Synchronously diagnosed pre-sacral neurofibroma and cutaneous spitzoid melanoma: a fortuitous association?
© Fadare and Hileeto; licensee BioMed Central Ltd. 2004
Received: 30 July 2004
Accepted: 13 September 2004
Published: 13 September 2004
At a U.S prevalence of 1 in 3000, Neurofibromatosis type-1 (NF-1) is a relatively common disorder. Amongst a variety of others, occurrence of 2 or more neurofibromas in the same patient represents one of the major diagnostic criteria for this disorder. Rarely, ocular, cutaneous or anorectal malignant melanomas may be identified in patients with NF-1, This rare association has caused controversy as to whether patients with NF-1 have an inherently higher risk for melanomas or whether the associations can be explained by chance alone.
The purpose of this report is to highlight the unusual confluence of rare clinicopathologic features in a patient without NF-1. The patient was diagnosed with an 8.5 cm pre-sacral neurofibroma and was shortly thereafter diagnosed with a cutaneous malignant melanoma showing spitzoid features. Pre-sacral neurofibromas are rare in patients without NF-1; likewise, malignant spitzoid melanoma, a controversial histopathological entity, is distinctly uncommon.
The synchronous diagnoses of these neural crest derived tumor entities in a patient without neurofibromatosis lends credence to the view that when these two lesions occur in patients with NF-1, the association is coincidental.
Neurofibromatosis type-1 (NF-1) is a common autosomal dominant disorder characterized by multiple neurofibromas, café-au-lait spots, freckling of the inguinal or axillary regions, gliomas, iris hamartomas, and malignant peripheral nerve sheath tumors [1, 2]. Neurofibromas are typically well-delineated and are composed of an admixture of various cell types, such as Schwann cells, fibroblasts and perineural-like cells and cells showing intermediate features [1, 2]. Although as outlined above, multiple neurofibromas are characteristic of patients with NF-1, however, most cases of neurofibroma which are diagnosed in general are sporadic in nature. The vast majority of neurofibromas are cutaneous and less commonly are intraneural, within the soft tissues or viscera. Presacral neurofibromas or neurofibromas with presacral involvement are uncommon in patients without NF-1, and have been the subject of sporadic case reports over the past half-century [3–16]. Likewise, spitzoid melanoma or melanomas showing spitzoid-like features form only a small percentage of all malignant melanomas. This diagnosis is based on the rare finding that some melanomas displays cytologic features that are similar to those identified in the benign Spitz nevus . The controversy associated with this lesion stems from the fact that some dermatopathologists do not believe in its existence and prefer to designate melanocytic proliferations meeting traditional criteria for malignancy as malignant melanomas, irrespective of the Spitzoid features . To our knowledge, a synchronous presacral neurofibroma and cutaneous spitzoid melanoma have never been reported in a patient without neurofibromatosis. More importantly, the absence of NF-1 in our patient may have implications for the potential association between malignant melanoma and NF-1.
The potential association between NF-1 and malignant melanoma has been the source of controversy in the medical literature. The common neural crest origin of these conditions has provided an attractive framework for this discussion. However, it is unclear whether patients with NF-1 have an inherently higher propensity to develop malignant melanomas than the general population. In a follow-up study of 70 NF-1 patients reported to the Swedish Cancer registry, 24% of the 70 patients developed 19 malignancies, only 1 of which was a melanoma . However, the precise prevalence of melanomas in NF-1 patients is largely unknown. Most melanomas that arise in the setting of NF-1 are ocular. In a recent literature review, Honavar et al  identified only 19 reported cases overall. Cutaneous and anorectal melanomas have also been rarely reported in patients with NF-1 [21–27]. The rarity of this association given the frequency of NF-1 (1 in 3000) suggests that the probability of NF-1 patients developing malignant melanoma is no more than the general population. However, this needs to be tested in a rigorous population-based study. Ishii et al  recently reported a loss of heterozygosity (LOH) at the NF-1 gene in an anal melanoma occurring in an NF-1 patient. This suggests that the well-known Knudson's two-hit hypothesis may be operational, and that somatic loss of the second allele of the putative tumor suppressor function of the NF-1 gene causes development of this particular somatic malignancy. Again, more cases need to be studied to exclude the possibility that LOH for NF-1 occuring as a late event in the tumorigenesis of sporadic melanomas.
Our case provides another framework for the discussion of the potential association between NF-1 and malignant melanoma. Our patient has no evidence of either of the neurofibromatosis syndromes. The rarity of the clinicopathologic features of both lesions identified in this patient (the unusual presacral location of the neurofibroma and the spitzoid melanoma) suggests that their association in this patient is coincidental, even though both are neural crest derived neoplasms. This presumption contradicts the notion that in patients with NF-1, malignant melanomas that rarely develop are part of their neurocristopathy. For residents of the United States, the lifetime probability of developing cutaneous melanoma is 1 in 55–82 (approximately 1.5%) . As previously noted, NF-1 is a relatively common condition with a prevalence of 1 in 3000. Since no more than 100 cases of melanoma (all sites combined) developing in NF-1 patients have been reported, the incidence is significantly lesser than the 1.5% that can be attributed to chance alone.
Although the patient described in this report did not have characteristic clinical features of NF-1, an important possibility that requires consideration is that she has segmental NF-1. Segmental NF-1 is thought to result from a post-zygotic mutation in the NF-1 gene resulting in a somatic mosaicism [29, 30]. In these patients, characteristic NF-1-associated diseases are limited to a localized part of the body [29, 30]. In our patient, a presacral neurofibroma was associated with an upper thigh cutaneous melanoma, putting both lesions in the general same region, albeit without true co-localization. Additionally, melanoma is not a diagnostic criteria for NF-1, as associated lesions are required to be for the definition of segmental NF-1. The location of the current patient's neurofibroma is also somewhat unusual for segmental NF-1. In two combined series that investigated 163 patients with segmental NF-1, there was not a single case of a retroperitoneal neurofibroma [29, 30]. In one of these series , neurofibromas alone were the most common manifestation of segmental NF-1. However, in all such cases, the neurofibromas were either dermal, on major peripheral nerve trunks or both. Although these findings argue against segmental NF-1 in the current patient, the possibility certainly remains. Thus, the findings in this case should be viewed within the context of that possibility.
In conclusion, we report here the previously unreported synchronous diagnosis of a presacral neurofibroma and a spitzoid malignant melanoma in a patient without NF-1. Furthermore, the finding of a sporadic neurofibroma and malignant melanoma occurring in a patient without NF-1 lends credence to the view that when these lesions occur in patients with NF-1, the association may be coincidental.
Patient consent was obtained for the presentation of her records.
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