 2 arose in common blue nevi and I in a cellular blue nevus. Very few complete clinical and histologic descriptions and illustrations of cellular blue nevi of the conjunctiva are present in the English-language literature. 2.3 Therefore, we present the clinicopathologic description and illustration of a cellular blue nevus of the conjunctiva, which has a documented 47-year history.
Originally received: March 3, 1992. Revision accepted: May 26, 1992. I Department of Ophthalmology, Vancouver General Hospital and University of British Columbia, Vancou ver, British Columbia. 2 Department of Pathology, Vancou ver General Hospital and University of British Columbia, Vancouver, British Columbia. Presented at the Michael Hogan Eye Pathology Society meeting, Stanford, October 1990.
The authors received no specific financial support for this study, and have no financial interest in any company or product discussed in it. Reprint requests to Valerie A. White, MD, Department of Pathology, Vancouver General Hospital, 855 W 12th Ave, Vancouver, British Columbia, Canada, V5Z IM9.
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Case Report A 71-year-old woman presented with a pigmented conjunctival lesion. The patient was apparently born with a pigmented birthmark involving the skin of the right side of the face that had completely disappeared by adolescence. In 1942, at age 25 , a brown pigmented lesion of the right lower lid and inferior forn ix was noted. In 1959, at age 42, the patient was seen at Moorfield's Eye Hospital in London, England, where nonconfluent pigmented lesions involving the right inferior fornix, caruncle, and lateral canthal area were seen. No biopsies or active treatment were undertaken at that time. Photographs were taken and were provided to us by the patient (Fig I). In October 1989, at age 71 , the patient presented to the Ocular Oncology Clinic at Vancouver General Hospital with a raised and heavily pigmented black nodular lesion involving the entire right inferior fornix and medial canthal region extending to the lid margin and punctum (Fig 2). Eversion ofthe upper lid showed involvement of the temporal third of the lid margin associated with a nodular mass of the palpebral conjunctiva, as well as a lacrimal cyst (Fig 3). There was a nodule and marginal pigmentation of the lid medially. In addition, there was perilimbal pigmentation, which is in fact evident in the 1959 photographs. The remainder of the ocular examination was unremarkable, as were the fundus and periocular skin. Because of the extent and confluence of the lesions, the patient was taken to the operating room. An excision of the right lower lid forniceal lesion and multiple conjunctival and lid margin biopsies were performed.
Blicker et al . Cellular Blue Nevus
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Ophthalmology
Volume 99, Number 11, November 1992
Top left, Figure 1. Photograph of the patient taken in 1959. Notice the lower forniceal and lid margin involvement, as well as the perilimbal pigmentation. Top right, Figure 2. Photograph of the patient taken in 1989. Notice the growth of the lesions over the 30-year period and the new areas of noncontiguous involvement. Second row left, Figure 3. Photograph of the upper fornix taken in 1989. Notice the palpebral conjunctival and lid margin involvement. Second row right, Figure 4. Low-power photomicrograph of conjunctival excision ftom the lower fornix shows lightly pigmented, irregularly shaped lobules of cellular blue nevus in the substantia propria. Notice the lack of involvement of the overlying epithelium (hematoxylin-eosin; original magnification, X5). Third row left, Figure 5. High-power photomicrograph shows that the cells comprising the cellular blue nevus have minimal nuclear pleomorphism, inconspicuous nucleoli, and no mitotic figures (hematoxylin-eosin; original magnification, X80). Third row right, Figure 6. Photomicrograph taken near the margin of the nevus shows central cellular lightly pigmented area and peripheral area containing dendritic heavily pigmented nevus cells (hematoxylin-eosin; original magnification, X50). Bottom left, Figure 7. At the margins of the lesion, dendritic melanocytes surround adipocytes and blood vessels without destruction (hematoxylineosin; original magnification, X50). Bottom right, Figure 8. Biopsy from the eyelid margin shows common blue nevus (hematoxylin-eosin; original magnification, X50). (
Pathology Histologically, the sections from the lower forniceallesion showed the presence of a melanocytic proliferation situated entirely within the substantia propria, without involvement of the epithelium. The tumor was disposed within irregularly shaped nodules, some of which were contiguous with each other (Fig 4). The proliferation was composed of minimally pleomorphic, small, plump, spindle-shaped cells with small nucleoli (Fig 5). The main body of this portion of the lesion showed minimal pigmentation centrally within more plump cells, as well as a network of collagen fibers that surrounded single cells and collections of cells. The melanocytes at the margins of nodules assumed a more elongated, dendritic appearance, and were more heavily pigmented (Fig 6). These cells surrounded individual adipocytes, as well as normal appearing blood vessels and nerves without causing destruction (Fig 7). A chronic focal inflammatory infiltrate was present in the epithelium. No mitotic figures were present. The lesion stained moderately strongly with HMB-45 (Enw Diagnostics, New York, NY, monoclonal) and focally for S I ()() protein (Research Development Corporation, Toronto, Ontario, Canada, polyclonal). Results of the biopsy of the caruncle showed similar features. The biopsies of the inferomedial bulbar conjunctiva and eyelid margins showed elongated, heavily pigmented, spindle-shaped cells consistent with common blue nevus (Fig 8).
Discussion Cellular blue nevi are most commonly located in the buttock, sacrococcygeal region, scalp, face, and back of the hands and feet, and also have been described in the chest, breast, cervix, spermatic cord, and lung. 4 - 6 In contrast to common blue nevi, cellular blue nevi appear histologically to have biphasic pattern. There are
a
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highly cellular, lightly pigmented nodules consisting of uniform appearing spindle-shaped cells with small nuclei with little mitotic activity. These nodules are surrounded by sclerotic lesions containing more elongated, dendritic, heavily pigmented cells that are characteristic of common blue nevi. The described lesion was believed to be a cellular rather than a common blue nevus because of its large size, lack of pigmentation centrally within the larger nodules, and presence of plump rather than dendritic-shaped cells. Due to the rarity of cellular blue nevi of the conjunctiva and to the paucity of descriptions available, this distinction can be difficult to make. Staining with HMB-45 has been described as occurring in most common blue nevi and cellular blue nevi of the skin, and is therefore not unexpected in the conjunctiva.7 Because of their position in the subepithelial tissues of both skin and conjunctiva, blue nevi tend to have an appearance that may be distinct from other nevi and from malignant melanomas. Blue nevi can appear to be blue due to the Tyndall effect. That is, the shorter wavelengths of light are scattered while the longer wavelengths (blue) are reflected, giving an overall blue appearance. In fact, blue nevi may appear blue, slate gray, brown, or black in color, depending on both the thickness and the depth of location. This variability is particularly true in the conjunctiva, where the epithelium is thin.I,B Our patient's lesion was black. It is generally reported that common blue nevi have little or no malignant potential, and that cellular blue nevi may have a low malignant potentia1. 5,6 Malignant blue nevus has been defined as a malignant melanoma arising from a pre-existing cellular blue nevus, 6 or alternately as a malignant variant of blue nevus. 9 Whether the latter in fact exists as a separate clinical entity is not certain. In one study, 11 of 12 malignant blue nevi of the skin arose in a background of cellular blue nevus. lO Histologically, these lesions demonstrate marked cellular pleomorphism, nuclear atypia, normal and atypical mitotic figures, and areas of necrosis. 9 ,l0 The outcome is usually poor with
Blicker et al . Cellular Blue Nevus metastases to lymph nodes and viscera, as well as local recurrences. 9 ,IO The term malignant blue nevus also has been used in the dermatologic literature to describe well-differentiated cellular blue nevi with the presence of blue nevus cells in regional lymph nodes. It has been postulated that these cells may be passively squeezed into lymphatic channels from where they lodge in the lymph nodes. 6 There does not seem to be more malignant potential or a worse prognosis in these patients. The term benign metastasizing cellular blue nevus has been proposed to describe these lesions. s The case described here gives an unusual history of a pigmented birthmark of the face that subsequently completely disappeared over a number of years. It was not clinically apparent at the time of examination, which suggests deep dermal involvement. The relationship of the cellular blue nevus to the facial pigmentation or the possible existence of oculodermal melanocytosis (Nevus of Ota) is unclear. This case also provides a documented history of at least 47 years of slowly progressive growth of a cellular blue nevus, with possibly new foci arising, or local contiguous and noncontiguous spread. It cannot be ruled out that the lesion may in fact have been present since birth. This would give a history of71 years of growth. No malignant transformation was noted in any of the excised tumor. There still remains much to be elucidated about the natural history and possible malignant potential of cellular blue nevus of the conjunctiva. This case oflong-term slow
growth without signs of malignant transformation or metastases adds to the accumulated knowledge.
References 1. Grossniklaus HE, Green WR, Luckenbach M, Chan Cc. Conjunctival lesions in adults. A clinical and histopathologic review. Cornea 1987;6:78-116. 2. Jay B. Naevi and melanomata of the conjunctiva. Br J Ophthalmol 1965;49: 169-204. 3. Spencer WH, Zimmerman LE. Conjunctiva. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook, 3rd ed. Vol. 1. Philadelphia: WB Saunders, 1985; chap. 2. 4. Lever WF, Schaumberg-Lever G. Histopathology of the Skin, 7th ed. Philadelphia: JB Lippincott, 1990;777-80. 5. Temple-Camp CRE, Saxe N, King H. Benign and malignant cellular blue nevus. A clinincopathological study of 30 cases. Am J Dermatopathol 1988;10:289-96. 6. Rodriguez HA, Ackerman LV. Cellular blue nevus. Clinicopathologic study offorty-five cases. Cancer 1968;21 :393405. 7. Wood WS, Tron VA. Analysis ofHMB-45 immunoreactivity in common and cellular blue nevi. J Cutan Pathol 1991;18:261-3. 8. Eller AW, Bernardino VB Jf. Blue nevi of the conjunctiva. Ophthalmology 1983;90: 1469-71. 9. Speakman JS, Phillips MJ. Cellular and malignant blue nevus complicating oculodermal melanosis (nevus ofOta syndrome). Can J Ophthalmol 1973;8:539-47. 10. Connelly J, Smith JL Jf. Malignant blue nevus. Cancer 1991;67:2653-7.
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