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2191
Subdiaphragmatic and Intrathoracic Paraspinal
Malignant Peripheral Nerve Sheath Tumors
A Clinicopathologic Study of 25 Patients and 26 Tumors
Helen P. Kourea, M.D.1
Mark H. Bilsky, M.D.2
Denis H. Y. Leung, Ph.D.3
Jonathan J. Lewis, M.D., Ph.D.2
James M. Woodruff, M.D.1
1
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
2
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
3
Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
Presented in part at the annual meeting of the U.S.
and Canadian Academy of Pathology, Washington,
DC, March 1996.
Supported by Grant No. CA#47179 from the National Institutes of Health.
The authors thank the following colleagues for
providing material and information on individual
cases: Dr. Manuel Banez, Dover, DE; Dr. Monica
Gallivan, Washington, DC; Dr. Thomas Gouge, New
York, NY; Dr. Sigurd Gundersen, La Crosse, WI; Dr.
Syed Hoda, New York, NY; Dr. Karen van Hoeven,
Philadelphia, PA; Dr. Ralph Hruban, Baltimore, MD;
Dr. Anantha Manepalli, St. Louis, MO; Dr. Jonathan
Melamed, New York, NY; Dr. Arthur Miller, New
York, NY; Dr. Thomas Rengel, Wausau, WI; Dr.
Susan Wester, La Crosse, WI; and Dr. John C.
Whitsell II, New York, NY.
Address for reprints: James M. Woodruff, M.D.,
Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York,
NY 10021.
Received October 28, 1997; accepted November
28, 1997.
© 1998 American Cancer Society
BACKGROUND. To determine the effects of anatomic site on the presentation and
diagnosis of malignant peripheral nerve sheath tumors (MPNSTs) and on the
treatment and outcomes of the patients, the authors initiated a study of these
tumors at different sites. An earlier report described MPNSTs of the buttock and
lower extremity, and the current series analyzes those presenting at intrathoracic
(IT) and subdiaphragmatic (SD) paraspinal sites.
METHODS. The authors reviewed data on patients with paraspinal MPNSTs who
were seen at Memorial Hospital during the period 1960 –1995 and for whom
histologic slides were available. Various clinicopathologic parameters and their
effects on patient outcomes were examined.
RESULTS. Twenty-five patients with 26 tumors were evaluated. Seven tumors were
IT and 19 were SD; 60% of the patients had neurofibromatosis type 1 (NF1). Most
patients presented with pain, and a diagnostic delay (of 3 months to 2 years) was
often noted. Mean tumor sizes for SD and IT tumors were 14.3 cm and 6.6 cm,
respectively. Most MPNSTs were composed of spindle cells in fascicles. Twentyseven percent exhibited divergent differentiation. Twenty-four tumors were high
grade, and a low grade component was identified in 8 tumors. Surgical resection
was attempted for 23 tumors (88%), but complete resection was achieved in only
6 cases (23%). Eighty percent of the patients died of their tumors, 2-year and 5-year
survival rates were 35% and 16%, and median survival was 8.5 months. Significant
prognostic factors were tumor size ,5 cm, the presence of a low grade component,
and complete tumor resection.
CONCLUSIONS. Paraspinal MPNSTs have more aggressive behavior than peripherally located tumors, mainly because of the difficulty encountered in resecting them
completely. Prognoses of patients with MPNST at this site appear to be affected by
resection status, tumor size, and tumor grade. Cancer 1998;82:2191–203.
© 1998 American Cancer Society.
KEYWORDS: malignant peripheral nerve sheath tumor, malignant schwannoma,
paraspinal tumor, neurofibromatosis, peripheral nervous system, pathology, treatment, surgery, prognosis.
M
alignant peripheral nerve sheath tumors (MPNSTs) are neoplasms arising from or recapitulating the innate cellular constituents of the peripheral nerve sheath, excluding tumors of the
epineurium or peripheral nerve vasculature.1 Although most examples are assumed to develop from Schwann cells,2 some may show
evidence of fibroblastic or perineurial cell differentiation;3 therefore,
the noncommittal term MPNST is preferred over malignant schwannoma.
MPNSTs, which occur infrequently, are usually high grade and
2192
CANCER June 1, 1998 / Volume 82 / Number 11
clinically aggressive. A number of different possible
prognostic factors have been cited, such as the presence of neurofibromatosis type 1 (NF1),4 –7 tumor
size,6 –10 mitotic activity,8 –9 necrosis,7 completeness of
resection,6,10,11 and postirradiation occurrence;12
however, the importance that has been attributed to
each has varied among different studies. For this reason, prognostic parameters for these tumors are not
well established.
Tumor location, which is known to be important
to the presentation, diagnosis, treatment, and prognosis of other malignant soft tissue tumors,13 has not
been studied in detail for MPNSTs. We therefore undertook a review of these tumors by anatomic site to
assess the role of tumor location. In the initial report
in this series, we analyzed tumors of the buttock and
lower extremity (BLE).9 The current study examines
clinicopathologic parameters of paraspinal MPNSTs
in subdiaphragmatic (SD) and intrathoracic (IT) locations and compares the outcomes of patients with
MPNSTs at different locations.
MATERIALS AND METHODS
The files of the Department of Pathology at the Memorial Sloan-Kettering Cancer Center (MSKCC) from
the period 1960 –1995 and the personal files of one of
the authors (J.M.W.) were reviewed, with the aim of
identifying neoplasms at paraspinal locations in the
thoracic cavity, retroperitoneum, and pelvis that were
diagnosed as MPNST, malignant schwannoma, neurogenic sarcoma, or neurofibrosarcoma. Tumors arising in the thoracic and abdominal walls or intra-abdominal organs were excluded. Only tumors for which
histologic slides were available were included in the
study.
Criteria for diagnosis were the same as those used
in the first study in this series.9 The diagnosis of
MPNST was made for tumors having the typical morphology,8,9 with supporting immunohistochemical (S100 protein expression)14,15 or ultrastructural evidence
of nerve sheath differentiation.16 Furthermore, this
diagnosis was rendered for malignant tumors clearly
arising in a peripheral nerve, schwannoma, or neurofibroma, and also for those arising in patients with
NF1 and morphology consistent with MPNST,8,9 even
if supportive immunohistochemical or ultrastructural
data were lacking.6,8,17 Not included were tumors of
epineurial soft tissue and endothelial tumors arising
from peripheral nerve vasculature.
All available medical records at MSKCC and other
institutions for the patients in this study were reviewed, and further follow-up information was obtained by contacting the referring physician when
necessary. A clear-cut statement that the patient had
NF1 was accepted as evidence of the disorder. The
clinical parameters examined were age; gender; history of NF1; type and duration of symptoms; past
medical and surgical history, including history of radiation therapy; tumor location (subdiaphragmatic
[SD] vs. intrathoracic [IT]); spinal tumor extension;
treatment modalities; recurrence; metastasis; and outcome.
All pathology reports and microscopic slides available were reexamined by two of the authors (H.P.K.
and J.M.W.). For patients who underwent more than 1
operation, 4 – 47 (average, 21) slides of tumor from all
surgical specimens, including those from reexcisions
or recurrences, were reviewed. Excluding the biopsies,
tumor samplings of each major resection specimen
provided 0.3– 4 (average, 1.8) hematoxylin and eosin–
stained slides per cm of tumor. In 6 of 7 consultation
cases, slides from all paraffin blocks were available;
the sampling provided 1–2 slides per cm of tumor. In
one consultation case, only sample slides were submitted.
Immunohistochemical studies were performed
according to published methods,18 when indicated, to
confirm nerve sheath origin and to exclude other tumors, such as leiomyosarcomas and synovial sarcomas. The antibodies used were against S-100 protein
(polyclonal, DAKO, Carpinteria, CA, dilution 1:10000),
desmin (monoclonal, DAKO, dilution 1:50), smooth
muscle antibody (SMA) (monoclonal, DAKO, dilution
1:2000), HHF-35 (monoclonal, DAKO, dilution 1:100),
and CAM5.2 (monoclonal, Becton Dickinson Labs, dilution 1:200).
Histopathologic parameters surveyed were tumor
size, histologic grade, mitotic rate, necrosis, and the
presence of divergent differentiation. Two histologic
grades, low and high, were recognized. Low grade
MPNSTs are more cellular than neurofibromas with
nuclear enlargement to three times the size of neurofibroma nuclei and nuclear hyperchromasia.1 Mitotic
figures are often present but rarely number more than
3 per 10 high-power fields (HPF), and their presence is
not necessary for the diagnosis of malignancy because
small biopsies may be devoid of mitotic activity. High
grade MPNSTs are characterized by nuclear enlargement, hyperchromasia, and usually marked cellular
crowding. Commonly mitoses exceed 4 per 10 HPF.
Necrosis is often present but is not necessary to diagnose a high grade MPNST. Tumors containing both
low and high grade areas are traditionally classified as
high grade, regardless of the amount of the latter
component. In this study, to evaluate the effect of
tumor grade on outcome, the presence of even a minor low grade component was recorded, and these
Paraspinal Malignant Peripheral Nerve Sheath Tumors/Kourea et al.
tumors were compared with entirely high grade MPNSTs by statistical analysis.
Determination of the surgical procedure performed was based on patients’ clinical records, including operative notes and histologic evaluation of the
surgical margins. Complete resection refers to cases
that had both gross and microscopically negative margins. Subtotal resection was defined as such by the
surgeon and confirmed by pathologic examination.
Grossly complete resection indicated cases that were
regarded by the surgeon as completely resected; of
these cases, some had microscopically positive margins, whereas others were indeed complete resections.
Open biopsy specimens were the only specimens
available in unresectable cases.
Statistical analysis to evaluate the effect of clinical
and pathologic parameters on survival was performed.
Parameters analyzed were age, gender, history of NF1,
diagnostic delay, tumor location (SD vs. IT), tumor
size, grade, mitotic rate, necrosis, divergent differentiation, postirradiation occurrence, and type of surgical treatment. Fisher’s exact test was used to study the
associations among categoric factors and to analyze
their influence on survival status. Age and mitotic
index were evaluated using the Wilcoxon–Mann–
Whitney test. Analysis of survival time was performed
by the log rank test and the Kaplan–Meier method.
Because of the relatively small number of cases in this
study, multivariate analysis was not performed. Statistical significance was set at P , 0.05.
RESULTS
Twenty-six tumors from 25 patients satisfied the criteria for inclusion in the study. Seven cases originated
from the consultation files of J.M.W. Fifteen patients
underwent surgery at MSKCC and 7 at other institutions. Tumors in the remaining three patients were
only biopsied. Individual patient data and a summary
of clinicopathologic findings are presented in Tables 1
and 2.
2193
sarcoma’’ of the lumbar spine (Case 12), Hodgkin’s
disease (Case 24), and breast carcinoma (Case 23).
Detailed data regarding the clinical presentation
were available for 20 patients. Pain, noted in 16 cases,
was the most common presenting symptom. SD tumors often produced pain localized in the back or
radiating to the leg, whereas patients with IT tumors
most often presented with localized chest pain. Weakness, paresis, or paresthesia were reported in five
cases. Less frequently occurring symptoms were anorexia, weight loss, fatigue, nausea and vomiting, dysphagia, shortness of breath, and leg edema during the
last trimester of pregnancy. In one case the tumor was
discovered incidentally during the workup for
menometrorrhagia (Case 15), and in another during
follow-up for an ovarian mucinous cystadenocarcinoma (Case 22); the latter patient had NF1 and two
MPNSTs.
Delay in making the diagnosis, ranging from 3
months to 2 years after symptomatology started, was
noted in 11 (55%) of the 20 cases with detailed clinical
history. The delay occurred more often with SD tumors (9 of 14 SD vs. 2 of 6 IT) and in the setting of NF1
(8 of 15 NF1 vs. 3 of 10 non-NF1). Notably, 7 of the 11
MPNSTs were associated with neurofibroma. During
these intervals the patients were thought to suffer
from orthopedic problems (arthritis or back strain) or
cardiovascular disorders.
Other neoplasms noted in the patients’ clinical
history, in addition to those that prompted earlier
radiation therapy, were multiple melanomas associated with familial melanoma syndrome (Case 10),
ovarian mucinous cystadenoma (Case 11), ovarian
mucinous cystadenocarcinoma (Case 22), osteoma of
the mandible (Case 2), ‘‘neurilemoma’’ of the chest
(Case 10), multiple cutaneous basal cell carcinomas
(Case 19), and a thyroid adenoma. All but the last
patient had NF1, a finding in keeping with the observation of other nonneural tumors occurring in patients with this disorder.19 –20
Clinical Features
Sixty percent of the 25 patients had NF1. The overall
mean age at presentation was 31.6 years, with NF1
patients presenting at younger ages (mean age, 26.4
years); the mean age did not significantly differ with
tumor location (SD vs. IT). Both genders were equally
affected overall (M:F 5 1.1:1), but a slight female predominance was noted among patients with NF1 (M:
F 5 0.7:1) and a male predominance among those
with non-NF1 (M:F 5 2.3:1). Five non-NF1 patients
with prior radiation therapy (20%) developed MPNSTs
after an interval of 7–10 years; the original tumors
were seminoma (Cases 17 and 18), ‘‘reticulum cell
Tumor Location
Nineteen (73%) of the 26 tumors were SD (Table 1)
involving the retroperitoneum, psoas muscle, and/or
pelvis, and 7 (27%) were IT. Tumor involvement of a
spinal nerve root or lumbosacral plexus was noted in
12 cases. The tumor encroached on the spinal column
in 10 cases in the form of vertebral body involvement
(Cases 15, 20, 22, and 24), tumor extension along the
nerve root up to the vertebral foramen (Cases 6 and
11), epidural encroachment with or without spinal
cord compression (Cases 1 and 18), and epidural and
intradural disease (Cases 2 and 10).
NF1
Age/
gender
17/F
32/F
33/F
38/M
24/M
29/F
33/M
31/F
1
1
1
1
1
1
1
1
4 (1982)
5 (1986)
6 (1989)
7 (1990)
8 (1990)
9 (1994)
10 (1994)
11 (1995)
27/M
68/M
2
2
2
18 (1994)a
26/M
39/M
1
2
2
2
22 (1992)c
a
24 (1978)a
25 (1986)
53/F
(R)sup. MED,
paratracheal
(L) MED
(L)MED
RTP
(L) T1
MED
(L) post. MED
(R)MED, UT
Sacral
(R)RTP
(R)psoas
(R)RTP
RTP
(R)RTP
RTP, MES
(R)RTP
(L)RTP
(R)RTP
(R)RTP
(L) iliac fossa
(L)RTP
RTP
(L) presacral
(R)RTP, psoas
(L)RTP, lumbosacral
(L) pelvis, psoas
Location
2
T9
T9
1
T1
2
T5–T8
2
S2,sacral plexus, ganglia
2
Ileo-inguinal, ileo-hypogastric
L5, ganglion
2
2
2
L3,L4,L5
2
L3,L4,L5
2
Sacral plexus, sciatic
L2,L3,L4 ganglion
1
Sciatic
L1, ganglion
2
L3,L4, sacral plexus
Nerve
2
2
1
1
2
2
1
1
2
1
2
2
1
1
2
2
1
1
2
1
1
1
2
1
1
2
NFMA
.10
.5
4.5
4.5
2.0
5.0
10.5
9
2.5
18
5.2
.10
25
24
14
.16
16
6.5
40
9.0
17.8
4
.10
11.0
.25
14.5
Tumor
size (cm)
Focal
2
2
2
N/E
Prominent
Prominent
N/E
Prominent
Prominent
2
Prominent
Prominent
Prominent
Prominent
Prominent
N/E
2
N/E
Prominent
Prominent
Focal ,5%
Prominent
Prominent
Prominent
Prominent
Necrosis
50
30
3
9
16
23
17
7
46
3
15
18
39
23
19
N/E
20
59
30
49
2
27
12
16
6
MF/
10HPF
High
High
High 1 low
Low
High
High 1 low
High 1 low
High
High
High
High 1 low
High
High
High 1 low
High
High
High
High
High
High
High
Low
High
High 1 low
High
High
Grade
b
STR
STR
CRb
CRb
STR
STR
STR
Bx.
1
1
2
2
2
2
2
2
2
2
2
CRb
STR
CRb
2
STR
1
2
STR
1
1
2
1
STRb
STR
2
1
b
STR
Bx
STR
Bx
CR
2
b
STRb
1
1
1
2
2
b
Chemo
Rx
CRb
STR
STR
STR
STR
Surg
Rx
1
2
2
2
2
2
1
1
2
2
2
1
1
2
1
1
2
1
2
2
2
2
1
1
2
1
Rad
Rx
2
2
1
(6)
1
(13)
1
(2)
1
(UNK)
2
N/A
N/A
1
(3)
1
(6)
1
(UNK)
1
(UNK)
1
(9)
1
(3)
2
1
(12)
1
(9)
1
(2)
N/A
2
1
(2)
2
1
(0.5)
2
2
Recur
(mos to)
1
(3)
1
(UNK)
1
(21)
2
2
1
(7)
1
(15)
2
2
1
(27)
1
(14)
1
(0.5)
1
(5)
1
(1)
2
1
(0)
1
(10)
1
(0)
1
(26)
1
(0)
2
2
1
(23)
2
2
(5)
Mets
(mos to)
DOD (7)
DOD (27)
DOD (7)
NED (35)
DOD (27)
DOD (11)
DOD (3)
AWD (14)
NED (61)
DOD (40)
DOD (4)
DOD (14)
DOD (26)
DOD (7)
DOD (10)
DOD (4)
DOD (22)
DOD (10)
DOD (6)
DOD (2)
NED (153)
DOD (5)
NED (221)
DOD (23)
DOD (5)
Outcome
(mos)
AWD: alive with disease (at the end of the study); Bx: biopsy only; Chemo Rx: chemotherapy; CR: complete resection; DOD: dead of disease; HPF: high power fields (340); (L): left; MED: mediastinum; MES: mesentery; Mets.: metastasis; MF: mitotic figures; Mos: months; MPNST: malignant peripheral nerve
sheath tumor; N/E: not evaluable; N/A: not applicable; NED: no evidence of disease; NF1: type 1 neurofibromatosis; NFMA: neurofibroma; Post.: posterior; Rad Rx: radiation therapy; Recur: recurrence; (R): right; RTP: retroperitoneum; Surg Rx: surgical treatment; STR: subtotal resection (positive gross or
microscopic margins); Sup: superior; UNK: unknown; UT: upper thorax.
a
The patient had a postirradiation tumor.
b
Gross complete resection.
c
Patient had 2 MPNSTs that were clinically identified simultaneously. The intrathoracic tumor was resected first.
23 (1970)
41/M
1
19/F
17/M
1
21 (1992)
20/M
20 (1982)
Intrathoracic MPNSTs
19 (1976)
1
23/M
47/M
2
2
16 (1990)
17 (1991)a
40/M
33/F
37/F
2
2
14 (1986)
15 (1989)
12 (1972)
13 (1984)
a
25/F
26/F
1
1
2 (1977)
3 (1982)
Subdiaphragmatic MPNSTs
1 (1970)
1
11/F
Case no.
TABLE 1
Data on 25 Patients with Paraspinal MPNST
2194
CANCER June 1, 1998 / Volume 82 / Number 11
Paraspinal Malignant Peripheral Nerve Sheath Tumors/Kourea et al.
2195
TABLE 2
Clinicopathologic Features of Paraspinal MPNSTs
No. of patients
No. of tumors
Age (yrs)
Mean
Range
Gender
Female
Male
Postirradiation tumors
Associated nerve
Associated neurofibroma
Tumor size .5 cm
Mean size
Divergent differentiation
Median length of FU
(mos)
Range of FU (mos)
Recurrence
Range (mos)
Metastasis
Range (mos)
Median (mos)
DOD
2-year survival
5-year survival
10-year survival
NF1
No NF1
Overall
15
16
10
10
25
26
26.4
11–41
39.3
23–68
31.6
11–68
9 (60%)
6 (40%)
0
11 (69%)
11 (69%)
13 (81%)
12.7 cm
2 (12%)
3 (30%)
7 (70%)
5 (50%)
5 (50%)
3 (30%)
8 (80%)
11.5 cm
5 (50%)
12
13
5 (20%)
16 (62%)
14 (54%)
21 (81%)
12.3 cm
7 (27%)
10
2–221
6 (46%)
0.5–6
10 (67%)
0–23
5
12 (80%)
27%
20%
20%
14
4–61
9 (90%)
2–13
7 (70%)
0–27
15
8 (80%)
50%
12%
12%
11
2–221
15 (65%)
0.5–13
17 (68%)
0–27
7
20 (80%)
35%
16%
16%
FIGURE 1. The cut surface of an ovoid, 18 3 12 3 7 cm subdiaphragmatic
malignant peripheral nerve sheath tumor reveals a fleshy, bulging, tan, focally
gelatinous, hemorrhagic, and partly necrotic tumor surrounded by a thin
pseudocapsule (Case 16).
DOD: dead of disease; FU: follow-up; NF1: neurofibromatosis type I.
Biopsy Evaluation
Sixteen patients underwent open biopsy, and a diagnosis of sarcoma or MPNST was rendered in 13 cases,
atypical neurofibroma in 2, and schwannoma in 1.
Three patients had unresectable tumors and received
no additional surgical treatment.
FIGURE 2.
A low grade malignant peripheral nerve sheath tumor, arising
focally in a subdiaphragmatic plexiform neurofibroma, is shown. Findings
include hypercellularity, fascicular arrangement of cells, nuclear enlargement,
and crisp hyperchromasia. A mitotic figure is present (Case 4).
Macroscopic Pathologic Findings
Tumors measured 2– 40 cm in greatest dimension
(mean size, 12.3 cm). SD tumors were usually larger
than IT, with mean sizes of 14.3 and 6.6 cm, respectively. NF1 status did not impact on tumor size (Table
2). Most tumors were well circumscribed, ovoid
masses, often with a bosselated surface. A pseudocapsule was mentioned in only 4 cases, whereas a few
tumors were partly encased by a thin, translucent
membrane that likely represented serosa reflected
over the tumor. Some tumors were removed piecemeal or during more than one surgical procedure. Cut
surfaces were tan-white, gray, yellow-gray, or brownish, at times gelatinous or glistening, with areas of
hemorrhage (Fig. 1). Necrosis, noted grossly in 12 tumors, was mostly focal but in a few cases was exten-
sive. Rare tumors were partly cystic. Tumor consistency varied from firm and rubbery to fleshy.
Histologic Features
Twenty-two tumors (85%) involved a nerve and/or
originated from a neurofibroma (Tables 1 and 2).
Twenty-four tumors were high grade MPNSTs, six with
a low grade component, whereas the remaining two
tumors were exclusively low grade MPNSTs and arose
within a plexiform neurofibroma. The first entirely low
grade tumor (Case 4) consisted mostly of plexiform
neurofibroma that completely encompassed two microscopic malignant foci showing hypercellularity,
fascicular arrangement of the tumor cells, nuclear en-
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CANCER June 1, 1998 / Volume 82 / Number 11
FIGURE 3. The most common histologic pattern in malignant peripheral
nerve sheath tumors is crowded, hyperchromatic, mitotically active spindle
cells arranged in short and long fascicles (Case 24). Note the difference
between the cellularity of this high grade tumor and that of the low grade tumor
shown in Figure 2.
FIGURE 4. A distinctive histologic pattern in malignant peripheral nerve
sheath tumors, sometimes referred to as a ‘‘tapestry’’ pattern, is created by
alternating loosely and densely cellular tumor areas (Case 8).
FIGURE 6. A spindle cell tumor of T-1 nerve root has the features of a
malignant peripheral nerve sheath tumor with rhabdomyosarcomatous differentiation (malignant triton tumor) (Case 23).
FIGURE 5.
Cells in most malignant peripheral nerve sheath tumors are
spindled, with elongated hyperchromatic nuclei, a moderate amount of faintly
eosinophilic cytoplasm, and indistinct cell membranes.
largement, and hyperchromasia (Fig. 2). The malignant component of the second entirely low grade
MPNST involved slightly less than half of the preexisting neurofibroma. The low grade component noted in
six of the high grade tumors consisted of cells with
enlarged, hyperchromatic nuclei embedded in a moderately fibrotic background, which therefore did not
reach the cellularity of the high grade component. In
one of these tumors most of the malignant component
was low grade (Case 2), whereas in another it represented approximately 40% of the examined tumor
(Case 22) and in the remaining cases low grade areas
represented 5–10% of the examined tumor.
The histologic appearance of the MPNSTs was
similar to previous descriptions.8,9 The most frequent
pattern resembled fibrosarcoma (Fig. 3). A second distinctive pattern, noted in 11 tumors, consisted of alternating hypocellular and hypercellular tumor fascicles (Fig. 4). Storiform and diffuse growths were less
frequent. Tumor cells were spindled with usually hyperchromatic, curved, and tapered nuclei and, less
frequently, elongated, blunt-ended nuclei with vesicular chromatin (Fig. 5). Nuclear pleomorphism was
uncommon. Mitotic activity exceeded 4 mitoses per 10
HPF in 21 of 24 tumors. Necrosis, often geographic,
was present in most cases. Vessels were thin-walled
and sinusoidal but on occasion thick-walled and hyalinized. Divergent differentiation,21–22 in the forms of 3
MPNSTs with rhabdomyosarcomatous differentiation
(malignant triton tumors)23–27 (Fig. 6) and 4 glandular
MPNSTs,28 –32 was more frequent among non-NF1
Paraspinal Malignant Peripheral Nerve Sheath Tumors/Kourea et al.
2197
FIGURE 7.
In this glandular malignant peripheral nerve sheath tumor, the
glandular epithelium is histologically malignant (Case 25).
FIGURE 8. A
cases (Tables 1 and 2). In one case, the glandular
epithelium was histologically malignant (Fig. 7), an
unusual finding.
Immunohistochemical studies showed reactivity
for S-100 protein in 10 of 13 tumors (4 of 6 NF1 and 6
of 7 non-NF1 cases) as scattered cells in a predominantly negative tumor. Focal, weak positivity for
HHF-35 was noted in 3 of 12 tumors and for SMA in 1
of 7. S-100 protein reactivity was essential in establishing the diagnosis of MPNST in two cases. Rare cells in
one of nine MPNSTs were reactive for desmin. None of
the malignant triton tumors were evaluated immunohistochemically. Keratins were positive only in the
epithelial elements of three glandular MPNSTs (tumors that were described in detail previously)32 and
negative in another two cases.
received only radiation therapy. The chemotherapeutic regimens varied in terms of both the agents and the
dosages used, but they included doxorubicin in seven
cases. Radiation was delivered by external beam or
iodine-125 implants, in dosages varying from 2000 to
5940 centigray. In 3 cases, both the radiation dosage
and the chemotherapy regimen were unknown. Due
to the wide variation in the additional treatment modalities, these were not evaluated by statistical analysis.
Therapy
The primary mode of treatment was surgical resection
for 23 tumors (88%) (Table 1). Complete resection was
achieved for 6 tumors from 5 patients. Seventeen tumors were subtotally resected; among these, 5 were
considered gross complete resections but had microscopic involvement of surgical margins. In the remaining tumors, stated reasons for subtotal resection were
1) involvement of the lumbar plexus or spine (in 7
cases), 2) vascular encasement (in 1 case), and 3)
presence of metastatic disease (in 3 cases).
Three patients (12%) with unresectable tumors
underwent open biopsy only; 2 received palliative chemotherapy or radiation therapy, and the third died
soon after diagnosis before administration of any
treatment.
Additional therapy was given to 14 patients: 3
patients received only chemotherapy, 7 patients had
chemotherapy and radiation therapy, and 4 patients
rhabdomyosarcomatous component of the tumor in Figure 6
(Case 23) encases dorsal nerve roots and invades cord parenchyma.
Outcome
Follow-up information was available for all patients
(Tables 1 and 2). The mean and median length of
follow-up were 30 and 11 months, respectively. Local
recurrence was experienced by 65% of patients within
a median interval of 5 months. Tumors recurred in
46% of NF1 patients, 90% of non-NF1 patients, 65% of
patients with tumors at SD sites, and 67% with tumors
at IT sites.
Metastasis occurred in 68% of the cases overall,
after a median interval of 7 months; 63% of SD tumors
and 71% of IT tumors metastasized. Lungs, brain/
spinal cord/meninges, and abdomen/peritoneum
were involved in 4 cases each; liver in 3 cases; pleura,
bone, and adrenals in 2 cases each; and bladder, chest
wall, soft tissue, spleen, and lymph nodes in 1 case
each. Extensive subarachnoid spread and spinal parenchymal involvement by embryonal rhabdomyosarcoma was found at autopsy in a patient with a malignant triton tumor (Fig. 8). Central nervous system
metastases occurred by subarachnoid spread in 2 patients and by systemic spread in 2 others (who also
had metastases to sites such as lungs, liver, and bone).
Four patients (16%) (Cases 2, 4, 16, and 22) with
five tumors were alive at last follow-up with no evi-
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CANCER June 1, 1998 / Volume 82 / Number 11
FIGURE 9. Overall survival is shown.
dence of disease (NED) at 221, 153, 61, and 35 months,
respectively, after diagnosis. All five tumors arose in
neurofibromas, four in the setting of NF1. Four of the
tumors were completely resected (in Cases 4 and 16,
and both tumors in Case 22). One tumor (Case 2),
although thought on macroscopic examination to be
completely resected, had focally positive microscopic
margins. This patient received preoperative and postoperative chemotherapy and radiation therapy. The
sizes of the tumors were 4 –18 cm, and the mitotic rate
was 2– 46 mitotic figures per 10 HPF. Two tumors were
entirely low grade, two were partially low grade, and
one was entirely high grade.
Two of the four surviving patients with NED had
spinal involvement by the tumor. The first patient
(Case 2) had a large retroperitoneal tumor with epidural and intradural extension that created a complete
myelographic block at the T12 level. The tumor was
removed in two stages. First, the intradural spinal
component was resected piecemeal via a laminectomy
and was found to be a neurofibroma. The second
procedure was an en bloc resection of the retroperitoneal portion of the tumor that involved the psoas
muscle; this was a high grade MPNST contained
within a neurofibroma. The second patient (Case 22)
had a thoracic mass extending along the T9 nerve root
through the T9 –10 neural foramen. Removal necessitated sacrifice of the nerve root with intradural exploration. Although part of the tumor was high grade, the
portion involving the T9 nerve root was a plexiform
neurofibroma.
Twenty patients (80%) died of disease (DOD)
within 2– 40 months (median survival, 8.5 months).
One patient was alive with recurrent and metastatic
disease after 14 months at the end of the study period.
Statistical Analysis
The overall 2- and 5-year survival rates were 35% and
16%, respectively (Table 2, Fig. 9). When survival status was used as an endpoint, complete resection or
gross complete resection was highly associated with
better survival (P , 0.01 for both). When survival time
was used as an endpoint, tumor size .5 cm (P 5 0.04,
Fig. 10) and presence of a high grade tumor (P , 0.015,
Fig. 11) were associated with shorter survival, whereas
complete resection (Fig. 12) and gross complete resection were associated with longer survival (P 5 0.02 and
P 5 0.06, respectively).
Parameters that were not shown to have an
effect on survival were age, gender, history of NF1,
diagnostic delay, tumor location (SD vs. IT), mitotic
rate, necrosis, divergent differentiation, and postirradiation tumor occurrence. Correlation was noted
between high tumor grade and 1) less likelihood for
gross complete resection (34% vs. 72% with low
grade tumors), 2) tumor size .5 cm (83% vs. 57%
with low grade tumors), and 3) more frequent use of
Paraspinal Malignant Peripheral Nerve Sheath Tumors/Kourea et al.
2199
FIGURE 10. Survival is shown by tumor size.
radiation therapy (84% vs. 61% with low grade tumors).
DISCUSSION
MPNSTs account for 5% of malignant soft tissue tumors;13 they have an estimated incidence of 0.001% in
the general population6 and 2% among patients with
NF1.20 Mention of MPNSTs at paraspinal location was
made in some of our earlier reports24,28,32,33 and in the
reports of others.4,8,10,11,12,21,26,34 – 44 Two series reported on a combined total of 11 patients with intraspinal MPNSTs.45,46 Although previous studies
noted that patients with ‘‘centrally’’ located tumors
had a worse outcome, these were limited by 1) lack of
detailed data, which prevented critical review of the
cases, especially in cases of remarkably long survival;11
b) small numbers of tumors;10 and 3) inclusion of NF1
cases only.8 The current study focuses on the paraspinal SD and IT locations to assess specific clinical and
histologic parameters and their relation to tumor behavior. In addition, paraspinal MPNSTs are compared
with a large series of MPNSTs of all anatomic sites6
and tumors of the BLE.9
Patients with paraspinal MPNSTs present more
frequently with pain than those with BLE tumors, who
usually present with an enlarging mass and neurologic
symptoms. Delay in making the diagnosis of paraspi-
nal MPNST after the onset of symptoms was noted in
55% of the patients; this was more frequent among
NF1 patients and often associated with the presence of
neurofibroma. It is likely that the symptomatology was
initiated either by the neurofibroma or by more rapid
enlargement of the tumor when malignant transformation occurred within the neurofibroma. The absence of a worse outcome among these cases, although paradoxical, might be accounted for in part by
‘‘containment’’ of the malignant component within
the neurofibroma for some time before the diagnosis,
and in instances possibly providing a ‘‘safe margin’’
during surgery. Because diagnostic delay was more
common in the setting of NF1, we suggest careful
investigation of ‘‘pain’’ in such cases to identify deepseated neurofibromas undergoing malignant transformation.
Biopsies of paraspinal MPNSTs present a tremendous interpretative challenge even for pathologists
who have considerable experience with soft tissue tumors. Of major concern is distinction from benign
tumors occurring in this region; those that most
closely simulate MPNST are cellular schwannoma46
and cellular or atypical neurofibroma. Cellular
schwannoma46 –51 mimics a malignant tumor with its
increased cellularity and mitotic activity, but it can be
differentiated by its generally bland nuclei, perivascu-
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CANCER June 1, 1998 / Volume 82 / Number 11
FIGURE 11. The survival of patients with entirely high grade tumors is compared with the survival of those with tumors that are partly or entirely low grade.
lar cellular whorls, and diffuse, strong S-100 protein
expression (in contrast to the S-100 reactivity of only
scattered tumor cells in MPNST). In addition, the
presence of thick-walled, hyalinized blood vessels and
clusters of lipid-laden histiocytes, although infrequently noted in cases of MPNST, favors the diagnosis of cellular schwannoma. Cellular neurofibroma
should not display diffuse nuclear enlargement or hyperchromasia. On the other hand, atypical neurofibromas (neurofibromas characterized by scattered hyperchromatic, pleomorphic, and sometimes multinucleated tumor cells)52 lack diffuse hypercellularity.
We regard neurofibromas with both diffusely increased cellularity and extensive nuclear enlargement
and hyperchromasia as low grade MPNSTs. The latter,
because of their potential association with a high
grade component, should be treated with complete
resection and microscopic evaluation of the surgical
margins.
Biopsies of three tumors in our study were erroneously interpreted as benign. In two instances, the
interpretation was atypical neurofibroma; in the third,
it was schwannoma. In one tumor designated atypical
neurofibroma, undue emphasis had been placed on
the absence of mitotic figures (Fig. 13), and in the
other the significance of both hypercellularity and
widespread nuclear enlargement had not been appreciated. The diagnosis of schwannoma was rendered
for a spindle cell tumor of a nerve that lacked marked
cellularity, nuclear atypia, or mitotic activity. On re-
view, a small collection of rhabdomyoblasts was
noted. Although a diagnosis of MPNST would have
have been difficult to make based on only the appearance of the spindle cell component, the identification
of rhabdomyoblasts pointed to a diagnosis of MPNST
with focal rhabdomyoblastic differentiation (malignant triton tumor) (Fig. 6). Regarding the importance
of mitotic figures, we would like to emphasize that
they may be found in cellular schwannomas and may
be absent in a biopsy of MPNST (even high grade), and
in isolation they do not indicate that a neurofibroma
has undergone malignant transformation. Because of
the above difficulties, accurate diagnosis is best
achieved by study of a generous sample that includes
tissue well beneath any apparent ‘‘capsule.’’ Distinction of MPNSTs from other malignant soft tissue tumors has been discussed in previous publications.15,31
Accurate tumor typing is important because of its
implications for planning surgical treatment.
The goal of treatment is surgical en bloc resection of the tumor and the achievement of negative
microscopic margins. Complete resection of a tumor that extends to the lumbar plexus or spine may
not be possible without causing neurologic damage;
for this reason, incomplete resection was performed
in some cases in this study. Discussion with the
patient regarding the potential risks and use of a
multidisciplinary surgical team approach may
therefore be indicated in selected cases. The latter
point is emphasized by one of our cases (Case 2), in
Paraspinal Malignant Peripheral Nerve Sheath Tumors/Kourea et al.
2201
FIGURE 12. Survival is shown by type of resection.
which two separate operations were necessary to
resect the spinal and retroperitoneal tumor components. Currently, at our institution, postoperative
chemotherapy in the form of MAID (mesna, doxorubicin [Adriamycin; Adria Laboratories, Columbus,
OH], ifosfamide, and dacarbazine) is given to patients with high grade tumors. Chemotherapy and
radiation therapy are often given to patients with
incompletely resected tumors.
Gross examination is inadequate for evaluating
completeness of resection because of the deceptively circumscribed, pseudoencapsulated appearance of MPNSTs and their potential to extend proximally and distally along involved nerves. All
macroscopic specimens should be inked and the
surgical margins adequately sampled. Information
relative to the completeness of tumor resection can
be obtained by frozen-section examination of the
margins of involved nerves. Admittedly, distinction
of a low grade MPNST from either a cellular schwannoma or a neurofibroma on frozen section may not
be possible, but recognition of a high grade, malignant spindle cell tumor is. A neurofibromatous component can mimic MPNST grossly by encasing
blood vessels, eroding vertebrae, growing into spinal foramina, or extending into the extradural and
intradural space. In such cases, although complete
resection is desirable, identification of neurofibroma at the surgical margins is not an ominous
finding.
FIGURE 13. This biopsy of a high grade malignant peripheral nerve sheath
tumor was originally misinterpreted as a neurofibroma due to the absence in
the biopsy of mitotic figures, a lack of appreciation of diffuse hyperchromasia,
and increased cellularity.
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CANCER June 1, 1998 / Volume 82 / Number 11
TABLE 3
Comparison of MPNST at Different Sites
MPNST
2-yr survival
5-yr survival
10-yr survival
DOD
Median
survival (mos)
Recurrence
Metastasis
All sites (6)
BLE (9)
Paraspinal
57%
35%
34%
39%
16%
23%
16%
68%
63%
80%
35
8.5
42%
40%
65%
68%
63%
68%
MPNST: malignant peripheral nerve sheath tumor; BLE 5 MPNST of buttock/lower extremity; DOD 5 dead of disease.
The prognosis of paraspinal MPNSTs is favorably affected by small size (,5 cm) and complete
resection, findings similar to those in previous studies.6,10 Furthermore, low tumor grade, even as a
minor component, is associated with better outcome. In contrast to prior studies,4,5,6,7,12 outcome
was not affected by the presence of NF1, diagnostic
delay, tumor location (SD vs. IT), postirradiation
occurrence, divergent differentiation, mitotic rate,
or necrosis. Study of additional cases would be useful to confirm these findings.
The outcomes of patients with paraspinal MPNSTs is worse than those of patients with MPNSTs
from all anatomic sites and BLE (Table 3). Recurrence rate and mortality are higher, and median, 2-,
5-, and 10-year survivals are shorter. Unlike the
predominance of metastases to the lung in BLE
tumors, paraspinal MPNSTs metastasize at similar
rates to the lung, central nervous system, liver, and
abdomen. Neoplastic seeding of the subarachnoid
space and even spinal cord involvement may occur
by way of proximal spread along spinal nerves. Because tumor size and metastatic rates in the
paraspinal and BLE groups are similar, we do not
agree with Guccion and Enzinger,8 who attribute the
more aggressive behavior of central tumors mainly
to larger size and greater likelihood of metastasis.
According to our findings, the worse outcomes are
due to incomplete tumor resection, which result in
more frequent and earlier recurrences.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
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