Clinical features, radiological profiles, and surgical outcomes of primary intracranial solitary plasmacytomas: a report of 17 cases and a pooled analysis of individual patient data

It was reported that SPC affected more male than female patients. A study that mainly included extracranial SPC reported a male to female ratio of 1.9:1 (169/89) [13]. Similar results were also observed in a recent study of 70 patients with sellar and clival plasmacytoma (5 patients from their center and 65 from prior publications) [10]. However, all 17 patients from our single center and the pooled 87 patients showed a minor female predominance (55.7% and 56.3%, respectively) for PISPC, which corresponded with the findings reported by Schwartz et al. [14]. Similar to previous studies [9], this neoplasm often developed in the fifth decade of life [8, 10, 14‐16]. Because the majority of the 17 tumors (88.2%) from our center were located at the skull base, most of these patients presented with CN defects [9]. The median symptom duration of 14 months indicated a relatively nonaggressive disease course.

Ferreira-Filho et al. reported that vertebral SPC could appear as a “mini brain” characterized by the hyperintense signal on T2 images with several cortical and radiated linear hypointense areas, which provided high value in preoperative diagnosis [17]. However, this sign was not observed in any MRI scans from our 15 cases. While nonspecific features could be identified, homogeneous enhancement on MRI [10, 18] combined with an osteolytic appearance on CT [19] was frequently observed. Notably, skull base SPC could mimic pituitary adenoma both radiologically and pathologically [20]. This emphasized the significance of immunohistochemical examination, on which PISPC stained positively for CD138 and CD79a [10]. However, there is no difference in diagnosis between skull base and nonskull base SPC because of the lack of characteristic MRI profiles of SPC, and the necessity to perform immunohistochemical examinations to establish an accurate diagnosis for tumors in both locations. The rate of intracranial plasmacytomas occurring in the context of MM was as high as 43.7% in our center and over 50% in other studies [8, 10]. An extensive workup to exclude MM was mandatory before the diagnosis of PISPC [21] because of the distinct treatment strategy and prognosis between PISPC and secondary plasmacytoma [8, 15].

Bindal et al. reported one recurrence, no deaths and no MM development over a mean 12-year observation period (4 cases), while Schwartz et al. reported 2 tumor recurrences, 5 tumors with MM, and 1 tumor-related death (7 cases). Another larger review of 65 cases reported a recurrence rate of 18% and an MM development rate of 38% [10]. By contrast, the median follow-up in our pooled study was 24 months, and the 5-year PFS, RFS, MMFS, and OS were 52.9%, 76.2%, 69.6%, and 76.0%, respectively. The observation that SPC tended to develop with MM more frequently than recur locally was described in Krause et al. [22]. When MM development occurred, most patients died soon.

A study of 258 cases that focused on extracranial SPC found that age > 60 years was a risk factor for OS, disease-free survival, and MMFS using a univariate analysis, and only the former two outcomes were independently influenced via multivariate analysis. They also identified that tumor diameter ≥ 4 cm was an independent risk factor for both RFS and OS and that SBP was the only risk factor for MM [13]. Studies on prognostic factors with exclusive emphasis on PISPC were scattered. In our study, increasing age independently predicted poor MMFS and OS. SPC was classically divided into SEP and SBP, which had a significant effect on OS and PFS [23] and was believed to be two different entities rather than a spectrum of one disease [24]. However, the intracranial definitions of SEP and SBP have been controversial in previous studies. Vengalathur et al. reported a plasmacytoma invading the anterior cranial fossa base and defined this tumor as an SEP [25]. Additionally, in a study by Schwartz et al., 6 skull base tumors were defined as intramedullary lesions [4]. Indeed, when the lesion was large enough, we usually failed to discern whether the tumor originated from adjacent dura and sinonasal tissues (SEP) or bone (SBP) (Fig. 1e–h). In our study, skull base and nonskull base locations were two parameters used to evaluate the impact of tumor location on outcomes. While we ultimately found that a skull base location was the predictor only for PFS, data from the case series showed that skull base PISPC was related to MM development [8, 14].

Surgical intervention was essential to make an accurate diagnosis and relieve CN deficits by reducing the mass effect [9, 10]. Bindal et al. pointed out that GTR alone, GTR plus RT, or biopsy plus RT could cure PISPC with no observation of MM development after a mean follow-up of 12 years. However, the argument that GTR alone could yield good outcomes was less persuasive because their studies only included 4 patients with PISPCs, all of whom were treated by adjuvant RT [8]. Our study, as well as others from extracranial series, failed to confirm the efficacy of GTR in patient outcomes [13]. Therefore, if the lesion was easily accessible, e.g., nonskull base IPC, GTR was still advocated [8, 14]; otherwise, NGTR or biopsy rather than GTR should be considered to avoid the potential complications, such as new CN dysfunctions or even death [26, 27]. Encouragingly, SPC has long been considered to be highly radiosensitive. A long 5-year RFS (86%) [13] and high local control rate (80%-100%) [1, 28] were reported in studies consisting of patients with SPC outside the cranium. The median RT dose of 44.4 Gy in our study was in accordance with the recommended dose of 40–50 Gy [1, 14, 29, 30]. Even when GTR was achieved, RT was still necessary, and it was advocated that radiation with a margin of 2 cm should be performed [1, 31]. For PISPC, Ferrari et al. reported that whole-brain RT with a local boost could yield good local control [32], and a similar outcome was also found in other patients with PISPC [4, 6, 8, 9, 21, 33] with a favorable local control rate regardless of whether the tumor was totally removed. Our study verified this argument and proved that the use of RT could prolong PFS and RFS independently. However, confirmation of whether RT could improve MMFS or OS requires a larger study. Though trends of higher 5-year MMFS and OS were observed in patients treated with RT when compared with those not treated with RT, the differences were not significant (Table 3).

The role of CMT in the treatment of SPC was questionable [1]. In this pooled analysis, we found that the 5-year OS of patients with CMT was significantly shorter than that of patients without CMT (52.5% vs 83.4%, p = 0.001), and a trend of poor 5-year MMFS (57.1% vs 73.5%, p = 0.164) was also found in the CMT subgroup. A study showed that a high Ki-67 index was associated with recurrence and MM development [14]. Given that 4 of 5 patients in the cases from our center had a reported Ki-67 index higher than 30%, the seemingly poor outcomes in the CMT subgroup were more likely because of the potential high-risk nature in these patients rather than the negative effect of CMT on outcomes. Similar results were also reported in one study that found a trend of a decreased 10-year OS in the RT alone subgroup compared to the RT plus CMT subgroup; however, a trend of a longer MMFS was also identified in that study [13]. Aviles et al. provided persuasive evidence of the efficacy of CMT in extracranial SBP in their prospectively designed study. They showed that RT plus CMT was able to achieve better PFS and OS than RT alone [30]. We agreed with the recommendation that patients with potential risk factors (age older than 65 years and tumors with high Ki-67 index or size > 5 cm [1]) should be considered for CMT. IMiDs (lenalidomide [21]) and a second-generation proteasome inhibitor (marizomib [34]) are potential therapeutic agents for high-risk PISPC because of good BBB penetrability and tumor sensitivity.