Two patients with rare mixed adenoneuroendocrine carcinomas of the rectum

Abstract

Mixed adenoneuroendocrine carcinomas of the gastrointestinal tract are until today poorly understood and thus very challenging for interdisciplinary therapy. We herewith report the first case series of patients with a primary mixed adenoneuroendocrine carcinoma of the rectum. Both cases were initially diagnosed as adenocarcinoma and only secondarily with mixed adenoneuroendocrine carcinoma and had a poor outcome due to a rapid tumor progression and resistance to chemotherapy. A 65-year-old female presented with local tumor recurrence and hepatopulmonary metastasis 1 year after primary surgery for adenocarcinoma of the rectum and consecutive radiochemotherapy regimen. Fluorouracil (5-FU) was followed by bevacizumab- and capecitabine-based chemotherapy but had to be discontinued due to side effects and progressive disease. Progressive local pain syndrome accompanied by recurrent bleeding episodes led to a local tumor-debulking operation. Afterward, mixed adenoneuroendocrine carcinoma as the underlying diagnosis in the final histopathological examination was detected. The patient died 3 months after the operation in the context of a fulminant tumor progress. A 63-year-old male patient underwent neoadjuvant radiochemotherapy and laparoscopic rectum resection. After 5 months, postoperative oxaliplatin/capecitabine-based adjuvant chemotherapy was switched to carboplatin/etopsid due to a progressive polyneuropathy and biopsy-proven pulmonary metastasis. The patient then had to be switched to local radiation of cerebral metastases and Topotecan due to cerebral bleeding episodes but died 18 months after the initial diagnosis. In conclusion of our case series, mixed adenoneuroendocrine carcinomas of the rectum should be considered as a rare but aggressive tumor entity. An early and detailed histopathological diagnosis is required in order to establish an individual interdisciplinary treatment concept.

Mixed epithelial endocrine neoplasms of the colon and rectum – An evolution over time: A systematic review

“…Mixed epithelial endocrine neoplasms of the colon and rectum are a rare, under documented entity with unique histology and clinical behavior. The exact pathogenesis of these neoplasms remains unclear as they are often characterized by significant histological heterogeneity that preclude accurate diagnosis[ 14 , 20 , 31 , 39 ]. Though, there are no unique identifiable risk factors, association with long standing intestinal inflammatory disease and MiNEN have been reported[ 24 ].…”

“…The exact pathogenesis of these tumors continues to be debated and multiple hypotheses have been proposed as to the origin and development of mixed tumors. Three main theories have been proposed: (1) The first theory proposes that the epithelial and the endocrine components arise independently from distinct precursor cells in a synchronous or metachronous manner; (2) The second theory proposes that the two components are derived from a common pluripotent stem cell progenitor that acquires biphenotypic bidirectional differentiation during carcinogenesis; and (3) The third theory though similar to the second in its origin from a common monoclonal origin, believes in a stepwise process-that the neuroendocrine trans/de differentiation develops from a non-neuroendocrine epithelial phenotype due to the progressive accumulation of molecular and genetic aberrations and/or stromal/tumor micro environmental changes such as field cancerization[ 15 , 18 , 39 - 42 ]. The last two theories are gaining popularity as it is now agreed that multipotent gastrointestinal stems cells gives rise to the endocrine cells of the gastrointestinal tract, contrary to previous belief of migrating from the neural crest cells[ 36 - 38 ].…”

“…There are no specific clinical presentations of mixed tumors as many present at an advanced stage with local and/or distant spread. As this is a pathological diagnosis, many a time, biopsy samples obtained are small and accurate recognition of the second component is difficult[ 39 ]. Symptoms of MANECs are nonspecific and similar to colorectal carcinomas.…”

“…The most important factor for improving outcome of MANEC remains early and accurate diagnosis with adequate histopathological examination to establish the presence of two components within the same neoplasm[ 39 , 71 ]. This often requires a diligent search for morphologically different areas on the haematoxylin and eosin stained sections and liberal use of immunohistochemical markers[ 20 ].…”

“…Although small cell type neuroendocrine carcinoma can be distinguished easily from adenocarcinoma by hematoxylin-eosin staining, it is often difficult to distinguish large cell type neuroendocrine carcinoma from adenocarcinoma on hematoxylin-eosin slides leading to the danger of pathologists overlooking these entities[ 14 , 77 ]. Neuroendocrine portion of MANEC display high proliferative activity with an average Ki-67 labeling index of 78.0% (30%-99%) in the neuroendocrine component, while lower expression of 25% in adenocarcinoma[ 39 , 46 , 77 ], with positivity for synaptophysin, while the adenocarcinoma is positive for pancytokeratin AE1/AE3, cytokeratin 20 and CDX2[ 39 , 80 ]. Two of three commonly used immunohistochemical neuroendocrine markers, chromogranin A, synaptophysin, CD56, and neuron specific enolase should be positive in the neuroendocrine portion to be deemed as MANEC[ 14 , 80 ].…”