STAT6 immunohistochemical expression in meningeal-based tumors: Diagnostic of solitary fibrous tumor/hemangiopericytomas

Ayushi Sahay; Vinayak Kadam; Aliasgar Moyiadi; Tejpal Gupta; Jayant Sastri Goda; Prakash Shetty; Rakesh Jalali; Epari Sridhar

doi:10.4103/IJNO.IJNO_9_19

ORIGINAL ARTICLE

Year : 2019 | Volume : 2 | Issue : 2 | Page : 112-118

STAT6 immunohistochemical expression in meningeal-based tumors: Diagnostic of solitary fibrous tumor/hemangiopericytomas

Ayushi Sahay¹, Vinayak Kadam¹, Aliasgar Moyiadi², Tejpal Gupta³, Jayant Sastri Goda³, Prakash Shetty², Rakesh Jalali³, Epari Sridhar¹
¹ Department of Surgical Pathology, Tata Memorial Center, HBNI, Mumbai, Maharashtra, India
² Department of Surgical Oncology, Tata Memorial Center, HBNI, Mumbai, Maharashtra, India
³ Department of Radiation Oncology, Tata Memorial Center, HBNI, Mumbai, Maharashtra, India

Date of Submission	23-May-2019
Date of Acceptance	03-Nov-2019
Date of Web Publication	10-Jan-2020

Correspondence Address:
Dr. Epari Sridhar
Department of Pathology, Tata Memorial Centre, HBNI, 8^th Floor, Annex Building, Parel, Mumbai - 400 012, Maharashtra
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJNO.IJNO_9_19

Abstract

Background: Updated 2016 WHO classification of central nervous system tumors has unified solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) as a single entity (SFT/HPC), Grading from I to III, in view of common genetic alteration namely fusion of NAB2 and STAT6 genes.
Aim: This study aims to evaluate the role of STAT6 immunohistochemical expression in a cohort of meningeal-based tumors and its correlation with other pathological parameters.
Materials and Methods: Sixty-two meningeal-based tumors were studied including 40 HPC/SFT (1 Grade I, 29 Grade II and 10 Grade III), 14 meningiomas (2 Grade I, 10 Grade II, 2 anaplastic meningiomas), three meningeal sarcoma, and five cases with features suspicious for SFT/HPC. The expression pattern of STAT6 and other histological findings were noted.
Results: Nuclear or nuclear + cytoplasmic STAT6 positivity was seen in 40/40SFT/HPC (100%), diffuse in 30 and focal in 10 cases. Only 1/14 cases of meningioma (7.1%) showed weak nuclear positivity. All cases of meningiomas and 2/3 cases of meningeal sarcoma showed cytoplasmic positivity. Of the five suspicious HPC cases, four showed diffuse strong nuclear STAT6 positivity, based on which they were confirmed as HPC. Interestingly, of the 40 STAT6 positive SFT/HPC, five showed epithelial differentiation (AE1/AE3 and/or epithelial membrane antigen [EMA]). CD34 was negative in 4/36 SFT/HPC. CD34 was focally positive in 3/5 suspicious HPC cases, two of which were focally EMA positive as well, and both cases showed nuclear STAT6 positivity. BCl2 was negative in 5/27 SFT/HPC, all of which were nuclear STAT6 positive.
Conclusions: Nuclear expression of STAT6 can serve as a highly sensitive and specific adjunctive diagnostic marker for meningeal-based SFT/HPC, especially in cases with nonconventional histology and immunohistochemical profile, where meningioma or high-grade meningeal sarcoma forms a diagnostic dilemma.

Keywords: Hemangiopericytoma, immunohistochemistry, meningioma, solitary fibrous tumor, STAT6

How to cite this article:
Sahay A, Kadam V, Moyiadi A, Gupta T, Goda JS, Shetty P, Jalali R, Sridhar E. STAT6 immunohistochemical expression in meningeal-based tumors: Diagnostic of solitary fibrous tumor/hemangiopericytomas. Int J Neurooncol 2019;2:112-8

How to cite this URL:
Sahay A, Kadam V, Moyiadi A, Gupta T, Goda JS, Shetty P, Jalali R, Sridhar E. STAT6 immunohistochemical expression in meningeal-based tumors: Diagnostic of solitary fibrous tumor/hemangiopericytomas. Int J Neurooncol [serial online] 2019 [cited 2023 Mar 25];2:112-8. Available from: https://www.Internationaljneurooncology.com/text.asp?2019/2/2/112/275541

Introduction

Meningeal-based tumors comprise of a variety of entities, most common among them being meningioma. Others comprise mesenchymal tumors, including solitary fibrous tumor/hemangiopericytoma (SFT/HPC), meningeal sarcomas, lymphoma, metastasis, and histiocytic lesions such as Rosai-Dorfman Disease ^{More Details}, melanocytic lesions, and rarely gliomas.^[1] Recently, with the demonstration of a common genetic alteration namely the NAB2-STAT6 fusion in both SFT and HPC, the recent 2016 World Health Organization (WHO) update of central nervous system (CNS) tumor classification unified them as a single entity-SFT/HPC, with different WHO Grades (I–III).^{[2],[3],[4],[5]} Dural-based SFT/HPC needs to be differentiated from meningiomas and meningeal sarcomas as these entities have different behavior, treatment, and outcomes.^[1],[6] These dural-based lesions show considerable clinical and radiological overlap, and histology plays an important role in diagnosis. However, occasional cases display marked histological and immunohistochemical overlap as well.

Recently, nuclear immunohistochemical expression of STAT6 has been shown the be of value in solving this diagnostic dilemma.^[7],[8] We undertook this study to evaluate the role of immunohistochemical STAT6 expression in a cohort of meningeal-based tumors and to correlate the same with other histological parameters.

Materials and Methods

Representative cases of meningeal-based lesions-meningiomas, SFT/HPC, and meningeal sarcoma were included in the study. Cases diagnosed between January 2003 and December 2016 were retrieved from the archives of the department of pathology, and the morphology was reviewed by two pathologists. Relevant clinical and pathological parameters (including immunohistochemical findings) were noted. Only cases with clearly documented intracranial/spinal location, where adequate material was available in the paraffin-embedded tissue blocks were included. One case with suboptimal tissue preservation was excluded. Among meningiomas, higher grade (WHO Grade II atypical and Grade III anaplastic), were included as they may more often be histologically confused with SFT/HPC. Specific histological subtypes of high-grade meningiomas (such as papillary, rhabdoid, chordoid, or clear cell) were excluded as they generally do not pose as a differential for SFT/HPC.

Whole tissue sections from paraffin blocks were cut to a thickness of 4 mm. The sections were deparaffinized using xylene and ethanol. The preparations were autoclaved in citrate buffer (pH 6.0) for antigen retrieval. The sections were exposed to 3% hydrogen peroxide for 10 min to block endogenous peroxidase activity and then washed with deionized water for 2 min or 3 min. Polyclonal rabbit antibody against c-terminal epitope of STAT6 (clone (S-20): sc-621, Santa Cruz Biotechnology, Santa Cruz, CA, USA) was used in a 1:200 dilution. The slides were incubated for 1 h at room temperature with the primary antibody and subsequently labeled using the EnVision system (Dako, Glostrup, Denmark). Diaminobenzidine was used as the chromogen and hematoxylin as the counterstain. Positive and negative controls were used with each batch. Nuclear and/or cytoplasmic STAT6 expression was noted across different entities. Staining was labeled as diffuse when >50% of cells showed staining and focal when <50% (but >10%) cells showed staining. In addition, the intensity of staining was graded as strong or weak. Cases where <10% cells showed nuclear staining or those with only cytoplasmic staining were interpreted as negative.

Results

Fifty-seven meningeal-based tumors diagnosed in our hospital from January 1, 2007, to June 30, 2017, were included, comprising 40 cases of SFT/HPC, 14 meningiomas, and three meningeal sarcomas. The case distribution with the WHO grades and corresponding nuclear STAT6 expression results are shown in [Table 1]. In addition, we also included five cases, in which there was a histomorphological suspicion of HPC, but which showed lack of or very focal hemangiopericytomatous vascular pattern, sheeting and overlapping immunohistochemical profiles with meningiomas (lack of CD34 and/or BCl2 expression, and/or epithelial marker expression), as category of borderline SFT/HPC. The clinicopathological features of these cases are shown in [Table 2].

Table 1: Results of nuclear STAT6 expression>

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Table 2: Nuclear STAT6 expression in cases with borderline features of solitary fibrous tumor/hemangiopericytoma

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Solitary fibrous tumor/hemangiopericytoma (n: 40)

The age range was 27–69 years (mean 36.5 years) and showed a male predominance (M: F = 1.5:1). The tumors were predominantly supratentorial (34/40). There was only one case of SFT/HPC Grade I, presenting as supratentorial frontoparietal tumor in a 40-year-old male. On morphology, the single WHO Grade I SFT/HPC was hypocellular, with tumor cells arranged in a storiform pattern with prominent collagenization. Mitotic activity was insignificant, and there was no necrosis. On immunohistochemistry, the tumor cells were diffusely positive for CD34 and BCl2 while negative for epithelial membrane antigen (EMA) and progesterone receptor. STAT6 showed diffuse strong nuclear positivity.

There were 27 cases of SFT/HPC WHO Grade II and 9 cases of SFT/HPC WHO Grade III (erstwhile termed HPC and anaplastic HPC, respectively), as per the current WHO criteria (<5 mitosis/10 HPF for WHO Grade II vs. >5 mitosis/10 HPF for WHO Grade III). Histologically, majority of these tumors were composed of oval to spindled cells (37/39) and showed hemangiopericytomatous vascular pattern (33/39 cases, 11 focally). Focal hyalinization was seen in a few cases (10/39). Mitotic activity in the WHO Grade II SFT/HPC ranged from insignificant to 4/10 HPF, while for WHO Grade III SFT/HPC, it varied from 5 to 30/10 HPF. Necrosis was seen only in a single case of WHO Grade II SFT/HPC while was absent in all WHO Grade III SFT/HPC. On immunohistochemistry, CD34 was positive in 89% of the cases (32/36; diffuse in 21 and focally in 11), and BCl2 in 81.5% (22/27; diffuse in 17 and focal in 5). Aberrant expression of epithelial marker in the form of EMA and/or AE1/AE3 was seen focally in 15% cases (5/33). Strong nuclear STAT6 expression was seen across all SFT/HPC grades, and at all locations (100%) [Figure 1]. The staining was predominantly diffuse (30/40, 75%) and was additionally seen in the cytoplasm in 10 cases (25%). All cases with a lack of classical SFT/HPC markers, i.e., CD34 and BCl2 as well as all cases with aberrant epithelial markers (EMA/AE1 AE3) showed nuclear STAT6 expression.

Figure 1: (a) SFT/HPC Grade II with classical hemangiopericytomatous vasculature and oval to spindled cells (H and E, ×200); (b) strong diffuse CD34 expression in SFT/HPC Grade II (×200); (c) BCl2 expression in HPC (×200); (d) focal AE1/AE3 expression in HPC/SFT (×400); (e) focal EMA expression in HPC/SFT (×200); (f) diffuse strong nuclear STAT6 (×200) and (g) strong nuclear + cytoplasmic expression of nuclear STAT6 (×200); (h) case of SFT with hyalinization (H and E, ×200); and (i) diffuse strong nuclear STAT6 expression (×200). SFT: Solitary fibrous tumor, HPC: Hemangiopericytoma

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Meningioma (n: 14)

The age range was between 23 and 71 years (mean 50.2 years) and was equally distributed between males and females. The WHO grade-wise distribution included two Grade I (1 each of fibroblastic and transitional histological types), 10 Grade II (all atypical meningiomas by histology), and 2 Grade III meningiomas (both anaplastic meningiomas by histology). Majority were supratentorial (12/14). EMA was diffusely positive in 85% of cases (6/7). Only 1 out of 14 meningiomas (7.1%) showed weak, focal nuclear STAT6, while the remaining 13 showed diffuse cytoplasmic expression. The case was reviewed and showed classical features of a Grade II meningioma with the presence of meningothelial whorls on histology [Figure 2].

Figure 2: (a) Histology of atypical meningioma with evident meningothelial cells and prominent whorling (H and E, ×400). MIB1 labeling index is high (inset, ×400); (b) STAT6 in the previous case showing weak, focal nuclear STAT6 expression (×400); (c) histology of another atypical meningioma (H and E, ×400) with (d) diffuse cytoplasmic STAT6 expression (×400)

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Meningeal sarcoma (n: 3)

There were three cases in 7, 18, and 38-year-old patients, two of whom were males and one female. One of the cases (18/M) was a mesenchymal chondrosarcoma with aberrant keratin expression. The round to spindle cell areas in this case showed Mic-2 and Bcl2 expression, along with focal AE1/AE3 while the chondroid areas were highlighted by S100. The second case, a temporoparietal tumor in a 7-year-old female, was a high-grade sarcoma on histology, which on immunohistochemistry showed aberrant focal keratin expression, but was negative for a wide panel of immunohistochemical markers including GFAP, S100, EMA, desmin, myogenin, CD34, Mic2, and SMA. INI1 was retained in the tumor. Thus, with a lack of any specific differentiation on histology as well as immunohistochemistry, the tumor was designated a high-grade sarcoma, NOS. Similarly, in the third patient, a 38-year-old male, with a frontal tumor, a highly pleomorphic spindle cell tumor with frequent mitosis and focal hemangiopericytomatous vascular pattern was seen on histology. No meningothelial whorls were noted. On immunohistochemistry, there was focal CD34 and S100 expression, while negativity for desmin, GFAP, EMA, HMB45, CD31, and SMA were noted. The tumor was thus designated a high-grade pleomorphic sarcoma.

None of the above three sarcomas showed nuclear positivity for STAT6; however, in two of the three cases, cytoplasmic STAT6 positivity was seen, focally in one and diffusely in the other [Figure 3].

Figure 3: (a) A case with borderline histology showing sheeting architecture and only focally thin-walled ectatic vessels (H and E, ×100); (b) strong nuclear and cytoplasmic STAT6 is one of the borderline cases (×400); (c) Histology of another borderline cases showing predominantly spindle cell morphology (H and E, ×400), with (d) negativity for STAT6 (×400)

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Borderline solitary fibrous tumor/hemangiopericytoma (n: 5)

There were five cases, which on morphology and immunohistochemistry, showed overlapping features of SFT/HPC with meningiomas and meningeal sarcoma, and were thus labeled ambiguous on histology, but SFT/HPC formed an important differential, and hence, these are discussed separately [Table 2]. Among these, three were male and two were female. All were seen in the adult age group (age range 29–54 years) and were supratentorial in location. Hemangiopericytomatous vascular pattern was seen only focally in 4/5 cases, while it was not seen in the fifth case. The presence of oval to spindled cells was seen in 3/5, while the other two cases showed a more spindled morphology. Immunohistochemistry, also, was not definitively conclusive, with either the absence of CD34 and/or BCl2 or focal EMA/AE1 AE3 expression. In these cases, a possibility of SFT/HPC (two Grade II and three Grade III) was suggested on the initial diagnosis. Intriguingly, in four out of the five cases, strong nuclear STAT6 positivity was seen. The staining was focal in two cases and diffuse in two cases, respectively. These cases were reviewed and confirmed as SFT/HPC. In the fifth case, which showed a more spindle cell morphology and lack of hemangiopericytomatous pattern but showed immunohistochemical expression of CD34 and BCl2, no nuclear or cytoplasmic STAT6 expression was identified [Figure 3]. In addition, this tumor was negative for other immunohistochemical markers such as Mic2, SMA, and S100. This case possibly represents a mesenchymal tumor, not otherwise specified with HPC-like areas [Table 2].

Discussion

Meningeal SFT/HPCs, at times, form a diagnostic dilemma with other meningeal-based tumors, especially WHO Grade II and III meningiomas, which are known to have a significantly different treatment, behavior, and outcomes. HPC is essentially a type of dural sarcoma, which can show extracranial metastasis in as many as 25%–60% cases, as well as local recurrences. Meningioma, on the other hand, has a tendency to recur locally and only occasionally metastasizes outside the CNS. High-grade mesenchymal, nonmeningothelial meningeal sarcomas, including fibrosarcomas, leiomyosarcomas, pleomorphic sarcomas, osteosarcoma, etc., are aggressive high-grade tumors (WHO Grade IV) with poor outcomes, and frequently show local recurrence and/or distant leptomeningeal seeding.^[2],[6],[9] They may also be confused with high-grade HPC, especially in limited biopsy material or when there is an unexpected immune profile. Conventionally, the immunohistochemical markers used for distinguishing meningiomas and HPC are CD34, BCl2, and EMA, however, they show a significant overlap with other entities, and no single marker is adequately specific and sensitive, particularly in cases with overlapping morphological features.^{[6],[10],[11],[12]}

Although in the soft tissues, due to overlapping histology, immunohistochemistry, and behavior, in 2013, the WHO classification of soft-tissue tumors merged HPC in SFT, and eliminated the term “HPC.” In the CNS however, the WHO classification continued to distinguish between the two, as meningeal HPC followed a notoriously more aggressive course, as already discussed above.^[9],[13] Nevertheless, with the demonstration of a common genetic alteration namely the NAB2-STAT6 fusion in both SFT and HPC, the recent 2016 WHO update of CNS tumor classification recognized their common origin, and unified them as a single entity as SFT/HPC, albeit with different WHO grades.^{[2],[3],[4],[5],[7],[14]} SFT/HPC WHO Grade I corresponds to erstwhile SFT, WHO Grade II corresponds to classical HPC, and WHO Grade III corresponding with what was earlier termed as anaplastic HPC, with >5 mitosis/10 HPF.^[2]

It has been shown that STAT6 protein, which is a signal transducer and activator of transcription, and normally localizes to the cytoplasm due to the inversion and juxtaposition of their genes on chromosome 12, fuses with the NAB2 protein which is a transcriptional repressor and localizes to the nucleus. The fusion results in the formation of a NAB2-STAT6 fusion protein which localizes to the nucleus and converts NAB2 into a transcriptional activator and results in tumorigenesis.^[3],[5] Since these genes are located in close proximity on chr 12q13, it is difficult to detect the fusion by conventional molecular analysis such as chromosome banding or fluorescence in situ hybridization. The initial studies describing this fusion gene in SFT/HPC relied on whole-exome sequencing, transcriptome sequencing, integrative sequencing, or RT-PCR, and proximity ligation assays for the detection of NAB2-STAT6 fusion protein.^{[3],[5],[7],[14]} However, Schweizer et al. demonstrated that when immunohistochemistry is performed for the carboxyterminal end of STAT6, the protein instead of localizing to the cytoplasm, localizes to the nucleus when there is NAB2-STAT6 fusion. Hence, nuclear relocalization of STAT6 protein expression serves as a surrogate marker for NAB2-STAT6 fusion.^[7] Being an immunohistochemical assay, the detection of this nuclear relocalization of STAT6 is thus a cheaper, and less technically demanding alternative to expensive and labor-intensive molecular tests, and hence more routinely available for diagnostic purposes.

Importantly, in the recent update of the WHO CNS tumor classification, the detection of STAT6 nuclear expression or NAB2-STAT6 fusion is highly recommended for confirmation of the diagnosis of SFT/HPC, and if not or cannot be performed, needs to be indicated as such in the report. They further recommend that in case of a negative result, alternative diagnosis should be considered, implying significantly, that a negative result all but rules out a diagnosis of SFT/HPC.^[2] In our study, strong nuclear STAT6 expression was demonstrated in all SFT/HPC, across all grades, and intracranial locations. Importantly, it was present in all cases which showed morphological variation (scarcity of typical ovo-spindled cells or HPC type vasculature) or immunohistochemical variation (lack of classical SFT/HPC markers, such as CD34 and BCl2, or presence of aberrant epithelial markers, such as EMA and AE1/AE3), thus emphasizing the sensitivity of nuclear positivity of STAT6 is diagnosing SFT/HPC. The staining was diffuse in majority (75%) of typical SFT/HPC and focal but strong in the remaining one-fourth of cases. This heterogeneous staining has been described previously by Yoshida et al., and Doyle et al., who postulated that this might be due to variability in fixation or tissue ischemia and recommended that this pitfall should be kept in mind while interpreting small biopsy specimen or under-fixed tissue.^[15],[16] In addition, we found not only nuclear but also significant cytoplasmic expression of STAT6 in 25% of our HPC cases. Although cytoplasmic expression of STAT6 in HPC was not described in the original study by Schweizer et al., it has been reported by Macagno et al. (69% of their HPC cases) and Ouladan et al. (10% of SFT cases), using the same antibody clone.^[7],[8],[17]

Nuclear STAT6 was negative in all three high-grade meningeal sarcomas in our study. Although the number of meningeal sarcoma in our study is small, STAT6 seems to be a reliable marker to differentiate high-grade anaplastic HPC (SFT/HPC Grade III) from high-grade nonmeningothelial, non-SFT/HPC mesenchymal tumors of the meninges. However, it should be remembered that nuclear STAT6 expression has been described in a few benign and malignant non-SFT mesenchymal tumors at extracranial locations. Most important of these, especially pertinent to meningeal location, are well-differentiated and de-differentiated liposarcoma, undifferentiated sarcoma, and desmoid tumors.^{[16],[17],[18]}

In addition to the classical and unambiguous SFT/HPC cases, we also included five cases, in which on initial reporting, SFT/HPC formed an important differential; however, there were overlapping morphological and immunohistochemical features with meningiomas and meningeal sarcomas (a scenario not uncommonly encountered in routine diagnostic practice). Based on our experience with the STAT6 expression of classical SFT/HPC, meningiomas, and meningeal sarcomas, we performed STAT6 immunohistochemistry on these five cases to see if we could conclusively assign them a specific diagnosis. We found strong nuclear STAT6 expression in four of the five cases and were able to decisively label those four as SFT/HPC.

The weak, focal nuclear positivity seen in one of our meningioma cases has also been described by others in literature. Yoshida et al. described weak nuclear + cytoplasmic positivity in all of the meningioma cases in their study, as well as a variety of other non-SFT tumors.^[15] Schweizer et al. demonstrated weak nuclear STAT6 positivity, similar to our case, in 3/90 meningiomas (two anaplastic, one atypical). On histological re-evaluation, they found that these three cases showed morphological features overlapping between high-grade meningioma and HPC, and thus these cases were separated from meningioma and termed as mesenchymal tumor, not otherwise classifiable.^[7] However, in our case, we found typical morphological features of a Grade II meningioma, with the presence of meningothelial whorls, which we felt precluded any reclassification. However, none of our meningioma cases, as well as those described in literature, show strong or diffuse nuclear STAT6, which, according to our analysis, was a hallmark of SFT/HPC. Demicco et al. analyzed STAT6 expression in 2366 mesenchymal tumors and found that most mesenchymal tumors express low levels of nuclear and cytoplasmic STAT6, significance of which is uncertain, and only strong nuclear STAT6 is sensitive and specific for SFT.^[18]

Strong nuclear staining was highly sensitive (100%) and specific (92%) for the diagnosis of meningeal SFT/HPC in our comparative study with meningiomas and rarer meningeal sarcomas. This is comparable to that described by Yoshida et al. (sensitivity100%), Schweizer et al. (sensitivity and specificity 97%), and Macagno et al. (sensitivity 90%, specificity 100%).^[7],[8],[15]

Conclusions

Our study confirms that strong nuclear expression of STAT6 is a highly sensitive and specific adjunctive diagnostic marker for differential diagnosis of meningeal-based tumors, to differentiate between SFT/HPC from its histological mimics namely meningiomas and meningeal sarcoma, particularly in cases which show overlapping morphological or immunohistochemical features, and lack of classical SFT/HPC markers. On the basis of our findings, we strongly recommend the addition of STAT6 to the existing diagnostic armamentarium of meningeal-based CNS tumors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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