Gastric Inflammatory Myofibroblastic Tumors in Children: An Unpredictable Course

Inflammatory myofibroblastic tumors (IMT) are lesions that most often affect young adults and children (1). These tumors have been found in numerous extrapulmonary sites, but rarely in the stomach (1). It is unknown whether this process is reactive or neoplastic. Despite similar pathologic features (1,2), some patients have a favorable course after surgical resection, whereas in others the tumors recur and occasionally lead to death. Inflammatory myofibroblastic tumors probably constitute a heterogeneous spectrum of entities that include reactive lesions and neoplastic, benign, and malignant mesenchymal tumors (1,3,4). We report two pediatric cases of gastric IMT with opposite courses, illustrating the polymorphism of these lesions and raising questions about prognosis and treatment. CASE REPORTS Case 1 A 12-year-old boy was admitted because of abdominal pain of 2 months and a 4-kg weight loss. Biologic tests revealed anemia associated with an elevated erythrocyte sedimentation rate. Endoscopy showed an ulcerated tumor of the posterior wall of the gastric body. Evaluation of biopsy specimens suggested IMT. Abdominal computed tomography showed an 8-cm, lobulated, and calcified tumor that had developed into the gastric wall and expanded to the splenic hilum without spreading to adjacent organs (Fig. 1). The patient underwent partial gastrectomy with splenic and gastroepiploic lymph node dissection. After a 4-year follow-up, no recurrence was observed.FIG. 1.: Abdominal computed tomography scan: voluminous heterogeneous mass in stomach (arrow). R, right; L, left.Pathologic and Genetic Findings The gross specimen consisted of a gastric multinodular mass protruding into the lumen and extending to the serosal surface. The cut surface was rubbery, gray-white, partially calcified, and without necrosis. Microscopic sections showed an infiltrative proliferation of bland spindle-shaped cells, arranged in interlacing bundles and whorls, or arranged loosely in a collagenous or myxoid background (Fig. 2). Numerous lymphocytes and plasma cells were scattered among them. Mitoses were scarce. Calcifications and ossifications were apparent in areas of marked hyalinization. Lymph nodes were not involved. Helicobacter pylori were not detected in the adjacent gastric mucosa. Immunohistochemical evaluation revealed cytoplasmic staining of spindle-shaped cells for vimentin and α–smooth muscle actin, whereas desmin, muscle-specific actin, S-100 protein, EMA, cytokeratin, NSE, CD68, bcl-2, and p53 were not expressed. The proliferative index (Ki67) was less than 5%. Ebstein-Barr virus RNA was not detected with in situ hybridization. Ultrastructural observation confirmed that the spindle-shaped cells consisted of myofibroblasts with a prominent network of rough endoplasmic reticulum, peripheral bundles of thin filaments, and discontinuous external lamina. Flow cytometry showed that this lesion was diploid.FIG. 2.: Bland elongated cells arranged in fascicles and admixed with plasma cells and lymphocytes (hematoxylin–eosin stain ×160).Case 2 Clinical Features An 11-year-old boy was admitted for persistent asthenia, inflammatory anemia, and 2 months of scapular pain. Thoracoabdominal computed tomography showed a heterogeneous 12-cm gastric tumor expanding into the lower third of the esophagus and into the mediastinum around the left pulmonary hilus. Barium opacification showed esophageal stenosis, confirmed by preoperative endoscopy, which showed a translucent, soft, and elevated tumor that narrowed the esophageal lumen. Evaluation of biopsy specimens suggested IMT. The patient underwent a partial esophagogastrectomy with left pneumonectomy. Because of the tumor extent, adjuvant chemotherapy was started with ifosfamide, vincristine, and actinomycin D. Nevertheless, a right pulmonary superior lobar localization developed rapidly and was resected. An uncontrolled abdominal recurrence ensued, despite three successive chemotherapy courses (vinblastine therapy; ifosfamide, carboplatin, and etoposide; and carboplatin, epirubicin, and vincristine). The child died 11 months after initial diagnosis. Pathologic and Genetic Findings At gross examination, the gastric wall was involved, with a multinodular lesion exhibiting gelatinous or firm, white, and whorled areas. This lesion spread through the gastric and esophageal walls, forming fingerlike projections around the left pulmonary hilus. The lesion was polymorphous at the microscopic level. The main features were the same as those observed in the previous case: a proliferation of spindle-shaped cells with myofibroblastic differentiation, and a diffuse inflammatory infiltrate composed of plasma cells and lymphocytes. The immunohistochemical profile of spindle-shaped cells was the same in both cases. These areas merged gradually into sheets of uncohesive round histiocytoid or ganglionlike cells characterized by vesicular nuclei, large prominent nucleoli, and abundant eosinophilic cytoplasm (Fig. 3). They were scattered in a myxoid matrix in which necrosis foci could be observed. Mitoses were quite numerous (1 mitosis/high power field). These cells expressed only vimentin, and about 30% showed nuclear staining for p53. The proliferative index (Ki67) reached 10%. As in the previous case, H. pylori and Epstein-Barr virus were not detected. A secondary pulmonary lesion was composed of spindle cells and lymphoplasmacytic infiltrate, with neither atypia nor histiocytoid cells. Electron microscopy was not available.FIG. 3.: Plump atypical cells in a myxoid background (hematoxylin– eosin stain ×200).Cytogenetic analysis of the primary lesion demonstrated a peridiploid clonal population: 45,XY,−6, −10,der(12)t(12; 14)(p13; q12),−14,add(19)(p13.2), +add(20)(q13.2),−22,+2mar for 12 mitoses. DISCUSSION Gastric IMT are very unusual in children. To our knowledge, 15 pediatric cases have been reported in the literature (2,5–10). The tumors predominantly affect females (ratio, 4 to 1) between 4 months and 15 years of age (median, 7 years) (6). They are often associated with weight loss, fever, asthenia, and an inflammatory biologic syndrome (anemia, thrombocytosis, elevated erythrocyte sedimentation rate, and hypergammaglobulinemia) (5,6). These abnormalities regress after surgical resection but may reappear during disease recurrence (5). Abdominal pain, dysphagia, vomiting, upper gastrointestinal hemorrhage, and melena are more infrequent symptoms, and suggest a gastrointestinal origin (5,6). These lesions are often large, ranging from 3 cm to 10 cm (average, 7 cm) and can be located anywhere in the stomach: the cardia, antrum, or prepyloric region (6). Gross examination has showed that the tumors grow as whitish or translucent, single or multiple, sometimes ulcerated, endoluminal polypoid nodules (6,9). They are infiltrative lesions and often extend through the gastric wall, sometimes reaching adjacent organs, including esophagus, duodenum, peritoneal cavity, spleen, pancreas, and liver (6,8,9). These features mimic malignancy on endoscopy and radiology (8). Nevertheless, most patients have a favorable course (5). Indeed, for the 13 children followed between 11 months to 12 years (median, 4 years), only one local recurrence was reported after large surgical excision, 16 months after the initial diagnosis, and the patient successfully recovered after a second resection (7). Neither metastasis nor death are directly related to gastric IMT in children (5,6). Diagnosis suggested by evaluation of biopsy specimens is usually confirmed with examination of gastric gross specimens (6). Differential pathologic diagnoses are scant. Because children are affected, stromal and smooth muscle tumors can be evoked, especially the inflammatory subgroup of gastrointestinal autonomic nerve tumors (12,13), along with leiomyosarcomas (14). Immunochemical and ultrastructural studies are useful. Rhabdomyosarcoma, infantile myofibromatosis, and abdominal fibromatosis are much less inflammatory (2,11). Gastric inflammatory fibroid polyp is a particular entity; some consider it to be an endoluminal IMT (11). However, its smaller size, well-defined margins, restriction to the mucosa or the submucosa, frequent association with gastric adenoma or adenocarcinoma, CD34 immunoreactivity, and constant innocuous course help to differentiate it from IMT (15,16). Although case no. 1 is similar to previous cases of pediatric gastric IMT already reported in the literature, this is not true of case no. 2, which seems more similar to the inflammatory fibrosarcoma that Meis and Enzinger (2) reported. These authors isolated, from IMT, a group of lesions that were histologically similar but locally more aggressive and that had frequent recurrences, metastatic potential, or a multicentric growth pattern. Such lesions arise only in the abdomen, mesentery, omentum, and retroperitoneum. The major difficulty in diagnosis lies in the lack of morphologic, phenotypic, and genotypic univocal features that would allow prognosis in IMT (2). Age, tumor-associated or systemic symptoms, tumor size, inflammatory infiltrate, degree of cellularity, mitotic rate, and necrosis do not relate to the prognosis (17). In contrast, the presence of nuclear atypia and ganglionlike cells, p53 expression (17), and DNA aneuploidy (1,3,17,18) suggest a more aggressive clinical course, although more extensive data are required for confirmation. Two of the four prognostic factors mentioned above were present in patient no. 2, but none were found in patient no. 1. Gastric IMT etiopathogenesis is still unknown. It may be an aberrant inflammatory repair process perhaps related to H. pylori chronic gastritis (6), or it may be a neoplasm, which is supported by the clonal chromosomal abnormalities observed in some IMT (18–20). The unpredictable prognosis raises questions about complementary treatment. No beneficial effect of chemotherapy or of radiotherapy after surgery has been proven (2,4,5,7). We report two additional cases of pediatric gastric IMT with different behaviors. At this time, pathologists do not consider childhood gastric IMT as definitively benign. Careful clinical, biologic, and radiographic follow-up is required after surgical resection.