Risk Factors for Recurrence of Schwannomas: A Mini-Review

Schwannoma (ICD-O code 9560/0) is a rare, slow-growing, benign tumor that affects the nerve sheaths. Currently, there are no definitive biomarkers that can accurately predict the likelihood of relapse. This leads to challenges in postoperative monitoring of patients, repeated surgeries, and a decline in quality of life. Therefore, there is a need to identify prognostic and predictive factors that can impact the progression of schwannomas. In this mini-review, we will discuss the role of the proliferative activity marker Ki67 and the tumor microenvironment in recurrent schwannomas.

Schwannoma (ICD-O code 9560/0) is a slow-growing benign tumor of the nerve sheaths that occurs with an incidence of 1 in 100,000 [1-2]. It exhibits a highly variable morphological picture. Histogenetically, tumors of the peripheral nerve sheaths originate from a limited number of cells: schwannocytes, fibroblasts, perineurial cells, and the variety of nosologies is determined by a combination of various neoplastic cells. Schwannocytes develop into schwannomas, neurofibromas, hybrid nerve tumors, malignant peripheral nerve sheath tumors (MPNST), and malignant melanotic peripheral nerve sheath tumors (MMPNST). Fibroblasts participate in the formation of neurofibromas, hybrid tumors of nerves and MPNST, and perineurial cells form perineuriomas and MPNST with perineurial differentiation [1-3]. Typically, schwannomas and neurofibromas develop sporadically, but in 10% of cases, they can be associated with neurofibromatosis types 1 and 2, and schwannomatosis [1,3]. Among benign tumors of the nerves, neurofibromas most often undergo malignant transformation. These tumors can recur and become malignant in MPNST, which is reflected in increased proliferative activity in an atypical neurofibroma of uncertain biological potential. The grade of this type of tumor has not been determined and was previously classified as grade 2. However, schwannomas of a similar subtype with a potentially unfavorable clinical course have not been identified. Since the time of Cushing, schwannomas have been considered a homogeneous group of slowly growing tumors [1-3]. To date, extremely rare cases of malignancy of schwannomas into malignant tumors of the peripheral nerve sheaths have been described, especially after radiation therapy [4-7]. Isolated reports indicate the possibility of developing angiosarcomas from schwannoma [8-10], as well as the appearance of rhabdomyoblastic differentiation [11-12]. 

After neurosurgical treatment, the clinical behavior of schwannomas can vary greatly. As a result, many specialists are interested in identifying factors that may influence the outcome. Currently, the most widely accepted measure of postoperative tumor control is the volume of surgical resection. Studies have shown that relapse rates after total resection range from 0.05% to 9.2%, while with subtotal resection, the rate can be as high as 44% [13]. This means that the risk of relapse is 10 times higher for patients who undergo subtotal resection compared to those who have total resection. Additionally, patients who undergo almost total resection (with removal of 95% of the tumor) have a 3 times higher risk of relapse compared to those who have total resection [14-15]. However, there have been cases of relapse even after total tumor resection [15]. Currently, there are no clear biomarkers that can accurately predict the likelihood of relapse. This leads to challenges in postoperative patient monitoring, potential need for additional surgeries, and a decrease in quality of life. Therefore, it is crucial to continue researching prognostic and predictive factors that may impact the progression of schwannomas [16].

The immunohistochemical marker Ki-67 is widely used in pathology as a prognostic and predictive marker in tumors of various locations. However, there are discrepancies in the use of Ki-67 as a "cut-off" for distinguishing between different types of tumors. For example, the 5th edition of the World Health Organization (WHO) classification of tumors of soft tissues and bones sets a "cut-off" of less than 20% for cellular schwannoma and ≥20% for malignant peripheral nerve sheath tumor. However, the 2021 WHO CNS classification states that Ki-67 values greater than or equal to 20% do not necessarily indicate a malignant tumor. Studies have shown that Ki-67 values in schwannomas can vary, with higher values often seen in recurrent tumors compared to non-recurrent tumors. For example, in the study by Graffeo et al., the Ki-67 index was 1.4% in recurrent tumors and 1.2% in non-recurrent tumors. Similarly, in the study by Iannella et al., the Ki-67 index was 3.2% in recurrent tumors and 1.4% in non-recurrent tumors. These findings suggest that Ki-67 can be a reliable indicator of tumor prognosis. In a retrospective cohort study by Lesser T.H. (1991), a direct correlation was found between the growth of schwannomas and an increase in the level of Ki-67. This was also observed in a study by Prueter J. (2019), which included patients with both total and subtotal resection. However, in a study by Graffeo C.S. (2018), Ki-67 values did not correlate with tumor recurrence, possibly due to the use of subtotal resection and a small sample size. In earlier WHO CNS classifications (2016), Ki-67 was used as a threshold of 20% for distinguishing neurofibromas from MPNST, but in 2021 it was replaced by counting the number of mitoses (greater than or equal to 1.5 mitoses/mm2), which may be more reproducible.  

In schwannomas, histological examination distinguishes between the Antoni A and Antoni B regions, which were first described in 1920 by the Swedish pathologist Nils Ragnar Eugene Antoni (1887-1968). These regions were named after Antoni, while a similar structure known as Verocay bodies was described earlier in 1910 by Uruguayan neuropathologist Jose Juan Verocay (1876-1927). Verocay bodies are acellular eosinophilic spaces surrounded by cellular processes and a palisade of schwannocyte nuclei, which Verocay believed could help differentiate between "neurinoma" tumors and neurofibromas [22-23]. The Antoni A region is characterized by elongated cells with spindle-shaped asymmetric nuclei and bundles of cells, including Verocay bodies. The less cellular Antoni B region contains cells with round-oval hyperchromatic nuclei, a myxoid or microcystic matrix, and macrophage infiltration. While mitoses are typically not observed in schwannomas, cellular variants may exhibit single mitoses and high levels of Ki-67, indicating a potential for proliferation due to the schwannocytes themselves [1-2,24]. 

It is well-established that the tumor microenvironment plays a crucial role in tumor progression [24]. In schwannomas, the main component of the microenvironment is macrophages [25]. Recent research has shown that macrophages are a heterogeneous population and can be divided into three subclusters [26]. In a study by Hannan C.J., a direct correlation was found between the infiltration of tumor-associated macrophages (TAMs) and schwannoma growth, regardless of tumor size. Additionally, there was a direct correlation with tumor vascularization, as evidenced by higher concentrations of monocyte-recruiting chemokines in patients with growing tumors [27-29]. Kontorinis G. et al (2016) also noted that increased levels of neutrophils and lymphocytes can serve as predictors of recurrence in sporadic schwannomas [30]. Several studies have demonstrated that adrenergic signaling from sympathetic nerves in the tumor microenvironment promotes tumorigenesis [24, 31]. In a study by Huo Z. (2024), higher levels of vascular endothelial growth factor (VEGF) were observed in schwannomas with an aggressive course, while the authors did not find a difference in the ratio of M1 and M2 macrophages between growing and stable tumors [32-33]. Currently, there is evidence supporting the effectiveness of the antiangiogenic drug Bevacizumab in treating vestibular schwannomas [34]. Additionally, the authors observed an increase in the density of CD68+ macrophages and proliferation of immune cells in recurrent tumors [17]. Wach J. et al found that Ki-67/MIB-1 values ≥ 5% were associated with more unfavorable outcomes in surgical treatment of vestibular schwannomas, such as the development of facial paralysis. However, these values were also directly correlated with the number of CD45+ and CD68+ cells in the tumor [25]. According to the results of studies by Nisenbaum E., higher levels of CD163+ expression in vestibular schwannomas were linked to hearing loss in patients [35].

Researchers need to conduct future studies to examine the relationships between histologic variants of schwannomas, levels of proliferative activity, and macrophage phenotypes and secreted cytokines, as they may be linked to tumor recurrence and progression. By studying these relationships, it is possible to discover new methods for treating and preventing schwannoma recurrence, such as targeted therapies.

Conflict of interest

The authors declare no conflict of interest.

Funding

The study was performed without external funding.

Author contributions

DM, DS, and YuZ contributed to the manuscript, revision, and investigation. All the authors read, approved, and equally shared the submitted version.