Introduction

The differential diagnosis of multiple brain tumors includes multifocal glioma, metastatic brain tumors, multiple brain abscesses and multicentric lymphomas. In medulloblastomas and ependymomas, subarachnoid seedings can be detected as tumoral nodules along the brain and spinal cord. Multiple brain tumors can also be seen in tuberous sclerosis (subependymal tubers and subependymal giant cell astrocytomas) and neurofibromatosis type I (optic gliomas and hemispheric astrocytomas) [1]. Unfortunately, similar imaging features can be seen in many tumor-like lesions including multiple sclerosis tumefactive plaques, resolving hematomas, vascular malformations, opportunistic infections in HIV patients and even metabolic disorders [2].

Some of these cases could be appropriately diagnosed regarding the nature of their brain lesions after laboratory and clinical examinations, as in multiple sclerosis, secondary infective diseases, metastatic tumors, and systemic diseases affecting the brain [3]. However, some argue that the histopathologic diagnosis for the brain lesion itself is required for a variety of reasons:

  1. 1.

    The primary tumor location will not be discovered in up to 15% of brain metastasis patients, despite thorough investigation [4].

  2. 2.

    Brain lesions may not be metastatic in about 11% of cases with a known history of systemic cancer [5].

  3. 3.

    Clinical impression based on advanced neuroimaging such as CT or MRI is not identical to a histopathological finding. Furthermore, the wide range of diseases seen in patients with multiple brain tumors highlights the importance of tissue diagnosis in avoiding the risks of therapy based solely on clinical laboratory and neuroimaging data. In practice, tumor-like lesions (such as the tumefactive plaque of multiple sclerosis) can be treated more conservatively, whereas tumors (such as lymphomas) should be treated aggressively. Misinterpretation could lead to overtreatment of a benign lesion or a considerable delay in getting a malignant one treated properly [3].

  4. 4.

    The current increase in the survival rate of patients with immunosuppressive and systemic diseases due to advances in diagnostic and therapeutic options resulted in increasing the variety of neuropathologic processes, thus demanding a thorough differential diagnosis of histopathology of intra-axial brain lesions [6].

  5. 5.

    For many cerebral space-occupying lesions diagnosed in CT scan or MRI, the histological diagnosis is the sole demonstrable confirmation of the disease, and treatment is based on this histopathological diagnosis [7,8,9].

The aim of this retrospective study was to determine the safety and feasibility of stereotactic biopsy for detection of the histopathological diagnosis of these multiple intra-axial brain lesions and to decide the further treatment plan through an effective decisional algorithm.

Patients and methods

Patient population and selection criteria

Patients with multiple intra-axial brain lesions and no neoplasms outside the nervous system were designated for our stereotactic biopsy protocol guided by our decisional algorithm (Fig. 1). Patients who met at least one of the following criteria were included in the study:

  1. 1.

    Lesions that are invasive but do not have a significant mass effect.

  2. 2.

    Lesions on CT or MRI that are poorly defined.

  3. 3.

    Suspicion of radiosensitive lesions, e.g., germinoma and lymphomas.

  4. 4.

    An undiagnosed intra-axial mass lesions in eloquent or deeply seated location that could not be diagnosed by craniotomy without high risk of morbidity.

Fig. 1
figure 1

A decisional algorithm to guide in dealing with multiple intra-axial brain lesions

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The prerequisites for patients’ selection.

  • Karnofsky performance scale > 70.

  • There are no systemic disorders that could be linked to the brain localization.

  • There were no cerebral circulation disorders and no evidence of demyelinating diseases.

Between 2012 and 2021, two hundred ninety-five patients underwent stereotactic serial biopsy for brain lesions at the Neurosurgery department of Tanta University Hospital. Multiple intracerebral lesions were found in 32 patients. These patients ranged in age from 27 to 66 years old (mean age 51), 20 were males and 12 were females. The heralding symptoms included focal neurological deficits in 22 cases, intracranial hypertension in 14 cases, and epileptic seizures in 12 cases (Table 1).

Table 1 Patients’ and peri-operative characteristics
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Multiple intra-axial brain lesions were categorized as having three or more lesions in different cerebral lobes. The number of radiologically revealed lesions in each patient ranged from 3 to 8 (mean 4). Left hemisphere lesions found in 18 patients, 8 patients had right hemisphere lesions, and 6 patients had lesions in both hemispheres.

Vasogenic edema around the lesion was treated with a steroid dosage of 4 mg dexamethasone three times per day. Steroids should not be given to patients with suspected lymphomas if stereotactic biopsy is being considered since doing so would make the lesion radiographically fade.

Preoperative clinical assessment

Before the stereotactic brain biopsy technique, all patients had a clinical, laboratory, and radiological evaluation. High-risk patients with history of bleeding diathesis were excluded. Patients taking antithrombotic drugs were told to stop taking them at least 7 days before the biopsy. A Karnofsky Performance Scale (KPS) [10] was used to evaluate all patients before and after the surgical procedure.

The work has been carried out per The Code of Ethics of the World Medical Association (Declaration of Helsinki) for human research. All patients signed an informed consent after detailed explanation of procedure-related risks and agreed that their data would be used for scientific evaluation.

Stereotactic technique

The Riechert–Mundinger (RM) or Cosman–Roberts–Wells (CRW) system was used for all stereotactic biopsies that were performed under magnetic resonance and CT image guidance for stereotactic localization. In each patient, a multiplanar reconstruction software called Praezis plus 3 (Inomed Company, Germany) was utilized to determine the optimal trajectory.

A direct trajectory via a single pial surface was chosen, and transgression of an ependymal surface was almost never required. All procedures were done under local anesthesia. Serial biopsies were obtained with a side-cutting needle along the maximal diameter of the lesion to acquire information about the zone of infiltration, vital neoplasm, and necrotic areas.

Histopathological assessments

The tissue samples were fixed in neutral buffered formalin at a 10% concentration before being submitted for histopathological analysis, with the exception of pus, which should be sent for antibiotic sensitivity testing and culture instead of formalin fixation. Hematoxylin and eosin (H&E) staining, as well as additional staining techniques such as immunohistochemical staining, was used to stain paraffin tissue slices. The histopathological diagnoses were based on 2016 Central Nervous System Tumor Classification system proposed by the World Health Organization (WHO) [11].

Results

The histopathological diagnosis of the biopsied lesions is shown in Table 2. The plan of the further treatment was guided by these histopathological findings. 14 patients (43.75%) had multifocal malignant gliomas, including anaplastic astrocytoma (18.75%) and multiform glioblastoma (25%). Multiple malignant gliomas were treated by chemotherapy and conventional radiotherapy. 12 patients (37.5%) had metastatic brain tumor from pulmonary adenocarcinoma; a subtype of non-small cell pulmonary cancer with no metastasis to other body parts before the biopsy. All patients with metastatic brain tumors were treated by external brain radiation only. Furthermore, two patients (6.25%) had malignant lymphoma that did not respond to preoperative corticosteroid (Fig. 2). Multiple primary brain lymphomas were treated by external radiotherapy and chemotherapy.

Table 2 Histopathological diagnosis in 32 patients with multiple intra-axial brain lesions made by stereotactic biopsy
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Fig. 2
figure 2

An illustrative case. Screen capture from a preoperative CT stereotactic brain biopsy planning. Histological diagnosis was multiple primary brain lymphomas

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Furthermore, four patients (12.5%) had multiple brain abscesses, and an abscess wall biopsy and an intra-abscess pus drainage were done to improve the clinical and neurological status (Fig. 3).

Fig. 3
figure 3

An illustrative case. Preoperative stereotactic planning MRI and 3D simulation with 3 trajectories. Histological diagnosis was multiple brain abscesses

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No mortality, because of the stereotactic biopsy procedure, was encountered; however, one patient, diagnosed with metastasis, had a small non-symptomatic intraparenchymal hematoma.

Discussion

Multiple brain lesions are a serious challenge for any neurosurgeon. We usually suggest biopsy as a start to help overcome patients' mental stress and enable the design of the next treatment step.

In the current study, 10.85% (32 of 295 cases) of the lesions were multiple and the histopathologic diagnoses were as following: metastases (37.5%), glioblastoma multiform (25%), grade III astrocytoma (18.75%), abscess (12.5%) and malignant lymphoma (6.25%).

Meshkini et al. [12] previously reported that 7.6% (158 of 2081 patients) of the brain lesion biopsies were multiple lesions. Over half of these cases had low-grade multiple gliomas, while over one-fifth of the cases had multiple malignant gliomas. Moreover, 10.2% had malignant lymphoma, whereas 4.6% had metastatic tumor and 2.7% of the cases had multiple brain abscesses.

Moreover, Franzini et al. [13] recorded that out of 940 cases, 100 (10.6%) showed multiple lesions; 37% were malignant gliomas, 15% were brain metastases, 15% were primary lymphoma, 12% with low-grade gliomas, 10% had infectious disease ranging between brain abscess and viral multifocal encephalitis and 6% were ischemic lesions, and others showed rare lesions.

On the other hand, Calisaneller et al. [8] showed that from 100 brain lesion biopsies, only 4.25% of the cases were multiple. The histopathological diagnoses were 61.71% neuro-epithelial tumors, 8.51% metastases and 10.64% infectious lesions.

Metastatic brain tumors must be considered first when multiple brain lesions are identified. In a patient with a known systemic malignancy, diagnosing brain metastases is a simple affair that can be accomplished by obtaining a biopsy from an extracranial site, which has a lower biopsy-associated risk than a brain lesion [1].

Brain metastases of unknown primaries (BMUPs) are frequently underestimated. A two-to-three months window is usually accepted for detecting the primary origin, because the initial workup is occasionally delayed by attention to the brain tumor [14]. The management of BMUPs patients requires the resection of an accessible single brain metastasis to reach a histopathological diagnosis. Inaccessible tumors need a stereotactic biopsy, and if < 3 cm, they are treated with stereotactic radiosurgery (SRS). Whole brain radiotherapy (WBRT) is either an adjuvant therapy in these two categories or is the primary treatment option if the previous two conditions are not met [15]. A potentially unneeded craniotomy may be avoided when a ‘‘non-surgical" tumor type is diagnosed.

Small cell lung cancer responds well to fractionated radiation in most cases secondary lymphoma, choriocarcinoma, and testicular tumors, for example, usually respond to fractionated radiotherapy, focal radiation, or systemic chemotherapy. Melanoma, renal cell carcinoma, and non-small cell lung cancer, on the other hand, are typically thought to be chemoresistant, while melanoma, renal cell carcinoma, and sarcoma are thought to be resistant to normal fractionated radiation [16, 17]. According to studies, radioresistant renal cell carcinoma and melanoma are more vulnerable to radiosurgery than other cancers [18].

Multifocal gliomas are gliomas spreading through commissural or the fornix and the corpus callosum, through cerebrospinal pathways, and/or by local metastasis [19]. Multicentric gliomas should be distinguished from multifocal tumors. Multicentric gliomas are encountered infrequently, with reports suggesting they account for 0.15–8% of glial tumors [20, 21].

According to Kotwica and Papierz [20], a large percentage of multifocal or multicentric gliomas have been misdiagnosed as brain metastases based on CT imaging without histopathological confirmation. Multiple gliomas occur outside the cortical–subcortical borders, deep within the white brain matter, according to Ozawa et al. [2]. The histopathology of these tumors must be investigated in order to provide an accurate prognosis, and high doses of radiotherapy are required in cases of glioblastoma, even more so than in patients with brain metastases. In circumstances where surgical excision of the lesion is not an option, stereotactic biopsy is probably the best alternative for allowing histopathologic examination [22].

Differentiation among glioblastoma, brain metastasis, and lymphoma with conventional structural MR scanning alone also remains challenging because the three intra-axial tumors often show a similar appearance on structural MRI, so stereotactic biopsy should be considered to resolve this dilemma. Unlike other high-grade intracranial malignancies, lymphoma is treated without surgery using a combination of radiation and high-dose chemotherapy. Surgical intervention is mainly confined to obtaining tissue for histopathologic diagnosis by performing a biopsy [23].

It's hard to differentiate between a pyogenic brain abscess and a necrotic tumor when a brain lesion presents a ring-like enhancement pattern on CT scan and MRI. Distinguishing between these two situations is critical since they require a completely different therapeutic approach as well as a different prognosis. A systematic approach and evaluation of the patient's history can help narrow the differential diagnosis [24]. Although prior studies have shown the ability of Dynamic Susceptibility Contrast-Enhanced (DSC) Perfusion MRI to distinguish abscesses from glioblastomas and metastases, they had certain limitations [25, 26]. Therefore, in cases of suspected brain abscess, it is essential to drain the abscess beside taking a stereotactic biopsy of the abscess wall and administration of antibiotics to help improve the patients’ clinical and neurological status.

Conclusions

Stereotactic biopsy is considered the best choice to allow histopathologic diagnosis of multiple brain lesions with minimal morbidity and no mortality. Histopathologic findings gained with stereotactic procedures guided the choice of proper treatment thus eliminating the hazards associated with blind treatments.