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ETV6-NTRK3–Positive Inflammatory Myofibroblastic Tumor of the Ileum

Report of an Infantile Case and Review of the Differential Diagnosis of Pediatric Intestinal Polypoid Lesions

Tanaka, Mio MD, PhD*; Terada, Nanako*; Yoshida, Misa MD, PhD*; Shinkai, Masato MD, PhD; Tanaka, Yukichi MD, PhD*

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doi: 10.1097/PCR.0000000000000352
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Abstract

Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblastic cell proliferation and often prominent inflammatory cell infiltration, and they occur predominantly in the abdomen, retroperitoneum, or pelvis of children and young adults.1 Inflammatory myofibroblastic tumors are sometimes found in the intestine and occasionally cause intestinal obstruction.2 Anaplastic lymphoma kinase (ALK) translocation is sometimes seen in IMTs, and an ALK translocation frequency of 60% was reported in a series of gastrointestinal tract/mesenteric IMTs.3

Recently, histologically definitive, ALK-negative IMTs harboring the ETS variant 6 (ETV6)neurotrophic receptor tyrosine kinase 3 (NTRK3) fusion gene have been reported.4–7 The ETV6-NTRK3 fusion gene has been detected in various tumors, including congenital/infantile fibrosarcoma (CIF), congenital mesoblastic nephroma, secretory breast carcinoma, and mammary analog secretory carcinoma.

We report an infantile case of a polyp arising in the ileum, diagnosed histologically as IMT and harboring the ETV6-NTRK3 fusion gene, and discuss the differential diagnosis of IMTs from other pediatric intestinal polypoid lesions.

CASE REPORT

A male infant had no overt problems until 2 months of age, when intussusception occurred along with vomiting. An ultrasound examination suggested an intestinal polyp and associated ileoileal intussusception. Open reduction of the intussusception was performed, and a polypoid lesion was found at the intussusceptum, located 40 cm from the ligament of Treitz. Polypectomy was performed. The postoperative course was uneventful, and follow-up clinical and ultrasonic evaluations at 2 years postoperatively indicated that the patient is healthy and disease-free.

On gross examination, the resected polyp was 23 × 18 × 16 mm and had a short stalk of 13-mm diameter. In cut section, the polyp had a homogenous fibrous appearance with a reddish tan periphery and yellowish white center (Fig. 1A). No cystic or necrotic regions were observed. Histologically, the lesion was located in the submucosa and partly involved the muscle layer. The surface of the polypoid lesion was mostly eroded, whereas the stalk was covered with mostly normal small intestinal mucosa. At the periphery of the lesion, proliferation of capillary-sized vessels (granulation tissue) was apparent (Figs. 1B, C). At the center, the lesion was composed of fascicles of fibroblastic and myofibroblastic spindle cells with oval to round nuclei within an inflammatory stroma composed of mainly lymphocytes and neutrophils (Fig. 1D). Although approximately 20 mitotic figures were seen in the spindle cells in 10 high-power fields (×400), no overt atypical cellular features were evident. Immunohistochemical evaluation (Table 1) showed that most of the spindle cells were positive for desmin and smooth muscle actin (Fig. 1E) but negative for ALK (Fig. 1F), myogenin, MyoD1, S100β protein, epithelial membrane antigen, cytokeratins, and CD68.

FIGURE 1
FIGURE 1:
Gross (A) and microscopic (B–D) findings and immunohistochemical studies (E, F) of the resected specimen. A, The specimen is a polypoid lesion with a short stalk. The cut section reveals homogeneous fibrous appearance, with a reddish tan periphery and yellowish white center. B and C, The surface of the polypoid lesion is mostly eroded. At the periphery, proliferation of capillary-sized vessels is observed (low [B] and high [C] magnification). D, At the center of the lesion, fascicles of fibroblastic and myofibroblastic spindled cells with infiltration of inflammatory cells, mainly lymphocytes and neutrophils, are observed. E and F, On immunohistochemistry, the spindled cells are focally positive for smooth muscle actin (E) and negative for ALK (F).
TABLE 1
TABLE 1:
Antibodies Used for Immunohistochemistry

ETV6-NTRK3 fusion gene was detected by reverse transcription–polymerase chain reaction (RT-PCR) using a fresh frozen sample of the polypoid tissue obtained from the polypectomy, and direct sequencing of the PCR products further revealed that exon 5 of ETV6 was fused to exon 15 of NTRK3 (Fig. 2).

FIGURE 2
FIGURE 2:
Result of the RT-PCR assay of the resected specimen. Direct sequencing of the purified RT-PCR products reveals chimeric transcripts consisting of ETV6 exon 5 fused to NTRK3 exon 15.

DISCUSSION

We have reported a case of a 2-month-old boy who developed intussusception associated with an ileal polyp, which was diagnosed histologically as IMT. The ETV6-NTRK3 chimeric gene was detected in the tumor. Only five cases of IMT harboring the ETV6-NTRK3 chimeric gene, occurring in the lung, liver, uterus, and soft tissue, have been reported previously.4–7 To the best of our knowledge, this is the first report of an intestinal IMT possessing the ETV6-NTRK3 chimeric gene.

The ETV6-NTRK3 chimeric gene has been detected in several tumor types, including CIF, which occurs mainly in infants. According to a literature review, approximately 20 cases of intestinal CIF, five of which possessed the ETV6-NTRK3 chimeric gene,8–12 have been reported; the age of these patients ranged from 0 to 11 days old. Whereas most CIFs of soft tissue are detected in children younger than 2 years, intestinal CIFs are detected earlier, often during the newborn period, probably because they cause intussusception or intestinal obstruction and thus result in clinical symptoms. In contrast, in our literature review, we identified more than 40 cases of intestinal IMT. Some of these tumors were ALK-positive, and the age range of the patients was 2 months to 85 years. At 2 months of age, our patient is the youngest reported case of intestinal IMT, but slightly older than patients with intestinal CIF.

Histologically, the tumor in our patient was considered IMT rather than CIF because of its cellularity, degree of nuclear atypia, and the considerable extent of inflammatory cell infiltration. The periphery of the polyp was reddish tan on gross examination, and proliferation of capillary-sized vessels was observed histologically. Florid vascular proliferation of colon associated with intussusception was described in a literature.13

Congenital/infantile fibrosarcomas histologically mimicking a vascular malformation have been reported.14,15 Furthermore, the surface of an intestinal polyp causing intussusception may show erosion and granulation tissue. Intestinal polyps diagnosed as pyogenic granuloma, some of which might show considerably high cellularity, or as ALK-negative IMTs, should be tested for the presence of ETV6 rearrangement. The histology of tumors diagnosed as CIF with proven ETV6 rearrangement should be reconfirmed for the differential diagnosis of IMT.

Total resection is often proposed for both IMTs and CIFs, and adjuvant chemotherapy is usually unnecessary if the tumor is removed completely. Chemotherapy is often effective for CIFs and IMTs that are clinically or histologically assumed to be malignant. The treatment strategy is often the same for IMTs and CIFs, whereas pyogenic granulomas should be treated as benign lesions. Careful histological diagnosis, sometimes combined with molecular analysis, is required to understand the nature of the tumor and provide the patient with the appropriate information.

CONCLUSIONS

We report an infantile case of an intestinal polyp, which was diagnosed by histology and immunohistochemistry as an ALK-negative IMT, and the ETV6-NTRK3 fusion gene was detected by RT-PCR. To the best of our knowledge, this is the first case of an intestinal IMT harboring ETV6-NTRK3. In the differential diagnosis of ALK-negative IMTs or hemangiomatous lesion showing considerably high cellularity, ETV6 rearrangement should be considered.

REFERENCES

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Keywords:

ETV6-NTRK3; inflammatory myofibroblastic tumor; intestinal polyp

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