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Gastrointestinal Stromal Tumor of the Uterus: A Case Report With Genetic Analyses of c-kit and PDGFRA Genes

Terada, Tadashi M.D., Ph.D.

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International Journal of Gynecological Pathology: January 2009 - Volume 28 - Issue 1 - p 29-34
doi: 10.1097/PGP.0b013e3181808000
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Gastrointestinal stromal tumors (GIST) were once considered smooth muscle or neurogenic tumors, but recent knowledge of the c-kit gene and platelet-derived growth factor receptor α (PDGFRA) gene have reported that GIST is associated with gain-of-function mutations of the c-kit gene and, less frequently, of the PDGFRA gene (1,2). GIST is believed to be derived from interstitial cells of Cajal (ICC) (pacemaker cells), which are present in the muscular layer of gastrointestinal walls (3–5). ICC expresses KIT protein (CD117) and CD34 (3). In practice, immunohistochemical demonstration of KIT and/or CD34 is a marker for a diagnosis of GIST (3).

Mesenchymal tumors resembling GIST and positive for KIT have been shown to be present in the soft tissue (6) and, less frequently, in abdominal organs such as the liver (7), gall bladder (8,9), pancreas (10,11), serosa (12), urinary bladder (13), fallopian tube (14), and vulvovaginal septum (15) other than the gastrointestinal tract. Such tumors are called extragastrointestinal stromal tumor. GIST in the uterus has been reported in the literature only once (16). This case is reported and compared with normal myometrium.


Clinical Summary

A 74-year-old Japanese woman was admitted to our hospital because of pelvic pain. Blood laboratory examination showed no significant abnormalities. Imaging modalities, including computed tomography and magnetic resonance imaging, revealed a large tumor in the posterior aspect of the uterus (Fig. 1). Enucleation of the tumor was performed under the clinical diagnosis of uterine tumor which was suspicious of subserosal leiomyoma. Hysterectomy was not performed. During the operation, the tumor was found to be located in the posterior uterus and attached to the uterus, similar to a subserosal leiomyoma, and no attachment to the gastrointestinal organs was recognized. Pathologically, the lesion was diagnosed as GIST, as described below. The patient was treated with imatinib. No recurrence or metastasis has been recognized 2 years after the operation.

FIG. 1.
FIG. 1.:
Computed tomography findings. A large tumor (long arrow) is present in the posterior aspect of the uterus (short arrow). The tumor is attached to the uterus.

Materials and Methods

The uterine tumor and 5 cases of normal uterus with resected ovarian benign tumors were fixed in 10% formalin and embedded in paraffin. Several 3-μm sections were cut from each paraffin block, and 1 was stained with hematoxylin and eosin.

Immunohistochemical studies were performed by Dako's Envision method, as previously described (17). The antibodies used were KIT (polyclonal, dilution 1:100, no pretreatment, Dako Corp, Glostrup, Denmark), CD34 (QBEND10, prediluted, microwave pretreatment, Dako), vimentin (Vim 3B4, 1:200, microwave pretreatment, Dako), PDGFRA (polyclonal, 1:100, microwave pretreatment, Santa Cruz, California), desmin (D33, 1:100, proteinase pretreatment, Dako), α-smooth muscle actin (1A4, 1:1000, no pretreatment, Dako), S100 protein (polyclonal, 1:1000, no pretreatment, Dako), p53 protein (DO7, 1:50, microwave pretreatment, Dako), melanosome (HMB45, 1:50, proteinase pretreatment, Dako), and Ki-67 antigen (MIB1, 1:100, microwave pretreatment, Dako).

Genetic analyses of the c-kit gene (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) were performed by the polymerase chain reaction (PCR) direct sequencing method. The exons of both genes were selected because they are frequent mutation sites (3–5). The primers are shown in Table 1. In brief, genomic DNA was extracted from paraffin blocks with proteinase K digestion and phenol/chloroform extraction, and subjected to PCR for 40 cycles (94°C for 1 min, 52°C for 1 min, and 72°C for 1 min), using a thermal cycler (GeneAmp PCR system 9700, Applied Biosystems, ABI, California). The annealing temperature was 53°C. PCR products were then subjected to electrophoresis in 2% agarose gel with ethidium bromide, and the PCR products were extracted. They were subjected to a computed automatic DNA sequencer (ABI PRIZM 3100 Genetic Analyzer, Applied Biosystems, ABI, California).

Primer sequence


Grossly, the tumor was relatively soft, tan in color, and measured 13×15×12 cm (Fig. 2). Microscopically, the tumor consisted of cellular atypical spindle cells with relatively hyperchromatic nuclei (Fig. 3A). A mild degree of nuclear pleomorphism was recognized. Necrotic areas were focally present. Mitotic figures were noted in 3 of 50 high-power fields. No epithelioid cells were recognized.

FIG. 2.
FIG. 2.:
Gross findings of the resected tumor. The tumor is tan and large.
FIG. 3.
FIG. 3.:
A, Histology of the tumor. The tumor is composed of cellular spindle cells. Hematoxylin and eosin, 400×. B, KIT immunostaining of the tumor. KIT is diffusely and strongly positive in the tumor cells, 200×. C, CD34 immunostaining of the tumor. CD34 is diffusely and strongly positive in the tumor cells, 200×. D, Platelet-derived growth factor receptor α (PDGFRA) immunostaining of the tumor. PDGFRA is weakly positive, 200×. E, KIT immunostaining of the normal myometrium of the normal uterus. KIT-positive stromal cells are scattered, 200×.

Immunohistochemically, the tumor cells were strongly positive for KIT (Fig. 3B), CD34 (Fig. 3C), and vimentin, and weakly positive for PDGFRA (Fig. 3D). They were negative for α-smooth muscle actin, S100 protein, HMB45, and desmin. Ki-67 labeling was 3%. Five normal uteruses used as controls showed KIT-positive and CD34-positive scattered spindle cells in the myometrium (Fig. 3E).

Genetic analyses of the c-kit gene (exons 9, 11, 13, and 17) and of the PDGFRA gene (exons 12 and 18) revealed a point mutation at codon 559 (GTT→GAT) of exon 11 of the c-kit gene (Fig. 4). Other exons showed no abnormalities. The 5 normal uteruses showed no genetic abnormalities of the 2 genes.

FIG. 4.
FIG. 4.:
Computer analysis of a part of the exon 11 of the c-kit gene. A mutation at codon 559 (GTT→GAT) is recognized.


In 2005, Wingen et al. (16) reported a uterine tumor positive for KIT and c-kit mutations, and insisted that this case was the first case of GIST in the literature. The present case was positive for KIT and c-kit mutations, suggesting that it is true GIST, and therefore the second case of GIST of the uterus. In the gynecologic field, GIST has been reported in the fallopian tubes (14) and vulvovaginal septum (15). Some researchers have claimed that extra-GIST are derived from the gastrointestinal tract, representing tumors that for some reason have detached from their gastrointestinal origin during development (4); however, this hypothesis has not been fully supported. The origin of the present case is the uterus because the tumor was attached only to the uterus. The possibility that the present tumor was derived from a gastrointestinal organ, detached from it, and finally attached to the uterus, is unlikely; therefore, it was concluded that the present tumor is a uterine tumor.

The diagnosis of GIST in the present case seems conclusive. The differential diagnosis involves KIT-positive non-GIST tumors, such as, small round cell tumors, myeloid tumors, mast cell neoplasm, some carcinomas (germ cell tumor and small cell carcinoma), and malignant melanoma (18). In the gynecologic field, it has been reported that some uterine sarcomas, including leiomyosarcomas, express KIT protein but such tumors lack mutations of the c-kit gene (19,20). The present case is therefore not a KIT-positive non-GIST uterine tumor in histology, immunohistochemistry, and molecular analysis.

The present study showed scattering KIT-positive and CD34-positive mesenchymal cells in the myometrium of the normal uteruses. Such stromal cells may be ICC or ICC-like cells although some may be mast cells. In recent years, ICC-like cells or ICC have been described in various organs, excluding the gastrointestinal tract (21). Ciontea et al. (22) revealed ICC-like cells in the myometrium by various techniques including KIT immunostaining and electron microscopy; therefore, the present case may be derived from ICC or ICC-like cells physiologically present in the myometrium. The present case also suggests that unusual spindle or epithelioid cell tumors of the uterus should be examined by KIT and CD34 immunostaining.

GIST is thought to be a potentially malignant tumor (3). Its malignant potential has been assessed using various parameters, such as tumor size, mitotic figures, necrosis, cell type, and Ki-67 labeling (4,23–26); however, the parameters and results vary among observers. For example, Miettinen and Lasota (4) and Miettinen et al. (24) categorized GISTs into 8 groups depending on the tumor size and mitotic rate. According to the World Health Organization (WHO) criteria (26), the malignant potential is assessed by tumor size, mitotic count, DNA-aneuploidy, and the cell proliferative index. Tumors less than 5 cm are usually benign, 5 to 10 cm uncertain malignant potential, and those of more than 10 cm are usually malignant. A mitotic count of less than 5/50 high-power fields has low malignant potential, and more than 10 is usually malignant. A Ki-67 index of more than 10% reflects higher malignant potential. Taken together, the present case is low-grade malignant according to the WHO criteria (26).

Hasegawa et al. (23) reported that a tumor size of less than 5 cm is low risk, 5 to 10 cm is intermediate risk, and more than 10 cm is high risk. The present case is high risk in the tumor size. Mitotic figures less than 5/50 high-power field is low risk, 5 to 10 intermediate risk, and more than 10 is high risk. The present case is low risk from the mitotic count. Necrosis is high risk, so the present case is high risk. Ki-67 labeling is related to the GIST risk. The present case is 3%, indicating low risk. Taken together, the present case is a GIST of intermediate risk according to the criteria of Hasegawa et al. (23).

The present study examined c-kit and PDGFRA genes. It was found that the present case showed a point mutation of exon 11 of the c-kit gene. It has been found that the mutation percentage of the c-kit gene is 80% in exon 11, 15% in exon 9, and less than 2% in exons 13 and 17 (3). The mutations percentage of the PDGFRA gene is 10% in exon 18 and less than 2% in exons 12 and 14 (3); therefore, the present case showed a common mutation pattern.

Imatinib has been developed to treat GIST (3,4), and was used for the present case. Imatinib is effective in GIST cases with c-kit mutations in exon 11 (3,4), and may have been effective in the present case because neither recurrence nor metastasis has been recognized 2 years after the operation.

In summary, a very rare case of uterine GIST with a point mutation of exon 11 of the c-kit gene is reported.


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Uterus; GIST; c-kit; PDGFA

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