Case 8 -

Neurocutaneous Melanosis (NCM) Miguel Reyes-Múgica, M.D. Yale University School of Medicine

Case History: The patient, a 3 year-old male was admitted to hospital with abdominal distention and a right pleural effusion. He had been followed for a number of years as an outpatient in the neurology clinic with persistent complex partial seizures (vide infra). At surgery a moderate quantity of blood tinged, cloudy ascitic fluid was present. Soft, white to tan-white, friable velvety tumor nodules and patches were plastered on the peritoneal surface of all the abdominal organs and omentum. A few of the nodules were variably pigmented, from brown to dark grey. Representative portions of tumor were resected for pathological examination. A right thoracostomy tube was inserted and some of the pleural fluid was submitted for cytocentrifuge preparation and cytologic examination. Past history This patient first presented at the age of 4 months with seizures and opisthotonus, and was found to have severe hydrocephalus and a posterior fossa cyst. The latter was associated with atrophy of the medial portions of the cerebellar hemispheres. Following clinical stabilization, a ventriculo-peritoneal shunt (VPS) was inserted, with some minor improvement in central nervous system function. However, his seizures persisted and a year later he was operated on for a tethered cord. At the time of this surgery the neurosurgeon noted darkly pigmented meninges. Pathological examination was consistent with meningeal melanosis. His epilepsy was treated with a variety of anti-seizure medications. His neurological development was moderately delayed. The infant was the product of a normal pregnancy and delivery. At birth, a large Mongolian spot and multiple cutaneous brown, pigmented macules of varying size and shape were noted. Approximately twenty lesions were present, a few up to 10 cm in maximum dimension. These were clinically followed by a pediatric dermatologist and showed no significant changes over time. The child has an oldest sister who is healthy. There was no pertinent family history. Discussion Pathology The morphologic pattern of this tumor shows a small to midsize cell population with perivascular pseudorosettes, pseudofollicular formations, multifocal melanin deposits, numerous mitotic figures of normal morphology, and a striking apoptosis rate (high MKI!). Foci of melanin are present. Neither significant necrosis nor intercellular matrix is evident. Case 8 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer The immunophenotype reveals a neuroectodermal/melanocytic lineage, showing expression of S-100 in both, a focal nuclear and diffuse cytoplasmic pattern; Melan A is focally present; HMB45 is also diffusely but mildly positive; PNL2 [1] is diffusely present in a dot cytoplasmic pattern; and strong, diffuse membranous CD99 expression (which may be found in up to 16% of melanomas). GFAP is negative. IMMUNOPHENOTYPE S-100 ++ Melan A + HBM45 ++ PNL2 +++ CD99 ++++ GFAP - Diagnosis This is an exceptional example of Neurocutaneous Melanosis (NCM) [2, 3] (fig 1) with dissemination of the melanocytic proliferation to the peritoneal surfaces facilitated by the VPS draining CSF (fig 2). Figures 1A & 1B Two patients with the characteristic Giant Congenital Nevi associated to NCM Figure 2A: MRI with gadolinium in a patient with NCM showing melanin deposits in the CSF spaces. Figure 2B: CSF cytology with atypical melanocytic cells A similar case came to my attention a few years ago. The boy presented at birth with multiple nevi, a large "bathing trunk" congenital nevus, and a bulky perineal nevocytoma (fig 3). [4] Figure 3A: Clinical picture of patient with NCM and Bulky Perineal Nevocytoma. Figure 3B: Brain biopsy taken at the time of placement of VPS. Note the melanin containing cells along the Virchow-Robin spaces. The patient also had hydrocephalus, a Dandy-Walker malformation and melanin-containing deposits in the thalamus, cerebellum and temporal lobes demonstrated by magnetic resonance imaging. Given the hydrocephalus, seizures and CNS malformation, a VPS was placed, and during that surgery, meningeal melanosis was also identified. The bulky perineal nevocytoma was excised. At 7 years of age, the patient presented also with abdominal distension, diarrhea and lethargy. An abdominal laparoscopy demonstrated multiple peritoneal implants with identical morphology to those observed in the current case. The patient developed increased hydrocephalus due to obstruction of the tip of the VPS, deteriorated rapidly and died. Despite a thorough discussion with the family, no autopsy was authorized. Also known as Neurocutaneous melanocytosis or Touraine syndrome, NCM is included within a wide spectrum of proliferative neurocristopathies. [5] NCM is a lethal condition characterized by a proliferation of nevomelanocytes in the central nervous system in association with large or giant (less commonly multiple) congenital melanocytic nevi in the skin, usually involving the midline or the head and neck. A few cases, however, may present without skin lesions. Its actual incidence is not known; however, although rare, it is suspected to occur more frequently than expected, and a family support group has been in existence for 10 years (NOI: http://www.nevus.org/home/modules/wfchannel/index.php?pagenum=3. Melanocytes (with the exception of those in the retina) are derived from neural crest cells. They are normally found predominantly at the dermo-epidermal junction in the skin, hair follicles and in the leptomeninges, places that they reach after an elaborate process of cellular migration and differentiation during the embryonic and fetal stages of development. Benign melanocytic cellular proliferations in the skin are among the most common forms of proliferative lesions and can be congenital or postnatally acquired. When they are present at birth, they are termed congenital melanocytic nevi (naevus=Latin for birthmark). Congenital melanocytic nevi (CMN) may be of different sizes and macroscopic appearances. Depending on their size, there are two distinct categories: small congenital nevi (SCN) and large congenital nevi usually referred to as giant congenital nevi (GCN). GCN have an estimated incidence of 1 in 20,000 live births. Although there seems to be no hereditary transmission of GCN, there is a recognized tendency to familial aggregation. Clinical implications There are three main problems associated with GCN: risk of malignant transformation, NCM, and cosmetic effects. The cosmetic complications are of major relevance, as they have an impact on the psychological development and social interaction of the affected child, in particular for those patients whose nevi involve exposed areas. Although no accurate estimate of the risk of malignant transformation has been agreed upon, the accepted cumulative risk in a lifetime is lower than 6%, and it keeps going down as new studies are published. [6] The risk of developing NCM is unknown but most authors consider it a rare complication of GCN. [7] In these patients, the melanocytic proliferation affects also the leptomeningeal structures, spreading throughout the spaces in contact with cerebrospinal fluid (CSF); the brain parenchyma may show focal areas of involvement presumably facilitated by dissemination through the perivascular spaces of Virchow-Robin. Furthermore, as seen in this case, some patients receiving a VPS used to relieve the obstructive hydrocephalus have been complicated with peritoneal seeding by the proliferating melanocytes. Patients that feature both, skin and leptomeningeal or brain melanocytic growth are diagnosed with Neurocutaneous Melanosis (NCM). Once neurologic symptoms begin, in most patients the disease progresses indefectibly, without long-term response to any form of known treatment. Although the full blown clinical presentation of NCM is a relatively rare event, forms with an incomplete phenotype (absent skin lesions), which may be not so rare, are known to occur and therefore, it is likely that an unknown number of patients with NCM may go undiagnosed. In addition, it has been suggested that a number of cases may have no neurologic symptoms, possibly in patients with milder forms of the disease and whose clinical course is also unknown. [8] The presence of associated anatomical defects such as Dandy-Walker malformation in many reported patients may be related to the contribution that neural crest cells furnish to the development of brain, cerebellar and meningeal structures. Biology From the morphological standpoint, NCM cells vary and range from benign-looking, nevus-like melanocytic collections, to bizarre, atypical and with an aggressive-looking appearance, sometimes indistinguishable from melanoma. However, in most cases, NCM lesions feature a phenotype intermediate between a benign nevus and malignant melanoma. It is possible that their biological features also correspond to an intermediate position in the spectrum of melanocytic disorders. To this date, few studies about biological characteristics of the proliferating cells in this condition have been published. We analyzed10 patients with confirmed NCM, and a 1-year old girl with a congenital nevus, whose sibling died with NCM. DNA was extracted from melanocytes of normal skin, nevi, brain lesions, and/or blood samples. PCR amplification and sequencing for the 3 exons of p16 and exon 2 of CDK4, two genes involved in the familial form of melanoma, was carried out. The R24C mutation of the CDK4 gene was evaluated by restriction enzyme digestion and/or by direct gene sequencing. No mutations were found in either p16 or CDK4. Preliminary results of clonality analyses carried out also by our group are consistent with a monoclonal (neoplastic) pattern of lyonization in melanocytic lesions of NCM patients. [9] Differential diagnosis Tumors known to disseminate through VPS include medulloblastoma, brain germ cell tumors, ependymoma, choroids plexus carcinoma, rhabdoid tumor, lymphoma, melanoma, gliomas/gliomatosis and teratocarcinoma. [10] The morphologic features of the "metastatic" cells in our case are challenging to interpret without the clinical history. They are relatively small, poorly differentiated, with small amounts of cytoplasm. In a young patient, this phenotype may resemble several of the "small round cell" tumors that need to be ruled out, in particular PNET/Ewing sarcoma or some of its congeners. However, given the past medical history, the clear evidence of melanin deposits, and the Immunophenotype, the diagnosis can be established. More challenging is to appropriately classify how "malignant" these "metastatic" foci are. If no VPS was placed, it is unlikely that the cells would have traveled and settled on the peritoneal surface. However, they are able to establish colonies, survive and proliferate, causing ascites and abdominal distention or secondary obstructive hydrocephalus. Conclusion The example discussed represents a "facilitated metastasis" of a nevomelanocytic proliferation primary in the CNS. The "metastatic" cells express melanocytic differentiation markers. The cells also show a great ability to seed and grow on the peritoneal surface, revealing an increased oncologic potential, as compared to non-neoplastic melanocytes. Additional biological studies on these rare examples may shed light into the pathogenesis of melanocytic malignancies. References Busam, K.J., et al., Immunohistochemical analysis of novel monoclonal antibody PNL2 and comparison with other melanocyte differentiation markers. Am J Surg Pathol, 2005. 29(3): p. 400-6. Kadonaga, J.N. and I.J. Frieden, Neurocutaneous melanosis: definition and review of the literature. J Am Acad Dermatol, 1991. 24(5 Pt 1): p. 747-55. Miller, V.S., Neurocutaneous Melanosis, in Neurocutaneous Disorders, E.S. Roach and V.S. Miller, Editors. 2004, Cambridge University Press: Cambridge. p. 71-76. Reyes-Mugica, M., F. Gonzalez-Crussi, and B.S.M.-E. Bauer, Gilberto, Bulky naevocytoma of the perineum: a singular variant of giant congenital pigmented naevus. Virchows Archiv A Patholic Anatomy and Histopathology, 1992. 420: p. 87-93. Reyes-Mugica, M., et al., Nevomelanocytic proliferations in the central nervous system of children. Cancer, 1993. 73: p. 2277-2285. Hale, E.K., et al., Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi--results from the NYU-LCMN registry. Br J Dermatol, 2005. 152(3): p. 512-7. Marghoob, A.A., et al., Number of satellite nevi as a correlate for neurocutaneous melanocytosis in patients with large congenital melanocytic nevi. Arch Dermatol, 2004. 140(2): p. 171-5. Agero, A.L., et al., Asymptomatic neurocutaneous melanocytosis in patients with large congenital melanocytic nevi: a study of cases from an Internet-based registry. J Am Acad Dermatol, 2005. 53(6): p. 959-65. Alvarez-Franco, M., et al., Neurocutaneous melanosis nevi do not carry mutations in melanoma-related genes p16 and CDK4. Laboratory Investigation, 2000. 80(1): p. 6P. Donovan, D.J. and R.D. Prauner, Shunt-related abdominal metastases in a child with choroid plexus carcinoma: case report. Neurosurgery, 2005. 56(2): p. E412; discussion E412.