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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

  • Xiu-Jian Ma
  • Da Li
  • Liang Wang
  • Shu-Yu Hao
  • Li-Wei Zhang
  • Jun-Ting Zhang
  • Zhen Wu
Open Access
Clinical Study

Abstract

Purpose

We aim to delineate the clinical characteristics of patients with primary intracranial solitary plasmacytoma (PISPC) and prognostic factors for their outcomes.

Methods

This study retrospectively reviewed 17 patients with PISPC from our center and an additional 70 cases of PISPC published previously to analyze outcome predictors.

Results

The entire cohort included 38 (43.7%) males and 49 (56.3%) females with a mean age of 54 years. Skull base tumors were found in 49 (56.3%) patients. Gross total resection (GTR) was achieved in 31 (35.6%) patients. Postoperative adjuvant treatments, including radiotherapy (RT) alone, chemotherapy (CMT) alone, and RT + CMT were administered in 49 (56.3%) patients, 3 (3.5%) patients, and 16 (18.4%) patients, respectively. After a median follow-up of 24 (mean 42.4) months, the 5-year disease progression-free survival (PFS), recurrence-free survival (RFS), multiple myeloma (MM)-free survival (MMFS), and overall survival (OS) were 52.9%, 76.2%, 69.6%, and 76.1%, respectively. Multivariate analysis unveiled that a skull base tumor location (HR 2.395, p = 0.040) and no RT (HR 3.115, p = 0.004) were negative prognostic factors for PFS, no RT (HR 10.526, p = 0.003) for RFS, each 1-year increase in age (HR 1.039, p = 0.049) for MMFS, and increasing age (HR 1.052, p = 0.043) and CMT (HR 6.022, p = 0.005) were risk factors for OS. However, GTR did not benefit the aforementioned outcomes.

Conclusion

For patients with presumed PISPC, a biopsy followed by RT is recommended for skull base PISPC. However, the role of CMT is still not clear. Our findings need to be verified in a larger prospective cohort in the future. Systematic review registration number CRD42018098782.

Keywords

Primary intracranial solitary plasmacytoma Multiple myeloma development Radiotherapy Chemotherapy 

Abbreviations

CI

Confidence interval

CMT

Chemotherapy

GTR

Gross total resection

HR

Hazard ratio

NGTR

Nongross total resection

OS

Overall survival

PISPC

Primary intracranial solitary plasmacytoma

RT

Radiotherapy

SPC

Solitary plasmacytoma

Introduction

Solitary plasmacytoma (SPC) is a rare localized monoclonal plasma cell dyscrasia with normal or low plasma cell infiltration (less than 10%) [1]. This disease is different from multiple myeloma (MM), which is characterized by hypercalcemia, renal failure, anemia, and bone lesions [2]. The majority of intracranial plasmacytomas described in previous studies were diagnosed secondary to MM or as a manifestation of MM (non-primary). The prognosis of these patients was very poor, and the median overall survival (OS) after diagnosis was only 6.7 months, although radiotherapy, chemotherapy (CMT), hematopoietic stem cell transplantation, and intrathecal injection were used after diagnosis [3]. By contrast, patients with PISPC had a better prognosis after surgical resection and postoperative adjuvant radiotherapy (RT) unless the tumor progressed to MM [4]. However, those reports are mostly case reports [5, 6, 7] and several small sample series [4, 8, 9] without statistical analyses, which are less convincing. Herein, we reported 17 cases from our center to describe the clinical characteristics of this tumor. An additional 70 cases from published studies were pooled to evaluate the prognosis and prognostic factors for the outcomes of patients with PISPC.

Methods and materials

Cases from our center

Between January 2008 and December 2016, 32 patients were pathologically diagnosed with intracranial plasmacytoma, 14 (43.7%) of whom had evidence of MM at diagnosis. Seventeen (53.1%) patients with PISPC were eligible for analysis because one patient was lost to follow-up. The Research Ethics Committee of Beijing Tiantan Hospital approved the study. All patients underwent MRI and/or CT before surgery. The extent of tumor resection was recorded as gross total resection (GTR), and nongross total resection (NGTR). GTR was defined as complete removal without residue, which was evaluated by postoperative contrast MRI. All specimens were sent for pathological examination after the operation. Postoperative immunohistochemical staining included CD138 and CD38 [10]. Tumor progression was defined as the event of MM development and/or local tumor recurrence, whichever occurred first. MM development was defined when any new evidence of MM was identified during follow-up. Local tumor recurrence was diagnosed when increasing tumor size was larger than 2 mm on the most recent MRI scans. We recommended that all patients undergo radiotherapy, and for patients with high-risk factors (high Ki-67 index) for the development of MM, new chemotherapy (IMiDs and proteasome inhibitor) [11] agents were recommended.

Literature research

This study retrieved published literature from January 1954 to January 2018 with the following keywords: “plasmacytoma” combined with “intracranial” or “skull base” or “central nervous system”. The enrollment criteria were as follows: (1) patients with PISPC confirmed by surgery and subsequent pathology; (2) patients with a follow-up of more than 6 months unless terminal events occurred; and (3) cases reported in the English literature. The exclusion criteria were as follows: (1) PISPC concurrent with other malignant tumors and (2) patients with plasmacytoma secondary to MM or a diagnosis with evidence of MM. Two authors (X.J.M. and D.L.) carefully scrutinized the source and date of each candidate to exclude duplicates. The collected information included the general condition of the patient (age at diagnosis, sex, and tumor location), treatment modalities (degree of surgical resection, RT, and CMT) and outcomes (tumor progression, MM development or local recurrence, and death).

Follow-up and statistical analysis

Both the prior cases (n = 70) and our series (n = 17) were pooled after a comparison of general clinical characteristics between both groups. The potential risk factors included older age, male, skull base tumor location, and other adverse predictors (e.g., NGTR, no use of RT or CMT) for progression-free survival (PFS), recurrence-free survival (RFS), MM-free survival (MMFS), and OS were evaluated. The log-rank (Mantel-Cox) test and a Cox regression model were used to perform univariate and multivariate analysis, respectively. The analysis was performed using IBM SPSS statistical software package software (version 22.0, IBM Corp.) with a significance set at p < 0.05.

Results

Fifteen (88.2%) patients suffered from cranial nerve (CN) deficits, which represented the most common presentations (Table 1). The median duration from the onset of symptoms to diagnosis was 14 (range 4–23) months. The clivus and/or sellar areas were the most frequently involved regions, found in 14 (82.4%) patients. Overall, 15 (88.2%) tumors were located in the skull base. The tumors often appeared isointense on T1 (80.0%) images and isointense (46.7%) or hyperintense (46.7%) on T2 images, and they exhibited homogeneous enhancement after the administration of gadolinium (93.3%) (Fig. 1). All tumors but one [case 16 originated from temporal dura and grew intracranially (Fig. 1i–l)] invaded the adjacent bone and exhibited osteolytic behavior, which was confirmed by CT scans.

Table 1

Clinical and radiological characteristics of 17 cases from our center

No.

Sex

Age (year)

Presentations, duration (mos)

Preop. diagnosis

Location; size (cm)

MRI features (T1/T2/En)

Extent of surgery

Initial treatment

Progression

PFS (mos)

Salvage treatment

OS (mos)

1

M

59

CN VI, 15

Chordoma

Clivus, 3.4

Iso-/iso-/Homo-

NGTR

No

Local (45)

45

GTR + RT

128.1

2

F

45

Headache and CN II, 16

Meningioma

Orbitotemporal, 6.9

NGTR

No

Local (3) + MM (120)

3

Gama/RT

125.6

3

M

35

CN VIII/IX, ataxia, 23

Schwannoma

Petrous apex, 3.3

Iso-/hypo-/Homo-

PR

RT (45 Gy)

MM (100)

100

RT

121.8

4

M

42

CN V/VI/VII/VIII/IX/X, 21

Chordoma

Clivus, 4.8

Iso-/hyper-/Homo-

PR

RT (50 Gy) + SC (T + other agents)

No

117.6

117.6

5

F

56

Dizziness and CN II, 14

Pituitary adenoma

Sellar, 4.3

Mild Hyper-/mild Hyper-/Homo-

PR

No

local (58)

58

No

60.2

6

M

54

CN VIII, 10

Chordoma

Clivus, 4.6

Iso-/hyper-/Homo-

PR

RT

No

96.7

96.7

7

F

58

CN II/III/V, 20

Meningioma

MCB, 3.8

NGTR

No

MM (41)

41

No

41.1

8

F

47

CN VI, 4

Chordoma

Clivus, 3.1

Iso-/hyper-/Homo-

GTR

RT (45 Gy) + SC

Local (7) + MM (7)

7

SC

28.2

9

M

68

None, 19

Eosinophilic granuloma

Frotal, 2.0

Iso-/iso-/Homo-

GTR

No

No

57.8

57.8

10

M

64

CN VI, 13

Chordoma

Clivus, 3.8

Iso-/iso-/Homo-

NGTR

No

Local (14)

14

RT + SC

52.0

11

F

47

CN II, 14

Chordoma

Clivus, 4.0

Iso-/hyper-/Homo-

PR

No

Local (10) + MM (10)

10

NGTR + RT + S(T)

42.4

12

F

73

Dizziness and CN VI, 6

Chordoma

Clivus, 4.0

Iso-/iso-/Homo-

PR

SC (B + T + L)

No

35.5

35.5

13

F

55

None, 11

Meningioma

Parasellar, 5.3

Hyper-/hyper-/Homo-

GTR

RT

MM (23)

23

SC (T)

35.4

14

M

50

CNVI, 14

Chordoma

Clivus, 5.6

Iso-/iso-Hyper-/Homo-

PR

RT (42 Gy)

No

33.3

33.3

15

F

54

Headache, aphasia, and CN IX/X, 14

Chordoma

Clivus, 5.4

Iso-/iso-/Homo-

PR

RT (40 Gy) + SC

MM (17)

17

SC

20.7

16

F

57

Headache, aphasia, and CNIX/X, 14

Meningioma

Temporal, 4.2

Hyper-/mild Hyper-/Homo-

GTR

No

No

27.4

27.4

17

F

69

CN III/VII, 9

Squamous carcinoma

PCB, 3.4

Iso-/iso-/Homo-

GTR

SC

No

20.2

20.2

B bortezomib, CN cranial nerve, GTR gross total resection, En enhancement, Homo- homogeneous, L lenalidomide, MCB middle cranial base, MM multiple myeloma, NGTR non-gross total resection, PCB posterior cranial base, RT radiotherapy, SC systemic chemotherapy, T thalidomide

Events occurred in the marked cases

Several scattered cysts were found in this case

Fig. 1

ad (case 1): Preoperative MRI and CT showed a clival lesion that had an isointense signal on T1 images (axial), isointense signal on T2 images (axial) and homogeneous enhancement after the administration of gadolinium (sagittal) with an osteolytic appearance (axial, bone window). This tumor was diagnosed as a chordoma before surgery. eh (case 5): The presumptive pituitary adenoma had a mild hyperintense signal on T1 images (axial), mild hyperintense signal on T2 images (axial) and homogeneous enhancement (sagittal) with an osteolytic appearance (axial, bone window). il (case 16): The right temporal mass had a mild hyperintense signal on T1 images (axial), mild hyperintense signal in T2 images (axial) and homogeneous enhancement (sagittal). The “dural tail sign” was observed, which was highly suggestive of meningioma. No osteolytic evidence was found on a CT scan (axial, brain window)

All 17 patients with PISPC received surgical interventions via craniotomy (10 cases) or endoscopic resection (7 cases) (Table 1). Seven (41.2%) patients accepted postoperative fractioned radiotherapy with a mean dose of 44.4 Gy (radiation dose data were available in 4 of the 7 patients). The remaining patients declined RT because of either economic burdens or poor neurological status. Five patients received chemotherapy, two (case 4 and case 12) of whom accepted thalidomide and/or bortezomib. Notably, 4 of the 5 patients had a Ki-67 index higher than 30%. Accordingly, surgery alone, surgery plus RT, surgery plus RT and CMT, and surgery plus CMT alone were used in 8 (47.1%), 4 (23.5%), 3 (17.6%), and 2 (11.8%) patients, respectively (Table 1). At the latest follow-up, the preoperative symptoms improved in 6 patients, stabilized in 6 patients, and worsened in 1 patient for the 13 alive patients; postoperative complications and neurological outcomes were detailed in Supplementary Table 1.

Pooled individual data

The flowchart of the case processing procedure, the summary and details of the characteristics of the pooled 87 patients are shown in Supplementary Fig. 1 and Table 2, and Supplementary Table 2, respectively. Overall, the mean and median ages were both 54.0 years, with a male proportion of 43.7%, and a skull base tumor location was observed in 56.3% of patients. Regarding treatment, GTR was achieved in 31 (35.6%) patients; radiotherapy (RT) alone, chemotherapy (CMT) alone, and RT + CMT were used in 49 (56.3%) patients, 3 (3.5%) patients, and 16 (18.4%) patients, respectively; and 19 (21.8%) patients did not receive any form of adjuvant treatment.

Table 2

Summary of characteristics of pooled 87 cases

Variable

Prior cases (n = 70)

Our series (n = 17)

Comparison

Overall

AN

Value

AN

Value

Statistics

p

Value

Mean age, yrs

70

53.8 ± 13.1

17

54.8 ± 10.1

0.318a

0.751

54.0 ± 12.5

Sex (% for Male)

70

31 (44.3%)

17

7 (41.2%)

0.054††

0.816

38 (43.7%)

Location (% for skull base)

70

34 (48.6%)

17

15 (88.2%)

8.747††

0.003*

49 (56.3%)

Surgery extent (% for GTR)

70

26 (37.1%)

17

5 (29.4%)

0.356††

0.550

31 (35.6%)

Strategy

70

 

17

 

8.277††

0.016*

 

 No (%)

 

11 (15.7%)

 

8 (47.1%)

  

19 (21.8%)

 RT (%)

 

45 (64.3%)

 

4 (23.5%)

  

49 (56.3%)

 CMT (%)

 

1 (1.4%)

 

2 (11.8%)

  

3 (3.5%)

 RT + CMT (%)

 

13 (18.6%)

 

3 (17.6%)

  

16 (18.4%)

Median follow-up, mos

70

21 (4-300)

17

42.2 (20.2–128.1)

3.341‡‡

0.001*

24 (0–300)

Progression (%)

70

20 (28.6%)

17

10 (58.8%)

5.541††

0.019*

30 (34.5%)

 PFS (1 year/3 year/5 year, %)

20

86.6/66.5/60.9

10

82.4/64.2/34.4

1.624§§

0.202

85.6/66.1/52.9

Recurrence (%)

64

6 (9.4%)

17

6 (35.3%)

8.215††

0.011*

12 (14.8%)

 RFS (1 year/3 year/5 year, %)

 

96.9/94.5/87.2

 

82.4/76.5/47.8

5.283§§

0.022*

93.5/90.1/76.1

MM development (%)

68

16 (23.5%)§

16

7 (43.8%)

2.360††

0.137

23 (26.4%)

 MMFS (1 year/3 year/5 year, %)

 

80.3/73.4/73.4

 

87.5/74.5/65.2

0.284§§

0.594

81.5/72.8/69.6

Death (%)

70

8 (11.4%)

17

4 (23.5%)

1.684††

0.239

12 (13.8%)

 OS (1 year/3 year/5 year, %)

 

97.1/83.7/83.7

 

100/87.1/65.3

0.060§§

0.806

97.7/84.1/76.0

AN available number

Among the 13 patients who accepted RT + CMT, 3 patients received intrathecal CMT, and 1 received high-dose CMT. The remaining received systemic CMT

One case of the 20 cases did not detail the progression form (whether local recurrence or MM development)

§No time to MM was reported in there of the 16 patients

‡‡Wilcoxon test

at-test (two-tailed)

††x2-test (two-tailed)

*p < 0.05 that indicates statistical significance

§§Log Rank test

Statistical analysis of prognostic factors for PFS, MMFS, RFS, and OS

The median follow-up in the entire group was 24 (mean 42.4) months. For the entire group, 30 (34.5%) patients suffered from disease progression with a 5-year PFS of 52.9%; tumor recurrence was observed in 12 (14.8%) patients with a 5-year RFS of 76.2%; 23 (26.4%) patients developed MM with a 5-year MMFS of 69.6%; and 12 (13.8%) patients died from disease progression with a 5-year OS of 76.1%. For the 23 patients who suffered MM development, 9 (39.2%) died with a median time of 18 (range 0–33) months. The 5-year survival rate after MM development was 45.5%.

The summary of potential factors that affected outcomes is demonstrated in Table 3 and is further detailed in Supplementary Tables 3–6. Kaplan–Meier analysis showed that a skull base location (P = 0.025), no RT (P = 0.006) and the use of CMT (P = 0.032) predicted a poor PFS. Multivariate analysis confirmed that a skull base tumor location (HR 2.395, 95% CI 1.041–5.509; p = 0.040) and RT (HR 3.115, 95% CI 2.611–6.711; p = 0.004) could independently affect PFS (Fig. 2a, b). Though age (p = 0.024), tumor location (p = 0.020), and RT (p = 0.001) had a significant impact on RFS in the univariate analysis, only the use of RT (Fig. 2c) was an independent factor for RFS (HR 10.526, 95% CI 2.611–41.667; p = 0.003). Interestingly, both univariate and multivariate analysis showed that age (Fig. 2d) was the only predictor for MMFS, with an HR (p = 0.049) of 1.039 (95% CI 1.000–1.080) per 1-year increase in age. For OS, age (p = 0.033), tumor location (p = 0.043), and CMT (p = 0.001) were identified as significant factors, and increasing age (HR 1.052, 95% CI 1.002–1.104; p = 0.043) and the use of CMT (HR 6.022, 95% CI 1.730–20.958; p = 0.005) were further verified as risk factors for this outcome (Fig. 2e, f).

Table 3

Summary of prognostic factors for outcomes

Values

PFS

RFS

MMFS

OS

5-year (%)

P (uni-)

P (multi-)

5-year (%)

P (uni-)

P (multi-)

5-year (%)

P (uni-)

P (multi-)

5-year (%)

P (uni-)

P (multi-)

Age

     

0.985

  

0.049§

  

0.043§

 Older age

38.0

0.096

 

65.8

0.024§

 

43.7

0.002§

 

73.9

0,033§

 

 Young age

76.8

Ref

 

100

Ref.·

 

76.6

Ref

 

90.8

Ref

 

Sex

 Male

69.0

0.352

 

81.5

0.545

 

78.9

0.176

 

83.9

0.878

 

 Female

44.2

Ref

 

72.4

Ref

 

63.2

Ref

 

70.8

Ref

 

Skull base

 Yes

40.3

0.025§

0.040§

63.5

0.020§

0.078

59.2

0.099

 

63.2

0.037§

0.110

 No

68.7

Ref

 

88.9

Ref

 

83.0

Ref

 

94.4

Ref

 

GTR

 Yes

54.2

0.332

 

74.7

0.458

 

69.8

0.933

 

79.8

0.631

 

 No

57.1

Ref

 

76.1

Ref

 

69.5

Ref

 

74.6

Ref

 

Radiotherapy

 No

15.1

0.006§

0.004§

40.3

0.001§

0.003§

58.7

0.261

 

57.9

0.700

 

 Yes

66.6

Ref

 

88.9

Ref

 

72.9

Ref

 

83.1

Ref

 

Chemotherapy

 

47.4

0.032§

0.073

79.9

0.332

 

57.1

0.164

 

52.5

0.001§

0.005§

 

56.4

Ref

 

77.6

Ref

 

73.5

Ref

 

83.4

Ref

 

Backward stepwise (likelihood ratio) method was used in Cox regression model. The HR (95% CI) value for each significant prognostic factor was detailed in Supplementary Tables 1–4

Uni- univariate analysis (log-rank test), multi- multivariate analysis (Cox regression model)

§p < 0.05 that indicates statistical significance

The cut-point age was evaluated via ROC Curve, which was 51-year old, 45-year old, 65-year old, and 53-year old for PFS, RFS, MMFS, and OS. Respectively (Supplementary Tables 3–6)

Fig. 2

Kaplan–Meier survival curves showed the different outcomes in patients with prognostic factors. Skull base PISPC had a poor PFS (a), and RT could improve PFS (b) and RFS (c) for patients with this tumor. Patients with older age (≥ 65 years for MMFS and ≥ 52 years for OS) suffered a worse MMFS (d) and OS (e). Patients who accepted CMT had an OS that was significantly shorter than those who did not receive CMT (f). Chi square values were obtained by log-rank (Mantel-Cox) testing during the Kaplan–Meier curve analysis

Discussion

The prognosis of secondary intracranial plasmacytoma was dismal. In a multicenter analysis enrolling 172 patients, even though novel systemic CMT agents (IMIDs and proteasome inhibitors) were administered, the median OS for patients with central nervous system involvement was 6.7 months [3]. In an early review, the median OS was even as low as 2 months [12]. However, regarding PISPC, no death was reported in a study with a mean follow-up of over 10 years [8]. These findings triggered the hypothesis that PISPC may be a distinct entity from secondary plasmacytoma, which encouraged us to conduct such a study to better understand PISPC. Briefly, we found that preoperative data provided limited clues to a precise diagnosis until pathological and immunohistochemical examinations were performed; increasing age could affect MMFS and OS, while a skull base tumor location could impact PFS; and finally, the use of RT could delay tumor progression and local recurrence, but a worse OS was observed in the subgroup of patients treated with CMT.

Clinical characteristics and diagnosis

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, 15, 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].

Outcomes and risk factors

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].

Treatment regimens

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.

Conclusion

PISPC is a rare lesion with a high preoperative misdiagnosis rate. Meticulous examinations to exclude MM are of great significance, as PISPC has a relatively favorable OS unless MM development occurs. Patients with increasing age had a poor MMFS and OS, and tumors with a skull base location had a poor PFS. We found that it was not necessary to achieve aggressive tumor resection, but RT could significantly improve PFS and RFS. However, the role of CMT is still not clear. Based on these findings, a biopsy followed by RT is recommended for skull base PISPC. Both high-risk factors for PISPC and the efficiency of CMT in high-risk patients need to be investigated in the future. Close follow-up was required so that prompt salvage treatment could be initiated in case of tumor recurrence or MM development. Our results need to be verified in future larger and/or prospective studies.

Notes

Acknowledgements

This work was supported in part by the Natural Science Foundation of China (Grant No.81672506 to Z.W. and 814742370 to J.T.Z.).

Compliance with ethical standards

Conflict of interest

All the authors declared that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingPeople’s Republic of China

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