Images in Immunotherapy and Precision Oncology: A Case Report of Neurofibromatosis-1 Open Access

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant genetic disorder that primarily causes the growth of tumors along nerves. It is one of the most frequent hereditary conditions, occurring in about 1 in every 3000–4000 individuals worldwide. NF1 is caused by mutations in the NF1 gene, which encodes a protein called neurofibromin. This protein acts as a tumor suppressor, regulating cell proliferation. The hallmark of NF1 is the development of neurofibromas, which are benign tumors that grow around nerves. They vary in size and can be found beneath the skin as well as in various organs. Other characteristics of NF1 include café au lait spots, freckling of the axilla and groin, Lisch nodules in the iris of the eye (which do not affect vision), and learning challenges. In 1987, the National Institutes of Health (NIH) Consensus Development Conference on Neurofibromatosis issued a document stating that a patient could be diagnosed with NF1 if they had two or more of the following: six or more café au lait macules, two or more neurofibromas or one plexiform neurofibroma, axillary or inguinal region freckling, optic glioma, two or more Lisch nodules, a distinctive osseous lesion or thinning of long bone cortex, or a first-degree relative with NF1.¹  Then, in 2021, the diagnostic criteria were revised to incorporate NF1 genetic testing when considering mosaic NF1.²  Recent studies suggest that patients with NF1 germline alterations develop malignant neoplasms more frequently than the general population, and that certain malignancies, including gliomas, malignant peripheral nerve sheath tumors (MPNSTs), and breast cancer, occur at a young age.³  There is also an increased risk of certain types of leukemia, such as juvenile myelomonocytic leukemia, in children with NF1.

NF1 differs from neurofibromatosis type 2 (NF2), also known as bilateral acoustic neurofibromatosis or central neurofibromatosis. NF2 is caused by autosomal dominant mutations in the NF2 gene. This gene encodes a protein called merlin (also known as schwannomin), which acts as a tumor suppressor.⁴  Mutations in NF2 result in the upregulation of the PI3k/Akt/mTor pathway, and tumors that are primarily schwannomas, which are typically noncancerous growths that arise from Schwann cells—the cells responsible for producing the protective myelin covering of nerve fibers. The most common tumor associated with NF2 is the vestibular schwannoma, which affects the nerves responsible for hearing and balance. These tumors can cause hearing loss, balance problems, and other neurological disorders. In addition to vestibular schwannomas, individuals with NF2 can develop other types of tumors, including meningiomas, ependymomas, and peripheral nerve schwannomas. Some patients have shown disease stabilization or regression with the mTor inhibitor temsirolimus or the farnesyltransferase inhibitor salirasib (the latter interfering with RAS function).⁵ 

We report an unusual case of an MPNST, gastrointestinal stromal tumor (GIST), and pheochromocytoma in a patient with NF1. These malignancies were found during autopsy after the patient succumbed to sepsis from an infected right shoulder spindle cell sarcoma.

A 58-year-old woman with a medical history of scoliosis, emphysema, benign uterine fibroids, hypertension, and NF1 presented to clinic with right shoulder swelling and purulent discharge (Fig. 1). Wound cultures were positive for pseudomonas; hence the patient was started on antibiotics, and a biopsy of the lesion was suggestive of spindle cell sarcoma. Positron emission tomography imaging (Fig. 2) showed metastatic foci involving the right axilla. The patient’s daughter also had a history of neurofibromatosis, but there was no family history of malignancy. A few weeks later, the patient presented to the hospital with rapid growth of the right shoulder lesion as well as new pain at rest. At the time of presentation, the patient’s Eastern Cooperative Oncology Group (ECOG) score was 3, but the patient quickly deteriorated due to worsening infection status and opted for hospice care. Informed consent for publication was obtained. An autopsy report showed the coexistence of three synchronous malignancies. The first was an MPNST that was found on her right arm at the level of her shoulder (15 × 7.5 × 6.8 cm, 830.9 g), which was metastatic to the periaortic and peripancreatic lymph nodes as well as the lungs. The second malignancy was synchronous GISTs at different locations involving the duodenum, small intestine, appendix, and large intestine. The largest GIST measured 2.1 cm and was found in the jejunum. Lastly, a 0.5-cm pheochromocytoma was seen on her right adrenal gland.

Patients with NF1 tend to be at a higher risk for developing malignancy due to the germline mutations associated with the condition. The NF1 gene is a tumor suppressor protein that is responsible for regulating the RAS cell growth pathway.⁶  Loss of RAS control leads to increased activity of MEK and other signaling pathways, which might work together to increase cell growth and survival—predisposing patients with NF1 to malignancy (Fig. 3).⁶  Regarding targeted therapies, the US Food and Drug Administration approved the MEK inhibitor selumetinib on April 10, 2020, for pediatric patients above age 2 years with NF1 who have symptomatic, inoperable plexiform neurofibromas.⁷  This approval was granted based on the results of the SPRINT (ClinicalTrials.gov Identifier: NCT01362803) open-label, single-arm, multicenter trial. This study found that after 1 year of treatment with selumetinib, 70% of patients achieved a partial response and 56% had a durable response.⁸  In terms of safety, the most common side effects were nausea, vomiting, diarrhea, asymptomatic rise in creatinine phosphokinase, acneiform rash, and paronychia, with only 10% of patients discontinuing treatment due to toxicities.⁸ 

One deadly type of tumor in patients with NF1 is MPNST, a highly aggressive sarcoma arising from neurofibromas.⁹  Our patient had such a tumor (Fig. 1). MPNSTs typically present as rapid enlargement or new-onset pain of a preexisting neurofibroma.⁹  Patients with MPNSTs have a poor prognosis as they seem to be unresponsive to standard chemotherapy or radiation.⁹  Early diagnosis and surgical removal are of the utmost importance, but early diagnosis is difficult as NF1 patients sometimes display thousands of neurofibromas slowly growing over the years. The main treatment is surgical removal when feasible.¹⁰ 

The most common mesenchymal tumors of the gastrointestinal tract in NF1 patients are GISTs.^11,12  These tumors most commonly present with gastrointestinal bleeding, and other symptoms include intestinal obstruction, abdominal pain, perforation, or a palpable pelvic mass. Our patient also had a GIST. In recent years, studies have identified aberrant tyrosine kinase activity as the key molecular modulator in the pathogenicity of these tumors.^11,13  This discovery has allowed for the successful treatment of patients using the tyrosine kinase inhibitor imatinib.^11,13  However, in patients with NF1, studies have noted that these GISTs are phenotypically and genotypically different from sporadic GISTs.¹²  Thus, no standard therapy for NF1-related GISTs has been established. Fortunately, a recent case report showed that six cycles of regorafenib successfully treated NF1-related GISTs of the bladder and duodenum.¹⁴  Other clinical trials are currently evaluating the efficacy of tyrosine kinase inhibitors in treating GISTs in patients with NF1.

Finally, NF1 carries an increased risk for pheochromocytomas, which are rare tumors of the adrenal medulla that secrete catecholamines, and these tumors are found in 0.1–5.7% of patients.¹⁰  This tumor also occurred in our patient. These tumors present with hypertension and adrenergic symptoms such as episodic headache, sweating, and tachycardia. The primary treatment for pheochromocytoma is surgical removal, as the majority of these neoplasms are benign.¹⁵  However, when these neoplasms are malignant, they are likely to be widely metastatic and difficult to treat. Fortunately, case reports have shown that sorafenib and sunitinib—tyrosine kinase inhibitors targeting the VEGFR pathway and thus angiogenesis—may have activity in metastatic pheochromocytomas.¹⁶ 

In summary, the germline mutations involved in NF1 predispose patients to develop additional malignancies. MPNSTs and pheochromocytomas require early identification and surgical removal. For NF1-related GISTs, recent cases suggest that there is a role for the use of tyrosine kinase inhibitors such as regorafenib.¹⁴  Targeting these orphan diseases with molecular matched therapy including the MEK inhibitor selumetinib for NF1 itself is a novel precision oncology approach.^6,17