Neuroendrocrine tumors of the uterine cervix: A therapeutic challenge for gynecologic oncologists

Highlights

• Histology, pathogenesis and prognosis of cervical neuroendocrine tumors are reviewed.

• The therapeutic approach is mainly adapted from that of lung neuroendocrine tumors.

• A treatment algorithm tailored to tumor stage and extent is suggested.

Abstract

Neuroendocrine tumors (NETs) are aggressive diseases developing from neuroendocrine cells that most frequently involve the gastro-entero-pancreatic tract and the lung, but more rarely are found in almost all body tissues. Limited biological and clinical data are currently available for NETs in uncommon sites, such as female genital tract. NETs represent 0.9% to 1.5% of the tumors of the uterine cervix. They are more likely to have lymph-vascular space invasion and lymph node involvement, and to develop local and distant relapses when compared with the mostly common cervical squamous cell carcinomas or adenocarcinomas. Positive immunostaining for synaptophysin, chromogranin, CD56, and neuron-specific enolase is often detected in cervical NETs .

The most recent editions of the World Health Organization Classification of Gynecologic Tract tumors grouped cervical carcinoid tumor and atypical carcinoid tumor into low-grade NETs and cervical small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma into high-grade NETs. High-risk HPV DNA is detected in almost all cervical high-grade NETs. No treatment guidelines, based on prospective, well-designed clinical trials, are currently available due to the rarity of these tumors. Many authors have reported different multimodality approaches, mainly derived from NETs of the lung. These usually consist in radical hysterectomy followed by adjuvant chemotherapy or concurrent chemoradiation for early stage disease, definitive concurrent chemoradiation sometimes preceded by neoadjuvant chemotherapy and followed by adjuvant chemotherapy for locally advanced disease, and palliative chemotherapy for metastatic disease. In this systematic review, we address the histologic classification of cervical NETs, analyze their pathogenesis and overall prognosis, and evaluate the different treatment modalities described in the literature, in order to offer a possible algorithm that may help the clinicians in diagnosing and treating patients with these uncommon and aggressive malignancies.

Introduction

Neuroendocrine differentiation in tumors is defıned as the secretion into the bloodstream of bioactive substances, usually peptide hormones or bioamines, by the neoplastic cells [1]. Most neuroendocrine tumors (NET)s originate from neuroendocrine cells distributed throughout the gut, the respiratory epithelium, and parafollicular cells within the thyroid. Pituitary, parathyroid, and adrenomedullary neoplasms have certain common characteristics with these tumors but are considered separately. More rarely NETs are found in almost all body tissues [2], [3]. Unlike previously thought, there is emerging evidence that NETs constitute a heterogeneous group of neoplasms. Some of the clinical and pathologic features of these tumors are characteristic of the organ of origin, but other attributes are shared by neuroendocrine neoplasms irrespective of their anatomic site. A variety of different organ-specific systems have been developed for nomenclature, grading, and staging of NETs. Differentiation refers to the extent to which the neoplastic cells resemble their non-neoplastic counterparts, and grade refers to the inherent biologic aggressiveness of the tumor. In general, well differentiated NETs are either low or intermediate grade, and poorly differentiated NETs are considered high grade in all cases. In particular, low grade-NETs and high grade-NETs are actually two different categories of tumors with different etiology, pathogenesis, clinical presentation, pathologic features, molecular alterations, prognosis, and response to therapy. Low grade-NETs typically arise in patients with neuroendocrine neoplastic syndromes, such as Multiple Endocrine Neoplasia (MEN1) or von Hippel Lindau syndrome, and most are relatively indolent. Pathologically, they show architectural and cellular features reminiscent of non-neoplastic neuroendocrine cells, including nested and trabecular growth pattern and coarsely stippled nuclear chromatin. Neurosecretory proteins, in particular chromogranin A and synaptophysin, and other cell markers such as CD56, which is a neural cell adhesion molecule, are commonly present. High grade-NETs are high grade carcinomas with some features associated with the neuroendocrine phenotype and less frequent or limited expression of immunohistochemical markers. Most of our knowledge on NETs derives from tumors of the gastrointestinal tract and lung, and many of the current treatments benefit from the recommendations from pulmonary cancers.

NETs of the uterine cervix are very rare malignancies, and therefore no clear recommendations are currently available for the treatment strategy. Moreover, most are high grade-NETs and are indeed a therapeutic challenge for the gynecologic oncologist. In this systematic review, we firstly reviewed the histologic classification of cervical NETs and secondly, we analyzed the pathogenesis and the overall prognosis of cervical NETs. Thirdly, we evaluated the different treatment modalities described in the literature, in order to offer a possible algorithm that may help the clinicians in diagnosing and treating patients affected by these aggressive diseases.