Rapid postradiation malignant transformation of a pilocytic astrocytoma in an adult with neurofibromatosis type 1: illustrative case

Abstract

BACKGROUND

Juvenile pilocytic astrocytoma (JPA) is the most common primary brain tumor of childhood and is rarely seen in adults. Neurofibromatosis type 1 (NF1), a common tumor predisposition syndrome, demonstrates a strong association with low-grade gliomas, most notably pilocytic astrocytoma, which are relatively indolent. Unlike its juvenile counterpart, reports of adult pilocytic astrocytoma (APA) vary widely in terms of disease progression from benign to much more malignant courses. Moreover, current studies discussing APA report different treatment approaches and outcomes (e.g., malignant transformation of JPA and APA with or without radiation), as little is known regarding the management of recurrent tumors and how adjuvant therapies may alter disease progression.

OBSERVATIONS

The authors report the unique case of an adult male with NF1 and APA who underwent rapid malignant conversion after intensity-modulated radiation therapy.

LESSONS

The authors demonstrate that caution should be taken in utilizing radiotherapy instead of resection in cases of APA and NF1, with close monitoring for posttreatment recurrence.

https://thejns.org/doi/10.3171/CASE24241

Juvenile pilocytic astrocytoma (JPA), a World Health Organization (WHO) grade I astrocytoma, is the most common pediatric brain tumor, with an incidence of 0.82 per 100,000 persons. It frequently arises in the posterior fossa as a part solid and cystic mass with an enhancing mural nodule.^{1, 2} In contrast, adult pilocytic astrocytoma (APA) is rarer, with an incidence of 0.23 per 100,000 persons for ages 20–34 and under 0.09 per 100,000 persons after 40 years of age. APA is more likely to occupy the supratentorial space than JPA.^{2, 3} While JPA tends to follow a benign course, the disease progression of APA is less clear, with studies reporting higher recurrence rates and an increased incidence of a more aggressive course.^3–5 Furthermore, treatment with radiation therapy has been linked to cases of malignant transformation in both JPA and APA.^6–8

Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome characterized by the development of skin neurofibromas, optic or hypothalamic hamartomas, café au lait spots, and a heightened risk for central nervous system tumors, most commonly pilocytic astrocytoma (PA), which occurs in 15% of patients with NF1.⁹ PA associated with NF1 typically involves the optic pathway, with a tendency toward a benign natural history, whereas tumors involving other regions of the brain, including the cerebellum, occur in only 3%–5% of NF1 patients.^{9, 10} The natural history of nonoptic pathway tumors in NF1 is poorly studied.

We present the unusual case of an adult with NF1 and PA with postradiation, rapid malignant transformation, and cerebrospinal fluid seeding.

Illustrative Case

A 32-year-old male with a past medical history of NF1 presented for evaluation of his previously diagnosed left cerebellar PA. The astrocytoma was diagnosed and initially managed at an outside institution and was incidentally discovered 8 years previously by screening magnetic resonance imaging (MRI) of the brain. After several years of observation, the lesion progressed, prompting multiple biopsies. The biopsies demonstrated mild hypercellularity with atypical astrocytic cells and rare Rosenthal fibers; there was no evidence of mitotic figures, vascular proliferation, or necrosis (Fig. 1A and B). Additionally, a Ki-67 labeling index of 1% was observed, and the tumor did not stain with antibodies to IDH-1 (R132H) and p53. These findings were consistent with the diagnosis of PA, WHO grade I. The patient subsequently underwent laser interstitial thermal therapy for lesional ablation. The postoperative course was complicated by brain abscess formation, requiring treatment with suboccipital craniotomy for drainage and washout, as well as antibiotics.

FIG. 1.

Biopsy specimen (A and B) from 2014 shows atypical glial cells with mild hypercellularity without evidence of mitotic figures, vascular proliferation, or necrosis. Resection specimen from 2018 shows malignant transformation with necrosis (C), mitoses (D), and rare residual Rosenthal fibers (E). Hematoxylin and eosin, original magnification ×100 (A and C); ×200 (B and D); and ×400 (E).

The tumor later recurred, and chemotherapy with temozolomide was initiated, but the lesion continued to progress. Intensity-modulated radiation therapy was administered at a total of 5400 cGy in 30 fractions, but the lesion rapidly recurred despite radiotherapy, with enlargement of the left cerebellar lesion involving the hemisphere and vermis, as well as new leptomeningeal enhancement. The patient was subsequently started on carboplatin chemotherapy, and the lesion remained stable with treatment for 1 year. However, the patient experienced another relapse, and carboplatin was restarted at a different healthcare system (Fig. 2A–C).

FIG. 2.

From left to right, axial, coronal, and sagittal T1-weighted postcontrast MRI sequences. A–C: Preoperative images demonstrating an enhancing left cerebellar lesion. D–F: Immediate postoperative images demonstrating stable changes from a suboccipital craniotomy and resection of the left cerebellar lesion with no gross residual.

On initial evaluation at our institution, the decision was made to proceed with excision. The patient underwent a suboccipital craniotomy with gross-total resection (GTR) of the left cerebellar mass (Fig. 2D–F). Pathology demonstrated malignant transformation to a high-grade astrocytoma with evidence of numerous mitotic figures, anaplasia, pseudopalisading necrosis, and infiltration into adjacent normal cerebellum (Fig. 1C–E). Additionally, a Ki-67 labeling index of 20%–30% and no immunoreactivity against IDH-1 (R132H) was noted.

The patient initially did well postoperatively; however, he re-presented to the emergency department 3 months later with nausea and gait instability. MRI with and without contrast demonstrated diffuse leptomeningeal metastasis and enhancing lesions on the tectum and pineal gland, creating cerebral aqueductal stenosis with resultant obstructive hydrocephalus (Fig. 3A–C). The patient underwent ventriculoperitoneal shunt placement, and cerebrospinal fluid cytology confirmed leptomeningeal disease. Initially, the patient improved symptomatically following shunting, but then rapidly deteriorated, and MRI at that time showed further disease progression (Fig. 3D–F). The patient was transitioned to comfort measures and died upon extubation.

FIG. 3.

From left to right, caudal to cranial T1-weighted postcontrast MRI sequences. A–C: Three-month postoperative images demonstrating diffuse leptomeningeal metastasis and enhancing lesions on the tectum and pineal region causing cerebral aqueductal stenosis with resultant obstructive hydrocephalus. D–F: Four-month postoperative images demonstrating significant interval progression of leptomeningeal disease with pronounced enhancing tumor involving particularly the left cerebellar surgical site, pineal region, and midbrain.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

PA, a WHO grade I tumor, arises most commonly in the posterior fossa in children.^{1, 10} In contrast to JPA, APA is a rare tumor that is more often supratentorial. Due to its rarity, the natural progression of the tumor is poorly understood.^{3, 8}

Multiple studies have demonstrated a favorable prognosis for APA, including rates of survival and progression similar to those of JPA.^{8, 11} Notably, Bell et al., in a study of 10 patients with APA who were all over 30 years of age, demonstrated 0% mortality, with all patients able to function independently at a mean follow-up of 33 months.¹² Bond et al. retrospectively reviewed 46 patients with APA and reported 5% mortality at a mean follow-up of 76 months.¹³ Tumor recurrence was noted in 13% of cases, which was significantly associated with subtotal resection (STR).

Conversely, multiple other studies have demonstrated a worse prognosis for APA, with higher recurrence rates, including cases of malignant transformation. Theeler et al., in the largest series of sequentially reviewed APA cases (n = 127), demonstrated a 43% recurrence rate and 13% mortality.¹ Ryu et al., in a cohort comparison study, compared 19 JPA cases to 20 APA cases, showing similar rates of tumor recurrence after treatment of JPA and APA (16% versus 15%).¹⁴ Interestingly, APA recurred within a shorter interval and, in 1 patient, underwent malignant transformation resulting in death (Table 1). Stüer et al., in a similar study of 44 APA patients, demonstrated progression or recurrence in 30% of patients, and out of 8 available histological samples from recurrences, 50% exhibited anaplasia.¹⁵ Overall, these studies suggest that APA can have a more aggressive course than JPA, which has been very rarely reported to undergo malignant transformation outside the setting of prior radiation.¹⁶ Our present case is in line with these studies’ findings and indicates that patients with APA may require careful surveillance for recurrence and malignant transformation.

TABLE 1.

Summary of reported cases and time course of progression

Authors & Year	No. of Cases	Cases w/ Progression	Sex of Cases	Adjuvant Treatment of Cases	Average Time to Progression (mos)
Ellis et al., 200918	20	3	2 M, 1 F	2, Gamma Knife; 1, fractionated radiotherapy	16
Peters et al., 201116	2	2	2 M	Alkylating therapy	30
Ryu et al., 201514 (adult cases)	20	3	2 M, 1 F	1, alkylating therapy & fractionated radiotherapy; 1, fractionated radiotherapy; 1, no adjuvant treatment	17

Surgical treatment of JPA provides a durable cure and is the preferred treatment modality. GTR of JPA is associated with low recurrence rates, with Dodgshun et al. reporting event-free survival of 95% and overall survival of 100% at 5 years postresection.¹⁷ Regarding the efficacy of GTR as a treatment for APA, Theeler et al. found progression-free survival of 179 months after GTR versus 79 months with STR, and Bond et al., in a meta-analysis of 415 APA cases, reported a significantly lower recurrence rate after GTR than after STR at 27% vs 73%, respectively.^{1, 13, 17} Therefore, achieving GTR over STR is essential to improving patient survival and reducing the likelihood of the recurrence of APA. Given this reported efficacy of GTR and our patient’s suboptimal response to radiotherapy alone, we recommended attempting GTR as the first-line treatment.

Malignant transformation of PA has been associated with radiation therapy, as the majority of histologically verified cases of JPA anaplastic conversion have occurred following radiotherapy.^{6, 14, 16, 18} However, a potential confounder is the fact that radiotherapy is more likely to be utilized in adults, given the potential late complications of childhood radiation treatment, such as cognitive decline, endocrine deficiencies, growth delay, and vascular damage.¹⁸ Additionally, there may also be an association between radiotherapy and APA conversion to anaplastic astrocytoma. Ellis et al., in a study of 20 APA cases, demonstrated a malignant shift to anaplastic astrocytoma in 15% of cases, all of which occurred following fractionated radiotherapy or Gamma Knife radiosurgery (Table 1).¹⁸ Ultimately, larger studies are required to further support an association between malignant transformation of APA and radiotherapy, but given reports of this association, we recommend caution in utilizing radiotherapy with these patients and consideration of GTR instead.

Moreover, our patient’s course was further complicated by his history of NF1, where PA is the most common intracranial neoplasm and typically involves the optic pathway.¹⁹ In comparison to non–NF1-associated PAs, NF1 PAs have a genetic makeup more similar to high-grade astrocytomas, and a non–optic pathway location and diagnosis in adulthood have been associated with worse survival.^{14, 19} However, the natural history of non–optic pathway gliomas remains poorly studied.

Furthermore, patients with NF1 receiving radiation therapy exhibit a significantly increased risk of secondary tumor development.^{10, 19} Additionally, there are also cases of anaplastic conversion of PA in patients with NF1 who receive DNA-damaging treatment. Peters et al. reported the cases of a 14-year-old male with NF1 and an optic tract JPA and a 16-year-old male with NF1 and cerebellar JPA who both exhibited rapid malignant conversion to anaplastic astrocytoma after receiving alkylating chemotherapy (Table 1).¹⁶ Our study is unique in demonstrating malignant transformation in a patient with NF1 and APA. Currently, there is only one other case of NF1 in an adult with malignant transformation. Ryu et al. reported a patient with a hypothalamic APA, which progressed despite maximal chemotherapy, requiring 45 cGy of fractionated radiation (Table 1).^{14, 16} Four months after radiation, rapid tumor recurrence occurred with spread to all 4 ventricles. The patient’s tumor continued to progress despite further chemotherapy, and the patient died from the disease. These findings suggest a predisposition to malignant transformation in patients with NF1, likely due to the DNA damage from alkylating chemotherapy or radiation therapy, but this relationship requires further investigation. Therefore, we recommend caution when considering utilizing radiotherapy over resection for APA in these patients.

Regarding treatment options, there is great interest in targeted therapies for recurrent low-grade tumors such as JPA. One well-studied treatment is selumetinib, which is a selective kinase inhibitor of the enzyme mitogen-activated protein kinase (MAPK or MEK) subtypes 1 and 2.²⁰ It is approved for the treatment of plexiform neurofibroma in patients aged 2 years and older, but it is currently being studied in phase II clinical trials for the treatment of NF1-associated recurrent optic pathway and recurrent low-grade gliomas with promising results. Of the 25 eligible and evaluable patients, 6 (24%) had a partial response, 14 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment with a 2-year progression-free survival of 78% ± 8.5%.^{20, 21} Targeted therapies such as selumetinib offer a promising treatment for patients with recurrent APA and may help to prevent malignant transformation.

Our case report has significant limitations in terms of scope, but as there are few reported studies discussing this malignant transformation in the literature, our findings provide insight into the appropriate management of these patients. Future multicenter studies with aggregated patient outcomes may shed more light on this phenomenon, particularly as more targeted therapies are developed and reach clinical practice to treat recurrent APA.

Observations

Our current report of a patient with NF1 and APA supports the clinical literature, suggesting that APA may have a more aggressive course than JPA with an increased propensity for recurrence and malignant transformation. Moreover, patients with NF1 and APA may be at an increased risk of conversion to an anaplastic tumor, and alkylating chemotherapy or radiation therapy may predispose the tumor to a rapid conversion.

Lessons

We recommend that clinicians use caution in selecting patients with PA and NF1 for these aforementioned therapeutic approaches and advocate for GTR as the initial treatment for APA. Furthermore, these patients should be followed closely after initiating treatment for early identification of tumor recurrence and malignant change.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Welch, Kaul, Almefty. Acquisition of data: Welch, Kaul, Prayson. Analysis and interpretation of data: Welch, Kaul, Rong. Drafting the article: Gupta, Welch, Kaul. Critically revising the article: Gupta, Welch, Kaul, Rong, Almefty. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Gupta. Administrative/technical/material support: Almefty. Study supervision: Almefty. Histopathological photographs: Rong.

Correspondence

Rohan V. Gupta: Temple University Hospital, Philadelphia, PA. rohan.gupta@tuhs.temple.edu.