Older woman presents with unilateral conjunctival pigmentation
There were diffuse depositions of pigment 360° on the bulbar conjunctiva with dense focal deposits superiorly and inferiorly.
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An 87-year-old white woman was referred to the New England Eye Center for evaluation of conjunctival pigmentation of her left eye.
The patient’s primary ophthalmologist noticed the pigmentation during a routine cataract evaluation 1 month before presentation. The patient could not recall when she first noticed the pigmentary changes, but her daughter noted that they were not present 5 months prior.
The patient had intermittent foreign body sensation in the left eye with blinking; otherwise, she had no complaints, including pain in or around the eye, change in vision, light sensitivity, distortion, flashes or floaters. Her ocular history was notable only for cataracts in both eyes. She was not on any ophthalmic medications. Her medical history included hypertension, hyperlipidemia, coronary artery disease status post stent placement and polymyalgia rheumatica. She had no history of skin cancer. Her medications included aspirin, lisinopril, metoprolol tartrate, pravastatin, ranitidine and prednisone 5 mg daily. Her family history was significant for breast cancer in both her brother and sister and colon cancer in her sister. There was no known family history of ocular disease. She was a former smoker (quit 40 years ago, 10 pack years), drank alcohol only socially and had no known allergies. Her review of systems was unremarkable.
Examination
Visual acuity was 20/40 in the right eye, which did not improve with pinhole, and 20/100 in the left eye, which improved with pinhole to 20/40. Pupils were equal in size and briskly reactive to light with no afferent pupillary defect. IOP was 13 mm Hg in each eye, with full extraocular motility and confrontation visual fields.
The eyelids and adnexa were normal, without lesions, masses or palpable lymph nodes. Anterior segment exam of the left eye showed diffuse depositions of pigment 360° on the bulbar conjunctiva with dense focal deposits superiorly (11:30 to 2:30 o’clock) and inferiorly (4:30 to 6:30 o’clock), with approximately 0.5 mm extension onto the inferior cornea. The diffuse pigmentation extended to the semilunar fold nasally, but there was no caruncle pigmentation. Superiorly at the limbus, the pigmentation was elevated. In all other areas, the lesions were flat without feeder vessels. Lid eversion revealed no pigmentation on the palpebral conjunctiva. There were no pigmented lesions on the palpebral or bulbar conjunctiva in the right eye. Additionally, there was moderate nuclear sclerosis in the right eye and brunescent nuclear sclerosis in the left eye. Dilated funduscopic examination was unremarkable.
What is your diagnosis?
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Conjunctival pigmentation
The differential diagnosis for unilateral conjunctival pigmented lesions can be categorized into malignant and benign etiologies.
There are three main categories of malignant conjunctival neoplasms: melanoma, ocular surface squamous neoplasia (OSSN) and lymphoma. Conjunctival melanoma may appear as a flat, brown-colored patch or a more focal, nodular mass with thickened feeder vessels. It is most often observed in light-skinned patients who are middle-aged or older. OSSN is the most common primary conjunctival malignant neoplasm; however, it is usually non-pigmented with a fleshy appearance and vascularization. Risk factors for OSSN include exposure to ultraviolet light, male gender, immunosuppression, smoking history and human papilloma virus exposure. Conjunctival lymphomas most often present as subepithelial conjunctival salmon-colored patches or masses.
Conjunctival nevus is the most common primary ocular lesion. Often unilateral, nevi are well-circumscribed discrete lesions that develop earlier in life and are generally stable over time. They can be brown or tan, or completely amelanotic or cystic. In our elderly patient who presented with the development of new pigmentation over months, this diagnosis seems unlikely. Primary acquired melanosis (PAM) is difficult to discern from conjunctival melanoma because it may also present as a unilateral, flat, brown-colored patch in a middle-aged light-skinned person. Benign acquired melanosis is generally observed in patients with dark-pigmented skin. Although its appearance can be diffuse and patchy like our patient, it is almost always bilateral. The appearance of our patient’s unilateral flat, brown lesions that were uniform in pigmentation with no visible feeder vessels makes a diagnosis of conjunctival hemangioma, conjunctival papilloma or conjunctival dermoid less likely.
Additional workup
The patient underwent multiple map biopsies of three areas of conjunctival pigment: near the superior rectus insertion, the dense focal area at 2 o’clock and the dense focal area at 5 o’clock. Pathology demonstrated PAM with severe melanocytic atypia/malignant melanoma in situ. There was no evidence of stromal invasion or intraocular extension.
Discussion
Conjunctival melanoma arises from melanocytes in the basal epithelium. Lesions typically appear as dark brown pigmentary changes but may also be amelanotic. Conjunctival melanoma represents 2% of ocular tumors and 12% of conjunctival tumors, arising from PAM in the majority of cases (with a smaller percentage arising de novo and an even smaller percentage arising from nevi). PAM is a conjunctival lesion that consists of melanocytic hyperplasia and atypical changes developing from a previously normal area of conjunctiva. As the tissue changes, it can transform from a benign state, such as increased basal pigmentation with mild melanocytic hyperplasia and no atypia (PAM with no atypia or mild atypia), to malignant melanoma. PAM with severe atypia may progress to melanoma in 13% to 46% of cases, with a higher risk for more advanced malignancy in larger lesions. The only method to decisively determine whether the lesion is benign or malignant is by biopsy with pathological analysis.
The most common location for development of conjunctival melanoma is near the limbus. These lesions are less likely to metastasize than lesions in the caruncle or palpebral conjunctiva. Unlike OSSN, which rarely metastasizes, conjunctival melanomas may metastasize via lymphatics to local lymph nodes of the head and neck. If lymph node involvement is suspected after thorough physical examination or if the conjunctival lesion is extremely large and involves the fornices or palpebral conjunctiva, lymph node mapping using radiologic imaging and excision should be considered.
Treatment of conjunctival melanoma involves complete surgical excision if possible, using a “no-touch” technique as described by Shields and colleagues with a 4-mm clear margin and double freeze-slow thaw cryotherapy to the surgical margins. Partial lamellar sclerectomy or alcohol epitheliectomy may be used in cases of scleral or corneal extension, respectively. While excisional biopsy is preferred, incisional biopsy may be performed in extensive cases. If the lesion is extensive or has invaded the orbit, exenteration may be necessary as a palliative measure. Supplemental therapies after surgery include cryotherapy, topical or subconjunctival immunotherapy with interferon alpha-2b, topical chemotherapy with mitomycin C or 5-fluorouracil, and radiation therapy. The prevention of recurrence in conjunctival melanoma using cryotherapy, and its use as a primary treatment for PAM, often allows for the delay or even avoidance of radical surgeries. All patients with conjunctival melanoma should be referred to a medical oncologist for further workup and detection of potential metastases. For patients with unresectable or metastatic conjunctival melanoma, gene sequencing and use of checkpoint inhibitors is an emerging therapy available in collaboration with medical oncology.
Course continued
Treatment options were discussed with the patient and her family, and she decided to proceed with excisional biopsy and intraoperative application of MMC and cryotherapy. Amniotic membrane reconstruction was also performed. In addition to treatment of the conjunctiva, the patient had slight corneal invasion that was managed with cryotherapy.
Source: Kate V. Dennett, MD, Helen K. Wu, MD, and Nora M.V. Laver, MD
Two months later, she was found to have recurrences at several locations (Figure 1), which were removed with cryotherapy. The patient continues to be followed every 2 to 3 months and has required recurrent focal cryotherapy for recurrence every 2 to 7 months (Figures 2 and 3). Over several years of follow-up, she remains free of lymphadenopathy and metastases. However, 3 years after the excisional biopsy, she developed herpes simplex keratitis in the left eye, which significantly decreased her vision to 20/400. It is unclear what role, if any, the treatment of her conjunctival melanoma may have played in the activation of herpetic keratitis, specifically the use of MMC or the physical stress of recurrent focal cryotherapy. She is currently on long-term prophylaxis with acyclovir.
- References:
- Augsburger JJ, et al. Tumors of the conjunctiva. In: Yanoff, Duker JS, eds. Ophthalmology. 5th ed. Elsevier; 2018:196-205.
- Morkin MI, et al. Ocular surface tumors. American Academy of Ophthalmology Focal Points. 2020;38(6):1-9.
- Shields CL, et al. Asia Pac J Ophthalmol (Phila). 2017;doi:10.22608/APO.201710.
- Shields CL, et al. Surv Ophthalmol. 2004;doi:10.1016/j.survophthal.2003.10.008.
- Vora GK, et al. Surv Ophthalmol. 2017;doi:10.1016/j.survophthal.2016.06.001.
- For more information:
- Kate V. Dennett, MD, Helen K. Wu, MD, and Nora M.V. Laver, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Christine Benador-Shen, MD, and Malgorzata Dymerska Peterson, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.