Regarding the case presented by Dr. Cruz-Contreras et al.,1 on a “Neuroendocrine tumor of the ileum”, the authors conclude with a diagnosis that is, in itself, contradictory. Therefore, several points should be clarified, including the current nomenclature.

The authors state at the beginning of their scientific letter that neuroendocrine tumors originate from cells located within the neuroendocrine system, but it should be clarified that they also arise in organs that are not considered part of that system, such as the respiratory tract or genital tract, among others.2

Following the diagnostic approach, the conclusion reached was “carcinoma with a moderately differentiated neuroendocrine pattern...and confirmatory immunohistochemical tests”. First, it is important to clarify that the term “neuroendocrine” does not refer to a pattern, but rather to a type of differentiation. A pattern refers to the form of growth and arrangement (or architecture) of cells, such as “nested”, “solid”, “trabecular”, etc.

More important is awareness of the latest edition (the fifth) of the World Health Organization (WHO) classification of neuroendocrine neoplasms (NENs).2 They are divided into well differentiated neuroendocrine tumors (NETs), which are then subdivided into three grades, according to the proliferation index (G1, G2, and G3); on the other hand, there are neuroendocrine carcinomas (NECs), which are morphologically divided into large cell NECs and small cell NECs (Table 1). By definition, NECs are poorly differentiated; in fact, the current WHO classification does not recognize a “moderately differentiated” category.

The distinction between a NET and a NEC is primarily morphologic, and when there is doubt, especially in grade 3 NETs, immunohistochemical markers, such as ATRX and p53, may be helpful in differentiating them. Even though NETs and NECs both exhibit neuroendocrine differentiation, they are considered biologically distinct tumors, arising from different molecular pathways.3 Neuroendocrine differentiation is corroborated through markers, such as chromogranin, synaptophysin (the least specific), and INSM1. The use of CD56 is not currently recommended.

Their adequate classification is vitally important, given that treatment and prognosis are radically different. NETs tend to be managed with curative resections, somatostatin analogues, peptide receptor radionuclide therapy, or in selected cases, alkylate-based adjuvant therapy. NECs are treated with aggressive systemic therapies due to their highly malignant behavior, including platinum/etoposide-based chemotherapy, with survival rates of less than one year despite treatment.4

Specifically mentioning Ki-67 is important because its use is not limited to determining NET grades, and the 10% cutoff point also guides surgical decisions and medical treatment.5

The appropriate classification of NENs has a direct impact on the treatment, follow-up, and prognosis of affected patients. Thus, keeping up to date with terminology and having close communication between the pathologist and clinician are essential.