CASE REPORT
Combination Topical Therapy for Conjunctival Primary Acquired Melanosis With Atypia and Periocular Lentigo Maligna Emily M. Bratton, MD,* Siri Knutsen-Larson, MD,† Vikram D. Durairaj, MD, FACS,‡ Darren G. Gregory, MD,§ and J. Ramsey Mellette, MD¶
Purpose: To report the case of a patient who initially presented with primary acquired melanosis (PAM) without atypia of the conjunctiva and later developed lentigo maligna of the eyelids and PAM with atypia of the conjunctiva. We illustrate the utility of combination topical therapy with adjunctive cryotherapy to treat extensive eyelid and conjunctival lesions.
Methods: Case report with a review of the current literature. Results: Combination of imiquimod 5% cream (Aldara, 3M Pharmaceuticals) and cryotherapy for periorbital lentigo maligna with topical interferon-a2b for conjunctival PAM with atypia led to clinical resolution of pigmented lesions for 21 months. Conclusions: In our experience, combination topical therapy provides an effective alternative to surgery with superior cosmetic and functional outcomes. Key Words: lentigo maligna melanoma, lentigo maligna, primary acquired melanosis, conjunctival malignant melanoma, Mohs micrographic surgery, mapped serial excision (Cornea 2015;34:90–93)
CASE REPORT An 83-year-old woman with a long-standing, irregular pigmented lesion of the left eyelids and conjunctiva (Fig. 1) presented to our oculoplastics clinic in September 2011. On initial presentation, she had diffuse hyperpigmentation of the left upper eyelid, medial canthus, and bulbar and palpebral conjunctivae. Per patient reports and medical records, the pigmentation of her conjunctiva and ipsilateral eyelid were chronic. In 1986, she presented to an outside institution with left conjunctival pigmentation (Fig. 2). Biopsy revealed primary acquired melanosis (PAM) without atypia, Received for publication April 30, 2014; revision received August 24, 2014; accepted August 26, 2014. Published online ahead of print November 12, 2014. From the *Department of Ophthalmology, University of Colorado, Aurora, CO; †Department of Dermatology, University of Colorado, Aurora, CO; ‡Texas Oculoplastic Consultants, Austin, TX; §Department of Ophthalmology, Division of Corneal and External Disease, University of Colorado, Aurora, CO; and ¶Department of Moh’s Micrographic Surgery, University of Colorado, Aurora, CO. The authors have no funding or conflicts of interest to disclose. Reprints: Emily M. Bratton, MD, Department of Ophthalmology, University of Colorado, 1675 Aurora Court, Mail Stop F-731, Aurora, CO 80045 (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
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and no treatment was indicated. In 1996, she presented again with a 6-month history of increased bulbar, inferior forniceal, and corneal pigmentation (Fig. 2). Biopsy of the conjunctiva revealed chronic hypertrophic conjunctivitis with eosinophils, for which she underwent cryotherapy. In 2001 and 2007, she presented with new pigmentation of the left upper eyelid. Biopsy revealed lentigo maligna (LM), and she underwent cryotherapy to the eyelids on both occasions. In August 2011, she presented again with increasing pigmentation of the left upper eyelid. Biopsy was consistent with LM with extension to all surgical margins, and she was referred to the University of Colorado for further evaluation and treatment. At initial presentation to our clinic, she underwent a shave biopsy of the left middle and lateral upper eyelid, which revealed LM. In October of 2011, she underwent an incisional map biopsy of the left upper and lower eyelid and conjunctiva, which again revealed LM. Further workup included positron emission tomography/computed tomography and magnetic resonance imaging of the brain and orbits, which revealed no evidence of metastatic disease. Given the extensive nature of the disease with conjunctival, eyelid margin, and eyelid involvement, staged surgical excision was not considered to be a therapeutic option. Given the disfiguring and invasive nature of orbital exenteration, the patient opted for topical treatment of the eyelids and conjunctiva concurrently. Of note, sentinel lymph node biopsy was not offered given the previously biopsied LM Breslow depth of 0.2 mm. The ophthalmology and dermatology departments treated the eyelids with imiquimod 5% cream (Aldara; 3M Pharmaceuticals, St Paul, MN) and concurrent cryotherapy. The cream was applied 3 times weekly to the left upper and lower eyelids for 3 months and an additional 5 times weekly after 3 months, for a total therapy course of 4 months. She also underwent cryotherapy of the upper and lower eyelids at 1, 2, and 3 months. Interferon-a2b (IFN-a2b) ophthalmic solution (one million international units per milliliter) 4 times daily was initiated at the same time for the conjunctiva for 4 months. She tolerated all topical and cryotherapy treatments well, without adverse side effects. She was monitored every 2 to 3 months. The eyelid and conjunctival pigmentation clinically completely resolved at 4 months. She continued to follow-up every 2 to 3 months. Twenty-five months after initial presentation to our institution and 21 months after completion of topical therapy, the patient was noted to have a new hyperpigmented patch on her left medial brow (Fig. 3). A biopsy was performed, which revealed actinic keratosis. Mild stippled hyperpigmentation of the temporal bulbar conjunctiva was also noted (Fig. 3). The patient will be followed up in 3 to 4 months, and if the temporal bulbar hyperpigmentation has enlarged, interferon treatment will be reinitiated.
DISCUSSION PAM with atypia and lentigo maligna melanoma (LMM) can be very difficult to treat, especially with extensive Cornea Volume 34, Number 1, January 2015
Cornea Volume 34, Number 1, January 2015
Combination Topical Therapy Conjunctival PAM
FIGURE 1. Appearance at initial presentation: irregular, flat patchy melanocytic lesion of the upper and lower eyelids with extension past the lower and upper eyelid margin of the left eyelid. The same patchy, irregular pigmentation can be seen on the bulbar conjunctiva and the upper palpebral conjunctiva, involving the upper eyelid.
FIGURE 2. Left: conjunctival pigmentation first noted in 1986. Right: conjunctival pigmentation at followup in 1996. Ó 2014 Lippincott Williams & Wilkins
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FIGURE 3. External follow-up photograph showing recurrence of a hyperpigmented lesion (biopsy illustrated actinic keratosis) and stippled hyperpigmentation of the temporal bulbar conjunctiva at the last follow-up.
involvement of the eyelids, eyelid margin, and conjunctivae concurrently. Periocular LM and LMM are unique entities that often demonstrate irregular and subclinical extension at the peripheral margins of the lesion.1–4 Surgical excision and Mohs micrographic surgery (MMS), with or without adjunctive therapy, have been the mainstay of treatment in the past.5 Given common subclinical extension, typical surgical margins for cutaneous melanoma are not sufficient for complete surgical excision in LM and LMM of the face and periocular structures. Treatment with MMS has a recurrence rate of 0% to 33%, and large surgical margins are required to completely remove the lesion.5,6 Lack of consensus for appropriate margins and variable recurrence rates in MMS have led to the development of more customized staged surgical excision techniques, with a lower rate of recurrence.1,6–8 Because of the need for extensive margins for complete surgical excision, topical treatment provides an effective alternative in the periocular region. Topical therapy for periocular cutaneous LM and LMM proves difficult because of the possibility of toxicity to the ocular surface. Imiquimod cream (Aldara) is an immuneresponse modifier that activates both the innate and cellmediated immune pathways. It has been used for a variety of skin cancers, including melanoma.9 A recent review of the literature revealed 82% clearance when used to treat melanoma in situ of the skin.9 Specific periocular treatment has also been documented. Demirci et al10 described treatment with topical imiquimod 5% cream for 5 patients with biopsy-proven periocular LM with good clinical response and no toxicity to the conjunctiva or cornea. Regarding conjunctival involvement, the treatment is dependent on the size of the lesion and involvement of ocular
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and adnexal structures. PAM with atypia is conventionally treated with complete surgical excision. Shields et al11 noted that patients with management of PAM by excision had a 58% recurrence rate and 11% transformation to melanoma. Because excision has been shown to result in residual areas of PAM with atypia, excision typically necessitates adjunctive therapy. These therapies consist of double freeze–thaw cryotherapy, radiotherapy, and topical therapy.12,13 Adjunctive cryotherapy has shown a high rate of recurrence as well.5 Regarding topical treatment of the conjunctiva, one of the more challenging aspects resides in the adverse effects of treatments effective on skin when applied to the ocular surface. IFN-a2b is an immunomodulator that inhibits viral RNA replication. It has a direct effect on tumor cells, in addition to modulating humoral and cellular immunity. It has been used for some basal cell carcinomas of the skin with variable success and has been described as an effective treatment for conjunctival malignant melanoma (CMM) without toxicity to the ocular surface and with no recurrence.14 Our patient’s therapy is the first documented case of topical combination therapy of imiquimod cream, cryotherapy, and IFN-a2b topical therapy of LM of the eyelid and PAM with atypia of the conjunctiva. In cases of periocular LM/LMM and PAM with atypia or CMM, surgical excision is not always the desirable therapeutic option. This topical regimen avoids invasive surgical procedures, spares the globe and vision, and results in low patient morbidity with ideal cosmetic outcome. It is important to note that the time course of treatment and surveillance of the patient in our case of using this novel combination of treatments has yet to be elucidated. Our treatment course of 4 months resulted in complete clinical resolution of the disease for more than 2 years Ó 2014 Lippincott Williams & Wilkins
Cornea Volume 34, Number 1, January 2015
after initial presentation to our institution; however, further prospective studies are needed to determine the optimal time of treatment. In addition, we demonstrate clinical resolution of the lesion. Further studies may be strengthened by histological confirmation of resolution. Application of this combination topical treatment to more invasive lesions, CMM, and LM melanoma, is unknown.
REFERENCES 1. Boulos PR, Rubin PA. Cutaneous melanomas of the eyelid. Semin Ophthalmol. 2006;21:195–206. 2. Folberg R, McLean IW, Zimmerman LE. Primary acquired melanosis of the conjunctiva. Hum Pathol. 1985;16:129–135. 3. Arlette JP, Trotter MJ, Trotter T, et al. Management of lentigo maligna and lentigo maligna melanoma: seminars in surgical oncology. J Surg Oncol. 2004;86:179–186. 4. Robinson JK. Margin control for lentigo maligna. J Am Acad Dermatol. 1994;31:79–85. 5. McLeod M, Choudhary S, Giannakakis G, et al. Surgical treatments for lentigo maligna: a review. Dermatol Surg. 2011;37:1210–1228.
Ó 2014 Lippincott Williams & Wilkins
Combination Topical Therapy Conjunctival PAM
6. Malhotra R, Chen C, Huilgol SC, et al. Mapped serial excision for periocular lentigo maligna and lentigo maligna melanoma. Ophthalmology. 2003;110:2011–2018. 7. Demirci H, Johnson TM, Frueh BR, et al. Management of periocular cutaneous melanoma with a staged excision technique and permanent sections the square procedure. Ophthalmology. 2008;115:2295–2300.e3. 8. Then SY, Malhotra R, Barlow R, et al. Early cure rates with narrowmargin slow-Mohs surgery for periocular malignant melanoma. Dermatol Surg. 2009;35:17–23. 9. Ellis LZ, Cohen JL, High W, et al. Melanoma in situ treated successfully using imiquimod after nonclearance with surgery: review of the literature. Dermatol Surg. 2012;38:937–946. 10. Demirci H, Shields CL, Bianciotto CG, et al. Topical imiquimod for periocular lentigo maligna. Ophthalmology. 2010;117:2424–2429. 11. Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the conjunctiva: risks for progression to melanoma in 311 eyes. The 2006 Lorenz E. Zimmerman lecture. Ophthalmology. 2008;115:511–519. 12. Shields JA, Shields CL. Atlas of Eyelid and Conjunctival Tumors. Philadelphia, PA: Lippincott Williams & Wilkins; 1999. 13. Francis IC, Coroneo MT, Thompson JF. Surgical management of conjunctival melanomas. Arch Ophthalmol. 1999;117:1098–1099. 14. Finger PT, Sedeek RW, Chin KJ. Topical interferon alfa in the treatment of conjunctival melanoma and primary acquired melanosis complex. Am J Ophthalmol. 2008;145:124–129.
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Combination Topical Therapy for Conjunctival Primary Acquired Melanosis With Atypia and Periocular Lentigo Maligna Emily M. Bratton, MD,* Siri Knutsen-Larson, MD,† Vikram D. Durairaj, MD, FACS,‡ Darren G. Gregory, MD,§ and J. Ramsey Mellette, MD¶
Purpose: To report the case of a patient who initially presented with primary acquired melanosis (PAM) without atypia of the conjunctiva and later developed lentigo maligna of the eyelids and PAM with atypia of the conjunctiva. We illustrate the utility of combination topical therapy with adjunctive cryotherapy to treat extensive eyelid and conjunctival lesions.
Methods: Case report with a review of the current literature. Results: Combination of imiquimod 5% cream (Aldara, 3M Pharmaceuticals) and cryotherapy for periorbital lentigo maligna with topical interferon-a2b for conjunctival PAM with atypia led to clinical resolution of pigmented lesions for 21 months. Conclusions: In our experience, combination topical therapy provides an effective alternative to surgery with superior cosmetic and functional outcomes. Key Words: lentigo maligna melanoma, lentigo maligna, primary acquired melanosis, conjunctival malignant melanoma, Mohs micrographic surgery, mapped serial excision (Cornea 2015;34:90–93)
CASE REPORT An 83-year-old woman with a long-standing, irregular pigmented lesion of the left eyelids and conjunctiva (Fig. 1) presented to our oculoplastics clinic in September 2011. On initial presentation, she had diffuse hyperpigmentation of the left upper eyelid, medial canthus, and bulbar and palpebral conjunctivae. Per patient reports and medical records, the pigmentation of her conjunctiva and ipsilateral eyelid were chronic. In 1986, she presented to an outside institution with left conjunctival pigmentation (Fig. 2). Biopsy revealed primary acquired melanosis (PAM) without atypia, Received for publication April 30, 2014; revision received August 24, 2014; accepted August 26, 2014. Published online ahead of print November 12, 2014. From the *Department of Ophthalmology, University of Colorado, Aurora, CO; †Department of Dermatology, University of Colorado, Aurora, CO; ‡Texas Oculoplastic Consultants, Austin, TX; §Department of Ophthalmology, Division of Corneal and External Disease, University of Colorado, Aurora, CO; and ¶Department of Moh’s Micrographic Surgery, University of Colorado, Aurora, CO. The authors have no funding or conflicts of interest to disclose. Reprints: Emily M. Bratton, MD, Department of Ophthalmology, University of Colorado, 1675 Aurora Court, Mail Stop F-731, Aurora, CO 80045 (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
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| www.corneajrnl.com
and no treatment was indicated. In 1996, she presented again with a 6-month history of increased bulbar, inferior forniceal, and corneal pigmentation (Fig. 2). Biopsy of the conjunctiva revealed chronic hypertrophic conjunctivitis with eosinophils, for which she underwent cryotherapy. In 2001 and 2007, she presented with new pigmentation of the left upper eyelid. Biopsy revealed lentigo maligna (LM), and she underwent cryotherapy to the eyelids on both occasions. In August 2011, she presented again with increasing pigmentation of the left upper eyelid. Biopsy was consistent with LM with extension to all surgical margins, and she was referred to the University of Colorado for further evaluation and treatment. At initial presentation to our clinic, she underwent a shave biopsy of the left middle and lateral upper eyelid, which revealed LM. In October of 2011, she underwent an incisional map biopsy of the left upper and lower eyelid and conjunctiva, which again revealed LM. Further workup included positron emission tomography/computed tomography and magnetic resonance imaging of the brain and orbits, which revealed no evidence of metastatic disease. Given the extensive nature of the disease with conjunctival, eyelid margin, and eyelid involvement, staged surgical excision was not considered to be a therapeutic option. Given the disfiguring and invasive nature of orbital exenteration, the patient opted for topical treatment of the eyelids and conjunctiva concurrently. Of note, sentinel lymph node biopsy was not offered given the previously biopsied LM Breslow depth of 0.2 mm. The ophthalmology and dermatology departments treated the eyelids with imiquimod 5% cream (Aldara; 3M Pharmaceuticals, St Paul, MN) and concurrent cryotherapy. The cream was applied 3 times weekly to the left upper and lower eyelids for 3 months and an additional 5 times weekly after 3 months, for a total therapy course of 4 months. She also underwent cryotherapy of the upper and lower eyelids at 1, 2, and 3 months. Interferon-a2b (IFN-a2b) ophthalmic solution (one million international units per milliliter) 4 times daily was initiated at the same time for the conjunctiva for 4 months. She tolerated all topical and cryotherapy treatments well, without adverse side effects. She was monitored every 2 to 3 months. The eyelid and conjunctival pigmentation clinically completely resolved at 4 months. She continued to follow-up every 2 to 3 months. Twenty-five months after initial presentation to our institution and 21 months after completion of topical therapy, the patient was noted to have a new hyperpigmented patch on her left medial brow (Fig. 3). A biopsy was performed, which revealed actinic keratosis. Mild stippled hyperpigmentation of the temporal bulbar conjunctiva was also noted (Fig. 3). The patient will be followed up in 3 to 4 months, and if the temporal bulbar hyperpigmentation has enlarged, interferon treatment will be reinitiated.
DISCUSSION PAM with atypia and lentigo maligna melanoma (LMM) can be very difficult to treat, especially with extensive Cornea Volume 34, Number 1, January 2015
Cornea Volume 34, Number 1, January 2015
Combination Topical Therapy Conjunctival PAM
FIGURE 1. Appearance at initial presentation: irregular, flat patchy melanocytic lesion of the upper and lower eyelids with extension past the lower and upper eyelid margin of the left eyelid. The same patchy, irregular pigmentation can be seen on the bulbar conjunctiva and the upper palpebral conjunctiva, involving the upper eyelid.
FIGURE 2. Left: conjunctival pigmentation first noted in 1986. Right: conjunctival pigmentation at followup in 1996. Ó 2014 Lippincott Williams & Wilkins
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FIGURE 3. External follow-up photograph showing recurrence of a hyperpigmented lesion (biopsy illustrated actinic keratosis) and stippled hyperpigmentation of the temporal bulbar conjunctiva at the last follow-up.
involvement of the eyelids, eyelid margin, and conjunctivae concurrently. Periocular LM and LMM are unique entities that often demonstrate irregular and subclinical extension at the peripheral margins of the lesion.1–4 Surgical excision and Mohs micrographic surgery (MMS), with or without adjunctive therapy, have been the mainstay of treatment in the past.5 Given common subclinical extension, typical surgical margins for cutaneous melanoma are not sufficient for complete surgical excision in LM and LMM of the face and periocular structures. Treatment with MMS has a recurrence rate of 0% to 33%, and large surgical margins are required to completely remove the lesion.5,6 Lack of consensus for appropriate margins and variable recurrence rates in MMS have led to the development of more customized staged surgical excision techniques, with a lower rate of recurrence.1,6–8 Because of the need for extensive margins for complete surgical excision, topical treatment provides an effective alternative in the periocular region. Topical therapy for periocular cutaneous LM and LMM proves difficult because of the possibility of toxicity to the ocular surface. Imiquimod cream (Aldara) is an immuneresponse modifier that activates both the innate and cellmediated immune pathways. It has been used for a variety of skin cancers, including melanoma.9 A recent review of the literature revealed 82% clearance when used to treat melanoma in situ of the skin.9 Specific periocular treatment has also been documented. Demirci et al10 described treatment with topical imiquimod 5% cream for 5 patients with biopsy-proven periocular LM with good clinical response and no toxicity to the conjunctiva or cornea. Regarding conjunctival involvement, the treatment is dependent on the size of the lesion and involvement of ocular
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and adnexal structures. PAM with atypia is conventionally treated with complete surgical excision. Shields et al11 noted that patients with management of PAM by excision had a 58% recurrence rate and 11% transformation to melanoma. Because excision has been shown to result in residual areas of PAM with atypia, excision typically necessitates adjunctive therapy. These therapies consist of double freeze–thaw cryotherapy, radiotherapy, and topical therapy.12,13 Adjunctive cryotherapy has shown a high rate of recurrence as well.5 Regarding topical treatment of the conjunctiva, one of the more challenging aspects resides in the adverse effects of treatments effective on skin when applied to the ocular surface. IFN-a2b is an immunomodulator that inhibits viral RNA replication. It has a direct effect on tumor cells, in addition to modulating humoral and cellular immunity. It has been used for some basal cell carcinomas of the skin with variable success and has been described as an effective treatment for conjunctival malignant melanoma (CMM) without toxicity to the ocular surface and with no recurrence.14 Our patient’s therapy is the first documented case of topical combination therapy of imiquimod cream, cryotherapy, and IFN-a2b topical therapy of LM of the eyelid and PAM with atypia of the conjunctiva. In cases of periocular LM/LMM and PAM with atypia or CMM, surgical excision is not always the desirable therapeutic option. This topical regimen avoids invasive surgical procedures, spares the globe and vision, and results in low patient morbidity with ideal cosmetic outcome. It is important to note that the time course of treatment and surveillance of the patient in our case of using this novel combination of treatments has yet to be elucidated. Our treatment course of 4 months resulted in complete clinical resolution of the disease for more than 2 years Ó 2014 Lippincott Williams & Wilkins
Cornea Volume 34, Number 1, January 2015
after initial presentation to our institution; however, further prospective studies are needed to determine the optimal time of treatment. In addition, we demonstrate clinical resolution of the lesion. Further studies may be strengthened by histological confirmation of resolution. Application of this combination topical treatment to more invasive lesions, CMM, and LM melanoma, is unknown.
REFERENCES 1. Boulos PR, Rubin PA. Cutaneous melanomas of the eyelid. Semin Ophthalmol. 2006;21:195–206. 2. Folberg R, McLean IW, Zimmerman LE. Primary acquired melanosis of the conjunctiva. Hum Pathol. 1985;16:129–135. 3. Arlette JP, Trotter MJ, Trotter T, et al. Management of lentigo maligna and lentigo maligna melanoma: seminars in surgical oncology. J Surg Oncol. 2004;86:179–186. 4. Robinson JK. Margin control for lentigo maligna. J Am Acad Dermatol. 1994;31:79–85. 5. McLeod M, Choudhary S, Giannakakis G, et al. Surgical treatments for lentigo maligna: a review. Dermatol Surg. 2011;37:1210–1228.
Ó 2014 Lippincott Williams & Wilkins
Combination Topical Therapy Conjunctival PAM
6. Malhotra R, Chen C, Huilgol SC, et al. Mapped serial excision for periocular lentigo maligna and lentigo maligna melanoma. Ophthalmology. 2003;110:2011–2018. 7. Demirci H, Johnson TM, Frueh BR, et al. Management of periocular cutaneous melanoma with a staged excision technique and permanent sections the square procedure. Ophthalmology. 2008;115:2295–2300.e3. 8. Then SY, Malhotra R, Barlow R, et al. Early cure rates with narrowmargin slow-Mohs surgery for periocular malignant melanoma. Dermatol Surg. 2009;35:17–23. 9. Ellis LZ, Cohen JL, High W, et al. Melanoma in situ treated successfully using imiquimod after nonclearance with surgery: review of the literature. Dermatol Surg. 2012;38:937–946. 10. Demirci H, Shields CL, Bianciotto CG, et al. Topical imiquimod for periocular lentigo maligna. Ophthalmology. 2010;117:2424–2429. 11. Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the conjunctiva: risks for progression to melanoma in 311 eyes. The 2006 Lorenz E. Zimmerman lecture. Ophthalmology. 2008;115:511–519. 12. Shields JA, Shields CL. Atlas of Eyelid and Conjunctival Tumors. Philadelphia, PA: Lippincott Williams & Wilkins; 1999. 13. Francis IC, Coroneo MT, Thompson JF. Surgical management of conjunctival melanomas. Arch Ophthalmol. 1999;117:1098–1099. 14. Finger PT, Sedeek RW, Chin KJ. Topical interferon alfa in the treatment of conjunctival melanoma and primary acquired melanosis complex. Am J Ophthalmol. 2008;145:124–129.
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