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World J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central London 1477-7819-2-311536309710.1186/1477-7819-2-31Case ReportSynchronously diagnosed pre-sacral neurofibroma and cutaneous spitzoid melanoma: a fortuitous association? Fadare Oluwole 1oluwole.fadare@yale.eduHileeto Denise 1denise.hileeto@yale.edu1 Department of Pathology, EP 2-631, Yale-New Haven Hospital, 20 York Street, New Haven, CT 06504, USA2004 13 9 2004 2 31 31 30 7 2004 13 9 2004 Copyright © 2004 Fadare and Hileeto; licensee BioMed Central Ltd.2004Fadare and Hileeto; licensee BioMed Central Ltd.This is an open-access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background
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.

Case presentation
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.

Conclusions
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.
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Background
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 [17]. 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 [18]. 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.

Case presentation
In September 2000, a 35-year-old female without any history or clinical stigmata of NF-1 presented to her primary physician with complaints of a dull, localized left upper leg pain of several months' duration. An abdominal mass was palpated during a physical examination. Magnetic resonance imaging (MRI) as well as a computed tomographic (CT) scan of the abdomen and pelvis showed a large well-defined, near spherical mass in the left false pelvis which enhanced heterogeneously at a mean Hounsfield value of 44 units (Figure 1). The mass displaced the external iliac vein medially and psoas muscle laterally. It also abutted the upper surface of the left ovary without truly invading any of these or other surrounding structures. However, the mass was believed to be in the course of the left genitofemoral nerve and lumbar plexus. The decision was made to resect the mass. Intraoperatively, the tumor's capsule was found to be densely adhered medially to the external iliac vessels, with at least 10 external venous branches directly supplying the tumor. The tumor was carefully marsupialized out of the retroperitoneal area and the decision was made to leave the residual capsule, since an attempt at its removal would have entailed a highly morbid procedure that was not felt to be justified based on the histopathologic appearance of the tumor on frozen sections. Intraoperatively, a pigmented macular lesion with faintly irregular edges was noted in the left upper thigh, which was biopsied. Pathologic examination showed a malignant melanoma with spitzoid features. The precise circumstances regarding the duration of the lesion and whether there had been any increase in its size was unclear. She subsequently underwent a wide local excision (4 × 12 cm skin ellipse was removed) and sentinel lymph node biopsy, both of which showed no residual melanoma. The patient's postoperative course over the subsequent 2 years was remarkable for a relatively slow but progressive improvements in the neurologic symptoms related to her surgery. However, she showed no evidence of either tumor recurrence at last follow-up, 26 months postoperatively.

Figure 1 Computed tomographic scan of the pelvis showing a large, well-circumscribed presacral mass

Pathologic findings
The resected mass was spherical, weighed 270 grams and measured 8.5 × 7 cm × 7 cm (figure 2). The specimen was sectioned to reveal a myxoid tan-yellow cut surface (figure 3). Microscopically, the specimen was uniformly hypocellular, and showed a haphazard admixture of wavy Schwann cells and collagen fibers dispersed in a mucopolysaccharide matrix (figure 4). No increased cellularity, nuclear pleomorphism, increased mitotic activity or tumor coagulative cell necrosis was identified. On immunohistochemistry the tumor was positive for S100, Neurofilament, vimentin, and negative for epithelial membrane antigen, in combination with the morphological features a diagnosis of neurofibroma was made. Pathologic examination of the skin lesion showed a malignant melanoma (6 mm in diameter) with spitzoid features: epithelioid and spindle atypical melanocytes growing in a solid, asymmetric, non-maturing pattern with deep mitotic figures (up to 3 mitotic figures/mm2). The individual cells displayed nuclear pleomorphism with prominent nucleoli and the epithelioid forms showed abundant cytoplasm (Figures 5, 6, 7, 8). Immunohistochemically, both the spindle and epithelioid cells showed strong and diffuse immunoreactivity for S100 and HMB-45. The proliferative index of the tumor was 30–40% as assessed with the immunohistochemical marker ki-67. This lesion was at a Clark's level IV and at a depth of 2.1 mm. Growth phase was vertical and ulceration was absent. A few tumor-infiltrating lymphocytes were present and there was no definitive evidence of regression.

Figure 2 Macroscopic appearance of the external surface of the presacral mass

Figure 3 The cut surface of the presacral mass showing glistening myxoid, tan-yellow appearance

Figure 4 Microscopic appearance of the presacral mass showing a haphazard admixture of wavy Schwann cells and collagen fibers dispersed in a mucopolysaccharide matrix (Hematoxylin and Eosin, 20×)

Figure 5 Photomicrographic panoramic view of the patient's cutaneous biopsy showing an asymmetric lesion with a basal confluent growth (Hematoxylin and Eosin 2×)

Figure 6 Photomicrograph of the junctional component of the tumor showing Spitzoid features of the lesional cells. Note that the junctional nests do not display a uniform vertical orientation towards the epidermis, as is expected in most Spitz nevi. (Hematoxylin and Eosin 40×)

Figure 7 Interemediate-power view of the cutaneous lesional cells, showing the admixture of spindle and epithelioid cells (Hematoxylin and Eosin 20×)

Figure 8 Photomicrograph showing the cytologic features of the lesion. Note the nuclear pleomorphism and prominent nucleoli. This focus was near the deep edge of the lesion, reflecting a lack of histological maturation (Hematoxylin and Eosin 20×)

Discussion
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 [19]. 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 [20] 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 [21] 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%) [28]. 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 [29], 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.

Competing interests
None declared.

Authors' contributions
OF and DH made substantial contributions to the intellectual content of the paper. Both co-wrote the manuscript. Both the authors have seen the final version of the manuscript and approved it for publication.

Acknowledgement
Patient consent was obtained for the presentation of her records.
==== Refs
Von Deimling A Foster R Krone W  Kleihues P, Cavenee WK  Neurofibromatosis type 1 World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Nervous System 2000 Lyon: IARC Press 216 222 
Burger PC Scheithauer BW Vogel FS  Surgical Pathology of the Nervous system and its coverings 2002 4 New York: Churchill Livingstone 
Feldenzer JA McGauley JL McGillicuddy JE  Sacral and presacral tumors: problems in diagnosis and management Neurosurgery 1989 25 884 891 2601818 
Toporas M Rusu E Blechner M  [Presacral retrorectal neurofibroma] Rev Chir Oncol Radiol O R L Oftazmol Stomatol Chir 1981 30 387 389 
Andress MR Thomas ML  Presacral neurofibroma demonstrated angiographically Australas Radiol 1971 15 360 361 5149413 
Mainetti JM Ichcovich MN Ayarragaray AC  Presacral neurofibroma Prensa Med Argent 1971 58 950 952 5129077 
Delgaudio A  Presacral retroperitoneal neurofibroma simulating an aorto-iliac aneurysm Minerva Chir 1964 19 480 486 14177755 
Nucci RC Beyer FD Jr Retroperitoneal and presacral neurofibroma. A case report Obstet Gynecol 1962 20 668 670 13939194 
Goldenberg IS Alderman DB  Neurofibroma following presacral neurectomy Am J Obstet Gynecol 1958 76 1204 1206 13595001 
Hudson OC Ross ST  Presacral neurofibroma Am J Surg 1955 90 1005 1006 13268766 10.1016/0002-9610(55)90736-4 
Bass JC Korobkin M Francis IR Ellis JH Cohan RH  Retroperitoneal plexiform neurofibromas: CT findings AJR Am J Roentgenol 1994 163 617 620 8079855 
Handa VL Jain K McCue K Schneider PD  Posthysterectomy vault eversion with a large retroperitoneal mass Int Urogynecol J Pelvic Floor Dysfunct 2001 12 279 281 11569659 
Topsakal C Erol FS Ozercan I Murat A Gurates B  Presacral solitary giant neurofibroma without neurofibromatosis type-1 presenting as a pelvic mass-a case report Neurol Med Chir (Tokyo) 2001 41 620 625 11803590 
Argyrakis A Teichmann A Kuhn W  Solitary neurofibroma of the lumbosacral plexus J Neurol Neurosurg Psychiatry 1985 48 844 846 4031940 
Chopra JS Chander K Kak VK  Solitary plexiform neurofibroma at an unusual site. Report of a case in the lumbar region Neurol India 1972 20 104 105 4635582 
Hunter VP Burke TW Crooks LA  Retroperitoneal nerve sheath tumors: an unusual cause of pelvic mass Obstet Gynecol 1988 71 1050 1052 3374919 
Spitz S  Melanomas of childhood. 1948 CA Cancer J Clin 1991 41 40 51 1898635 
Mones JM Ackerman AB  "Atypical" Spitz's nevus, "malignant" Spitz's nevus, and "metastasizing" Spitz's nevus: A critique in historical perspective of three concepts flawed fatally Am J Dermatopathol 2004 26 310 333 15249862 
Zöller MET Rembeck B Odén A Samuelsson M Angervall L  Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population Cancer 1997 79 2125 2131 9179058 10.1002/(SICI)1097-0142(19970601)79:11<2125::AID-CNCR9>3.3.CO;2-B 
Honavar SG Singh AD Shields CL Shields JA Eagle RC Jr Iris melanoma in a patient with neurofibromatosis Surv Opthalmol 2000 45 231 236 10.1016/S0039-6257(00)00154-5 
Ishii S Han S Shiiba K Mizoi T Okabe M Horii A Nagura H Matsuno S Sasaki I  Allelic loss of the NF-1 gene in anal malignant melanoma in a patient with neurofibromatosis type 1 Int J Clin Oncol 2001 6 201 204 11706558 
Silverman JF Blahove M Collins JL Norris HT  Cutaneous malignant melanoma in a black patient with neurofibromatosis (von Recklinghausen's disease) Am J Dermatopathol 1988 10 536 540 3146227 
Mastrangelo MJ Goepp CE Patel YA Clark WH Jr Cutaneous melanoma in a patient with neurofibromatosis Arch Dermatol 1979 115 864 865 110269 10.1001/archderm.115.7.864 
Gallino G Belli F Tragni G Ferro F Massone PP Ditto A eo E Cascinelli N  Association between cutaneous melanoma and neurofibromatosis type 1: analysis of three clinical cases and review if the literature Tumori 2000 86 70 74 10778770 
Garcia-Casasola G Casado A Ciguenza R Gonzalez Larriba JL Alvarez-Sala JL  Rectal melanoma and von Recklinghausen's disease Rev Clin Esp 1992 190 475 476 1626097 
Ben-Izhak O Groisman GM  Anal malignant melanoma and soft-tissue malignant fibrous histiocytoma in neurofibromatosis type 1 Arch Pathol Lab Med 1995 119 285 288 7887787 
Karakayali G Gunger E Lenk N Gur G Kacar A Alli N  Neurofibromatosis and cutaneous melanoma: coincidence or association J Eur Acad Dermatol Venerol 1999 12 190 192 10.1016/S0926-9959(98)00135-4 
Jemal A Tiwari RC Murray T Ghafor A Samuels A Ward E Feuer EJ Thun MJ  Cancer statistics 2004 CA Cancer J Clin 2004 54 8 29 14974761 
Ruggieri M Huson SM  The clinical and diagnostic implications of mosaicism in the neurofibromatoses Neurology 2001 56 1433 1443 11409413 
Listernick R Mancini AJ Charrow J  Segmental neurofibromatosis in childhood Am J Med Genet 2003 121A 132 135 12910491 10.1002/ajmg.a.20183

