Unpredictable Evolution of Pilocytic Astrocytoma in Adults: A Case Series and Diagnostic Challenges

Introduction

Pilocytic astrocytoma is a tumor of astrocyte origin, occurring predominantly in children and young adults. According to the latest World Health Organization (WHO) classification (2021), it is considered a grade 1 circumscribed astrocytic glial tumor. Pilocytic astrocytoma accounts for approximately 15% of central nervous system tumors in individuals 0 to 20 years old, with an incidence rate of 0.84 per 100 000 in this age group [1–4]. In the general population, the incidence is 3.4 per 1 000 000 people. After the age of 19 years, the frequency of pilocytic astrocytoma decreases, representing 0.8% of central nervous system tumors [5,6].

Pilocytic astrocytoma has a slow growth rate and is found predominantly in males [1,2]. The most frequent location is in the cerebellum, followed by the optic tract, hypothalamus, and brainstem. The location of pilocytic astrocytoma in the optic tract is strongly associated with neurofibromatosis type 1 [1,7]. Clinically, it has an insidious onset, the symptoms being closely related to its location. Affection of the optic tract causes decreased visual acuity, and damage to the hypothalamus causes endocrine manifestations, such as diabetes insipidus and obesity [2,8]. However, it most frequently manifests through headache, ataxia, nausea, and vomiting [3].

Computed tomography (CT) and magnetic resonance imaging (MRI) show a well-defined lesion, which presents solid areas that may be associated with calcifications and micro- or macrocystic components. Morphopathologically, pilocytic astrocytoma is characterized by a growth pattern that is either solid, densely fibrillar with the presence of Rosenthal fibers, or microcystic with eosinophilic granular bodies [2,8–11]. Vascular hyalinization changes, calcifications, infarction-like necrosis, and perivascular lymphocytosis are associated [10,11]. These imaging and histopathological aspects can present diagnostic pitfalls because they are not completely specific and can also be found in other astrocytic tumors, oligodendrogliomas, non-glial tumors, or high-grade gliomas [8–11].

Currently, a favorable prognostic factor is the complete excision of the tumor, which results in a 10-year survival rate of 70% for adults and 90% to 95% for the pediatric population [1,9]. Unlike the pediatric population, the rates of recurrence, progression, and malignant transformation in adults are higher, and molecular alterations are less common [5–7]. The main negative prognostic factors involved in death or recurrence in patients include dysmetabolic syndrome (obesity, increased insulin resistance, and hyperglycemia), incomplete resection, dissemination in leptomeninges, hypothalamic location, and the presence of the tumor in adults [5,9]. In the last 10 years, only 1 clinical trial has included adult patients with pilocytic astrocytoma.This trial is currently underway and is based on testing tovorafenib in patients with melanoma or other solid tumors, including pilocytic astrocytoma [12].

Given the rarity and diagnostic challenges of pilocytic astrocytomas in adults, understanding their clinical presentation, imaging characteristics, and immunohistochemical profiles is critical for improving diagnosis and treatment. In this study, we analyze 4 cases of pilocytic astrocytomas in adults, according to the CARE checklist, focusing on detailing atypical clinical and imaging presentations, histopathological diagnostic challenges, and immunohistochemical prognostic implications, to contribute to the limited body of literature on this topic.

Case Reports

CASE 1:

A 58-year-old White woman with no personal pathological history, no comorbidities, and no family history of tumor pathology presented to the Emergency Department accompanied by relatives for intense headache, aphasia, and right hemiparesis. These manifestations began in the morning of the same day, starting upon awakening.

Laboratory test results did not reveal any abnormalities. MRI examination showed hyperintensity on T2 and FLAIR with iso- to hypointensity on T1 around the left middle cerebral artery. The imaging suggested stroke. This was supported by the clinical presentation and its sudden onset. The patient was hospitalized with antithrombotic treatment and hemodynamic monitoring, but did not show any improvement in symptoms. After 24 h, a CT scan was performed, demonstrating an imprecisely delimited intracranial process, with a maximum diameter of 2 cm and discrete perilesional enhancement, located in the frontotemporal region. The imaging characteristics were difficult to define, with no evidence of perilesional edema or midline shift. The conclusion of the report was suspected glioblastoma.

Neurosurgical resection was performed, and several tissue fragments, gray-pink in color and soft in consistency, with total dimensions of 4×4×1.5 cm, were submitted for histopathologic examination. Microscopically, an astrocytic proliferation was observed, composed of dense areas of fibrillar astrocytes alternating with microcystic, paucicellular regions containing protoplasmic astrocytes and rare eosinophilic bodies (Figure 1A, 1B). The diagnosis was pilocytic astrocytoma grade 1, with suspicion of incomplete excision; no normal brain tissue was visualized. Immunohistochemical testing showed negative results for IDH1, p53, and Nestin, and a Ki-67 index of approximately 1%, supporting the diagnosis of pilocytic astrocytoma (Figure 1C–1F). MGMT (O6-methylguanine-DNA methyltransferase) and PTEN (phosphatase and tensin homolog) were favorable, with MGMT negative and PTEN preserved, representing positive prognostic factors in the patient’s course (Figure 1G, 1H). The main tumor entities considered in the differential diagnosis were diffuse astrocytoma, IDH-mutant, WHO grade 2 (IDH1 mutant, p53 positive), and glioblastoma (p53 positive, Nestin positive).

Postoperatively, the patient’s blood pressure was monitored, and glucocorticoids were administered to prevent cerebral edema. The control imaging examination detected tumor residue with a maximum diameter of less than 1 cm. The patient’s postoperative course was uneventful, with no complications. Headache and aphasia resolved within 2 weeks after surgery. Motor dysfunction diminished with exercise, and the patient was able to use her right limbs without difficulty after 3 months. The remission of symptoms reinforced the presumption of positive prognostic factors based on immunohistochemical findings. The patient came for regular follow-up appointments, and no increase in the size of the tumor residue was observed. After a 5-year follow-up period, the patient was alive and did not present cognitive or motor deficits (Table 1).

CASE 2:

A 63-year-old White woman with no previous surgical interventions and a comorbidity of 8-year history of hypertension, with adherence to treatment of angiotensin-converting enzyme inhibitors and calcium channel blockers, and a family history of non-small cell lung carcinoma (father) presented to the hospital for headache and vertigo. The symptoms began 2 weeks earlier but increased in intensity and led her to see a doctor, believing it was related to high blood pressure. She was examined by a cardiologist, who did not notice any changes in the underlying disease and recommended a CT examination of the cephalic region.

CT showed a well-defined, infratentorial, intraneuraxial mass in the right cerebellar hemisphere, measuring 41 mm in maximum diameter, associated with digitiform edema and causing an impression on the fourth ventricle. The patient did not want to remain hospitalized, but after 2 days, she returned for MRI, which revealed similar changes, with minimal uniform contrast enhancement over the lesion, most likely indicating a secondary tumor lesion. Further investigation was not performed to confirm the imaging suspicion of metastasis, and neurosurgical intervention was performed to resect the lesion.

Multiple tissue fragments with total dimensions of 4×3.3×2.8 cm, gray-pink in color and of soft consistency, were submitted for histopathologic examination. Microscopic evaluation revealed a biphasic proliferation of astrocytes, consisting of dense areas of fibrillar astrocytes interspersed with microcystic regions and areas of vascular hyalinization (Figure 2A, 2B). The diagnosis was pilocytic astrocytoma, WHO grade 1, with suspicion of incomplete excision, as no normal brain tissue was identified. Immunohistochemical studies showed IDH1 negativity, Ki-67 labeling index of approximately 2%, and negative staining for p53 and Nestin, findings that supported the diagnosis of pilocytic astrocytoma (Figure 2C–2F). The prognostic markers MGMT (negative) and PTEN (negative) indicated a guarded prognosis for disease evolution (Figure 2G, 2H). The main tumor entities considered in the differential diagnosis were diffuse astrocytoma, IDH-mutant, WHO grade 2 (IDH1 mutant, p53 positive), and oligodendroglioma (p53 wild type, IDH1 mutant).

Postoperatively, the patient’s blood pressure was monitored, while she continued the basic medication, and glucocorticoids were administered to reduce the edema, which subsided in 3 weeks. The follow-up imaging examination revealed tumor residue with a maximum diameter of 11 mm. The symptoms present at hospital admission resolved upon discharge. The patient returned to a single follow-up, where it was found that the size of the residual tumor was stationary. Six years after surgery, the patient returned to the Emergency Department with symptoms of headache, vomiting, and vertigo. Given her history, a CT scan was performed, revealing a tumor in the right cerebellar fossa, which had increased in size from 11 mm to 40 mm since the last examination. The patient did not want hospitalization and was transferred to another hospital, resulting in loss to follow-up. In this case, the guarded prognosis indicated by immunohistochemical findings, together with comorbidities, may explain the unfavorable course, characterized by tumor progression (Table 1).

CASE 3:

A 63-year-old White woman with no personal medical history, no comorbidities, and no family history of cancer presented to the hospital by referral for an intense headache. This headache had begun 2 months earlier, had increased in intensity, and had not responded to treatment with nonsteroidal anti-inflammatory drugs or analgesics.

Laboratory test results showed no abnormalities. CT examination revealed a supratentorial intraneuraxial, space-occupying mass in the left parieto-occipital region, relatively well demarcated, with a maximum diameter of 41 mm, associated with mild digitiform edema and no midline shift. A primary tumor process was suspected, a possible low-grade astrocytoma.

Neurosurgical resection was performed, and several tissue fragments with total dimensions of 5.8×4.5×1.1 cm, gray-pink in color and friable, were submitted for histopathologic examination. A biphasic astrocytic proliferation was observed microscopically, featuring dense areas of fibrillar astrocytes with few Rosenthal fibers, interspersed with microcystic areas and regions of infarct-like necrosis (Figure 3A, 3B). Immunohistochemical studies showed IDH1 negativity, Ki-67 approximately 2%, and negative staining for p53, supporting the diagnosis of pilocytic astrocytoma (Figure 3C–3E). The fact that Nestin showed weak immunopositivity (Figure 3F) could suggest an aggressive variant of this entity. However, the 2 prognostic factors MGMT (negative) and PTEN (preserved) represented positive prognostic factors in the evolution of the case (Figure 3G, 3H). The main tumor entities considered in the differential diagnosis were high-grade astrocytoma, although the necrosis was ischemic in type (IDH1 mutant, p53 positive), and glioblastoma (p53 positive, strongly positive for Nestin, with a high proliferative index).

Postoperatively, hemodynamic parameters were monitored, and glucocorticoids were administered to reduce edema, which subsided in 10 days. The follow-up imaging examination did not reveal any tumor residue. There were no postoperative complications. The headache resolved before discharge. The patient attended regular follow-ups, and no events were recorded. After 5 years, the patient remained alive and free of disabilities caused by the tumor (Table 1).

CASE 4:

A 76-year-old White woman with no history of prior surgical procedures and with 2 comorbidities – diabetes mellitus (treated with metformin) and hypertension (treated with angiotensin-converting enzyme inhibitors and calcium channel blockers) – and no family history of cancer presented to the hospital with a referral for severe headache and epileptic seizures. The headache had begun 2 months earlier and had gradually increased in intensity, remaining unresponsive to analgesics. The epileptic seizures began 1 month earlier and were characterized by focal convulsions with impaired consciousness lasting 10 to 20 s, associated with empty swallowing and uncontrolled gesturing, with a frequency of 1 to 2 seizures per week. The family thought it was a calcium deficiency and administered vitamin D3 and effervescent calcium. A neurologist took over the case, observed no changes in the biological analyses, and ordered a CT scan.

CT revealed a supratentorial, intraneural, space-occupying mass in the left frontal lobe, relatively well demarcated, measuring up to 44 mm in maximum diameter, non-contrast-enhancing, with digitiform edema and causing a 4-mm midline shift. The imaging appearance suggested metastases. MRI was also performed, revealing isointensity in T1, and after administration of gadolinium, uniform contrast enhancement was observed, strengthening the suspicion of metastasis.

Neurosurgical resection was performed, and multiple tissue fragments with total dimensions of 5×3×1.1 cm, gray-pink in color, of low consistency alternating with areas of firm consistency were taken. Microscopic examination reveals a well-defined proliferation that was distinctly separated from the adjacent cerebral parenchyma (Figure 4A). This proliferation consisted of fibrillar astrocytes, with certain areas displaying oligodendroglial characteristics. Notably, there was an increased presence of processes that exhibited a cobweb-like morphology. Additionally, focal microvascular proliferation with a glomeruloid appearance was noted (Figure 4B), along with rare eosinophilic granular bodies. The immunohistochemical studies established the diagnosis of pilocytic astrocytoma grade 1 through negative IDH1, Ki-67 approximately 1%, negative p53, and negative Nestin (Figure 4C–4F). The markers MGMT (negative) and PTEN (preserved) suggested a positive prognosis (Figure 4G, 4H); however, when considered alongside the patient’s age and comorbidities, the overall prognosis was guarded. The main tumor entities considered for the differential diagnosis were an oligodendroglioma (IDH1 mutant, p53 positive), a high-grade astrocytoma (IDH positive, Nestin positive), and a glioblastoma (p53 positive, Nestin positive).

Postoperatively, the patient’s blood pressure was monitored, while the basic medication was continued, glucocorticoids were administered to reduce the edema, and antiepileptic treatment (benzodiazepine) was added. Follow-up imaging did not detect tumor residue. The patient presented for a single follow-up, during which she reported that epileptic seizures had become less frequent, occurring 1 to 2 times per month, and of shorter duration, occasionally without loss of consciousness. Despite this improvement, the prolonged neurological impairment, compounded by persistent seizures, contributed to the patient’s death 18 months after surgery (Table 1).

Discussion

The first case demonstrates a slightly atypical presentation mimicking a stroke, initially suggested by imaging, but later revealing a tumor, with the diagnosis of a circumscribed low-grade glial proliferation confirmed histopathologically and immunohistochemically. Immunohistochemistry indicated a favorable prognosis, which, despite incomplete resection, and when considered alongside the clinical data and patient history, was consistent with a favorable outcome.The second case demonstrates an atypical presentation, characterized by delayed medical consultation and symptom overlap with pre-existing comorbidities. Imaging suggested a secondary tumor process, which histopathology confirmed to be primary. Immunohistochemistry confirmed the diagnosis and indicated a guarded prognosis. When combined with comorbidities and incomplete surgical resection, these factors contributed to lesion progression over time. The third case demonstrates an atypical presentation, with a unique symptom of intense headache, and delayed presentation to the doctor. Imaging initially suggested a low-grade astrocytoma, which was confirmed histopathologically as a pilocytic astrocytoma. Although the tumor cell population exhibited features suggestive of increased aggressiveness (weakly positive Nestin), complete excision and favorable prognostic markers were associated with a positive clinical course. The last case demonstates typical symptomatology, but with a delay in presenting to the doctor, in an elderly patient with 2 comorbidities. Imaging suggested a secondary tumor process, which was disproved histopathologically. Although surgical resection was complete and immunohistochemical prognostic factors were favorable, advanced age, persistence of symptoms, and the presence of comorbidities led to an unfavorable evolution.

Pilocytic astrocytoma is a circumscribed glial tumor that represents 5% of all central nervous system tumors. The incidence decreases with age, being a rare entity in older adults [13]. A study by Muhsen et al of 15 patients found that the average age of individuals with pilocytic astrocytoma was 25 years, with 60% of cases being male [14]. According to the study by Mair et al. in a group of 46 patients with a mean age of 32.5 years, there was a predominance of males (56.5%) compared with females (43.5%) [5]. In another study, including 12 patients, Hu et al also observed more frequent involvement in males than in females, with a sex ratio of 1.4: 1 [15]. In our study, we reported 4 cases of pilocytic astrocytoma that were all identified in women, with a mean age of 65 years (range, 58 to 76 years). A particular aspect in these cases was the presence of comorbidities, which as associated with the unfavorable evolution in these patients. We did not find, in the specialized literature, the association of comorbidities with pilocytic astrocytoma, but only with high-grade gliomas [16].

The manifestations of pilocytic astrocytoma are nonspecific, characterized by the mass effect that the lesion produces. In addition, due to the slow growth rate, lesions can manifest subtly, delaying diagnosis. The same nonspecificity also affects imaging [13]. These aspects were also highlighted by Costanzo et al in hypothalamic pilocytic astrocytomas, in which clinical picture and imaging suggested tumor processes with endocrine implications or metastases of neuroendocrine tumors. Such misdiagnoses have important implications for selecting optimal treatment, exposing patients to additional risks, and contributing to poor prognosis [17].

Pilocytic astrocytoma presents a wide spectrum of features and is most commonly described as a well-demarcated, space-filling mass, which can be confused with other tumor lesions. There is no available rate of misdiagnosed or misinterpreted cases, but many imaging features are nonspecific and can lead to other diagnoses, such as lymphomas, high-grade gliomas, or metastases. For example, Ferriastuti et al, analyzed the case of a 10-year-old boy. The first imaging examination revealed that the anterior displacement of the eyeball and the widening of the optic canal were determined by a left intraconal slight heterogeneous solid and lobulated mass. After CT imaging, the presumptive diagnosis was glioma, lymphoma, or meningioma. On MRI, the lesion was described as a solid mass located in the left retrobulbar intraconal to the proximal side of the left optic nerve. The final diagnosis following microscopic examination was pilocytic astrocytoma [18]. Our 4 cases highlight the diagnostic challenges of pilocytic astrocytoma in adults, particularly its potential to mimic higher-grade gliomas on imaging. These findings emphasize the critical role of histopathological and immunohistochemical evaluation in confirming the diagnosis and guiding prognosis. For instance, negative IDH1 and low Ki-67 indices consistently differentiated pilocytic astrocytoma from other gliomas, underscoring the need for these markers in diagnostic workup. To increase the accuracy rate of the image, artificial intelligence techniques have been integrated, allowing radiomics to extract additional information through texture analysis, wavelet transform–based features, Gabor transform–based features, and support vector machine analysis. By applying these new techniques, ependymomas, glioblastomas, or high-grade gliomas can be differentiated from pilocytic astrocytoma, until histopathological and immunohistochemical confirmation [19–21].

In the microscopic diagnosis of pilocytic astrocytoma, certain histopathological features can also be identified in other central nervous system tumors. The presence of calcifications can be identified in oligodendrogliomas. In grade 3 oligodendroglioma, microscopic foci of tumor necrosis may be observed and must be distinguished from infarct-like necrosis [22]. In the case of grade 2 astrocytoma, microcystic lesions, perivascular lymphocytic inflammatory infiltrate and, less commonly, Rosenthal fibers and eosinophilic granular bodies can be observed [13,23]. Polymorphic xanthoastrocytoma can have eosinophilic granular bodies, Rosenthal fibers, perivascular lymphocytic inflammatory infiltrate, and multinucleated giant cells [24,25]. Microvascular proliferation and necrosis can suggest a grade 4 astrocytoma or glioblastoma [26]. The differential diagnosis may also include entities that do not originate from glial cells, such as microcystic meningioma or a dysembryoplastic tumor [27,28].

Immunohistochemical examination plays an important role in the diagnosis of certainty, since both imaging and microscopic examination can create confusion between the different glial proliferations (astrocytic or oligodendroglial) and even other tumor entities, as previously mentioned. The usual markers are represented by GFAP, S100, and OLIG2, but strong and diffuse expressions for SOX10 and p16 can be found. NeuN, chromogranin, CD34, and IDH1 are negative [8,13]. We used the markers IDH1, p53, KI-67, Nestin, MGMT, and PTEN to study and evaluate the activity of these tumors.

IDH1 is an enzyme found in peroxisomes, with mutations occurring in oligodendrogliomas and astrocytomas of grades 2 to 4. In pilocytic astrocytoma, IDH1 is negative [29]. In the study by Sharma et al, the histopathological and immunohistochemical characteristics of various astrocytic and oligodendroglial tumors were examined. They did not notice IDH1 mutations in grade 1 astrocytomas, compared with those of grade 2, 3, and 4, which presented mutations in proportions of 66.7%, 50%, and 20.7%, respectively [30]. According to the collected data, the 4 cases in the present study demonstrate a negative reaction to IDH1.

Ki-67 is a nuclear marker of cell proliferation that is low in pilocytic astrocytomas. Focal areas can present areas with increased values [29]. In the case of gliomas, Ki-67 has the function of stratifying the grade of malignancy. In addition, a higher proliferative index is associated with a poor prognosis and response to immunotherapy [31]. Ki-67 and p53 are useful markers for grading astrocytomas. Thus, in the study of Abdel-Maqsoud and Ali, low expressions of the 2 markers were noted in the case of grade 1 astrocytomas. Also, the triad of negative IDH1/IDH2, negative p53, and low Ki-67 has the role of differentiating pilocytic astrocytomas from other gliomas [31–33]. In accordance with the data presented, all our cases presented a low Ki-67 index and negative p53.

Nestin is an immunohistochemical marker that is cytoplasmically positive in glial cells, especially undifferentiated ones. A study analyzing various grades of astrocytomas found that Nestin expression was weak or absent in pilocytic astrocytomas. Its immunointensity gradually increases with histopathological grade [34]. In our study, 3 of the cases exhibited a negative Nestin reaction, while only 1 case displayed a weakly positive reaction.

Studying the MGMT reaction in pilocytic astrocytomas is important for determining the chemoresistance and prognosis of patients [35]. In a study of 79 cases, 21.5% (17 cases) showed MGMT promoter methylation. This aspect showed a different and more heterogeneous distribution of genetic factors, compared with their pediatric equivalents, suggesting a higher risk of progression. Thus, MGMT promoter status in pilocytic astrocytomas is associated with a higher recurrence rate and short progression-free survival [36]. Compared with the data in the literature, our 4 cases showed a negative MGMT reaction, equivalent to a methylated status of the gene.

PTEN is a useful immunohistochemical marker in guiding tumor prognosis. Mutation of the PTEN gene through loss of expression is a hallmark of tumorigenesis and proliferation and induces posttranslational modifications in low-grade gliomas, resulting in malignant progression. Also, loss of PTEN has a role in altering immune suppression mechanisms in antitumor responses as well as influencing sensitivity to radiochemotherapy [37,38]. In a study analyzing 31 patients with pilocytic astrocytoma, out of a total of 511 cases, preserved PTEN expression was observed in 69% of cases. Partial and total loss of PTEN expression was recorded in 17% and 14% of cases, respectively. This loss is associated with anaplasia phenomena in cellular morphology, conferring increased aggressiveness and increased cellular proliferation [39,40]. In the case of our study, PTEN expression was completely preserved in 2 cases and partially in 1 case. Only 1 case showed a complete loss of expression of the immunohistochemical marker, which was associated with tumor residue progression.

Therefore, MGMT and PTEN markers guide the degree of tumor aggressiveness, determining the risk of prognosis, progression, and tumor recurrence [35,37]. Jiang et al studied the recurrence rate in 16 patients with pilocytic astrocytoma and observed 6 cases (37.5%) of tumor recurrence [41]. Also, Kulak et al analyzed 499 patients with pilocytic astrocytoma. Data on tumor recurrence were available in 321 cases, identified in 109 patients (34%). In the same study, the follow-up of the 109 patients showed a second recurrence in 18.3% of them [42]. In our 4 cases, 1 presented progression of the tumor residue, and 1 case raised suspicion of malignant progression of the lesion. All these data must be viewed not only through immunohistochemical changes, but also through the clinical aspect, corroborating not only with clinical manifestations, but especially with the patients’ comorbidities.

The most important prognostic factor is gross total resection. The presence of residual tumor can lead to tumor recurrence. A 38.9% recurrence rate was identified in cases of incomplete resection, as opposed to 4% in cases of complete resections [43,44]. The study by Muhsen et al highlights recurrence rates between 13% and 40% in cases of gross total resection and between 4% and 60% in cases of subtotal resection. Patients in these studies had a 5-year overall survival rate between 67% and 85.3% [15]. Progression-free survival in pilocytic astrocytomas ranges from 16.5 months to more than 178.8 months. This rate is influenced by advanced age and body mass index [5]. In our study, the presence of a single comorbidity led to a recurrence of symptoms after 78 months in 1 case, and the presence of 2 comorbidities associated with advanced age led to a shortened survival of 18 months. This hypothesis needs to be investigated in large centers that can collect a larger sample of adult patients with pilocytic astrocytoma.

According to the European Association of Neuro-Oncology, complete resection of the tumor lesion can have a curative effect, associating improvement of hydrocephalus in cases in which it was present. Total tumor resection has advantages over subtotal resection, which can lead to tumor progression, hydrocephalus, and rarely hemorrhage. Radiotherapy is indicated for treatment when tumor progression occurs, when the tumor is inoperable, or when the tumor is aggressive [45]. However, the usefulness of radiotherapy as a complementary measure to surgical excision does not bring great benefits; on the contrary, its damaging effects are associated with shortened survival [46,47]. Also, other factors that favor recurrence or progression of pilocytic astrocytoma are age older than 40 years, high body mass index, solid tumor architecture, presence of an exophytic tumor component, and tumor invasion [5,43]. González-Vargas et al observed that radiotherapy is the most important factor in anaplastic transformation of pilocytic astrocytoma. The microscopic presence of eosinophilic granular bodies, microcystic components, or bipolar cells are elements identified in the preliminary stage of tumoral anaplastic transformation [48].

Future research directions must include molecular aspects, such as therapies targeting the MAPK pathway. In the pediatric population with this pathology, BRAF p.V600E alterations and BRAF-KIAA1549 fusion have been observed, with effective possibilities for targeted therapy [15,46,49]. In adults, these changes have a much lower frequency, between 5% and 9.2%. Their presence would bring benefits in correcting some diagnostic errors by increasing the accuracy of the diagnosis of certainty, for example, the BRAF-KIAA1549 fusion is specific to pilocytic astrocytoma, as well as in possible targeted therapies [49,50]. Studies of BRAF inhibitors have noted some good results, with complete response rates of 54% in adults with low-grade gliomas (grade 1 and 2), with a progression rate of 5% for the same category [51].

In this study, we presented 4 cases of pilocytic astrocytoma in adults, emphasizing the rarity of these tumors within this population. The nonspecific symptoms and the polymorphic characteristics observed in both the imaging and histopathological assessments posed challenges in reaching a definitive diagnosis. Immunohistochemical studies played a crucial role not only in confirming the diagnosis, through markers such as IDH, Ki-67, p53, and Nestin, but also in guiding prognosis and assessing the risk of recurrence, with markers like MGMT and PTEN. Additionally, molecular testing can be incorporated into the diagnostic process. Thus, clinical applicability targets the clinician (importance of the anamnesis with emphasis on manifestations and comorbidities), the surgeon (importance of complete resection), the pathologist (importance of correct diagnosis by developing specific protocols and providing aspects related to prognosis), the oncologist (possibility of adjuvant treatments in cases requiring more aggressive therapy), and the researcher (in discovering new pathogenic mechanisms and developing new therapeutic possibilities). Ultimately, we conclude that each case is unique, exhibiting various characteristics and evolutions while still adhering to the underlying tumorigenesis and potential outcomes. Two major limitations of the present study are the absence of molecular test results and imaging pictures, for which we only have the reports.

Conclusions

Pilocytic astrocytoma in adults is a rare entity with diagnostic and prognostic challenges due to its atypical clinical and imaging presentations. Our cases demonstrated the critical role of histopathological and immunohistochemical markers, particularly IDH1 negativity and low Ki-67 indices, in distinguishing pilocytic astrocytoma from higher-grade gliomas. Also, the MGMT and PTEN markers proved effective in assessing prognosis, but they must be associated with other factors, such as the patient’s clinical situation. The observed variability in clinical outcomes, including recurrence and progression, underscores the importance of complete surgical excision and long-term follow-up. These findings highlight the need for standardized diagnostic protocols and further research into the molecular underpinnings of pilocytic astrocytoma in adults to optimize patient management and outcomes. Thus, the clinician must consider the age and comorbidities of the patients and correlate them with the immunohistochemical picture in the correct assessment of the prognosis. In addition to this role, the correlation of these aspects associated with the type of resection and the imaging-histopathological characteristics may provide key insights into the unpredictable clinical course and diagnostic challenges of pilocytic astrocytomas.