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We present a case of a pre-adolescent female with Neurofibromatosis type 1

(NF1) who developed squamous cell carcinoma (SCC) on the dorsum of the

nose. This rare presentation has been reported in the literature only twice

and in both instances involved adult patients. SCC itself is very rare in

children and is usually seen in those with a predisposing condition like

immunosuppression, radiation exposure or genodermatoses of which our

patient did not have. We also discuss the possible pathogenesis of epithelial

tumor development in patients with NF1, a historically non-epithelial tumor

producing disorder.

IntroductionNeurofibromatosis type 1 is an autosomal dominant genetic disorder

characterized by the presence of cafe-au-lait macules (CALMs),

neurofibromas, nerve sheath tumors, lisch nodules and freckling in the

axillary or inguinal region. Almost every organ system in the body can be

affected from renal dysfunction with essential hypertension and learning

difficulties to scoliosis. Skin manifestations like CALMs and plexiform

neurofibromas will usually appear congenitally or within the first year of

life, whereas other skin findings like simple neurofibromas appear later in

childhood. Generally all criteria for diagnosis of NF1 are met in 97% of

patients by age 8 years and in 100% of patients by age 20 years. Patients are

at increased risk of developing a number of different central nervous and

non-epithelial neoplasms.9 It is very rare for patients with NF1 to develop

cutaneous squamous cell carcinoma.

Abstract

Case Report

Discussion

Figures 2 & 3: Shave biopsy from patient’s nasal dorsum shows atypical keratinocytes invading the dermis with overlying parakeratosis and peripheral

pseudoepitheliomatous hyperplasia

Dermatopathology

Conclusions

In conclusion, this is the third reported case of cutaneous SCC in a patient

with NF1, and the first reported case in a pre-adolescent patient. To our

knowledge, this is the first documented case of SCC of the nose diagnosed

in a patient with NF1. Due to the rarity of the condition, we were not able to

find guidelines for management of pediatric squamous cell cancer and

perhaps with its increasing incidence this issue may be addressed in the

future. Our case along with prior studies conducted, suggest an increase in

risk for developing epithelial tumors in patients with NF1 warranting further

study in this topic. With this knowledge, clinicians can be more informed

about all the risks pertaining to NF1 and will hopefully consider SCC when

they come across any abnormal lesions that are found in predisposed

individuals.

References

1. Seminog OO, Goldacre MJ. Risk of benign tumours of nervous system,

and of malignant neoplasms, in people with neurofibromatosis:

population-based record-linkage study. Br J Cancer. 2013;108:193–8.

2. 2. Ishida M, Okabe H. Cutaneous squamous cell carcinoma in a patient

with neurofibromatosis type 1: A case report. Oncology Letters.

2013;6(4):878-880.

3. Friedrich RE, Al-Dam A, Hagel C. Squamous cell carcinoma of the sole

of the foot in neurofibromatosis type 1. Anticancer Res.2012;32:2165–2168.

4. Hermonen J, Hirvonen O. Neurofibromin: expression by normal human

keratinocytes in vivo and in vitro and in epidermal malignancies. Lab

Invest. 1995;73(2):221-8.

5. Atit RP, Mitchel K, Nguyen L, Warshawsky D, Ratner N.

Neurofibromatosis type 1 and Tumor suppressor is a modifier of carcinogen

induced pigmentation and papilloma formation in C57BL/6 mice. J Invest

Dermatol. 2000;114(6): 1093–1100.

6. de la Luz Orozco-Covarrubias M et al. Malignant cutaneous tumors in

children. J Am Acad Dermatol. 1994 Feb;30(2 Pt 1):243-9.

7. Hamm H, Höger PH. Skin tumors in childhood. Dtsch Arztebl Int 2011;

108(20): 347–53.

8. Chow CW, Tabrizi S, Tiedemann K, Waters K. Squamous carcinomas in

children and young adults: a new wave of a very rare tumor?. Journal of

Pediatric Surgery (2007) 42, 2035–2039.

9. Bolognia JL, Jorizo JL, Rapini RP. Dermatology. 3rd Edition.

Philadelphia. Elsevier;2012: Chapter 61, p. 925-927.

10. Kotwal A. Cutaneous squamous 132 carcinoma in a child. Journal of

Plastic, Reconstructive & Aesthetic Surgery (2009) 62, e194ee195.

11. Guillot B, Dalac S, Delaunay M, Baccard M, Chevrant-Breton J,

Dereure O, et al. Cutaneous malignant melanoma and neurofibromatosis

type 1. Melanoma Res. 2004;14:159---63.

Correspondence

Chris Mancuso, DO

Saint Barnabas Hospital

Bronx, NY

mancusoderm@gmail.com

Christopher Mancuso, DO*, Mojgan Hosseinipour** MSIV DO, Craig Austin***, MD, Charles Gropper****, MD, Cindy Hoffman*****, DO

*Dermatology resident, OGME-IIII Saint Barnabas Hospital Department of Dermatology, Bronx, NY**MSIV Lake Erie College of Osteopathic Medicine Erie, PA

***Dermatopathologist Fishkill, NY**** Dermatology Director of Saint Barnabas Hospital, Bronx, NY

***** Dermatology Residency Program Director, Saint Barnabas Hospital Department of Dermatology, Bronx, NY

A Rare Case of SCC in a Pediatric Patient with NF-1

An 11 year old female with a past medical history of NF1 and positive

family history of NF1 including mother and sibling, presented to the

dermatology clinic for evaluation of a lesion on her nose that was present

for the past 6 months (Figure 1). There was no bleeding, pain or change in

size. She denied similar lesions elsewhere. On physical examination the

patient had a smooth pink papule measuring 7 mm in diameter on the

dorsum of the nose with overlying scale-crust, as well as multiple well-

defined brown patches and macules on the trunk and extremities.

Differential diagnosis included: verruca vulgaris, irritated molluscum

contagiosum, and pyogenic granuloma. Cryotherapy using liquid nitrogen

was performed on the lesion for presumed verruca vulgaris. Three weeks

later the patient returned to clinic with the lesion having grown in size

since the last visit. The patient then had a shave biopsy of the nasal lesion

which showed atypical squamous cell proliferation invading the dermis

consistent with SCC. The patient then underwent Mohs micrographic

surgery for complete surgical removal.

NF1 is an autosomal dominant genetic disorder due to mutations in the NF1 gene located at chromosome 17q11.2. Tumors in NF1 are

predominantly derived from connective tissue and neurofibromas are the most common type of benign tumor that develops in these patients.1

Patients with NF1 are at increased risk of developing non-epithelial tumors including optic gliomas, astrocytomas and malignant peripheral nerve

sheath sarcomas.2 NF1 gene codes for neurofibromin, a protein which acts as a GTPase-activating protein. This leads to negative regulation of

Ras-Mitogen-activated protein kinase, which is involved in cell survival and proliferation. Neurofibromin acts as a tumor suppressor by hastening

the transition from GTP to GDP causing Ras to be non-functional.9 With Ras non-functional, tumor formation does not occur. While evidence

linking epithelial tumors to NF1 is admittedly scant, there have been some studies investigating a possible role NF1 may have in their

carcinogenesis. It is known that neurofibromin can be found in normal human epidermis. A Finland study by Hermonen et al. used reverse

transcriptase PCR, immunohistochemistry, and molecular hybridizations to characterize the expression of NF within keratinocytes. They found

evidence that neurofibromin acts as a regulator of the basal keratinocytes in normal skin and that dysregulation could potentially cause the

development of epithelial tumors like basal cell carcinoma and squamous cell carcinoma.4 Another study in mice by Atit et al. showed further

evidence for NF1’s role in epithelial carcinogenesis. They studied mice who were heterogeneous for null mutations in NF1, exposing them to

known carcinogens. Heterogeneous mice developed papillomatous growths as well as sustained increases in keratinocyte proliferation, while wild

types with the same exposure did not. In addition, all mice with papillomas were shown to have activation of Ras, a crucial step in the process of

carcinogenesis, supporting its involvement in epidermal tumors.5 There are very few reported cases of epithelial tumors, specifically cutaneous

squamous cell carcinoma (SCC), in patients with NF1. Ishida and Okabe reported a case of SCC of the forehead in an 80 year old female patient

with a history of NF1.2 Friedrich et al. reported a case of SCC arising on the sole of the foot in a 67 year old male patient with NF1.3

Interestingly, NF1 also appears to have some relationship with cutaneous melanoma. In a study of 11 patients with melanoma and concurrent NF1

patients had a mean Breslow depth of 3.2mm, considerably deeper than their non-NF1 counterparts. In fact, NF1 is the third most affected gene in

melanoma.11

Squamous cell carcinoma is the second most common cutaneous malignancy in adults. Classically it occurs in older adults on chronically sun

exposed areas as well as in those with radiation exposure, chronic wounds, arsenic exposure and immunodeficiency. Children rarely develop any

cutaneous cancers, with an incidence of 1.4 per 1000 patients. One study by a large pediatric hospital showed that out of ~36k dermatology

patients, 53 cutaneous malignancies were diagnosed. Of that number 6% were squamous cell cancer.6 In children cutaneous malignancies are

mainly seen in association with underlying skin conditions like albinism, xeroderma pigmentosum, nevus sebaceous, and gorlin syndrome,

although all of the classic predisposing factors can come into play.7 According to one article, pediatric squamous cell cancer of all types appears to

be increasing in prevalence over the past two decades. They believe it to be caused by multiple factors including recurrence of SCC after radiation

treatments years later and increased HPV infection prevalence.8 Cutaneous malignancy should be considered early on in any child with

predisposing factors and atypical presentation.10 It is important to use a dermatopathologist comfortable with diagnosing pediatric lesions.

Clinicians may also consider performing a second wider biopsy, so as to not miss or delay diagnosis. At times an adult dermatopathologist may be

better suited in diagnosis of these classically late presenting lesions. Treatment of these lesions is recommended and full excision is warranted as

squamous cell cancers in children have poor a prognosis.8 Our patient underwent Mohs micrographic surgery for full examination of tumor

margins and best cosmetic outcome on this young female’s face. Months out she has shown no signs of recurrence and is happy with her cosmetic

appearance. She is being followed by ophthalmology, neurology, dermatology, and has been offered genetic counseling for her underlying NF1.

We expect to have her follow up once a year for a full skin exam to monitor for further skin cancer development.

Figure 1: Clinical presentation of lesion on patient’s

nasal dorsum

Figure 2: Shave biopsy of nasal dorsum low power Figure 3: Shave biopsy, higher power nasal dorsum