A Pediatric Case of Neurofibromatosis Type 1–Associated Malignant Peripheral Nerve Sheath Tumor of the Scalp

Summary:

Neurofibromatosis type 1 is an autosomal dominant disorder predisposing patients to plexiform neurofibromas, benign tumors with an 8%–13% lifetime risk of malignant transformation into malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive sarcomas with poor prognosis. We present the case of a 13-year-old neurofibromatosis type 1 patient with a large, pedunculated, scalp plexiform neurofibroma who underwent subtotal surgical excision to improve her appearance and ability to wear hats. The patient was treated preoperatively with selumetinib for size reduction, and the procedure was bloody. Pathology revealed that the neurofibroma had an intralesional high-grade MPNST. Margin status for the malignant component was inconclusive. Immunohistochemistry revealed loss of H3K27me3 expression, indicative of aggressive tumor biology. The patient underwent adjuvant chemotherapy followed by a re-excision of the surgical site, which showed no residual tumor.

Neurofibromatosis 1 (NF1) is an autosomal dominant genetic disorder, affecting approximately 1 in 3000 individuals worldwide.¹ Inactivating mutations of the NF1 tumor-suppressor gene on chromosome 17 predispose patients to develop neurofibromas, benign peripheral nerve sheath tumors that are a hallmark of NF1. Plexiform neurofibromas (PNs) occur in up to 50% of patients with NF1 but fewer than 20% require intervention during childhood.¹ PNs can cause pain, disfigurement, and functional impairment. Management includes surveillance, surgical resection, and mitogen-activated protein kinase inhibitors such as selumetinib.^2,3 Although typically benign, PNs carry a lifetime risk of 8%–13% for malignant transformation into malignant peripheral nerve sheath tumors (MPNSTs).¹ Concerning features of malignant transformation include rapid growth, new-onset pain, and changes in tumor consistency.^1,2 We present a pediatric patient with NF1 with a presumed benign large scalp PN, later found on pathology to be a high-grade MPNST.

CASE PRESENTATION

A 13-year-old woman with a history of clinically diagnosed NF1, optic pathway glioma, and brain glioma, presented with a large, progressively enlarging pedunculated PN emanating from the right parieto-occipital scalp (Fig. 1). Over the course of 2 years, the mass grew to approximately 15 × 10 cm, becoming increasingly painful during this period. Magnetic resonance imaging (MRI) revealed a lesion consistent with PN, without concerning features for malignancy, and showed typical growth for NF on serial MRIs. Given the tumor’s substantial size, the patient was started on preoperative selumetinib to reduce tumor volume, alleviate symptoms, and facilitate safer surgical resection. Preoperative computed tomography (CT) revealed the large PN with small venous drainage into the superior sagittal sinus.

Fig. 1.

Preoperative images of scalp tumor. A, Superior view. B, Lateral view.

Given the tumor’s size and challenging anatomical location, a subtotal excision was performed. The mass was carefully excised using a small jaw Ligasure to reduce blood loss and wide undermining of the scalp was necessary to facilitate tension-free closure. Postoperative recovery was uneventful. Pathology unexpectedly confirmed a high-grade MPNST within the PN, with intraneural and cutaneous components (Fig. 2). Immunohistochemistry showed loss of H3K27me3 expression, but absence of malignancy at the tumor margin could not be confirmed. Baseline staging with MRI and positron emission tomography (PET) revealed residual neurofibroma but no evidence of metastatic disease. Genetic testing obtained after confirmation of malignancy identified a pathogenic NF1 variant (c.943C>T, p.Q315*) and mutations in CDKN2A, SUZ12, and TP53, consistent with MPNST. The patient began adjuvant chemotherapy following the SARC006 protocol⁴ with doxorubicin/ifosfamide and ifosfamide/etoposide. Following 4 cycles of chemotherapy, she underwent re-excision of the scar and underlying periosteum, with no residual MPNST found on pathology. She has completed chemotherapy, and the scalp wound healed well. (See figure, Supplemental Digital Content 1, which displays a postoperative image of scalp surgical site after re-excision and completion of a total of 6 cycles of chemotherapy, https://links.lww.com/PRSGO/E235.)

Fig. 2.

Histopathology of plexiform neurofibroma with malignant intraneural and cutaneous components. A, 10x magnification. B, 20x magnification.

DISCUSSION

MPNSTs are aggressive soft tissue sarcomas, with an incidence of approximately 1 in 100,000 in the general population and 1 in 3500 among individuals with NF1.⁵ Nearly half of MPNST cases are associated with NF1, whereas others are sporadic or linked to prior radiation exposure, with a latency period averaging 16 years of postradiation.^5,6 MPNSTs typically affect young to middle-aged adults and commonly occur in the extremities, pelvis, or trunk, with rare cases involving the scalp.^1,7 In the pediatric population, MPNSTs have been reported to account for less than 10% of all cases.⁶ Prognosis remains poor, marked by frequent local recurrence and metastasis, despite curative surgical intent. A meta-analysis involving 28 studies from 1966 to 2020 reported a 5-year survival rate of approximately 49% overall.⁵

The progression of PN to MPNST involves a series of genetic and histopathologic changes. Morphologically, PN transitions to MPNST through gradual loss of neurofibroma architecture, increased cellularity, and atypia. The histopathologic progression from PN to MPNST is characterized by loss of S100 protein expression, decreased p16, and loss of H3K27me3 expression.⁸ H3K27me3 loss serves as a useful diagnostic marker for distinguishing MPNSTs from mimics, indicating aggressive tumor biology and poor prognosis.⁹ In this patient, genetic alterations to CDKN2A and SUZ12 played a significant role in driving malignant transformation.

Clinical indicators of malignant transformation such as rapid growth, increasing firmness, and persistent pain disrupting sleep are well documented;⁸ distinguishing between PN and MPNST clinically remains a challenge. Imaging plays a crucial role in the assessment of malignant transformation, with modalities including regional or whole-body MRI, diffusion-weighted MRI, and fluorodeoxyglucose-PET-CT.⁸ However, the absence of definitive consensus guidelines complicates routine surveillance. Although fluorodeoxyglucose-PET-CT is highly sensitive for detecting MPNST, its use raises concerns about exposing patients with NF1 to excess radiation as these patients already have elevated lifetime risk of malignancy. Radiographic features concerning for malignancy include heterogeneous contrast enhancement, irregular borders, multilobulated, target sign, and rapid interval growth.⁸ Our patient had an interval increase in tumor size on MRIs taken a year apart, but the growth was consistent with the approximately 20% expected linear growth patterns of PN in children reported in the literature.⁸

Although no standard of care has been established for pediatric MPNSTs,⁶ complete surgical resection with negative margins is the only known curative approach.^5,10 Achieving negative margins poses challenges due to the anatomical complexity and proximity to vital structures in the head and neck region.⁷ The highly vascular nature of neurofibromas and extensive size of the tumor in this patient led to significant but anticipated, intraoperative bleeding. Several authors have advocated preoperative embolization to reduce intraoperative bleeding,⁷ but we did not pursue this strategy because collateral damage to adjacent healthy scalp would have made primary closure impossible. As reported by Konno and Kishi,¹¹ the Ligasure vessel-sealing system was found to be highly effective for hemostasis.

Adjuvant chemotherapy and radiation therapy remain controversial in managing MPNSTs, particularly in pediatric cases.^6,8 Commonly used regimens, such as doxorubicin combined with ifosfamide or etoposide, have demonstrated partial responses in a subset of patients with high-grade and metastatic MPNSTs. However, the overall chemosensitivity of MPNSTs remains poor.⁵ For high-grade soft tissue sarcomas, radiation is recommended for incomplete resections or extremity cases to improve local control but has not been shown to improve overall survival and carries risks of secondary malignancies. Our patient underwent adjuvant chemotherapy to address residual high-grade disease after initial subtotal excision, and re-excision was performed to reduce the need for possible radiation therapy. Fortunately, more aggressive adjuvant treatment will be unnecessary given the lack of residual tumor in the re-excised specimen.

DISCLOSURE

The authors have no financial interest to declare in relation to the content of this article.