Orbital cellular blue nevus complicated by malignant melanoma

Abstract

Melanocytic lesions encompass a spectrum of disorders ranging from benign lesions to malignant pathology. The cellular blue nevus (CBN) represents a particularly rare entity that can occur in the periocular area. Although these lesions are considered to represent benign proliferation of deeply located melanocytes that have failed migration to the epithelium, concern has been raised regarding malignant transformation of atypical CBN. The ability to predict this change with subsequent locally aggressive behaviour and potential distant metastasis is a controversial and unresolved issue. We present a patient with an initially slowly progressive orbital CBN over 40 years, culminating in malignant transformation. A 59-year-old male patient presented with a 3-week history of increasing left eye blurred vision and eyelid swelling, as well as a blind spot in his visual field. There was no recent history of trauma and initially the patient did not mention any significant medical or ophthalmic history. Examination revealed a best-corrected visual acuity of 20/20 OD and 20/40 OS. There was a left relative afferent papillary defect with tense proptosis. The left eye was chemotic with significant ocular motility restriction in all gazes. An urgent CT scan demonstrated a large, diffuse, poorly enhancing intraconal as well as extraconal orbital mass, with extraorbital extension through the superior and inferior orbital fissures as well as into the pterygopalatine fossa. It exhibited mass effect on the inferior, medial, and lateral extraocular muscles as well as the optic nerve, all of which were displaced superiorly. There was increased sclerosis of bone adjacent to the lesion. The patient had an immediate canthotomy and cantholysis to relieve orbital pressure and was referred for an urgent magnetic resonance imaging (MRI) of orbits (Fig. 1) and subsequent anterior orbitotomy with mass biopsy. A transconjunctival orbitotomy facilitated with a swinging eyelid approach was used to access the orbit. Almost immediately upon initiating the surgery a large pigmented mass was noted to occupy most of the inferior orbicularis and extended posteriorly (Fig. 2). At this point, the immediate concern was a possible diagnosis of malignant melanoma (MM). We proceeded to obtain anterior debulking biopsies. Counseling of the patient and family took place postoperatively. Microscopic examination demonstrated a dense and diffuse tumour involving the deep dermis, subcutaneous tissue, and muscle composed of vaguely interconnected nodules surrounded by sclerotic stroma. The nodules consisted of a variable admixture of plump spindle-shaped cells with pale cytoplasm and oval vesicular nuclei and dendritic melanocytes with variable amounts of melanin (Fig. 3). Features of MM, such as necrosis, mitoses, or nuclear pleomorphism, were not identified in the sections examined. Tumour cells were positive for Melan-A and MITF, and weak for the S-100 protein. Ki67 (proliferative marker) showed low proliferative activity within the lesion (<2%). On the basis of these findings, a histopathological diagnosis of CBN was made. At the following visit, the patient advised us that, in childhood, he had sustained a traumatic laceration to the ipsilateral lower eyelid after falling off his bicycle. Over the following years, “bruising” of the lower eyelid never resolved, leading him to consult a plastic surgeon at age 38 years. Suspected retained foreign material lead to surgical exploration. The operative report detailed “a great deal of particulate matter not only in the skin and subcutaneous tissue but also in the underlying orbicularis.” This required “significant” amounts of orbicularis to be resected with the material noted to extend into the cheek and temporal area. The defect was repaired using a full-thickness skin graft. Pathology determined the biopsied matter to be “cellular blue nevus” (CBN) but no further characteristics were provided. At this stage, on account of persistent symptoms, the patient elected to have further debulking and diagnostic surgery. This was performed in collaboration with neurosurgery and involved a combined pteronial and inferior orbitotomy. Analysis of submitted specimens (Fig. 4, Fig. 5) demonstrated a melanocytic tumour invading adipose tissue and exhibiting marked nuclear pleomorphism and atypia with large nucleoli. Ki67 immunostaining showed a proliferation index of approximately 10%. A consensus diagnosis of MM was made between conferring ocular and neuropathologists. Repeat systemic work-up revealed new-onset lung lesions and the patient is now under oncologic treatment.Fig. 5Immunostaining for Ki67 (20× magnification) demonstrates a proliferation index of approximately 10%. The positive cells (blue arrow) should be distinguished from cells containing melanin in their cytoplasm.View Large Image Figure ViewerDownload Hi-res image Download (PPT) CBN was first described by Jadassohn-Tieche1Jadassohn-Tieche M. Über benigne melanome (‘chromatophorome’) der haut-‘blaue naevi’.Virchows Arch Pathol Anat Physiol Klin Med. 1906; 186: 212-229Crossref Scopus (80) Google Scholar and has a prevalence in the eyelid area of approximately 0.24%.2Deprez M. Uffer S. Clinicopathological features of eyelid skin tumors. A retrospective study of 5504 cases and review of literature.Am J Dermatopathol. 2009; 31: 256-262PubMed Google Scholar The orbit does not normally contain precursor melanocytic cells; hence, the development of orbital melanomas is dependent on a metastatic origin or an initially benign phenomenon such as congenital melanocytosis. The medical literature is limited to isolated case reports of CBN with descriptions in some cases of “large” or “giant” nevi.3Löffler K.U. Witschel H. Primary malignant melanoma of the orbit arising in a cellular blue nevus.Br J Ophthalmol. 1989; 73: 388-393Crossref PubMed Scopus (26) Google Scholar There are case reports describing CBN with respect to their anatomical location, size, and concern regarding malignant transformation.3Löffler K.U. Witschel H. Primary malignant melanoma of the orbit arising in a cellular blue nevus.Br J Ophthalmol. 1989; 73: 388-393Crossref PubMed Scopus (26) Google Scholar, 4Silverberg G. Kadin M. Dorfman R. et al.Invasion of the brain by a cellular blue nevus of the scalp. A case report with light and electron microscopic studies.Cancer. 1971; 27: 349-355Crossref PubMed Scopus (66) Google Scholar, 5Bittencourt A.L. Monteiro D.A. De Pretto O.J. Infiltrating giant cellular blue nevus.J Clin Pathol. 2007; 60: 82-84Crossref PubMed Scopus (11) Google Scholar Both the common and cellular blue nevi represent benign congenital entities within a spectrum of melanocytic tumours that contain dendritic and spindled melanocytes. Common blue nevi generally occur on the hands, feet, head, and neck region, whereas the cellular type has a propensity for the thigh and sacrococcygeal region.6Gündüz K. Shields J.A. Shields C.L. et al.Periorbital cellular blue nevus leading to orbitopalpebral and intracranial melanoma.Ophthalmology. 1998; 105: 2046-2050Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar They can present as blue-gray lesions or nodules often within the dermis and subcutaneous layers. It is the cellular type that can exhibit locally aggressive disease and in rare instances undergo transformation to MM. Concern regarding malignant transformation into a “malignant blue nevus” or “malignant cellular blue nevus” with the consequent fear of an aggressive course and metastasis has led many clinicians to pursue clearer diagnostic classification of when the benign or malignant classification is appropriate. This is further complicated by concern regarding malignant focal areas within a biopsy-proven benign lesion. Although the malignant potential and transformation of blue nevi is considered low,7Kirzhner M. Jakobiec F.A. Kim N. Focal blue nevus of the eyelid margin.Ophthal Plast Reconstr Surg. 2011; 27: 338-342Crossref PubMed Scopus (9) Google Scholar the ability to predict which lesions are capable of focally aggressive behaviour or eventual metastasis is a controversial and unresolved issue. This is normally considered related to histopathological characteristics such as mitotic activity, nuclear pleomorphism, cytogenic atypia, necrosis, and lymphocytic infiltrate.7Kirzhner M. Jakobiec F.A. Kim N. Focal blue nevus of the eyelid margin.Ophthal Plast Reconstr Surg. 2011; 27: 338-342Crossref PubMed Scopus (9) Google Scholar CBN is considered a distinct pathological entity originating from incompletely migrated neural-crest–derived melanocytes. The critical distinguishing features between it and MM include its clinical behaviour and demonstrated markers of malignancy such as nuclear atypia, pleomorphism, proliferation, and invasion. Immunohistochemical stains can aid differentiation between melanocytes that are typically benign in character, and pigment-bearing macrophages (melanophages). The aggressive presentation in our patient with compressive optic neuropathy confirmed our original suspicion of a malignant process. Loghavi et al.8Loghavi S. Curry J.L. Torres-Cabala C.A. et al.Melanoma arising in association with blue nevus: a clinical and pathologic study of 24 cases and comprehensive review of the literature.Mod Pathol. 2014; 27: 1468-1478Crossref PubMed Scopus (37) Google Scholar have described their series of 24 cases of MM arising in association with blue nevi in nonorbital locations. They demonstrated factors related to recurrence-free survival or earlier metastasis in certain patients. However, they could not correlate conventional prognostic indicators usually associated with traditional melanomas. This highlights the somewhat unique behaviour of this pathology. Management in our patient was complicated by a number of factors. These included good visual acuity, comfortable patient status, no significant mass effect, no evidence of frank melanoma in the initially biopsied tissue, and the long subclinical history. Löffler and Witschel3Löffler K.U. Witschel H. Primary malignant melanoma of the orbit arising in a cellular blue nevus.Br J Ophthalmol. 1989; 73: 388-393Crossref PubMed Scopus (26) Google Scholar have described the case of a young patient who managed well initially through biopsies (and suspected debulking through this process) although eventual exenteration was required 7 years later because of severe pain and mass effect. The initial biopsies were separated by a period of 12 months and showed evidence of mitosis, nuclear atypia, and necrosis in the samples. In our patient, low mitotic activity was seen combined with no other concerning features. Silverberg et al.4Silverberg G. Kadin M. Dorfman R. et al.Invasion of the brain by a cellular blue nevus of the scalp. A case report with light and electron microscopic studies.Cancer. 1971; 27: 349-355Crossref PubMed Scopus (66) Google Scholar in their description of a giant CBN invading the scalp and brain determined large tumour size, infiltrating margins, atypical nucleoli, and necrosis to be predictive of the aggressive nature of the condition in their patient. Despite the 40-year history of our case, the location of the lesion resulted in eventual compromise of structures located within the confined orbit. This case highlights some of the issues pertaining to management of this rare yet complex clinical entity. Eventual progression to, or subclinical presence of, MM must be considered in all CBN cases. The distinction between CBN and MM is often difficult and requires appreciation of clinical presentation and progression. Early involvement of experienced pathologists and oncology is recommended to ensure appropriate management. The authors have no proprietary or commercial interest in any materials discussed in this article.