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Angiogenesis, a process related to tumor growth and malignancy, is stimulated by several growth factors. Among these is vascular endothelial growth factor (VEGF), which acts on endothelial cells by binding with 2 specific receptors, VEGFR1 and VEGFR2. Recent studies have demonstrated that VEGF expression is correlated with microvessel density (MVD) and tumor progression. Digestive endocrine tumors are heterogeneous neoplasms exhibiting variable biological aggressiveness and behavior that often are not predictable on morphologic grounds alone. The aims of this study were to evaluate the expression of VEGF, VEGFR1, and VEGFR2 in digestive endocrine tumors and to examine its correlation with MVD and malignancy. A total of 84 specimens from endocrine neoplasms and normal gut and pancreatic tissue were immunohistochemically studied using specific antibodies directed against VEGF, VEGFR1, VEGFR2, endothelial antigens, and gastroenteropancreatic hormones. Ultrastructural immunocytochemistry was performed to identify the cellular localization of VEGF and the VEGFRs. In normal tissues, VEGF immunoreactivity was detected in G cells and PP cells. Ultrastructurally, VEGF was localized within secretory granules. The VEGFRs were not significantly expressed by normal endocrine cells. VEGF-immunoreactive (IR) cells were detected in 40 of 83 tumors, mainly G cell and enterochromaffin cell neoplasms. VEGFR1-IR cells were found in 44 of 82 tumors, and VEGFR2-IR cells were found in 55 of 82 tumors, with no predilection for any specific tumor type. The expression of VEGF and its receptors did not correlate with MVD or malignancy. These results suggest that in normal tissues, endothelial functions may be regulated by VEGF produced by some endocrine cells and that a VEGF/VEGFR binding mechanism may be involved in tumorigenesis, but not in tumor progression and aggressiveness. HUM PATHOL 34:18-27. Copyright 2003, Elsevier Science (USA). All rights reserved.

In April, 2004, a 62-year-old man with epistaxis, rhinorrhea, and sensation of nasal obstruction attended an appointment at the ear, nose, and throat department that found a solid mass of the right nasal cavity with no clinical evidence of lymph-node or distant metastases as confi rmed by CT and MRI (fi gure 1A). Biopsy of the mass revealed a proliferation of undiff erentiated cells with scant cytoplasm, hyper chromatic nuclei, and high mitotic rate, which formed infi ltrating nests in the stroma of the nasal mucosa (fi gure 2A). Tumour cells showed immuno reactivity for cytokeratin AE1/AE3, synaptophysin, neuron-specifi c enolase (fi gure 2B), CD56, and p53, but not for CD45. The histological features and the immunophenotype were suggestive of a poorly diff erentiated neuroendocrine small-cell carcinoma of the nasal cavity. The patient underwent somatostatin-receptor scintigraphy, which showed tracer uptake in the nasal region only. Blood concentrations of neuron-specifi c enolase, chromogranin A, carcinoembryonic antigen, and Cyfra 21-1 were unremarkable. The patient was treated with carboplatin (area under curve=6) on day 1 and etoposide (100 mg/m) on days 1–3 for seven cycles from May to October, 2004. In October, 2004, CT and MRI showed partial reduction of the mass (fi gure 1B). The patient sub sequently underwent transcranial-endoscopic endo nasal resection of the neoplasm with partial removal of the ethmoid and inferior conchae, the nasal septum, the fl oor and the lateral walls of the right nasal cavity, and the right maxillary sinus. Histologically, the tumour showed two main components. The predominant component was represented by clusters of mature synaptophysin and CD56-positive ganglion cells dispersed in a schwannianlike glial fi brillary acidic protein (GFAP)-positive background (fi gure 2C). Ganglion cells also stained positively for somatostain-receptor 2A (fi gure 2D). The second component was characterised by a proliferation of malignant cells, with abundant eosinophilic cytoplasm strongly positive for actin and desmin (fi gures 2E and 2F). This component was consistent with a rhabdomyosarcoma. The proliferation of undiff erentiated cells seen in the nasal biopsy done during the fi rst clinical investigation was not clearly identifi ed. Only scattered malignant cells that were immunoreactive for cytokeratin AE1/AE3 were seen in the surgically resected tumour tissue. The occurrence of a rhabdomyosarcoma associated with ganglio neuromatous and undiff erentiated components led us to diagnose a malignant ectomesenchymoma. Postsurgical adjuvant treatment with concurrent chemotherapy (weekly cisplatin [45 mg total] and radiotherapy [50 Gy total]) to the right nasal cavity was given from March to April, 2005. The patient was still alive at last follow-up in September, 2006, and had complete remission of the tumour, which was confi rmed both radiologically (fi gure 1C) and histologically. Malignant ectomesenchymoma is a rare multiphenotypic soft-tissue tumour with both mesenchymal and neuroectodermal components. It is believed to arise from pluripotential migratory neural crest cells (ectomesenchym) that can diff erentiate into neuroectodermal and mesenchymal tissues. The mesenchymal component usually consists of rhabdomyoblastic elements, although other malignant mesenchymal components have also been described. Neuroectodermal elements are mainly represented by ganglion cells and neuroma-like structures. About 50 cases have been reported in studies published in English. This neoplasm most frequently aff ects children, although a few cases in Lancet Oncol 2007; 8: 358–60