AJR 2005; 184:S58-S61
© American Roentgen Ray Society
Gastrointestinal Stromal Tumor with Metastases in an Adult Woman Treated with Imatinib Mesylate: MDCT Findings
Pedro Javier Bustillo Busalacchi, Sr.1,
Miguel Angel Corral de la Calle1,
Amparo Torroba2 and
Silvia Torres del Río1
1 Servicio de Radiodiagnóstico, Hospital Morales Meseguer,
C/Marqués de los Vélez s/n, Murcia 30008, Spain.
2 Servicio de Anatomía Patológica, Hospital Morales Meseguer,
Murcia 30008, Spain.
Received February 12, 2004;
accepted after revision May 13, 2004.
Address correspondence to P. J. Bustillo Busalacchi
(pjbbusalacchi{at}ono.com).
Introduction
Gastrointestinal stromal tumors (GISTs) are the most common
mesenchymal tumors of the gastrointestinal tract. They differ genetically from
typical leiomyomas, leiomyosarcomas, and schwannomas
[1], and their origin remains
under debate [2]. Recently,
imatinib mesylate, a tyrosine kinase inhibitor, has been under investigation
as a treatment for GISTs. We report on a 59-year-old woman with GIST and
metastases who was treated with imatinib mesylate, which resulted in
progressive calcification and a decrease in size of the nodules. To our
knowledge, these findings have not been previously reported in the
literature.
Case Report
A 59-year-old postmenopausal woman presented with asthenia, anorexia, and
weight loss in the previous 3-4 months. Sonography revealed mesenteric
nodules, many with multiple plump nuclei
(Fig. 1). Two nodules appeared
to be calcified and to have cystic degeneration. Gross nodular thickening of
the omentum was seen. No significant ascites was found. MDCT confirmed the
sonography findings with greater precision and also showed an additional
lobulated cystic lesion with peripheral calcification adjacent to the cecum
(Fig. 2). A 14-gauge needle
biopsy of the omental infiltration led to a presumptive diagnosis of GIST.
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Fig. 1. —59-year-old woman with stromal tumor of jejunal wall and
omental and peritoneal metastases. Sonographic image shows multiple mesenteric
nodules, some of which contain stromal calcification (white arrow) or
cystic degeneration (black arrow). Marked omental thickening with
lobulated contours (asterisk) is seen.
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Fig. 2. —59-year-old woman with stromal tumor of jejunal wall and
omental and peritoneal metastases. MDCT scan shows striking omental thickening
(asterisk) caused by confluence of multiple nodules. Multiple
mesenteric nodules (white arrowhead) and cystic mass with peripheral
calcification adjacent to cecum (black arrow) are also seen.
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An exploratory laparotomy showed a mural multinodular jejunal tumor (4
x 3 x 3 cm) and multiple, grapelike masses in the omentum and
mesentery. When cut, the jejunal tumor appeared dense and whorled, with
hemorrhagic and necrotic areas (Fig.
3). The section of greater omentum was similar to that of the
jejunal tumor. Histologically, the jejunal tumor and subperitoneal metastases
consisted of small bundles of spindle and epithelioid cells in a storiform
pattern. One or two mitoses per 50 high-power field (400x) were
identified. Although on histology the size, location, and mitotic rate of what
was considered the primary tumor indicated a low- to intermediate-grade
malignancy, the tumor's biologic behavior was aggressive.
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Fig. 3. —59-year-old woman with stromal tumor of jejunal wall and
omental and peritoneal metastases. Gross photograph of lobulated tumor with
hemorrhagic and necrotic areas (4 x 3 x 3 cm) in interior.
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On immunohistochemistry, the tumor cells proved positive for CD117 protein,
CD34 protein, and vimentin, and negative for actin, S-100 protein,
chromogranin, desmin, and cytokeratin. The final diagnosis was GIST of the
jejunal wall with multiple omental and peritoneal metastases.
The patient enrolled in a multicenter therapeutic trial of imatinib
mesylate, a tyrosine kinase inhibitor; the clinical response was good.
Subsequent MDCT studies (Figs.
4A,
4B,
4C) showed progressive
calcification and a decrease in the size of the central mesenteric and omental
nodules that became evident 5 months after the start of the therapy. At the
last control at 18 months, the nodules appeared as dots that were almost
completely calcified; little soft tissue mass was evident. However, the mass
medial to the cecum had not significantly changed.
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Fig. 4A. —59-year-old woman with stromal tumor of jejunal wall and
omental and peritoneal metastases. MDCT scan at same level as in
Figure 2. Images show decrease
in size of nodules at 2 months (A), progressive calcification that
began as central dots (white arrows) at 5 months (B), and
complete calcification of nodules at 18 months (C). In B, thick
arrows indicate omental calcifications, thin arrow indicates mesenteric
calcification.
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Fig. 4B. —59-year-old woman with stromal tumor of jejunal wall and
omental and peritoneal metastases. MDCT scan at same level as in
Figure 2. Images show decrease
in size of nodules at 2 months (A), progressive calcification that
began as central dots (white arrows) at 5 months (B), and
complete calcification of nodules at 18 months (C). In B, thick
arrows indicate omental calcifications, thin arrow indicates mesenteric
calcification.
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Fig. 4C. —59-year-old woman with stromal tumor of jejunal wall and
omental and peritoneal metastases. MDCT scan at same level as in
Figure 2. Images show decrease
in size of nodules at 2 months (A), progressive calcification that
began as central dots (white arrows) at 5 months (B), and
complete calcification of nodules at 18 months (C). In B, thick
arrows indicate omental calcifications, thin arrow indicates mesenteric
calcification.
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Discussion
Gastrointestinal stromal tumors are part of a group of mesenchymal
neoplasts that occur predominantly in the gastrointestinal tract.
Histologically, immunohistochemically, and genetically, they differ from
typical leiomyomas, leiomyosarcomas, and schwannomas
[1]. On microscopy, 70%-80% of
GISTs are composed of spindle cells and 20%-30% have epithelioid morphologic
features; the cells can appear in a variety of histologic patterns
[2].
Over the past three decades, there has been considerable debate on the
nomenclature, cellular origin, diagnosis, and prognosis of GISTs. On light
microscopy, GISTs have an appearance similar to that of smooth muscle
neoplasms; thus, most were classified as leiomyosarcomas
[3]. The proposed origin of
GISTs is the interstitial cell of Cajal, an intestinal pacemaker cell, because
both have the immunohistochemical marker CD 117, a c-kit protein, and
the Cajal cell has ultrastructural characteristics of smooth muscle and neural
differentiation, accounting for the variants of GIST
[3]. The presence of tumors
that are phenotypically identical to GISTs and primarily located in the
omentum and mesentery suggests GISTs do not originate exclusively from the
interstitial cell of Cajal [1].
Miettinen and Lasota [4]
suggest that GISTs originate from a more primitive stem cell, from which Cajal
cells and smooth muscle cells arise.
GISTs have specific immunohistochemical properties. The most specific
marker is CD117, a tyrosine kinase growth factor receptor with oncogenic
potential that is a major diagnostic criterion
[4]. Seventy percent of GISTs
also express CD34 protein [5,
6]; other possible markers
include vimentin and actin (20%-30%)
[4,
5]. Most GISTs are negative for
desmin (2%-4% positive) [1,
5] and, unlike schwannomas, for
the S-100 protein (10% positive)
[5]. In the past, many tumors
diagnosed as leiomyomas, leiomyoblastomas, or leiomyosarcomas were found to be
positive for CD117 and are now considered GISTs. Schwannomas, true leiomyomas,
and true leiomyosarcomas are genetically different from GISTs and do not meet
the immunohistochemical criteria for its diagnosis
[2]. Among the seven families
of transmembrane tyrosine kinases, gain-of-function or activating mutations in
the c-kit proto-oncogene occur in at least 60%-70% of GISTs
[5].
The median age of patients with GISTs is 58 years, with most tumors
occurring in people who are middle-aged and older
[3]. Although they are rarely
seen in those less than 40 years old, GISTs have been reported in patients
between 16 and 94 years old
[2]. They are the most
frequently occurring mesenchymal gastrointestinal neoplasms, representing
approximately 5% of sarcomas
[3] and approximately 2.5% of
gastric tumors [2].
Primary tumors of the mesentery and omentum are usually solid masses larger
than 10 cm [1]. In more than
two thirds of patients, the primary GIST is larger than 5 cm
[3]. Approximately 10%-30% are
malignant, and the risk for malignancy increases when they are located outside
the stomach, are larger than 5 cm, extend into adjacent organs, and have a
high mitotic rate [2,
3]. Of malignant GISTs, 47%-61%
present with metastases, 53%-57% with hepatic involvement, and 21%-35% with
peritoneal involvement. Lymph node metastases, although seen in pathology
reports, are not usually recognized with radiologic cross-sectional techniques
(0%-6%) [3]. Surgical
lymphadenectomy is not warranted.
On CT, most GISTs are well-defined extrinsic masses with a heterogeneous
attenuation reflecting internal areas of hemorrhage, cystic degeneration, or
necrosis, characteristics that were present in 67% of 116 malignant GISTs in
one study [6]. The presence of
gas, calcification, and intestinal obstruction is uncommon, even when the
tumor is large. The only clear correlation between the radiologic appearance
of GISTs and their malignant potential are their size, location, and,
obviously, the presence of metastases
[6]. Low-attenuation liver
metastases and peritoneal spread can be revealed on CT. Liver metastases can
be hyperattenuating in an arterial phase
[2] and show elements of an
internal cyst. Peritoneal metastases can appear as multiple nodules involving
the peritoneal surface or subperitoneal space
[6], which can show the origin
of a clinically unidentified primary tumor, as in our case. Ascites is an
unusual finding, even in cases of extensive peritoneal involvement.
The only traditional therapy that has proved effective is surgical
resection, with complete resection a significant prognostic variable. Cases in
which the tumor has metastasized do not respond to chemotherapy or radiation.
In 2001, Hirota et al. [7]
first described a gain-of-function mutation that affects the extracellular
domain of KIT in a small number of GISTs
[7]. In vitro experiments have
showed the efficacy of tyrosine kinase inhibitors against these proliferating
cells.
Soon after the description by Hirota et al., Joensuu et
al.[8] reported on a patient
with metastatic GIST that was successfully treated with the tyrosine kinase
inhibitor STI571, which is now known as imatinib mesylate. This drug belongs
to a new generation of molecularly targeted chemotherapy agents. Its active
metabolite blocks the adenosine triphosphate (ATP)-binding site of tyrosine
kinases. Early reports of morphologic response describe a tendency toward
liquefaction of the metastatic deposits before a significant reduction in size
occurs, which may take up to several months
[8]. Histopathologically, there
is a reduction in the number of cells, although anomalous CD117 positive cells
may persist. A hypocellular myxohyaline stroma with prominent hemorrhage and
little or no necrosis is also found
[8]. Although there is no
histopathologic proof, we hypothesize that in our case, the calcification of
the myxohyaline and hemorrhagic stroma led to the presentation on CT after
treatment. To our knowledge, this presentation has not been previously
reported in the literature.
References
- Miettinen MM, Monihan J, Sarlomo-Rikala M, et al. Gastrointestinal
stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and
mesentery: clinicopathologic and immunohistochemical study of 26 cases.
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Introduction
Case Report
