Clinical implications of mismatch repair deficiency screening in patients with mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN)

Abstract

Introduction

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) are rare tumors, mainly encountered in the gastroenteropancreatic tract. Based on the limited available data, MiNEN is usually a highly aggressive neoplasm combining a high-grade neuroendocrine and a non-neuroendocrine component, associated with a poor prognostic outlook. Deficient DNA mismatch repair (MMR) results in microsatellite instability, which is a useful screening marker for identifying patients with Lynch syndrome and a prognostic factor for chemotherapeutic interventions. Little information on MMR status in MiNEN is available in published studies. Therefore, the purpose of this study was to explore the status and putative role of MMR on MiNEN.

Methods

We investigated the MMR status in 44 cases and characterized their clinicopathological features and prognoses. Immunohistochemistry was performed for four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2).

Results

Mean age at diagnosis was 61 years, and 75% of the patients were male. Lymph node metastases were observed in 14 (35.9%) patients. The most common tumor localizations were gastric (28 patients, 63.6%). Lack of immunohistochemical expression of MMR proteins was shown in 38.6% of cases. The common deletion rates of one or more proteins were 29.4% (5/17) for MLH1/PMS2 and 23.5% (4/17) for MLH1. Correlation between clinicopathological parameters showed that MMR deficiency was significantly associated with early TNM stage and better prognoses in patients with MiNEN.

Conclusion

MiNENs showed frequent losses of MMR protein expression, which contributes to the knowledge of the pathological and clinical aspects of MiNEN tumors.

Introduction

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) are defined by a combination of at least two morphologically different populations of neoplastic cells, one neuroendocrine and one non-neuroendocrine, with each component accounting for at least 30% of the neoplasm [1]. Data from the current literature are limited and inconsistent, largely due to variable tumor descriptors and differing inclusion criteria in patient-based studies. Mixed neuroendocrine non-neuroendocrine neoplasms have historically had numerous definitions. In 2010, the World Health Organization (WHO) classified such neoplasms of the gastrointestinal tract as “mixed adenoneuroendocrine carcinomas” (MANECs), which histologically comprised two components: an adenocarcinoma, and a neuroendocrine element, each of which represented at least 30% of the tumor and was malignant [1]. In 2017, MANECs of the pancreas were renamed “mixed neuroendocrine non-neuroendocrine neoplasms” (MiNENs), and in 2019, this classification was extended to all neoplasms of the digestive tract which met the MiNEN diagnostic criteria [1,2].

Based on available evidence, MiNEN is an extremely rare diagnosis. It is an aggressive malignancy associated with poor survival outcomes, with the majority of cases bearing a high-grade neuroendocrine component [3]. Owing to its dual histology, the physiological behavior and final outcome of MiNEN differs from that of separate neuroendocrine and non-neuroendocrine carcinomas. However, despite formal recognition of the dual nature of these tumors, established and agreed clinical practice guidelines for treatment of patients with MiNEN have yet to be ratified. Clinically, MiNEN typically presents at an advanced stage, requiring very intensive treatment strategies.

It is well known that many genetic factors provide critical information to guide antineoplastic therapy for patients. The most-frequent alterations in MiNEN involve well-characterized oncogenes and/or their protein products, such as TP53, KRAS, BRAF, RB1, PTEN, APC, PI3KCA, and MYC [4]; microsatellite instability (MSI) has been proposed as putative driver of events in MiNEN [5]. MSI refers to the increase of highly repetitive DNA sequences (microsatellites) typically caused by mutations of mismatch repair (MMR) genes used to repair DNA replication errors, which induces the formation of tumors [6]. Numerous studies have found that MSI detection can be used as primary screening for Lynch syndrome, and it is an important prognostic factor in colorectal cancer and a prognostic molecular biomarker for adjuvant chemotherapy and immunotherapy [[7], [8], [9]]. MSI has been proposed as a putative driver of MiNEN [10]. While genetic testing remains the gold standard for MSI detection, the College of American Pathologists recommends an initial four antibody immunohistochemistry panel for MLH1, MSH2, MSH6, and PMS2 to detect the presence or absence of protein products, which is the most widely available and most commonly used method of screening for deficient mismatch repair (dMMR) [11]. Depletion of expression of at least one MMR protein provides compelling indirect evidence for MSI. Furthermore, MSI-high (MSI-H) tumors have shown some resistance to conventional chemotherapeutic agents [12]. The therapeutic benefits of PD-1 inhibitors and other immunotherapies in treating MSI-H and dMMR tumors have dramatically increased the clinical demand for MSI testing, even in tumor types with low expected MSI rates [13].

Although MMR deficiency in colorectal cancer has been extensively investigated, there is very limited published data on the role of MMR status in MiNEN, and the relationship between MMR status and clinicopathological features is also unclear. This study retrospectively collected data from a series of patients with a diagnosis of MiNEN compliant with the 2019 WHO classification, assessed the utility of simple and fast immunohistochemistry techniques in detecting MMR status in MiNEN, and evaluated the correlation between dMMR phenotypes and various clinical parameters.