928 S. Nagase et al.

Vaginal tumors with histologic and

immunocytochemical feature of gastrointestinal
stromal tumor: two cases and review of the
literature
S. NAGASE*, Y. MIKAMIy, T. MORIYAz, H. NIIKURA*, K. YOSHINAGA*, T. TAKANO*,
K. ITO*, J. AKAHIRAz, H. SASANOz & N. YAEGASHI*
*Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan;
yLaboratory of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan; and zDepartment of Pathology,
Tohoku University Graduate School of Medicine, Sendai, Japan

Abstract. Nagase S, Mikami Y, Moriya T, Niikura H, Yoshinaga K, Takano T, Ito K, Akahira J, Sasano H,
Yaegashi N. Vaginal tumors with histologic and immunocytochemical feature of gastrointestinal stromal tumor:
two cases and review of the literature. Int J Gynecol Cancer 2007;17:928–933.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract
(GI). Although positive immunohistochemistry for c-kit protein (CD117) and CD34 is critical in establish-
ing diagnosis, the clinicopathologic features of CD117-positive mesenchymal tumors without obvious con-
nection to the GI tract are not well documented. We describe the clinicopathologic features of two cases of
extra-GIST. Case 1 was a 42-year-old woman who presented with a submucosal tumor located in the poste-
rior vaginal wall. Case 2 was a 66-year-old woman who presented with a mass that bulged from the right
side of the middle vaginal wall. Both tumors were excised locally. The results of microscopic examination
and immunohistochemistry for both cases indicated the diagnosis of GIST. Case 2, in addition, showed
oncogenic mutation in KIT exon 11. Case 1 is healthy without evidence of recurrence 4 years after surgery.
Case 2 started imatinib therapy after resection of a recurrent mass. Gynecologists as well as diagnostic
pathologists should be aware of GIST manifesting as a vaginal mass. Recognition of microscopic patterns
and characteristic immunohistochemical phenotype, plus genetic study, is mandatory for establishing the
correct diagnosis of GIST.

KEYWORDS: CD117-positive, EGIST, GIST, imatinib, vaginal mass.

Gastrointestinal stromal tumor (GIST) is the most
common mesenchymal tumor of the gastrointestinal
tract (GI); it is thought to originate from interstitial
cells of Cajal, an intestinal pacemaker cell. Approxi-
mately 60% of GISTs arise in the stomach, 30% in
the small intestine, 5% in the esophagus, and 5% in
the colon and rectum(1). Recently, tumors showing
features of GIST have been described in extra-gastro-
intestinal sites including the omentum, mesentery,
retroperitoneal space, and urinary bladder serosa(2–4).
Although positive immunohistochemistry for c-kit
protein (CD117) and CD34 is critical in establishing
diagnosis(5,6), the clinicopathologic and immunohisto-
chemical features of CD117-positive mesenchymal tu-
mors without apparent connection to the GI tract are
not well documented.
In this report, we describe the clinicopathologic fea-
tures of two cases of extra-GIST (EGIST) presenting as
a vaginal mass and review the relevant literature.

Case report
Satoru Nagase, MD, Department of Obstetrics and Gynecology,
Tohoku University Graduate School of Medicine, 1-1 Seiryo-Machi, Case 1
Aoba-Ku, Sendai 980-8574, Japan. Email: nagases@mail.tains.tohoku.
ac.jp A 42-year-old, gravida 3, para 3 Japanese woman was
doi:10.1111/j.1525-1438.2007.00892.x referred to the hospital for a vaginal tumor detected
# 2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 914–933

during cancer screening. On admission, examination
demonstrated a movable mass protruding into the
vagina from the posterior vaginal wall. Tumor size
was 3.5 cm in largest diameter, and two thirds of it
was in the vaginal lumen. The overlying mucosa was
otherwise intact. Digital rectal examination was unre-
markable. Enucleation of the tumor via the vagina
was performed. The tumor was macroscopically sepa-
rated from the rectal wall, and the lesion was excised
relatively easily without any complications. On gross
examination, the tumor appeared well circumscribed
with a fibrous capsule (Fig. 1A) and was whitish to
grayish in color, without macroscopic evidence of
necrosis or hemorrhage on the cut surface.
Microscopically, the tumor was a cellular neoplasm
composed of fascicles of spindle cells, intervened or
encircled by delicate fibrovascular stroma. The spindle
cells showed mild to moderate nuclear abnormalities
characterized by elongation, relatively coarse chroma-
tin texture, and occasional nucleoli. The amount of
cytoplasm per cell was moderate to abundant. The
mitotic count was up to 1/50 high power fields (HPF),
but abnormal mitotic figures were not identified
(Fig. 1B). Tiny foci of necrosis were identified, but
extensive coagulative necrosis was absent. In the
periphery, the tumor was rather fibrotic due to accu-
mulated collagen fibers and well demarcated with
a thin fibrous pseudocapsule that was very close to
the resection margin.
Immunohistochemically, the tumor was diffusely
positive for CD34 (1:100, Nichirei, Tokyo, Japan)
(Fig. 2A), c-kit protein (CD117) (1:200, MBL, Nagoya,
Japan) (Fig. 2B), and vimentin (1:500, Dako Corp.,
Figure 1. A) Gross appearance of tumor for
case 1. Resected tumor was well circum-
scribed with a thin capsule and whitish to
grayish in color. B) Microscopic view of case 1
(hematoxylin and eosin, 350). The tumor con-
sisted of spindle cells arranged in a fascicular
pattern with intervening fine fibrovascular
stroma. C) Microscopic view of case 2 (hema-
toxylin and eosin, 3100). The tumor showed
an interlacing fascicular pattern, resulting in
a superficial resemblance to a smooth muscle
tumor.
# 2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 914–933
Vaginal tumors showing features of GIST 929
Carpinteria, CA), but negative for a-smooth muscle
actin (1:300, Dako Corp.) and desmin (1:100, Dako
Corp.). Only focal staining for h-caldesmon (1:50,
Takara Bio Inc., Otsu, Japan) was identified in the cen-
tral portion of the tumor. Immunostaining was nega-
tive for S100 protein (1:300, Dako Corp.), estrogen
receptor (1:50, Novocastra Labs, Newcastle, UK), cyto-
keratin (AE1/AE3) (1:300, Dako Corp.), and CD68
(1:200, Dako Corp.). The Ki-67 labeling index, evalu-
ated as the ratio of MIB-1 (1:100, Dako Corp.)-positive
nuclei per 1000 neoplastic cells, ranged from 20% to
30% in the cellular areas, but less than 3% in fibrotic
areas. The diagnosis was GIST, and the patient
received no further therapy. She has been well without
evidence of recurrence for the 4 years since surgery.
Case 2
A 66-year-old, gravida 2, para 2 woman presented
with a mass bulging from the right side of the middle
vaginal wall. She had a previous history of vaginal
tumor 9 years before the current presentation, which
had yielded a histopathologic diagnosis of leiomyoma.
At 61 years, a vaginal tumor roughly the size of a wal-
nut appeared in the posterior vaginal wall and was
excised. Histopathologic diagnosis was smooth mus-
cle tumor of uncertain malignant potential. When the
tumor recurred 8 months later, a diagnosis of leio-
myosarcoma was made by biopsy. Subsequently, the
recurrent tumor was reexcised with rectal mucosa via
a vaginal approach. Although the resection margins
were free of tumor microscopically, a mass measuring
2 cm in diameter developed in the posterior vagina
930 S. Nagase et al.
at 62 years, 8 months after the previous procedure.
The mass was excised locally, and microscopic exami-
nation showed identical tumor interpreted as leiomyo-
sarcoma. Her history had then been uneventful for 4
years.
At the current presentation, pelvic examination re-
vealed a mass measuring 5 cm in diameter located in
the right paravaginal space. The inferior border of the
tumor was 5 cm from the vaginal introitus, and the
overlying vaginal mucosa was intact. Colonoscopic
examination demonstrated no mucosal lesion. Com-
puted tomography showed a well-circumscribed
dense soft-tissue mass (57 3 50 mm) with no evidence
of distant metastasis or lymph node swelling. After
embolization of the feeding artery, the tumor was
excised via the vagina without complication. The his-
tologic features of this tumor were also interpreted as
those of leiomyosarcoma. Ten months later, a firm
irregular mass was identified along the right side of
the vaginal wall 2 cm from the vaginal introitus; it
was regarded as recurrent tumor. The mass was reex-
cised in similar fashion. Microscopically, the tumor
was composed of a densely packed proliferation of
spindle cells arranged in an interlacing fascicular pat-
tern. Coagulative tumor necrosis was not identified.
Mitotic count ranged from 2 to 3 per 50 HPF. Appar-
ently, the tumor had a close resemblance visually to
leiomyosarcoma in some areas (Fig. 1C). Immunohis-
tochemical study demonstrated diffuse and strong
staining for CD34, c-kit protein (CD117), and vi-
mentin. In contrast, staining for a-smooth muscle
actin, S100 protein, and desmin was negative. The Ki-
67 labeling index was up to 30% in cellular areas.
# 2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 914–933
Figure 2. Immunohistochemistry showing
neoplastic cells positive for A) c-kit protein
and B) CD34 (3200).
These results indicated the diagnosis of EGIST.
Review of glass slides of tumor excised 10 months pre-
viously demonstrated that the present tumor was
morphologically similar to the previous tumor, and
thus, the diagnosis of recurrent EGIST was made. To
confirm the diagnosis of EGIST at the molecular level,
we performed KIT mutational analysis. Genotyping of
tumor cells revealed a 21-bp deletion at codon 552–559
in exon 11. The patient presented with a vaginal recur-
rence 3 months after the diagnosis of EGIST was
made. A local excision was performed immediately,
and imatinib therapy was initiated. She is currently
healthy 6 months after surgery although imatinib
therapy was discontinued after a month due to side
effects.
Discussion
Although GISTs are thought to arise from intestinal
cells of Cajal, these tumors have been reported as pri-
mary tumors outside the GI tract, with this latter
group comprising about 5–7% of all GISTs(2,7). The
majority of EGISTs have involved the mesentery,
omentum, and retroperitoneum. Therefore, the current
cases, which presented as palpable vaginal masses
with gynecological complaints, are unique. To the best
of our knowledge, only seven cases of GIST presenting
as a vaginal mass have been reported previously(8–12).
The clinicopathologic features of previously reported
cases and the current two cases are summarized in
Table 1. Patient age ranged from 38 to 75 years, and
tumor size ranged from 3.5 to 8 cm. Two previous tu-
mors were thought to originate from the rectum,
 Table 1. Clinicopathologic features of seven reported cases of GIST-like tumors presenting as a vaginal mass, including the current two cases
Case 1 2 3 4 5 6 7 8 9
Author Weppler Ceballos Nasu Takano Lam Lam Lam
Reference 8 9 10 11 12 12 12
Publication year Present case Present case 2005 2004 2004 2006 2006 2006 2006
Age (years) 42 66 66 75 54 38 36 48 61
Tumor size (cm) 3.5 5 8 4.5 8.5 7 4 6 8
Treatment Local excision Local excision Imatinib Local excision Radical excisiona Radical nd nd nd
excisionb
Recurrence 2 1 nd 1 2 2 1 1 2
Histologic features
Cell pattern Spindle cell Spindle cell Spindle cell Spindle cell Spindle cell Spindle cell Spindle cell Spindle cell Spindle cell
Mitosis (per 50 HPF) ,1 2–3 .5 12–15 5–10 1–2 15 12 16

#
Necrosis 1 2 2 1 1 nd 2 1 2
Cellularity High High High High High nd Moderate Moderate Moderate
Risk category Low Intermediate High High High Intermediate High High High
Immunochemical features
CD117 1 1 1 1 1 1 1 1
CD34 1 1 1 1 1 1 1 1 1
Vimentin 1 1 1 1 1 nd nd nd nd
Smooth muscle actin 2 2 2 2 1 (focal) 1 (focal) 2 2 2
S100 2 2 2 2 2 2 2 2 2
Desmin 2 2 2 2 1 (focal) 2 nd nd nd
Cytokeratin 2 nt 2 2 2 nd 2 2 2
h-caldesmon 1 nt nd 1 nd nd nd nd nd
Ki-67 20–30% 30% nd nd nd nd nd nd nd
Estrogen receptor nt nt 2 2 2 2 2 2 2
KIT mutation nt Exon 11, 21-bp nd nd nd nd Exon 9, insertion, Exon 11, deletion, Exon 11, V560E,
deletion, codon 502–503 codon 558–562 codon 560
codon 552–559
nd, not described, nt, not tested.
a
An abdominoperineal resection of the rectum (Miles operation) with posterior vaginal wall resection and pelvic lymphadenectomy.
b
Low anterior resection of the rectum and partial resection of the posterior vagina.
Vaginal tumors showing features of GIST
931

2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 914–933
932 S. Nagase et al.
whereas the other five originated from the perirectal
spaces and had no rectal involvement. Because ana-
tomic location of EGIST in the pelvic cavity, particu-
larly adjacent to the female genital tract, is
uncommon, and the concept of EGIST has only
recently appeared, EGIST might be excluded from the
differential diagnosis of spindle-cell neoplasms and
could be confused with the more common leiomyoma
or leiomyosarcoma. In fact, case 2’s tumor was origi-
nally diagnosed as leiomyosarcoma based on micro-
scopic features observed on hematoxylin and eosin
(H&E)–stained slides. This experience indicates the
diagnostic importance of immunohistochemistry with
antibodies against c-kit protein (CD117) and CD34. It
should be noted that a variety of tumors can be posi-
tive for c-kit protein and CD34. Therefore, an antibody
panel including smooth muscle and neural markers
should be employed and the results interpreted with
great caution; immunohistochemistry data should
always be considered in combination with morpho-
logic features. Furthermore, the addition of molecular
genetic study to immunohistochemistry not only con-
firms the correct diagnosis but also supports the exis-
tence of EGIST as an entity because it is well
established that somatic mutation of the KIT gene is
associated with the pathogenesis of GIST. The correct
diagnosis and molecular analysis are clinically impor-
tant because of the current management strategy of
imatinib for advanced disease.
Prediction of the malignant potential of GIST has
been stratified by tumor size and mitotic count into
four categories: very low, low, intermediate, and
high(13). As shown in Table 1, six of nine cases were
classified as high risk. Compared with conventional
GIST, Reith et al.(2) reported that frequent mitotic activ-
ity (.2/50 HPF), high cellularity, and the presence of
necrosis indicate a potentially aggressive clinical course
for EGIST and that 92% of patients with two or more of
these three features have a poor outcome. Three of four
cases of recurrence in our series of vaginal EGIST cases
had two or more features and their risk was assessed
as high. Interestingly, the four cases involving relapse
were alive at the time their cases were published
despite recurrent disease. Taken together, resectable
EGIST presenting as a vaginal mass may have other
prognostic factors or site-specific characteristics that
distinguish them from other cases of EGIST.
The current definitive treatment for GIST, including
EGIST, is surgical resection, but the majority of pa-
tients have recurrent tumor despite complete resection
of primary tumor(14). Miettinen et al.(15) reported for
their series of cases of anorectal GIST that there was
no significant difference regarding survival depending
# 2007 IGCS and ESGO, International Journal of Gynecological Cancer 17, 914–933
on type of surgical procedure: In this series, most tu-
mors less than 5 cm were treated with local excision.
Because radical excision including anterior or abdomi-
noperineal resection carries the possible risk of anal
sphincter dysfunction, local excision might be pre-
ferred in cases involving the vaginal wall without
obvious connection to the rectum.
Imatinib was used for one patient with unresectable
tumor(8), and for our case 2 as adjuvant chemotherapy
after optimal resection. Imatinib mesylate (Glivec),
a tyrosine kinase inhibitor originally designed to treat
chronic myelogenous leukemia, is a current treatment
of choice for advanced GIST(16–18). Several clinical
studies of imatinib for advanced GIST have shown
a high overall response rate, with a partial response
rate, and stable disease rate of 45% and 32%, respec-
tively(19,20). Additionally, clinical response to imatinib
therapy has been reported to correlate with type of
KIT mutation; patients with mutation in KIT exon 11
appear to have a better response rate and longer inter-
val of progression-free survival than patients whose
mutation is in KIT exon 9(21–23). The efficacy of im-
atinib as adjuvant therapy after optimal resection or as
neoadjuvant therapy remains to be determined. A
Phase II intergroup trial by The American College of
Surgeons Oncology Group is ongoing; it is testing the
impact of adjuvant imatinib given at a dose of 400
mg/day for 12 months after complete macroscopic
surgical resection. In this study, 83% of patients com-
pleted treatment and are being followed to determine
overall survival(24). In addition, a Phase III trial by
American College of Surgeons Oncology Group is also
in progress. The latter study randomized patients into
two groups, that is, imatinib (400 mg/day) and pla-
cebo, 1 year after complete resection(25). Results are
awaited to validate the efficacy of imatinib as post-
operative adjuvant therapy.
In summary, gynecologists as well as diagnostic
pathologists should be aware of EGIST manifesting as
a vaginal mass. Recognition of microscopic patterns
and characteristic immunohistochemical phenotype is
mandatory for establishing the correct diagnosis. In
addition, the potential risk for recurrent disease indi-
cates the need for long-term follow-up. Further studies
are awaited to determine the clinical behavior of this
tumor and the role of adjuvant imatinib therapy.
Acknowledgments
The authors acknowledge Dr Tomoko Mitsuhashi for
helpful advice. This study was supported in part by
a grant-in-aid for Scientific Research on priority area

from the Ministry of Education, Science, Sports and
Culture, Japan; a grant-in-aid from the Ministry of
Education, Science, Sports and Culture, Japan; a
grant-in-aid from the Ministry of Health, Labor and
Welfare, Japan; and the 21st Century Center of Excel-
lence Program Special Research Grant (Tohoku Uni-
versity) from the Ministry of Education Science, Sports
and Culture, Japan.
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Accepted for publication December 5, 2006