CD44v6 expression in gastroenteropancreatic neuroendocrine neoplasms: Clinicopathological correlation and prognosis

Neuroendocrine neoplasms (NENs) are a group of neoplasms originating from neuroendocrine cells in various organs and have features of both neural and endocrine cells. The neural property is a presence of dense core granules similar to serotonergic neuron, while endocrine properties are synthesis and secretion of monoamines and/or peptide hormonal products [1], [2]. The histological diagnosis of NENs is usually confirmed by immunohistochemical detection of synaptophysin, chromogranin A, CD56 and neuron-specific enolase (NSE) [3]. Chromogranin A and synaptophysin are the markers most commonly used for the diagnosis of NENs [4], [5]. Chromogranin A is an acidic protein present in the secretory granules of neuroendocrine cells. Synaptophysin is a component of the presynaptic vesicle membrane.

NENs are relatively uncommon neoplasms that can be found in various organs/tissues, most frequently in the digestive system with histopathological range from well-differentiated to poorly differentiated neuroendocrine tumors. In 2019, with intention to standardize and improve prognosis predictions of this greatly diverse neoplasms, WHO digestive system tumors classification 2019 introduced a new nomenclature and classification for NENs. In this new classification, NENs are graded based on their morphological criterion into well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), and graded further based on the proliferation rate (G1, G2 and G3) [6].

Factors that determine the clinical course and outcome of patients with gastroenteropancreatic NENs (GEP-NENs) are complicated and multifaceted [7], [8]. Generally, NETs are slow growing tumor with good clinical outcome with the 5 years survival rate of 33% in pancreatic NETs (PanNETs), and 65–86% in non-functional PanNETs. However, some NETs behave like a malignant neoplasm with remote metastasis. NETs often require clinical follow-up because metastasis may occur many years after resection of the primary tumor. To predict the prognosis of NETs, several factors such as tumor grading, tumor staging, and Ki-67 proliferation index have been considered [9], [10]. Ki-67 proliferative index has high probability and statistical significance for prediction of the behavior of given NEN [11]. Other prognostic immunohistochemical markers such as CK19, KIT, CD99, p27, and CD44 have been reported, but they have not been fully validated and not routinely used [6].

CD44 is a single-chain type I transmembrane glycoprotein with multiple functions; for example, as an adhesion molecule to hyaluronan and other components of the extracellular matrices such as osteopontin and collagen and matrix metalloproteinases, as a lymphocyte homing receptor, and also involved in hematopoiesis and tumor metastasis [12], [13]. CD44 and its variant isoforms are encoded by one single gene located on chromosome 11 containing 19 exons. Among them, exons 6–15 are designated as variant exons (CD44v1-v10) [14], [15]. CD44 expression level showed significant inverse correlation with lymph node status, remote metastasis, and the mortality of PanNENs. CD44v6 and CD44v9 were downregulated in PanNENs [16]. CD44v6 expression was significantly lower in benign tumors compared to malignant ones [17]. However, in other studies on GEP-NENs, CD44v6 expression was not significantly correlated with lymph node or distant organ metastasis [18], [19].

Since CD44v6 expression in NENs is variable and its correlation with clinical features are controversial, in this study, we investigated the correlation between CD44v6 expression and clinicopathological features in GEP-NENs, with special emphasis on the patients’ survival.

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