Full text of DOI:10.1038/modpathol.3880230

Malignant Peripheral Nerve Sheath Tumors with t(X;
18). A Pathologic and Molecular Genetic Study
Maureen J. O’Sullivan, Michael Kyriakos, Xiaopei Zhu, Mark R. Wick,1 Paul E. Swanson, Louis P. Dehner,
Paul A. Humphrey, John D. Pfeifer
L.V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center,
St. Louis, Missouri.
KEY WORDS: Chromosomal translocation; malig-
nant peripheral nerve sheath tumor; specificity; sy-
novial sarcoma; t(X;18).
Spindle cell sarcomas often present the surgical pa-
thologist with a considerable diagnostic challenge.
Malignant peripheral nerve sheath tumor, leiomy-
osarcoma, fibrosarcoma, and monophasic synovial
sarcoma may all appear similar histologically. The
application of ancillary diagnostic modalities, such
as immunohistochemistry and electron micros-
copy, may be helpful in the differentiation of these
tumors, but in cases in which these adjunctive tech-
niques fail to demonstrate any more definitive evi-
dence of differentiation, tumor categorization may
remain difficult. Cytogenetic and molecular genetic
characterization of tumors have provided the basis
for the application of molecular assays as the new-
est components of the diagnostic armamentarium.
Because the chromosomal translocation t(X;18) has
been observed repeatedly in many synovial sarco-
mas, it has been heralded as a diagnostic hallmark
of synovial sarcoma. To formally test the specificity
of this translocation for the diagnosis of synovial
sarcoma, RNA extracted from formalin-fixed,
paraffin-embedded tissue from a variety of soft tis-
sue and spindle cell tumors was evaluated for the
presence of t(X;18) by reverse transcriptase-
polymerase chain reaction. Although 85% of the
synovial sarcomas studied demonstrated t(X;18),
75% of the malignant peripheral nerve sheath tu-
mors in our cohort also demonstrated this translo-
cation. We conclude that the translocation t(X;18) is
not specific to synovial sarcoma and discuss the
implications of the demonstration of t(X;18) in a
majority of malignant peripheral nerve sheath tu-
mors.
Mod Pathol 2000;13(11):1253–1263
Spindle cell sarcomas include a wide variety of tu-
mors, some of which, such as synovial sarcoma (SS)
and malignant peripheral nerve sheath tumor
(MPNST), may have overlapping histologic fea-
tures. Because SS has classically been recognized as
a neoplasm arising in the juxta-articular peripheral
soft tissue in adolescents or young adults (1–6), and
MPNST has been associated with peripheral nerves,
especially in persons with neurofibromatosis (NF-
1), clinical features have often been used as a
means to discriminate between the two tumors.
However, clinical features have become less diag-
nostically valuable with the documentation of SS
inpatients of a wider age range and in a greater
diversity of anatomic sites (7–14). Notably, putative
examples of both mono- and biphasic SS have been
described within, and in association with, major
nerves (15–19).
The immunophenotypic overlap between
MPNST and SS has further confounded their differ-
ential diagnosis. Although SS is classically consid-
ered to express the epithelial markers cytokeratin
(CK) and epithelial membrane antigen (EMA),
whereas MPNSTs classically express the neural
markers S-100 protein and CD57, a significant per-
centage of cases show immunophenotypic overlap
such that a subgroup of MPNSTs express EMA and
CK and a proportion of SSs express S-100 and CD57
(20–27). Similarly, even though electron micros-
copy may be helpful in differentiating SS from
MPNST, all too frequently the malignant spindle
cell population lacks any distinguishing fine struc-
tural features.
Copyright © 2000 by The United States and Canadian Academy of
Pathology, Inc.
VOL. 13, NO. 11, P. 1253, 2000 Printed in the U.S.A.
Date of acceptance: June 27, 2000.
With the identification of the nonrandom chro-
mosomal translocation t(X;18)(p11.2;q11.2) in a
majority of SSs, it appeared that this translocation
could serve as a highly specific discriminator be-
tween SS and other soft tissue sarcomas. However,
1Present address: Division of Surgical Pathology, University of Virginia
Medical Center, Box 214, Charlottesville, VA 22908.
Address reprint requests to: John D. Pfeifer, L.V. Ackerman Laboratory of
Surgical Pathology, Campus Box 8118; 660 S. Euclid Ave., St. Louis, MO
63110; phone: 314-747-0276; fax: 314-362-8950; E-mail: pfeifer@
path.wustl.edu.
1253

past experience has repeatedly demonstrated dim-
inution of specificity with experience in the case of
any number of ‘specific’ markers. This study was
therefore initiated to determine the diagnostic
specificity of t(X;18) by studying a wide variety of
benign and malignant spindle cell tumors.
tumors (Table 1). All primary antibodies were incu-
bated overnight with the tissue sections in moisture
chambers at 4°C. Slides were then developed using
a
modified avidin-biotin peroxidase complex
method as described previously (28) on an auto-
matic stainer. Heat-induced epitope retrieval was
carried out for CD57, chromogranin A, CK-AE1/
AE3, CK-CAM5.2, CK-MAK6, CK19, desmin, EMA
and O13 studies. All heat-induced epitope retrieval
was completed in a 900W microwave oven at 70%
power; citrate heat-induced epitope retrieval was
microwaved for 7 min. CK7 cases were treated with
pepsin, warmed to 38°C with 0.04 g of pepsin in 10
mL H2O/1N HCl solution for 15 min. Sections
stained for collagen IV were treated with pronase,
warmed to 38°C with 0.001 g of pronase/1 mL of PB
pH 7.6 solution for 10 min.
Cases were categorized as having a immuno-
staining profile of classic SS, classic MPNST, or
equivocal/other as follows: EMA, CK, and vimentin
reactivity, in the absence of staining for CD57,
S-100, and collagen IV was considered indicative of
SS. Reactivity for S-100, CD57, and collagen IV in
the absence of staining for CK and EMA was con-
sidered supportive of MPNST. Cases with an immu-
nohistochemical profile that overlapped both pat-
terns were classified as equivocal.
MATERIALS AND METHODS
All cases studied were retrieved from the files of
the Lauren V. Ackerman Laboratory of Surgical Pa-
thology, Washington University Medical Center, St.
Louis, MO. In addition to hematoxylin-and-eosin–
stained sections, each case had at least one paraffin
block of tumor from which immunohistochemical
and molecular genetic studies could be performed.
Electron microscopy was carried out on a selected
subset of the tumors as defined below.
Histologic sections from all cases were reviewed
independently by the authors in conjunction with a
brief history. The final study group consisted of 141
specimens, including 40 SS specimens from 34 pa-
tients, 27 MPNST specimens from 20 patients, 16
leiomyomas, 11 leiomyosarcomas, 10 malignant fi-
brous histiocytomas (MFH), seven congenital in-
fantile fibrosarcomas (CIF), seven hemangiopericy-
tomas, six spindle cell thymomas, four solitary
fibrous tumors, four fibrosarcomas (FS), three epi-
thelioid sarcomas (ES), three neurofibromas (NF)
and one case each of benign Triton tumor, low-
grade spindle cell sarcoma, and pleomorphic rhab-
domyosarcoma.
Electron Microscopic Analysis
Electron microscopy was performed on 13 cases
of MPNST, for eight of which fresh tissue fixed in
3% glutaraldehyde in cacodylate buffer, postfixed in
osmium tetroxide, and embedded in epoxy resin,
was used. For the five additional cases, archival
tissue was dissected from the paraffin block, depar-
affinized in xylene, rehydrated, fixed in glutaralde-
hyde, and postfixed in osmium tetroxide before
embedding in epoxy resin. Seven SSs were also
examined, all processed from fresh tissue.
Immunohistochemistry
Immunoperoxidase studies were carried out us-
ing antibodies to cytokeratins (CK7, CK19, and a
pan-CK cocktail of AE1/AE3, CAM5.2, and MAK6),
EMA, desmin, smooth muscle actin, CD57 (Leu-7),
S-100 protein, collagen IV and CD99 (O13) applied
to 3- to 5-␮m formalin-fixed, paraffin-embedded
tissue sections on poly-L-lysine coated slides. Anti-
body to chromogranin A was applied to all biphasic
In all cases, thick sections stained with toluidine
blue were used to select areas for further study.
Ultrathin sections, stained with uranyl acetate and
TABLE 1. Immunoperoxidase Stains
Antibody
Species & Isotype
Dilution
Pre-Treatment
Manufacturer
CD57
Mouse IgM
Mouse IgG
Mouse IgG
Mouse IgG
Mouse IgG
Mouse IgG
Mouse IgG
Mouse IgG
Mouse IgG
Mouse IgG
Mouse IgG
Rabbit IgG
Mouse IgG
1:20
Citrate hier
None
Citrate hier
Citrate hier
Citrate hier
Pepsin
Citrate hier
Pronase
Citrate hier
Citrate hier
Citrate hier
None
Becton-Dickinson, San Jose, CA
Boehringer-Mannheim, Indianapolis, IN
Boehringer-Mannheim
Becton-Dickinson
Zymed, South San Francisco, CA
Dako, Carpinteria, CA
Dako
Dako
Dako
Dako
Signet, Dedham, MA
Dako
Chromogranin
CK-AE1/AE3
CK-CAM 5.2
CK-MAK6
CK7
1:20,000
1:150
1:150
1:50
1:3,200
1:100
1:50
1:400
1:3,000
1:200
1:3,000
1:20
CK19
Collagen IV
Desmin
EMA
O13
S-100
SMA
None
Biogenex, San Ramon, CA
Hier, heat-induced antigen retrieval.
1254 Modern Pathology

lead citrate, were examined using a Philips CM10
electron microscope. The finding of smooth cell
membranes containing maculae-adherences or
desmosomes, but without extensive cell processes,
were considered characteristic of SS, whereas com-
plex interdigitating cellular processes invested in a
basal lamina were considered characteristic of
MPNST (25, 29–32).
verse transcription, and PCR amplification as out-
lined for the initial evaluation.
DNA Sequencing
Cases sequenced included a subset of SSs and all
other cases in which reverse transcriptase-
polymerase chain reaction (RT-PCR) for t(X;18) pro-
duced a dominant band of the expected size by
ethidium bromide staining. Briefly, the PCR prod-
uct was cloned into vector pCR2.1 using the TA
cloning kit (Invitrogen, Carlsbad, CA) and then se-
quenced using the Taq dideoxy terminator cycle
sequencing kit (Applied Biosystems Inc., Foster
City, CA) and a fluorescent DNA sequencer (Model
373A; Applied Biosystems Inc.). DNA sequence
analysis was facilitated by BLAST sequence similar-
ity searches using the National Center for Biotech-
nology Information database (http://www.ncbi.
nlm.nih.gov/BLAST/).
Molecular Genetic Techniques
RNA Extraction
For all cases, RNA was extracted from formalin-
fixed, paraffin-embedded tissue. Four 10-␮m sec-
tions of tumor were deparaffinized using xylene
and ethanol washes, and digested overnight in
buffer (Tris pH 7.5, 20 mM EDTA, 1% sodium dode-
cyl sulfate) containing 25 mg proteinase K. Total
RNA was then extracted by a modified guanidine
isothiocyanate method using Trizol (Gibco/BRL,
Gaithersburg, MD) as described (33) and treated
with DNAse I before reverse transcription.
Southern Blot Hybridization
For selected cases, the PCR products were trans-
ferred to a nylon membrane and hybridized with a
32P-radiolabeled oligonucleotide probe specific for
the SYT-SSX fusion junction (Table 2) as described
(33).
Reverse Transcriptase-PCR
RNA samples were reverse-transcribed using
Mulv reverse transcriptase and the Gene Amp RNA-
PCR kit (Perkin-Elmer, Foster, CA). PCR reactions
were carried out using published (33) primers (Ta-
ble 2) and ampliTaq DNA polymerase, and con-
sisted of a 5-min 94°C hotstart, followed by 35 cy-
cles of annealing at 60°C for 1 min., extension at
72°C for 30 sec., and melting at 94°C for 40 sec. The
PCR products were visualized by ethidium bromide
staining after separation by 2% agarose gel electro-
phoresis. For each experiment, a cytogenetically
confirmed case of biphasic synovial sarcoma (pos-
itive control) and a reagent-only water blank (neg-
ative control) were assayed along with the tumor
specimens. As a control for intact RNA, PCR for the
house-keeping gene ␤2-microglobulin (Table 2)
was also performed on the cDNA from each case
(34). All PCR results (positive and negative) were
confirmed by up to four repeat PCR analyses; for
each repeat analysis, new RNA was prepared from
four additional sections of tumor, followed by re-
RESULTS
Immunohistochemistry
Among the synovial sarcomas studied, 65%
showed reactivity for pan-CK, 48% for CK7, and
36% for CK19. EMA was reactive in 94% of the cases,
CD99 (O13) in 85%, CD57 in 72%, and S-100 in 22%
(Table 3).
Among the peripheral nerve sheath tumors (PN-
STs) evaluated, which included 20 MPNSTs and
three neurofibromas, only 1% showed reactivity for
pan-cytokeratin, 18% for CK7, and none for CK19.
[These results are very much in line with recent
observations (35) that staining with keratin sub-
types can be of value in the differentiation of MPN-
STs from SSs.] Reactivity for the classic ‘neural’
markers CD57 and S-100 protein was observed in
55% and 62% of cases respectively, whereas 64%
stained for collagen IV. Eighty-six percent of MPN-
STs stained for CD99.
TABLE 2. Primers and Probe
Primer
Sequence
Designation
Three of the 11 biphasic synovial sarcomas (27%)
showed epithelial cell reactivity for chromogranin
A, while no reactivity was noted in any of the seven
MPNSTs evaluated, contrary to the findings re-
ported by others (36).
␤2-microglobulin
forward
␤2-microglobulin
reverse
5Ј-ACCCCCACTGAAAAAGATGA-3Ј
5Ј-ATCTTCAAACCTCCATGATG-3Ј
SSA forward
SSX reverse
SYT-SSX probe
5Ј-AGACCAACACAGCCTGGACCAC-3Ј
5Ј-TCCTCTGCTGGCTTCTTG-3Јa
5Ј-GAATATGACCAGATCATCATGCCCAAG-3Ј
Molecular Analysis
Twenty-nine of 34 cases of SS (85%) contained
the translocation t(X;18), which is consistent with
␤2 Microglobulin product size, 120 base pairs; SSA-SSX product size,
87 base pairs.
a Erratum in original paper (33).
t(X;18) in Malignant Peripheral Nerve Sheath Tumor (M. O’Sullivan et al.)
1255

TABLE 3. Immunoperoxidase Results
Pan-CK
CK7
CK19
EMA
Desmin
SMA
CD57
S-100
Coll IV
CD99
SS
PNST
MPNST
22/34
2/17
0/5
16/33
4/17
0/5
12/33
0/17
0/5
31/33
3/17
2/5
6/31
7/17
2/5
3/30
1/17
2/5
23/32
11/17
1/5
7/32
8/16
5/5
15/34
11/17
3/5
28/33
14/17
5/5
Data expressed as number of positive cases over total cases studied.
PNST, peripheral nerve sheath tumors with t(X;18) including 15 MPNSTs and two neurofibromas; MPNST, malignant peripheral nerve sheath tumors
without t(X;18).
published results (37) (Table 4). Eleven of the cases
were biphasic, and the remaining 23 were
monophasic spindle cell tumors. In four cases, tis-
sue from metachronous biopsy or excision proce-
dures was available, and in all four, analysis of the
additional material yielded concordant results.
Fifteen of 20 MPNSTs (75%) also had the trans-
location t(X;18) (Figure 1). The MPNSTs included in
the study could be divided into three groups: a
group of malignant Triton tumors; a group of tu-
mors either arising inpatients with documented
NF-1 and/or in direct association with a peripheral
nerve; and a group of tumors arising inpatients
FIGURE 1. Reverse transcriptase-polymerase chain reaction (RT-PCR)
demonstration of t(X;18) in malignant peripheral nerve sheath tumors
(MPNSTs) and fibrosarcoma (FS) as well as synovial sarcoma (SS). Lane
1, PCR molecular mass markers; lane 2, negative control water blank;
lane 3, positive control SS, cytogenetically proven to have t(X;18); lane
4, biphasic SS; lane 5, case 12 (rectovaginal septal MPNST in 60-year-
old woman without neurofibromatosis (NF-1); see Figure 4); lane 6,
case 6 (left proximal thigh MPNST in 16-year-old girl with NF-1); lane
7, case 4 (paraspinal MPNST in 13-year-old girl with NF-1); lane 8, case
15 (MTT of sciatic nerve in 44-year-old man without NF-1); lane 9, case
1 (MTT of anterior abdominal wall in 24-year-old woman with NF-1—
see Figure 2); lane 10, case 22 (upper arm FS in 50-year-old woman).
without NF-1 and unassociated with peripheral
nerve but having combined histological, immuno-
Case numbers refer to Table 5.
histochemical and fine structural features of
MPNST. Additional tissue was available from
follow-up surgical procedures in five cases, all from
the site of the primary tumor. For four of these
cases, analysis of the additional tissue yielded re-
sults concordant with those obtained from the orig-
inal tumor tissue; three consistently harbored t(X;
18), whereas one consistently lacked it. For one
case shown to have t(X;18) in the original tissue,
only two of three subsequent tumor excision spec-
imens contained the t(X;18).
The presence of a correctly-sized or absence of
an RT-PCR product as visualized by ethidium bro-
mide staining correlated with the presence (or ab-
sence) of a single band by Southern blot hybridiza-
tion (Figure 2 and data not shown) using a probe
FIGURE 2. Southern blot hybridization of the reverse transcriptase-
polymerase chain reaction (RT-PCR) product from selected cases using
a probe specific for the SYT-SSX fusion junction of t(X;18). Lane 2 is the
positive control synovial sarcoma (SS) cytogenetically proven to harbor
t(X;18). Lanes 3 through 5 showed no evidence of the appropriately-
TABLE 4. Results of t(X;18) Analysis by Tumor Type
sized PCR product by ethidium bromide staining, whereas lanes 6
(n ؍ 128)
through 10 (lane 7, case 2; lane 8, case 15; lane 9, case 16; and lane 10,
case 24) all showed the appropriately-sized PCR product by routine
ethidium bromide staining. Case numbers refer to Table 5.
Number of Number with
cases
t(X;18)
Synovial sarcoma
34
20
4
10
7
16
11
7
6
4
3
3
29 (85%)
15 (75%)
1 (25%)
1 (10%)
1 (14%)
0
0
0
Malignant peripheral nerve sheath tumor
Fibrosarcoma (adult)
Malignant fibrous histiocytoma
Fibrosarcoma (congenital-infantile)
Leiomyoma
specific for the SYT-SSX fusion junction (Table 2).
Furthermore, DNA sequence analysis of a subset of
SSs, as well as all other cases in which RT-PCR for
t(X;18) produced a dominant band of the expected
size, showed that the PCR product had 100% ho-
mology with the corresponding region of fusion
between SYT and SSX in t(X;18) (Figure 3 and data
not shown).
Leiomyosarcoma
Hemangiopericytoma
Spindle cell thymoma
Solitary fibrous tumor
Epithelioid sarcoma
Neurofibroma
0
0
0
2a (67%)
0
Others
3
The 15 MPNST cases (Table 5) bearing the trans-
location t(X;18) included three malignant Triton tu-
a The two positive neurofibromas were a cellular neurofibroma and an
atypical neurofibroma; see text for details.
1256
Modern Pathology

with coexpression of CD99 in the CIF. Clinical
follow-up was not available for the patients with the
MFH or FS that contained t(X;18); however, the CIF
harboring t(X;18), which admittedly arose in an un-
usual location on the scalp, behaved as expected
with partial regression after initial biopsy, and total
regression after partial resection.
Electron Microscopy
Electron microscopic (EM) examination demon-
strated definitive nerve sheath features in six of the
cases of MPNST investigated, all of which had RT-
PCR and sequence-based proof of t(X;18). In each of
these, fresh tissue was used for EM evaluation. A
further seven cases of MPNST had indeterminate
fine structural features on EM examination, mainly
because poor preservation (for five of these latter
cases, tissue was retrieved from paraffin blocks);
five of these seven cases had t(X;18) proven by
RT-PCR and sequence analysis. Of the seven cases
of SS evaluated by EM, six had fine structural fea-
tures of SS and one was indeterminate; t(X;18) was
demonstrated in six of these cases, including the
case with indeterminate ultrastructural findings.
Table 5 is a summary of the clinical details, im-
munohistochemical, electron microscopic, and
molecular findings for all MPNSTs, and for the cel-
lular and atypical neurofibromas, MFH, FS, and CIF
harboring t(X;18).
FIGURE 3. Representative DNA sequence of the reverse
transcriptase-polymerase chain reaction (RT-PCR) product from a
malignant peripheral nerve sheath tumor (MPNST) (case 2 of Table 5).
Lower region, chromatogram produced by the automated fluorescent
DNA sequencer; upper region, DNA sequence showing 100% homology
to the sequence of the fusion junction between SYT and SSX (indicated
by the vertical line) in t(X;18).
mors, one of which (case 1) arose in the anterior
abdominal wall of a patient with neurofibromatosis
(Figure 4), and two that arose in the soft tissue
around the hip and within the sciatic nerve, respec-
tively, inpatients without NF-1 (cases 14 and 15).
One MPNST (case 2) arose in a preexisting neuro-
fibroma of the brachial plexus in an NF-1 patient
(Figure 5), and four others (cases 3 to 6) arose
inpatients with NF-1. In cases 1, 3, and 4, material
available from sequential biopsies was also evalu-
ated and in each case the additional tumor samples
also harbored t(X;18). In case 1, fresh tissue consti-
tuted one of the additional specimens tested.
Seven cases (cases 7 to 13) were MPNSTs from
patients without a history of NF-1, where the diag-
nosis was based upon the combined histomorphol-
ogy, immunophenotype and fine structural analy-
sis. In case 12, an MPNST arising in the rectovaginal
septum of a 60-year-old woman, there were defin-
itive electron microscopic features of nerve sheath
differentiation (Figure 6). In addition to the MPN-
STs, one atypical neurofibroma and one cellular
neurofibroma (cases 16 and 17) also had the trans-
location t(X;18) (Figures 7 and 8). Neither patient
had clinical features of NF-1.
DISCUSSION
Cytogenetic studies identified the characteristic
translocation t(X;18)(p11.2;q11.2) that is present in
approximately 90% of SSs, of both mono- and bi-
phasic types (38–45). These studies led, in parallel,
to the view that t(X;18) is specific for synovial sar-
coma, a view has been supported by the few mo-
lecular studies evaluating other spindle cell tumors
for the translocation (37, 46–49). Nonetheless, Bal-
azs et al. (47) and Hiraga et al. (37) did, in fact,
demonstrate t(X;18) in MPNSTs, and van de Rijn et
al. (49) detected t(X;18) in a case with features of
both SS and MPNST, but these investigators subse-
quently rediagnosed the positive cases as SSs. We
hypothesized that this apparent bias of reclassifica-
tion of tumors as SS based upon observation of
t(X;18) has simultaneously been driven by, and per-
petuated, the belief that t(X;18) is specific for SS.
Our study was designed to investigate whether
spindle cell neoplasms other than SS can contain
t(X;18) and was designed to focus primarily but not
exclusively on MPNST, because SS and MPNST
have such well recognized histological, ultrastruc-
tural, and immunophenotypic similarities.
Apart from SSs and MPNSTs, one of four fibro-
sarcomas, one of seven CIFs, and one of 10 MFHs
were also shown to bear the translocation t(X;18).
The diagnoses in these cases were based on mor-
phology, and an immunophenotype showing
vimentin-only positivity for the FS and the MFH,
Our cases were evaluated and classified on the ba-
sis of standard morphologic and immunohistochem-
t(X;18) in Malignant Peripheral Nerve Sheath Tumor (M. O’Sullivan et al.)
1257

TABLE 5. Clinicopathologic and Molecular Correlations
Case
Age/Sex
Site
NF-1
Histology
Immunopositivity
CD99, Desmin
Neural
Neural
Equivocal
Neural
Neural
Neural
Neural
Neural
Neural
Neural
EM
t(X;18)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
24 F
33 M
17 F
13 F
17 M
16 F
81 M
34 M
52 M
48 F
49 M
60 F
Abdominal wall
Brachial plexus
Gluteal region
Paraspinal
Retroperitoneum
Thigh
Y
Y
Y
Y
Y
MTT
Indeterminate
Not done
Indeterminate
Not done
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
N
N
N
N
Y
Y
Y
MPNST
MPNST
MPNST
MPNST
MPNST
MPNST
MPNST
MPNST
MPNST
MPNST
MPNST
MPNST
MTT
Not done
Y
Indeterminatea
Indeterminate
Indeterminatea
Not done
Thigh
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
Chest wall
Chest wall
Buttock
Nerve sheatha
Nerve sheatha
Nerve sheatha
Nerve sheatha
Nerve sheatha
NS W/ Diverg Diffa
Not done
Not done
Not done
Indeterminate
Indeterminate
Not done
Forearm
Rectovaginal
Dorsal root S1
Hip
Sciatic nerve
Mediastinum
Scalp
Equivocal
Neural
CD57, SMA, Desmin
CD57, CD99, DES, CK, EMA
Neural
54 F
83 M
44 M
28 M
10 M
9 M
83 F
3 M
42 F
58 F
MTT
NF, atypical
NF, cellular
MPNST
MTT
Neural
Neural
Foot
Paranasal sinuses
Forearm
CD99, CD57, S-100, Desmin
CD99, S-100, Desmin
Neural
MTT
Axilla
MPNST
MPNST
FS
CIF
MFH
Paranasal sinuses
Arm
N
N
N
N
Neural
Not done
Not done
Not done
Not done
50 F
3/12 M
74 M
Focal CD57
Vimentin only
Vimentin only
Scalp
Hip
a Fresh tissue used for EM evaluation.
NF-1, neurofibromatosis-1; Y, yes; N, no; NF, neurofibroma; MTT, malignant triton tumor; MPNST, malignant peripheral nerve sheath tumor;
Translocation t(X;18): Y, present by RT-PCR and confirmed by sequence; N, absent. Neural, immunophenotype consistent with nerve sheath origin (S-100,
CD57, COL IV reactivity present). Nerve sheath, fine structural features of nerve sheath (see Materials and Methods). NS W/ Diverg Diff, nerve sheath with
divergent differentiation (i.e., MTT). FS, fibrosarcoma; CIF, congenital infantile fibrosarcoma; MFH, malignant fibrous histiocytoma.
questions pertaining to our methodology require
consideration. One relates to technical aspects of
our analysis, and the other to the diagnostic deter-
minants employed, particularly for the diagnosis of
MPNST versus SS, as this was the non-SS tumor
type most consistently associated with the t(X;18).
It is unlikely that technical factors account for the
findings in this study. First, we used PCR primers
that have been used by others in previously pub-
lished studies of formalin-fixed, paraffin-embedded
tissue. Southern blot hybridization using a probe
specific for the SYT-SSX fusion junction of t(X;18)
showed binding to the appropriately sized RT-PCR
product (Figure 2), and the identity of the PCR
FIGURE 4. Case 1: malignant triton tumor. A, spindle cell sarcoma
product was further confirmed by DNA sequence
with interspersed rhabdomyoblasts (hematoxylin and eosin). B,
analysis (Figure 3). Second, to minimize the likeli-
rhabdomyoblasts are highlighted by a desmin immunostain.
hood of cross-contamination, our protocol em-
ployed a single round of PCR rather than a set of
nested PCRs. Third, the water-only negative con-
trols included in each PCR reaction did not detect
any evidence of contamination. Fourth, all non-SS
cases were subjected to repeat analysis beginning
with extraction of RNA from freshly cut sections
from the tissue blocks. All non-SSs demonstrating
t(X;18)(p11.2;q11.2) were reanalyzed at least twice,
always with the same result; all non-SSs with an
initially negative result were also reanalyzed, again
with confirmation of the original result in all cases.
Similarly, analysis of a subset of SSs, whether pos-
itive or negative, was repeated and confirmed the
original result. As delineated in the Results, addi-
ical methods without knowledge of the RT-PCR re-
sults. Each tumor was thoroughly characterized
histologically, ultrastructurally (when available), and
immunohistochemically. In accordance with other
studies, we found that 85% of the SSs had the t(X;
18)(p11.2;q11.2) translocation. However, 75% of the
MPNSTs also harbored the same translocation. In
addition, one of four fibrosarcomas, one of seven
congenital-infantile fibrosarcomas, and one of 10
MFHs also contained the translocation, as did two
neurofibromas.
Given that the exclusivity of t(X;18) to SS is chal-
lenged by the results of this study, two fundamental
1258
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FIGURE 5. Case 2: Malignant peripheral nerve sheath tumor (MPNST) arising in a preexisting neurofibroma of the brachial plexus. A, low-power
view shows normal nerve, neurofibroma, and MPNST components (hematoxylin and eosin). B, high-power view of MPNST shows cellular, mitotically
active spindle cell sarcoma; C, junction of neurofibroma with MPNST. D, focal cytoplasmic CD57 immunoreactivity; E, diffuse membrane-associated
collagen IV immunoreactivity.
FIGURE 6. Case 12: Rectovaginal malignant peripheral nerve sheath tumor (MPNST). A, spindle cell sarcoma with nuclear palisading (hematoxylin
and eosin). B, diffuse membrane-associated collagen IV immunoreactivity. C, electron micrograph shows complex interdigitating membrane
processes.
tional tissue samples obtained from subsequent
surgical procedures yielded concordant findings by
RT-PCR testing. Fifth, the detection of t(X;18) in
tumors other than SS was clustered primarily in
cases of MPNST, rather than randomly in the other
tumor types, as might be expected if technical er-
t(X;18) in Malignant Peripheral Nerve Sheath Tumor (M. O’Sullivan et al.)
1259

of t(X;18) alone to serve as the superseding criterion
for a diagnosis of SS in these two cases would not
only have resulted in an incorrect diagnosis but also
would have erroneously categorized these two be-
nign lesions as malignant.
Only a limited number of prior studies have iden-
tified t(X;18) in tumors other than SS by molecular
methods similar to those we used (37, 47). However,
in these studies, the authors chose to explain their
results by reclassifying MPNSTs harboring t(X;18)
as SSs (37, 47, 49). For example, in the series re-
ported in abstract form by Balazs (47), four of nine
MPNSTs evaluated bore t(X;18), two of which ex-
tensively involved nerves and two of which ex-
pressed S-100 protein; however, a later publication
(49) indicates that all four tumors were most likely
synovial sarcomas involving nerve (although the
reasons for this reclassification are not discussed).
Other groups have reported a virtually perfect
correlation between the presence of t(X;18) and the
diagnosis of SS (26, 33, 46, 48). However, in two of
these studies (26, 33) examining the specificity of
t(X;18) for SS, the authors state that cases with
ambiguous morphologic, immunophenotypic,
and/or ultrastructural features were classified as SS,
apparently based solely on the demonstration of
t(X;18) by molecular genetic testing. Hiraga et al.
(37) reported demonstration of t(X;18) in three un-
classified sarcomas and one of 11 MPNSTs, but
because the latter tumor was not associated with a
large nerve and was composed of fascicles of “mo-
notonous symmetrical spindled cells” that were
nonreactive for S-100 protein, it was reclassified as
SS. None of 12 MPNSTs studied by van de Rijn et al.
(49) contained t(X;18), although one additional le-
sion that had light and electron microscopic fea-
tures of MPNST and showed immunoreactivity for
S-100 protein as well as EMA was re-classified as SS
on the basis of the presumed specificity of the SYT-
SSX fusion product it contained.
In many studies, therefore, demonstration of t(X;
18) has been the criterion standard for diagnosis;
morphologic diagnostic criteria were superseded by
a molecular finding interpreted with a bias that
t(X;18) is specific for SS. Nonetheless, as a recent
case report illustrates (51), other authors remain
less certain of the diagnostic significance of t(X;18)
in cases that have some histological features of
MPNST. Our results also challenge the concept that
t(X;18) is a specific tumor marker and suggest that
classification of a neoplasm as SS based solely on
the result of molecular genetic testing is inappro-
priate. In this context, it is noteworthy that none of
the prior studies specifically included MTTs or
cases of MPNST arising inpatients who have NF-1.
With increasing application of molecular genet-
ics, exceptions to the common perception that a
particular cytogenetic or molecular event is entirely
FIGURE 7. Case 16: A, atypical neurofibroma shows nuclear
pleomorphism (hematoxylin and eosin). B, S-100 immunostain shows
nuclear reactivity.
rors were responsible for the results. Although in-
dividual cases of fibrosarcoma, congenital-infantile
fibrosarcoma, and MFH harbored the translocation,
t(X;18) was not found in more than 40 additional
cases of benign and malignant spindle cell lesions.
Similarly, the results of this study can not be
explained by diagnostic inaccuracies; diagnoses
were based on well-established morphologic, im-
munohistochemical, and EM criteria, and were
carefully scrutinized, because SS, especially the
monophasic variant, and MPNST have such sub-
stantial morphologic and immunophenotypic over-
lap. As shown in Table 5, 15 patients had t(X;18)
translocation-positive malignant tumors of nerve.
Six MPNSTs occurred in persons with neurofibro-
matosis, including an MPNST (case 2) that arose
within a neurofibroma of the brachial plexus. In
addition to their origin in the clinicopathologic set-
ting of NF-1, each of these six neoplasms had his-
tologic and immunophenotypic features consistent
with MPNST. Three other translocation-positive tu-
mors were malignant Triton tumors; one arose in a
patient with NF-1 (case 1), one arose within the
sciatic nerve (case 15), and two had EM features of
nerve sheath differentiation (cases 14 and 15).
Our series also included MPNSTs occurring as
sporadic, nonsyndromic neoplasms. Seven of these
tumors (cases 7 to 13) were malignant spindle cell
neoplasms with histologic features consistent with
nerve sheath differentiation. Apart from case 13
(which arose in the S1 dorsal root), these tumors
did not arise in association with a nerve. However,
all seven showed immunohistochemical and/or ul-
trastructural evidence of nerve sheath differentia-
tion in accordance with the criteria for MPNST
outlined by Woodruff (50).
Two other tumors (cases 16 and 17) are also note-
worthy. Both were solitary neurofibromas which
harbored t(X;18), and each arose in a patient with-
out clinical evidence of NF-1. Allowing the presence
1260
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FIGURE 8. Case 17: A, cellular neurofibroma (hematoxylin and eosin). B, S-100 immunostain shows nuclear reactivity. C, diffuse membrane-
associated collagen IV immunoreactivity.
tumor specific have already emerged. For example,
an intraabdominal desmoplastic small round-cell
tumor (DSRCT), two classic neuroblastomas, and
two examples of mixed embryonal and alveolar
rhabdomyosarcoma (ARMS) have all been shown to
harbor translocations typical of Ewing sarcoma-
primitive neuroectodermal tumor (EWS-PNET)
rather than the translocations characteristically as-
sociated with DSRCT and alveolar rhabdomyosar-
coma (52–54). These cases are emblematic of the
dilemma presented by the results of our study.
Should we simply ignore the morphologic and im-
munophenotypic features of MPNST in the cases of
the present study with t(X;18) and consider these
tumors SSs? Similarly, should a DSRCT with an
EWS-ERG fusion transcript be considered an EWS-
PNET, or a mixed embryonal-alveolar rhabdomyo-
sarcoma be diagnosed as EWS-PNET with aberrant
rhabdomyoblastic differentiation?
The translocation (X;18) has apparently escaped
detection in most, but not all (51), of the limited
number of MPNST karyotypes reported to date,
which have shown an inconsistent and remarkably
complex array of cytogenetic abnormalities (55–59).
Discrepancies between the results of standard cy-
togenetic analysis and RT-PCR have, however, been
demonstrated for t(X;18). Sorensen and Triche re-
ported a case of SS in which RT-PCR and fluores-
cent in situ hybridization detected t(X;18) that was
not identified by cytogenetics (60). A so-called
masked translocation was found in another case of
SS (61) in which a second reverse translocation
obscured the t(X;18) on karyotypic analysis, yet an-
other example of RT-PCR or fluorescent in situ hy-
bridization as more sensitive methods for detecting
a translocation than standard metaphase cytoge-
netics. In more general terms, the period of in vitro
cell culture preceding cytogenetic analysis may fa-
vor tumor cell clones harboring specific chromo-
somal abnormalities, resulting in a karyotype that
reflects an in vitro growth advantage rather than a
genetic abnormality representative of the major
clone in vivo. We cannot easily explain why molec-
ular studies have not identified t(X;18) in more
cases of MPNST to date, but our results are not
unique (37, 47, 51).
Although t(X;18) has been demonstrated in the
spindled as well as the epithelial components of SS
(62), it is possible that, in the setting of MPNST, the
translocation is an epiphenomenon that merely re-
flects chromosomal instability and is therefore un-
related to the genetic events responsible for malig-
nant transformation. As noted previously, the
reported karyotypes of MPNST are quite complex
and the presence of t(X;18) may simply represent
one of multiple accumulated genetic abnormalities.
If t(X;18) is directly involved in the genesis of
MPNST and SS, then a genetic linkage may well
exist between these two entities, offering an expla-
nation for the recognized morphologic similarities
between them. Recent reports of t(X;18) in a case of
“biphasic synovial sarcoma with morphological
features of neural differentiation” [in which the cul-
tured tumor cells had a striking neural immuno-
phenotype (63)] and t(X;18) in a case which by
ultrastructural analysis had features of both syno-
vial sarcoma and nerve sheath differentiation (49),
are particularly interesting in light of such a hy-
pothesis.
t(X;18) in Malignant Peripheral Nerve Sheath Tumor (M. O’Sullivan et al.)
1261

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Three further cases in this study, one each of FS,
MFH, and CIF, harbored t(X;18). Given the light
microscopic and immunohistochemical character-
istics of these tumors, we believe that all three cases
were correctly diagnosed. Cytogenetic studies have,
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and one FS (64). It is possible to argue that these
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