Experimental and Molecular Pathology 99 (2015) 354359

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Experimental and Molecular Pathology

journal homepage: www.elsevier.com/locate/yexmp

Review

Malignant progression to anaplastic meningioma: Neuropathology,

molecular pathology, and experimental models
Patrick J. Cimino
Department of Pathology, Division of Neuropathology, University of Washington, Box 359791, 325 9th Avenue, Seattle, WA 98104-2499, United States

a r t i c l e i n f o a b s t r a c t

Article history: Meningioma is a common adult intracranial tumor, and while several cases are considered benign, a subset is
Received 16 August 2015 malignant with biologically aggressive behavior and is refractory to current treatment strategies of combined
Accepted 17 August 2015 surgery and radiotherapy. Anaplastic meningiomas are quite aggressive and correspond to a World Health
Available online 22 August 2015
Organization (WHO) Grade III tumor. This highly aggressive phenotype mandates the need for more efcacious
therapies. Designing rational therapies for treatment will have its foundation in the biologic understanding of
Keywords:
Meningioma
involved genes and molecular pathways in these types of tumors. Anaplastic meningiomas (WHO Grade III)
Anaplastic meningioma can arise from malignant transformation of lower grade (WHO Grade I/II) tumors, however there is an incom-
Malignant progression plete understanding of specic genetic drivers of malignant transformation in these tumors. Here, the current
Neuropathology understanding of anaplastic meningiomas is reviewed in the context of human neuropathologic specimens
and small animal models.
2015 Elsevier Inc. All rights reserved.

Contents

1. Anaplastic meningioma introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354

1.1. Clinical characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
1.2. Histopathology and immunohistochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
2. Genes and chromosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
2.1. Genetics of lower grade meningioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
2.2. Genomic changes associated with malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
3. Small animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
Grant numbers/source of support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
Disclosure/conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358

1. Anaplastic meningioma introduction
1.1. Clinical characteristics
Meningioma is the most common primary intracranial tumor in the
adult population, and is believed to arise from the arachnoidal cap cells
of the leptomeninges (Perry et al., 2007; Wiemels et al., 2010). Many
meningiomas are considered benign and amenable to surgical resection,
however a subset demonstrates aggressive biologic behavior and is
challenging to manage, based on characteristics such as tumor location
and increasing World Health Organization Grade (WHO) (Lowest
E-mail address: pjjc@uw.edu.
grade WHO Grade I; Highest grade WHO Grade III) (McGovern
et al., 2010; Perry et al., 2007; Sun et al., 2015). Anaplastic meningioma
(WHO Grade III) is a malignant tumor with variable reports of median
overall survival, with some series ndings ranging from 1.5 to 3.5 years
(Champeaux et al., 2015; Moliterno et al., 2015; Perry et al., 1999). Ana-
plastic meningiomas can present either as primary tumors or those aris-
ing from malignant transformation of lower grade (WHO Grade I/II)
meningiomas. Treatment of primary and recurrent anaplastic meningio-
ma consists primarily of gross total or near-total surgical resection
combined with various types of external beam radiotherapies (Sun
et al., 2015; Walcott et al., 2013). The age of b60 years and the use
of radiotherapy has been associated with longer overall survival in
anaplastic meningioma (Durand et al., 2009). The utility of various
targeted chemotherapies, such as somatostatin analogues, for

http://dx.doi.org/10.1016/j.yexmp.2015.08.007
0014-4800/ 2015 Elsevier Inc. All rights reserved.
 P.J. Cimino / Experimental and Molecular Pathology 99 (2015) 354359
meningioma management are actively under investigation (Chamberlain,
2012; Kaley et al., 2015; Norden et al., 2015). Poor prognostic indicators of
anaplastic meningioma include subtotal resection (increasing Simpson
Grade), posterior fossa or skull base location, tumors that arise from
lower WHO Grade I/II tumors (compared to De Novo occurrence),
increasing mitotic activity, and loss of chromosomal region 9p21
(region includes the cyclin-dependent kinase inhibitor genes CDKN2A
[encodes p16INK4A and p14 ARF ] and CDKN2B [encodes p15INK4B ])
(Bostrom et al., 2001; Moliterno et al., 2015; Olar et al., 2015;
Perry et al., 2002).
1.2. Histopathology and immunohistochemistry
Meningiomas are currently diagnosed and classied according to
specic histological criteria, as set forth by the WHO in 2007 (Table 1)
(Perry et al., 2007). Diagnostic features of anaplastic meningioma pres-
ent in routine hematoxylin and eosin-stained slides include either cyto-
logic anaplasia (carcinoma-, sarcoma-, or melanoma-like histology) or
an increased mitotic rate of at least 20 mitotic gures per 10 consecutive
high powered microscopic elds (Table 1). Rare cases of anaplastic me-
ningioma are reported to have areas of metaplastic adenocarcinoma-
like histomorphology (Patil et al., 2011). In challenging diagnostic
cases, immunohistochemical staining can help to support a diagnosis
of anaplastic meningioma. Like meningiomas of all grades, there is
patchy positive immunoreactivity for Epithelial Membrane Antigen
(EMA), as well as some immunopositivity for Prostaglandin D Synthase
and limited keratins (AE1/AE3, CK7, CK8, CK14, CK18, CK19) in anaplas-
tic meningioma (Fig. 1) (Liu et al., 2004; Miettinen and Paetau, 2002;
Rajaram et al., 2004; Yamashima et al., 1997). Less specic antigens de-
tected immunohistochemically in meningiomas can include vimentin,
Epidermal Growth Factor Receptor (EGFR), S100, and Sox10 (Jitawi
et al., 1988; Liu et al., 2004; Ng et al., 2015; Wernicke et al., 2010). Com-
pared to lower grade meningiomas, Progesterone Receptor (PR) nuclear
immunoreactivity tends to be lost in anaplastic meningioma, as illus-
trated in the case example in Fig. 1 (Bouillot et al., 1994; Brandis et al.,
1993; Hilbig and Barbosa-Coutinho, 1998; Hsu et al., 1997; Nagashima
et al., 1995; Perry et al., 2000). As opposed to PR, there are other pro-
teins that appear to have increased expression in anaplastic meningio-
ma when compared to lower grade tumors, such as the apoptosis
inhibitor TRAIL-R4, the immune modulator PD-L1 (CD274), DNA Topo-
isomerase II alpha, and Fatty Acid Synthase (Du et al., 2015; Haase et al.,
2010; Koschny et al., 2015; Liu et al., 2004; Roessler et al., 2002). So-
matostatin receptor 2a (SSTR2) is emerging as a highly sensitive and
Table 1
Meningioma classication according to current 2007 World Health Organization (WHO) diagnostic criteria.
WHO grade Diagnostic histomorphological characteristics
I Predominant histologic variant
Meningothelial
Fibrous
Transitional
Psammomatous
Secretory
Microcystic
Angiomatous
Lymphoplasmacyte-rich
Metaplastic
II Any grade I histologic variant Or Atypia by elevated mitoses
with brain invasion (4 to 19 mitoses per 10 high powered elds)
III Frank anaplasia Or Anaplasia by elevated mitoses
(Sarcoma-, carcinoma-, or (20 mitoses per 10 high powered elds)
melanoma-like histology)
355
specic diagnostic marker for meningiomas of all grades, and appears
superior to EMA and PR, especially in cases of anaplastic meningioma
(Menke et al., 2015).
2. Genes and chromosomes
2.1. Genetics of lower grade meningioma
The most common cytogenetic changes in meningioma, regardless
of grade, include alterations of chromosome 22 (monosomy or 22q par-
tial loss), which occur in approximately half of all sporadic cases
(Dumanski et al., 1987; Dumanski et al., 1990; Ruttledge et al., 1994;
Seizinger et al., 1987; Zang, 2001). The well-studied tumor suppressor
gene NF2, resides on chromosome 22q, and is altered itself in about
half of all cases of sporadic meningioma (Harada et al., 1996;
Ruttledge et al., 1994). There are cases where 22q loss is observed in
the absence of NF2 gene mutations, postulating that there is at least
one yet undiscovered gene in this chromosomal region responsible for
meningioma tumorigenesis (Ng et al., 1995). The importance of the
NF2 gene mutations in meningioma is highlighted by the fact that ap-
proximately half of individuals with the tumor predisposition syndrome
Neurobromatosis Type 2 (NF2), resultant from germline mutations in
the NF2 gene, develop meningiomas (Asthagiri et al., 2009; Goutagny
et al., 2012; Sanson et al., 1993). The NF2 gene encodes for a member
of the 4.1 protein superfamily, merlin, that acts as a linker protein to me-
diate interactions between the cell membrane and cytoskeleton
(MacCollin et al., 1993; Trofatter et al., 1993). Two additional 4.1 super-
family members, DAL-1/4.1B and 4.1R, are also altered in a subset of
lower grade meningiomas (Gutmann et al., 2000; Perry et al., 2000;
Robb et al., 2003). The protein Tumor Suppressor in Lung Cancer 1
(TLSC1), which can interact with DAL-1/4.1B, is also altered early in
some meningiomas, and loss of immunoreactivity increases in frequen-
cy with increasing WHO grade (Busam et al., 2011; Surace et al., 2004).
Recent large scale whole genome and exome sequencing efforts of
WHO Grade I and II meningiomas have identied recurrent non-NF2
gene mutations, including Tumor Necrosis Factor Receptor-Associated
Factor 7 (TRAF7), Smoothened (SMO), Kruppel-Like Factor 4 (KLF4), and
v-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT1) (Brastianos
et al., 2013; Clark et al., 2013; Reuss et al., 2013). Mutations in these
four genes in meningioma appear mutually exclusive to NF2 alterations.
The combination of gene mutations in TRAF7 and KLF4 (p.K409Q) seem
to characterize secretory meningioma (WHO Grade I) (Reuss et al.,
2013). While both NF2 and non-NF2 gene mutations are seen in WHO
Or 3 atypical features, including: Or Predominant histologic variant
Hypercellularity Clear cell
Sheet-like growth Chordoid
Macro-nucleoli
Small cell change
Spontaneous necrosis
Or Predominant histologic variant
Rhabdoid
Papillary
356 P.J. Cimino / Experimental and Molecular Pathology 99 (2015) 354359

Fig. 1. Case example of malignant progression to anaplastic meningioma from a benign meningioma. The patient is initially presented with an intracranial benign transitional type
meningioma (up to 1 mitosis per 10 high powered elds). The tumor recurred as an atypical meningioma with increased mitotic activity (up to 15 mitoses per 10 high powered elds)
and several atypical features (necrosis was not evaluable due to prior external beam radiotherapy treatment). Three years following initial presentation and multiple treatments, the tumor
recurred as an anaplastic meningioma with up to 23 mitoses per 10 high powered elds (arrows). Typical for the course of malignant transformation, the recurrent tumors retained patchy
cytoplasmic immunoreactivity for EMA and lost nuclear reactivity of PR. (Abbreviations: WHO World Health Organization, H&E Hematoxylin and Eosin, EMA Epithelial Membrane
Antigen, PR Progesterone Receptor.)

Grade I and Grade II meningiomas, atypical meningiomas (WHO Grade
II) are relatively enriched for NF2 mutations (and Chromosome 22 loss),
suggesting clinical relevance to this genomic divide (Clark et al., 2013;
Reuss et al., 2013). Although there is limited targeted sequencing data
available, TRAF7, SMO, or KLF4, gene mutations have not yet been re-
ported in anaplastic meningioma in the current literature. Larger data
sets will be needed to determine the true mutational frequency of
these genes in anaplastic meningioma. In an initial report, only a single
case of anaplastic meningioma (out of three total cases) demonstrated
an AKT1 (p.E17K) gene mutation (Brastianos et al., 2013). However, a
larger targeted sequencing study of 86 anaplastic meningiomas failed
to detect AKT1 gene mutations in any case (Sahm et al., 2013). In con-
trast to the relative lack of mutations in these four non-NF2 genes, NF2
gene mutations (and 22q loss) are frequently found in anaplastic me-
ningioma, indicating that NF2 may have some role in at least predispos-
ing meningiomas for malignant progression relative to TRAF7, AKT1,
KLF4, and SMO (Al-Mefty et al., 2004; Nunes et al., 2005; Perry et al.,
2001; Rajaram et al., 2004; Reuss et al., 2013). However, a signicant
subset of anaplastic meningiomas lack NF2 gene mutations, and it is
possible that there are yet unidentied genetic drivers that predispose
for, or drive, malignant progression.
2.2. Genomic changes associated with malignancy
Recurrent chromosomal abnormalities accumulate and characterize
meningiomas with increasing WHO grade (Al-Mefty et al., 2004; Perry
and Brat, 2010). As discussed above, chromosome 22 abnormalities
are early and frequent occurrences in WHO Grade I meningiomas,
which themselves tend not to demonstrate additional cytogenetic ab-
normalities. In addition to chromosome 22 abnormalities, recurrent
gains (1q, 9q, 12q, 15q, 17q, and 20q) and losses (1p, 6q, 10, 14q, and
18q) are variably found in WHO Grade II atypical meningiomas (Perry
and Brat, 2010). WHO Grade III anaplastic meningiomas demonstrate
further chromosomal instability with additional chromosomal losses
(1p, 6q, 9p21, 10, 14q, and 18q) and 17q23 amplication (region con-
taining the Ribosomal Protein S6 Kinase Polypeptide 1 [RPS6KB1] gene)
 P.J. Cimino / Experimental and Molecular Pathology 99 (2015) 354359 357

(Perry and Brat, 2010). Of these chromosomal abnormalities, loss of

Kalamarides et al. (2002),

Kalamarides et al. (2008),
Kalamarides et al. (2011)
Kalamarides et al. (2011)
Kalamarides et al. (2011)

Kalamarides et al. (2002)

Kalamarides et al. (2008)
9p21 (region includes genes CDKN2A [encodes p16INK4A and p14ARF]
and CDKN2B [encodes p15INK4B]) occurs in about 70% of anaplastic

Peyre et al. (2013)

Peyre et al. (2013)

Peyre et al. (2013)

meningiomas and is an important poor prognosticator that portends
signicantly reduced overall survival (Bostrom et al., 2001; Perry

Reference
et al., 2002). The mechanism of chromosomal instability in meningi-
oma progression is unclear, however may in part be contributed by
Checkpoint Kinase 2 (CHK2), which is involved in DNA damage re-
sponse pathways (Antoni et al., 2007). The encoding CHEK2 gene is
located on 22q, near NF2, and is alternatively spliced or deleted
(often co-deleted with NF2) in some meningiomas (Yang et al.,

Genetically engineered mouse (GEM) models related to meningioma progression. Abbreviations: Ad-Cre, Adenovirus-Cre leptomeningeal injections at postnatal day 2 (P2); PGDS, Prostaglandin D Synthase.
2012). In vitro studies using human meningioma cell lines conrm

Skull base, cerebral convexities, spine

Skull base, cerebral convexities, spine

Skull base, cerebral convexities, spine
a functional role for CHK2 in centrosome maintenance and chromo-
somal stability (Yang et al., 2012).
In addition to CDKN2A/B, relatively few gene level alterations have

Cerebral convexities, spine

Cerebral convexities, spine

been strongly associated with malignant progression of meningioma,
and include Telomerase Reverse Transcriptase (TERT) and N-myc
Downstream-Regulated Gene family member 2 (NDRG2). Telomerase ex-

Tumor location
pression and activity predicts poor clinical behavior, and increases in
atypical and anaplastic meningiomas (DeMasters et al., 1997; Langford

Skull base
Skull base
Skull base
et al., 1997; Simon et al., 2000). The mechanism of increased telomerase
expression is associated with activating mutations in the promoter of
the TERT gene (Goutagny et al., 2014). Activating TERT promoter muta-
tions are detected in increasing frequency in high grade meningiomas
and low grade meningiomas that subsequently undergo malignant pro-
gression (Goutagny et al., 2014). Integrative genomics, coupled with
immunohistochemical studies, identied NDRG2 as a tumor suppressor

14% Grade II, and 11% Grade III)

50% (composed of 75% Grade I,

72% (composed of 66% Grade I,

31% Grade II, and 3% Grade III)
that is frequently downregulated in anaplastic meningioma (Lusis et al.,
2005). NDRG2 is also found on chromosome 14q, which is recurrently
lost in anaplastic meningioma. Downregulation of NDRG2 is strongly as-
sociated with hypermethylation of the NDRG2 gene promoter, which is
present in approximately 70% of anaplastic meningioma. Hypermethy- Tumor frequency
lation of gene promoters other than NDRG2 occur frequently in atypical

1348%
and anaplastic meningioma, indicating that this mechanism of gene reg-
38%
43%
50%

12%
37%
ulation may play an important role in meningioma progression (Liu
et al., 2005; Murnyak et al., 2015). An additional gene with potential
contribution to malignant progression is the non-coding RNA (ncRNA)
gene, Maternally Expressed Gene 3 (MEG3), which is found on chromo-
somal region 14q32 that is recurrently deleted in anaplastic meningio-
Grade I: Meningothelial, brous, and transitional

Grade I: Meningothelial, brous, and transitional

Grade I: Meningothelial, brous, and transitional

Grade I: Meningothelial, brous, and transitional

ma (Zhang et al., 2010). A pilot study identied several meningiomas
Grade I: Meningothelial, not otherwise specied

to have decreased MEG3 expression (associated with promoter hyper-

Grade II: Brain invasion or increased mitoses

Grade II: Brain invasion or increased mitoses

methylation), as well as MEG3 allelic loss to occur frequently in higher
grade meningiomas (Zhang et al., 2010). Overall, the complexity of ge-
Grade I: Meningothelial and brous

Grade I: Meningothelial and brous

nomic alterations (cytogenetic, genetic, and epigenetic) already demon-

Grade III: Sarcoma-like histology

Grade III: Sarcoma-like histology

strated during the malignant progression of meningioma, dictates the
need for integrative genomic techniques to identify and characterize ad-
ditional pathogenic genes.

3. Small animal models

Grade I: Fibrous
Histology/grade

Initial mouse models of all grades of meningioma largely relied on

xenografts (orthotopic and heterotopic) of human meningioma-
derived cells into immunocompromised mice. The malignant human
meningioma cell lines IOMM-Lee and CH-157MN have most often
been used (recently reviewed in Kalamarides et al. (2010)). These trans-
plantation models do have some desirable features for studying menin-
giomas including recapitulating human histopathology, the ability to
Ad-Cre; Nf2ox2/ox2; Ink4ab+/

Ad-Cre; Nf2ox2/ox2; Ink4ab/

PGDS-Cre; Nf2ox2/; Tp53ox/
PGDS-Cre; Nf2ox2/; Ink4a/

Ad-Cre; Nf2ox2/ox2; Ink4a/

label cells and image them with bioluminescence, and demonstrating

Ad-Cre; Nf2ox2/ox2; Tp53+/

reproducible take rate and growth characteristics (Ragel et al.,

2008). However, there are challenges to interpreting xenograft nd-
ox2/

Ad-Cre; Nf2ox2/ox2

ings due to conditions that do not reect human tumors, including

altered tumor microenvironment in immunocompromised host mice,
PGDS-Cre; Nf2

tumor cells undergoing undetermined genetic and cellular selection relat-

ed to in vitro cell culture prior to transplantation, and tumors growing in
Table 2

GEM

abnormal inltrative growth patterns. To overcome these obstacles, re-

cent focus has turned to genetically engineered mouse (GEM) models of
358 P.J. Cimino / Experimental and Molecular Pathology 99 (2015) 354359
meningioma, which offer the advantages of in vivo spatial and temporal
control of gene manipulation.
GEM models of meningioma based on Cre-loxP-mediated inacti-
vation the Nf2 gene have been successfully employed and have pro-
vided some insight into the biology of initiation and progression of
meningioma (models summarized in Table 2). Conditional inactiva-
tion of the Nf2 gene (Nf2ox2/ox2 mice), either with Cre recombinase
under control of the endogenous Prostaglandin D Synthase (PGDS)
promoter or delivered exogenously via postnatal adenoviral injec-
tion into the leptomeninges, is sufcient to initiate and maintain
low grade (WHO Grade I) meningioma with variable penetrance
(Kalamarides et al., 2002; Kalamarides et al., 2011; Kalamarides
et al., 2008). Consistent with the observation that TP53 gene muta-
tions are exceedingly rare in human meningioma, the addition of
Tp53 hemizygosity to Nf2 inactivation in mice does not increase
frequency of tumor formation or lead to malignant progression
of meningioma (Joachim et al., 2001; Kalamarides et al., 2002;
Kalamarides et al., 2011). Concomitant Ink4a/p16Ink4a nullizygosity
in adenovirus injected mice signicantly increases the frequency of
meningioma formation, however it does not lead malignant pro-
gression (Kalamarides et al., 2008). However, loss of one or both
copies of the entire Cdkn2ab/Ink4ab gene locus (encoding the three
related genes p16Ink4a, p15Ink4b, and p19ARF) does lead to malignant
progression in a small subset of meningiomas as demonstrated by
the formation of Grade II and III meningiomas (Peyre et al., 2013).
Additionally, homozygous loss of the Cdkn2ab/Ink4ab gene further
increases the frequency of tumor formation (Peyre et al., 2013).
With a majority (66 to 75%) of the meningiomas in these mice oc-
curring as benign (Grade I) tumors, it appears that the loss of the
Cdkn2ab/Ink4ab gene added to bi-allelic Nf2 loss, is insufcient to
promote malignant progression in most tumors.
When cultured, Grade I and II tumor-derived cells from Nf2ox2/ox2;
Ink4ab/; and Ad-Cre mice demonstrate various mouse chromosomal
abnormalities, including gains (15, 15q, 19q), losses (4q, 7, 12, 14q),
and structural rearrangements (16 and 19) (Peyre et al., 2013). This
chromosomal instability mimics genetic abnormalities seen in increas-
ing grades of human meningioma. Orthotopic transplantation of these
Ad-Cre; Nf2ox2/ox2; and Ink4ab/ meningioma cells into the subdural
space of wild-type mice produces tumors of all grades, including a subset
that progresses to Grade III tumors (Peyre et al., 2013). While
the mechanisms of genomic instability and progression are not
completely understood, these mouse models underscore the impor-
tance of the synergistic effects of Nf2 and Cdkn2ab/Ink4ab, in combi-
nation with chromosomal instability, to induce malignant progression to
anaplastic meningioma. Furthermore, due to their genetic similarity
to human meningioma, these small animal models are promising as pre-
clinical platforms to test emerging therapeutic strategies in malignant
meningioma.
4. Conclusions
Given the associated high morbidity and mortality rates, there is a
therapeutic imperative for anaplastic meningioma. Chromosomal insta-
bility with recurrent cytogenetic alterations is often associated with ma-
lignant progression of meningioma. While some genes are known to
associate with anaplastic meningioma, there is still an incomplete un-
derstanding of the mechanism of progression. A multipronged approach
combining genomic strategies with experimental models will likely lead
to further candidate genes of interest. Small animal models of meningi-
oma progression will allow a preclinical platform to study these genes,
as well as rapidly test possible targeted therapies aimed at halting
malignant progression. Furthermore, a better understanding of the
genes involved in malignant progression may lead to better patient
risk stratication and help guide clinical decisions in the era of pre-
cision medicine.
Grant numbers/source of support
This work was supported with departmental funds provided by the
University of Washington Department of Pathology.
Disclosure/conict of interest
The author declares that there are no conicts of interest.
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