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Clinical pathologic reviews

Desmoplastic melanoma of the eyelid and conjunctival melanoma in neurofibromatosis type 1: A clinical pathological correlation Tal J. Rubinstein, MDa, Thomas P. Plesec, MDb, Arun D. Singh, MDa,* a b

Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio, USA

article info


Article history:

A 56-year-old woman with neurofibromatosis type 1 (NF1) presented with a left upper

Received 2 June 2014

eyelid amelanotic nodule with adjacent eyelid margin hyperpigmentation. Physical ex-

Received in revised form

amination additionally revealed primary acquired melanosis (PAM) on the palpebral con-

1 August 2014

junctiva of the same eyelid. Full thickness eyelid excision and conjunctival map biopsy

Accepted 5 August 2014

identified desmoplastic melanoma of the eyelid in addition to invasive conjunctival mel-

Available online 12 August 2014

anoma and conjunctival melanoma in situ. Sentinel lymph node biopsy was negative for

Stefan Seregard and Hans

metastasis. She was treated with surgical excision for the eyelid melanoma and topical

Grossniklaus, Editors

mitomycin C for the conjunctival melanoma. We discuss the rare entity of desmoplastic melanoma of the eyelid and its possible association with NF1. ª 2015 Elsevier Inc. All rights reserved.

Keywords: desmoplastic melanoma eyelid neurofibromatosis type 1 sentinel lymph node biopsy primary acquired melanosis

As a disease of neural crest derived tissue, neurofibromatosis type 1 (NF1) may also be linked to melanoma, a malignancy of melanocytes.38 Both cutaneous and ocular variants of melanoma have been observed in NF1, and the risk of developing melanoma in NF1 is elevated.3,4,11,18,38,40e42,46 Genetic analysis indicates mutations in the 17q11.2 locus of the NF1 gene in certain melanoma cells.2 Additionally, in vitro and mouse studies demonstrate that the loss of NF1 reduces BRAFinduced senescence, which is a process that drives senescence rather than malignant transformation.26 Furthermore, neurofibromas as seen in NF1 may express melanocyte differentiation markers.33

We describe a patient with NF1 with findings of two types of melanoma: desmoplastic melanoma of the eyelid and conjunctival melanoma. These two distinct types of melanoma in a patient with NF1 have, to our knowledge, not been previously described. We also review the literature on desmoplastic melanomas of the eyelid.


Case Report

A 56-year-old white woman presented for evaluation of a left upper lid lesion. She thought this had been present since early

* Corresponding author: Arun D. Singh, MD, Cleveland Clinic Cole Eye Institute, 9500 Euclid Ave, mailbox i-32, Cleveland, OH 44195. E-mail address: [email protected] (A.D. Singh). 0039-6257/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.survophthal.2014.08.001

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Fig. 1 e A: External photograph of the patient’s left eye. Lisch nodules are seen on the iris. B: External photograph of the patient’s neck with hyperpigemented macules consistent with cafe´-au-lait spots.

adulthood, but it had become friable with bleeding over the past 5 months. She did not note a change in its size. Her past medical history was significant for NF1 diagnosed at age 34 with the presence of cafe´-au-le spots, axillary freckling, neurofibromas, and Lisch nodules (Fig. 1). Additionally, she had been treated with external beam radiation and lumpectomy for breast cancer 5 years previously with remission. Her visual acuity was 20/20 bilaterally with correction. Pupils, extraocular movements, and intraocular pressures were normal. Examination of the eyelids demonstrated a 2  1 mm area of pigmentation of the left upper lid margin with a 1.5 mm amelanotic nodule adjacent to it. Slit lamp exam of the left eye demonstrated a 3  1 mm and a 5  4 mm area of primary acquired melanosis (PAM) on the palpebral conjunctiva without involvement of the bulbar conjunctiva (Fig. 2).

She initially underwent a shave biopsy of the upper eyelid that revealed a desmoplastic melanoma of at least 1.1 mm depth and perineural invasion with involvement of peripheral and deep margins. She subsequently had a pentagonal excision of the left upper eyelid, conjunctival map biopsies, and cryotherapy. Fresh-frozen sections of the lateral and medial margins were reported as negative, but permanent sections of the medial margins were positive, necessitating additional excision. The main eyelid lesion demonstrated spindle cell proliferation within the dermis of the eyelid (Figs. 3e5). The proliferation was relatively hypocellular, as it was accompanied by abundant fibrotic stroma, but contained enlarged, hyperchromatic and pleomorphic nuclei. The overlying epidermis contained an atypical melanocytic proliferation with areas of pagetoid spread. Immunohistochemistry for S-100 protein and HMB-45 were positive in both the epidermal and dermal

Fig. 2 e External photograph of the patient’s everted left upper eyelid. Noted within the photograph is an amelanotic nodule (large arrow) next to the prior shave biopsy site (small arrow). Also visible within the photograph are hyperpigmented lesions within the palpebral conjunctiva resembling the clinical diagnosis of PAM.

Fig. 3 e Initial biopsy specimen. The photomicrograph demonstrates atypical, but relatively paucicellular, dermal infiltrate embedded in a fibrous stroma on hematoxylin and eosin stain (103). The overlying epidermis reveals scattered atypical, vacuolated cells with pagetoid spread.


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Fig. 4 e HMB-45 immunostain highlights both the dermal and epidermal components of the melanoma.

components. The melanoma had a maximum thickness of 1.1 mm. No mitotic figures or ulceration were found. The map biopsies identified melanoma in situ and invasive melanoma (Figs. 6 and 7). Technetium-99m infiltrated into the eyelid identified four sentinel lymph nodes, all biopsy-negative for metastases. Because of the presence of conjunctival melanoma, adjuvant topical mitomycin C 0.04% eye drops (four times per day for 1 week and then 1 week off) were administered for a total of four cycles without complications. The patient has been tumor-free without evidence of recurrence free for approximately 2.5 years (Fig. 8).



Desmoplastic melanoma is a rare variant of melanoma that poses diagnostic challenges to both clinician and pathologist. Accounting for less than 4% of all types of melanoma,

Fig. 5 e Left side of photomicrograph shows neurofibroma. Right side of photomicrograph shows neurotrophic spread by melanoma, which is quite characteristic of desmoplastic melanoma (hematoxylin and eosin, 103).

Fig. 6 e Conjunctival map biopsy revealing full-thickness proliferation of atypical, vacuolated cells (hematoxylin and eosin, 203), characteristic of melanoma in situ.

desmoplastic melanoma may clinically resemble lesions such as dermatofibroma, neurofibroma, non-melanoma skin cancers, chalazion, or scars.8,36 Clinically, desmoplastic melanoma may be non-pigmented or multicolored and is papular, macular, or nodular in shape.8,23 Histologically, spindle celle shaped melanocytes are seen within a background of fibrosis and lymphocytes.23 The melanocytic cellularity within the specimen may be paucicellular, as seen in pure desmoplastic melanoma, or denser with a higher mitotic index, as seen in mixed desmoplastic melanoma.8 S-100 immunostaining is typically positive. HMB-45 is only positive in about 9% of cases, but was present here.13,31 Related melanoma in situ and neural invasion may be seen.23 That this patient had both NF1 and desmoplastic melanoma may not be coincidental. Gutzmer found an increased frequency of loss of heterozygosity in the NF1 locus in desmoplastic neurotrophic melanoma compared with common melanoma.19 The initial frozen sections of the medial margin were probably read as negative because of the paucity of melanoma

Fig. 7 e HMB-45 immunostain of the conjunctival map biopsy confirms melanocytic differentiation (hematoxylin and eosin, 203).


Unreported Local resection/reconstruction, 3 years radiotherapy

Unreported 2e3 years

Not noted Clinical-stye; histologicaldesmoplastic melanoma Left Lower



Moulin-Romsee25 2008

Alix et al1 2008


Histological- desmoplastic Not noted melanoma Left Lower

1 Dithmar9 1999


Histological-desmoplastic melanoma

Not noted

Local recurrence, orbital extension and orbital recurrence after exenteration Recurrence with invasion into orbit and maxillary nerve and involvement of trigeminal ganglion Recurrence with perineural invasion into cavernous sinus, maxillary nerve, masseter/pteryoid muscles

Surgical treatment of eyelid lesion otherwise unspecified

Unreported 7 months

Alive Not noted

Excision of local lesion/ reconstruction Excision of local lesion, later exenteration and radiation None noted 2 Glat15 1998

Not Not noted noted 50/F Left Upper

1 Roper31 1986


Left Lower

Clinical-basal cell carcinoma; histologicalchalazion Not noted


Deceased Not noted Edge excision/reconstruction, radiation Superior orbital extension and orbital recurrences

Deceased 2.5 years Exenteration, radiation, chemotherapy Local recurrence, orbital recurrence

Subcutaneous, central nervous system, and pulmonary Central nervous system and pulmonary Right Upper Clinical-lipogranuloma 58/F 1

Metastasis Initial diagnoses Eyelid No. of Age/ patients sex

Table 1 e Review of cases of desmoplastic melanoma of the eyelid


cells within desmoplastic tissues. As such, areas of fibrotic stroma may predominate in certain sections, which can make identification of melanocytes more difficult. We advise meticulous review of all slides with a presumptive diagnosis of desmoplastic melanoma, especially the permanent sections. Desmoplastic melanoma involving the eyelid is rare, with only seven cases found in the literature when searching in Medline/PubMed for the phrase desmoplastic melanoma eyelid (Table 1).1,10,17,29,36,43 Of these seven, two were included within a retrospective study, and little data were described specific to those patients.17 Of the remaining five, the average age was 57 years (range: 48e77 years), and three were male. The upper lid was involved twice, and the left side was involved four times. One patient also had ipsilateral conjunctival PAM, as in our case.43 Five had orbital or neural invasion and recurrences. Treatment methods varied from local excision to exenteration. Four patients received radiation and one received chemotherapy. Two died from metastatic disease. Conjunctival melanoma and/or PAM occur in patients with eyelid melanoma.6,16,22,25,35,43,44,47 We found only two cases of conjunctival melanoma and PAM in patients with NF1,41,46 our case being the third. Although links between NF1 and melanoma exist, with so few cases reported, it is unclear if the coexistence between these two conditions is coincidental. Sentinel lymph node biopsy (SLNB) has been utilized in conjunctival and eyelid melanoma to assess lymph node status as this procedure has been related to prognosis and disease-free survival in cutaneous melanoma.9,15,27,28,32,37 To our knowledge, SLNB has not been studied for desmoplastic melanoma of the eyelid. For cutaneous desmoplastic melanoma, the rate of sentinel lymph node positivity is between 0% and 9% for pure desmoplastic melanoma and up to 25% for the mixed type.5,7,8,12,14,20,21,24,30,34,39,45 A large series of 594 patients with desmoplastic melanoma identified only 15 (2.5%) with a positive sentinel lymph node.12 In that series, patients with ulcerated tumors and positive sentinel lymph nodes had worse overall survival, as did patients with tumors of Breslow depth more than 2.6 mm. While our patient’s SLNB was negative, monitoring for recurrences is important as histology demonstrated neural invasion.


Fig. 8 e External photograph of the patient’s left upper lid after surgical and medical treatments.

Sutula38 1982


Follow up


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This case represents several unique and possibly related pathologies in one patient. The possible link between NF1 and melanoma, in this case both conjunctival and desmoplastic melanoma, is strengthened. In addition, this case provides yet another example of desmoplastic melanoma of the eyelid. Future studies should focus on the possible genetic link between neurofibromatosis and melanoma, including desmoplastic melanoma. The identification of more cases of desmoplastic melanoma of the eyelid may lead to better treatments.


Method of literature search

Literature search was conducted using Medline/PubMed. Search words/phrases used included the following: desmoplastic melanoma, desmoplastic melanoma eyelid, desmoplastic melanoma sentinel lymph node, neurofibromatosis melanoma, sentinel lymph node melanoma. We included one article in French, and articles spanned from the years 1982 to the present. We included all cases of desmoplastic melanoma of the eyelid that were found on literature search by title or within the abstract and excluded case reports of desmoplastic melanoma elsewhere.


1. Alix T, Boutet C, Caquant L, et al. Intracranial spread of a melanoma of the face: the trigeminal pathway. Rev Stomatol Chir Maxillofac. 2008;109:172e4 2. Andersen LB, Fountain JW, Gutmann DH, et al. Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines. Nat Genet. 1993;3:118e21 3. Barringer CB, Gorse SJ, Rigby HS, et al. Multiple malignant melanomas in association with neurofibromatosis type 1. J Plast Reconstr Aesthet Surg. 2006;59:1359e62 4. Bin Amer Y, Al-Khenaizan S. Fatal malignant melanoma in a child with neurofibromatosis type 1. Int J Dermatol. 2007;46:967e70 5. Broer PN, Walker ME, Goldberg C, et al. Desmoplastic melanoma: a 12-year experience with sentinel lymph node biopsy. Eur J Surg Oncol. 2013;39:681e5 6. Carucci JA, Leffell DJ. Intralesional interferon alfa for treatment of recurrent lentigo maligna of the eyelid in a patient with primary acquired melanosis. Arch Dermatol. 2000;136:1415e6 7. Chen JY, Hruby G, Scolyer RA, et al. Desmoplastic neurotropic melanoma: a clinicopathologic analysis of 128 cases. Cancer. 2008;113:2770e8 8. Chen LL, Jaimes N, Barker CA, et al. Desmoplastic melanoma: a review. J Am Acad Dermatol. 2013;68:825e33 9. Cohen VM, Tsimpida M, Hungerford JL, et al. Prospective study of sentinel lymph node biopsy for conjunctival melanoma. Br J Ophthalmol. 2013;97:1525e9 10. Dithmar S, Meldrum ML, Murray DR, et al. Desmoplastic spindle-cell melanoma of the eyelid with orbital invasion. Ophthal Plast Reconstr Surg. 1999;15:134e6 11. Doherty SD, George S, Prieto VG, et al. Segmental neurofibromatosis in association with a large congenital nevus and malignant melanoma. Dermatol Online J. 2006;12:22

12. Egger ME, Huber KM, Dunki-Jacobs EM, et al. Incidence of sentinel lymph node involvement in a modern, large series of desmoplastic melanoma. J Am Coll Surg. 2013;217:37e44, discussion 44e5. 13. Garrido MC, Requena L, Kutzner H, et al. Desmoplastic melanoma: expression of epithelial-mesenchymal transitionrelated proteins. Am J Dermatopathol. 2014;36:238e42 14. George E, McClain SE, Slingluff CL, et al. Subclassification of desmoplastic melanoma: pure and mixed variants have significantly different capacities for lymph node metastasis. J Cutan Pathol. 2009;36:425e32 15. Gershenwald JE, Thompson W, Mansfield PF, et al. Multiinstitutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol. 1999;17:976e83 16. Giblin ME, Shields JA, Shields CL, et al. Primary eyelid malignant melanoma associated with primary conjunctival malignant melanoma. Aust NZ J Ophthalmol. 1988;16:127e31 17. Glat PM, Longaker MT, Jelks EB, et al. Periorbital melanocytic lesions: excision and reconstruction in 40 patients. Plast Reconstr Surg. 1998;102:19e27 18. Guillot B, Dalac S, Delaunay M, et al. Cutaneous malignant melanoma and neurofibromatosis type 1. Melanoma Res. 2004;14:159e63 19. Gutzmer R, Herbst RA, Mommert S, et al. Allelic loss at the neurofibromatosis type 1 (NF1) gene locus is frequent in desmoplastic neurotropic melanoma. Hum Genet. 2000;107:357e61 20. Gyorki DE, Busam K, Panageas K, et al. Sentinel lymph node biopsy for patients with cutaneous desmoplastic melanoma. Ann Surg Oncol. 2003;10:403e7 21. Han D, Zager JS, Yu D, et al. Desmoplastic melanoma: is there a role for sentinel lymph node biopsy? Ann Surg Oncol. 2013;20:2345e51 22. Hicks C, Liu C, Hiranandani M, et al. Conjunctival melanoma after excision of a lentigo maligna melanoma in the ipsilateral eyelid skin. Br J Ophthalmol. 1994;78:317e8 23. Jaimes N, Chen L, Dusza SW, et al. Clinical and dermoscopic characteristics of desmoplastic melanomas. JAMA Dermatol. 2013;149:413e21 24. Jaroszewski DE, Pockaj BA, DiCaudo DJ, et al. The clinical behavior of desmoplastic melanoma. Am J Surg. 2001;182:590e5 25. Jordan DR, Mamalis N, White GL Jr, et al. Amelanotic malignant melanoma of the conjunctiva with local metastasis to the eyelid. Can J Ophthalmol. 1990;25:34e7 26. Maertens O, Johnson B, Hollstein P, et al. Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discov. 2013;3:338e49 27. Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242:302e11, discussion 311e3. 28. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370:599e609 29. Moulin-Romsee G, Benamor M, Neuenschwander S. Desmoplastic neurotropic melanoma in a patient with trigeminal neuralgia: FDG PET/CT and MRI. Clin Nucl Med. 2008;33:353e5 30. Murali R, Shaw HM, Lai K, et al. Prognostic factors in cutaneous desmoplastic melanoma: a study of 252 patients. Cancer. 2010;116:4130e8 31. Ordonez NG. Value of melanocytic-associated immunohistochemical markers in the diagnosis of malignant melanoma: a review and update. Hum Pathol. 2014;45:191e205 32. Pfeiffer ML, Savar A, Esmaeli B. Sentinel lymph node biopsy for eyelid and conjunctival tumors: what have we learned

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in the past decade? Ophthal Plast Reconstr Surg. 2013;29:57e62 Pizem J, Nicholson KM, Mraz J, et al. Melanocytic differentiation is present in a significant proportion of nonpigmented diffuse neurofibromas: a potential diagnostic pitfall. Am J Surg Pathol. 2013;37:1182e91 Posther KE, Selim MA, Mosca PJ, et al. Histopathologic characteristics, recurrence patterns, and survival of 129 patients with desmoplastic melanoma. Ann Surg Oncol. 2006;13:728e39 Robertson DM, Hungerford JL, McCartney A. Pigmentation of the eyelid margin accompanying conjunctival melanoma. Am J Ophthalmol. 1989;108:435e9 Roper JP, Jones T, Common JD. Desmoplastic malignant melanoma masquerading as chalazion. Br J Ophthalmol. 1986;70:907e10 Savar A, Ross MI, Prieto VG, et al. Sentinel lymph node biopsy for ocular adnexal melanoma: experience in 30 patients. Ophthalmology. 2009;116:2217e23 Seminog OO, Goldacre MJ. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br J Cancer. 2013;108:193e8 Smith VA, Lentsch EJ. Sentinel node biopsy in head and neck desmoplastic melanoma: an analysis of 244 cases. Laryngoscope. 2012;122:116e20


40. Soon C, Humphreys F, Carr RA. Rectal melanoma arising in association with neurofibromatosis type I. Clin Exp Dermatol. 2008;33:207e9 41. Stacy RC, Kenyon KR, Jakobiec FA, et al. Conjunctival melanoma arising from primary acquired melanosis in a patient with neurofibromatosis type I. Cornea. 2010;29:232e4 42. Staicu C, Stefaniu I, Frasia M. Choroidal melanoma in a patient with type I neurofibromatosis. Oftalmologia. 2006;50:22e6 43. Sutula FC, Dortzbach RK, Bolles JC. Desmoplastic malignant melanoma of the upper eyelid. Ann Ophthalmol. 1982;14:141e3 44. Tahery DP, Goldberg R, Moy RL. Malignant melanoma of the eyelid. A report of eight cases and a review of the literature. J Am Acad Dermatol. 1992;27:17e21 45. Thelmo MC, Sagebiel RW, Treseler PA, et al. Evaluation of sentinel lymph node status in spindle cell melanomas. J Am Acad Dermatol. 2001;44:451e5 46. To KW, Rabinowitz SM, Friedman AH, et al. Neurofibromatosis and neural crest neoplasms: primary acquired melanosis and malignant melanoma of the conjunctiva. Surv Ophthalmol. 1989;33:373e9 47. Ueno H, Tamai A, Noda K, et al. Light and electron microscopic studies of malignant melanoma of conjunctiva and palpebra. Jpn J Ophthalmol. 1983;27:459e67

Desmoplastic melanoma of the eyelid and conjunctival melanoma in neurofibromatosis type 1: a clinical pathological correlation.

A 56-year-old woman with neurofibromatosis type 1 (NF1) presented with a left upper eyelid amelanotic nodule with adjacent eyelid margin hyperpigmenta...
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