Malignant transformation in a patient with type 1 neurofibromatosis: A case report

Abstract

Neurofibromatosis is an autosomal dominant disease. The most common skin manifestation of type 1 neurofibromatosis is plexiform neurofibromas. Malignant peripheral nerve sheath tumors are rare and aggressive malignancies that predominantly arise from peripheral nerves and various nerve sheath cells. This report presents the case of a male patient in his late 50s who was diagnosed with malignant transformation of type 1 neurofibromatosis and treated surgically. The clinical manifestations, histopathological characteristics, treatment, and outcomes of this rare clinical case provide insights for subsequent diagnostic evaluation and clinical decision-making.

Introduction

Neurofibromatosis (NF) is an autosomal dominant disease characterized by neurodevelopmental abnormalities resulting from genetic defects. ¹ Type 1 neurofibromatosis (NF1) is typically distinguished by the manifestation of café-au-lait skin pigmentation, axillary freckles, Lisch nodules, and cutaneous or subcutaneous tumors known as plexiform neurofibromas (PNs). ² PNs are histologically benign nerve sheath tumors that occur commonly in individuals with the tumor predisposition syndrome NF1. They consist of multiple cell types, including Schwann cells, fibroblasts, perineural cells, mast cells, and macrophages. ³ Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive malignancy, predominantly arising from peripheral nerves and diverse nerve sheath cells. Its management is exceedingly challenging, and the prognosis is extremely poor. MPNST may originate from the malignant progression of NF1. Patients with NF1 develop MPNST at an annual incidence rate of 1.6 per 1000 individuals, with the lifetime risk ranging from 8% to 13%.^4–6 This report presents a case of malignant progression in NF1, with the objective of improving clinical recognition and informing management strategies for this manifestation.

Case report

A male in his late 50s, who began developing soft skin masses of varying sizes on the trunk >40 years ago, was diagnosed with NF1 at a local hospital. Due to the absence of subjective symptoms or treatments, the number of skin tumors gradually increased and spread throughout the body (Figure 1). Six months ago, the patient noted an increase in size of the left armpit and back tumors, and the pain and discomfort had started affecting his daily life. Consequently, he sought further evaluation and treatment at our hospital. Since symptom onset, his mental state and appetite were acceptable, and he had not experienced any recent weight loss. The patient’s remaining medical history was unremarkable, and no pertinent family history was identified. Physical examination revealed generalized cutaneous neurofibromas covering the entire body. Local examination revealed hard, egg-sized, tender, nonmovable tumors on the left armpit and back. The range of movement of the left forearm, wrist, and hand was unimpeded. This case study received approval for publication from Qingdao Municipal Hospital, and written informed consent was obtained from the patient prior to publishing of anonymized data. The reporting of this study conforms to the Case Report (CARE) guidelines. ⁷

Figure 1.

Multiple globular cutaneous neurofibromas.

After admission, we performed a series of examinations to assess the patient’s general condition. When tumors in patients with NF1 exhibit rapid growth, ulceration, bleeding, and pain, it often indicates malignant transformation. Based on the patient’s medical history and clinical presentation, we considered the possibility of malignant transformation of NF1. Subcutaneous tumor resection in the axilla and back under general anesthesia was planned, and the resected specimens appeared as gray-white masses (Figure 2). Final pathological assessment confirmed MPNST (Figures 3 and 4). The tumor margins were negative, and no metastasis was observed in the surrounding lymph nodes. The patient was followed up for 1 year postoperatively; however, due to financial limitations, no further antitumor treatment was administered, resulting in tumor recurrence, systemic metastasis, and death 1 year later.

Figure 2.

Intraoperative specimens.

Figure 3.

Hematoxylin and eosin (H&E) staining results of postoperative pathology. The tumor exhibits extensive hemorrhage and necrosis, with tumor cells displaying a spindle-shaped and epithelioid appearance. The nucleoli are prominent, and mitotic figures are common. Mucinous degeneration is present in the stroma of some areas, supporting the diagnosis of malignant peripheral nerve sheath tumor (MPNST). The tumor margin is negative, with no metastasis observed in the surrounding lymph nodes. (H&E staining, 100× ((a) and (b)) and 200× ((c) and (d)).

Figure 4.

Immunohistochemical results. (a) CK(+); (b) CK8/18(+); (c) HMB-45(−); (d) INI-1(−); (e) Ki-67 (40%); (f) Melan-A(−); (g) S-100(+); (h) Sox-10(−); (i) Vimentin(+). CK: cytokeratin; HMB-45: human melanoma black-45; INI-1: integrase interactor 1; Sox-10: SRY-related HMG-box transcription factor 10.

Discussion

NF1 is a multisystem autosomal dominant genetic disorder and is among the most prevalent single-gene inherited diseases, with an incidence of approximately 1 in 2600 to 1 in 3000 births.^8,9 It can affect virtually all organ systems. Nevertheless, neurocutaneous syndromes are primarily characterized by distinctive lesions such as café-au-lait macules, intertriginous freckles, and cutaneous neurofibromas. This disease can also lead to more complex pathological conditions involving other systems and organs, particularly PN, which has the potential for malignant transformation. ¹⁰ Based on diagnostic criteria recommended by international consensus, a diagnosis of NF1 can be established in the absence of a parent diagnosed with NF1 when two or more of the following characteristics are present: (a) ≥6 café-au-lait macules measuring >5 mm in greatest diameter in prepubertal individuals and >15 mm in postpubertal individuals; (b) freckling in the axillary or inguinal region; (c) ≥2 neurofibromas of any type or 1 PN; (d) optic pathway glioma; (e) ≥2 iris Lisch nodules identified using slit lamp examination or ≥2 choroidal abnormalities, defined as bright, patchy nodules identified on optical coherence tomography/near-infrared reflectance imaging; (f) a distinctive osseous lesion such as sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone; and (g) a heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissues such as white blood cells. ¹¹

PN is a unique subtype of neurofibroma that develops along one or more nerve trunks or branches. In contrast to cutaneous neurofibromas, these lesions typically manifest during early childhood and are generally considered to be congenital in origin. ¹² Common clinical features may include cutaneous changes, including thickened, hyperpigmented skin with an orange-peel appearance, often accompanied with localized hypertrichosis. On palpation, these tumors frequently exhibit a heterogeneous consistency or nodularity and are commonly described as resembling a “bag of worms.”^13,14 PN may develop in virtually any anatomical region, including the head and neck, orbits, extremities, thoracic area, paraspinal nerve roots, abdomen, and pelvis. Although these tumors can remain asymptomatic, they can also induce pain and morbidity through compression of nearby tissues. Substantial pain directly associated with PN is relatively uncommon (affecting approximately 11%–30% of individuals); however, any reported discomfort warrants thorough clinical assessment, as it may indicate the presence of atypical neurofibromatous neoplasms of uncertain biologic potential or malignant progression into MPNST. ¹⁵ Approximately 10%–15% of PNs may eventually undergo malignant transformation into MPNST, typically associated with patients with PN carrying large (usually 1.4 megabase) genomic deletions (which remove the entire NF1 gene plus a variable number of flanking genes). ¹⁶

Surgery is generally recommended for PN when complete resection can be achieved without significant morbidity.^15,17 Nevertheless, complete excision is feasible in only a limited number of patients (approximately 15%), and postoperative regrowth (occurring in up to 43% of cases) as well as persistent complications, primarily neurological deficits (in 5%–18% of patients), are frequently observed. ¹⁵ In the context of MPNST, neither wide local excision nor limb amputation has demonstrated significant improvement in survival rates. Moreover, both approaches are often associated with considerable functional impairment and reduced quality of life, and the 5-year survival rate following chemotherapy remains <20%. ¹⁸ Therefore, it is crucial to detect malignant transformation early and conduct meticulous preoperative planning, particularly given that the surgical management of PN poses distinct challenges compared with that of other benign neoplasms of the nervous system. These lesions frequently exhibit multifocal involvement along neural pathways, often requiring the excision of multiple tumor nodules from the affected nerve or the sacrifice of functionally critical nerve structures. The established indications for surgical intervention in PN include the following: (a) lesions exhibiting clinical or radiological features of malignant transformation; (b) lesions demonstrating radiographic evidence of progressive enlargement; (c) tumors causing substantial neurological deficits and functional disabilities; and (d) tumors causing intolerable sensory symptoms. ¹⁹

In the present case, the patient reported that the left armpit and back tumors had increased in size, and the pain and discomfort had started affecting his life. Therefore, in combination with his medical history, we considered malignant transformation of PN into MPNST. Patients should be informed about potential postoperative complications, including tumor recurrence, regrowth, and permanent neurological deficits. Surface tumor resection surgery can be performed, and intraoperative pathological examination of the mass can confirm the diagnosis of MPNST.

Surgical intervention remains the primary therapeutic approach for PN. However, achieving complete tumor removal is often precluded by infiltration of functionally critical anatomical regions, frequently resulting in lesion recurrence following operative intervention. ¹⁵ These inherent constraints of operative management have prompted substantial research efforts toward the development of pharmacological and gene treatments for PN. ¹ Advances in elucidating NF1 pathophysiology, particularly the recognition of the critical role of mitogen-activated protein kinase (MEK) in Ras-mediated signaling, have positioned MEK inhibitors as promising agents for suppressing tumor progression. ²⁰ Selumetinib, an orally administered selective MEK inhibitor, can shrink tumors and alleviate pain symptoms in most patients with PN, thereby improving their quality of life. ²¹ However, it is crucial to recognize that MEK inhibitors are associated with inherent risks; the most common adverse effects include rash, diarrhea, peripheral edema, fatigue, acneiform dermatitis, and cardiac and ophthalmologic side effects. Therefore, further studies are warranted to evaluate the long-term efficacy and safety of related drug treatments. ²²

In conclusion, NF1 is a multisystem genetic disorder that includes PN and exerts a profound impact on appearance, function, and quality of life. NF1 also demonstrates the potential for malignant transformation. In addition to monitoring, symptom management, and surgery, effective targeted medical therapies such as MEK are available for treating NF1. Therefore, the clinical implementation of therapies for NF1 requires careful consideration of multiple factors and should be performed with the input of a multidisciplinary team experienced in managing NF1.