Mixed neuroendocrine and adenocarcinoma of gastrointestinal tract: A complex diagnosis and therapeutic challenge.

In this editorial we comment on the manuscript describing a case of adenocarcinoma mixed with a neuroendocrine carcinoma of the gastroesophageal junction. Mixed neuroendocrine and non-neuroendocrine neoplasms of the gastrointestinal system are rare heterogeneous group of tumors characterized by a high malignant potential, rapid growth, and poor prognosis. Due to the rarity of these cancers, the standard therapy is poorly defined. The diagnosis of these tumors is based on combination of morphological features, immunohistochemical and neuroendocrine and epithelial cell markers. Both endocrine and epithelial cell components can act independently of each other and thus, careful grading of each component separately is required. These cancers are aggressive in nature and the potential of each component has paramount importance in the choice of treatment and response. Regardless of the organ of origin, these tumors portend poor prognosis with increased proportion of neuroendocrine component. Multidisciplinary services and strategies are required for the management of these mixed malignancies to provide the best oncological outcomes. The etiopathogenesis of these mixed tumors remains obscure but poses interesting question. We briefly discuss a few salient points in this editorial.

Mixed neuroendocrine non-neuroendocrine neoplasms in gastroenteropancreatic tract.

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are a heterogeneous group of malignant neoplasms that can settle in the gastroenteropancreatic tract. They are composed of a neuroendocrine (NE) and a non-NE component in at least 30% of each tumour. The non-NE component can include different histological combinations of glandular, squamous, mucinous and sarcomatoid phenotypes, and one or both of the components can be low-or high grade malignant. Recent changes in the nomenclature of these neoplasms might lead to great deal of confusion, and the lack of specific clinical trials is the main reason why their management is difficult. The review aims to clarify the definition of MiNEN and analyze available evidence about their diagnosis and treatment options according to their location and extension through careful analysis of the available data. It would be important to reach a general consensus on their diagnosis in order to construct a classification that remains stable over time and facilitates the design of clinical trials that, due to their low incidence, will require long recruitment periods.

Adenocarcinoma admixed with neuroendocrine carcinoma of the cervix: A case report and review of literature.

A 40-year-old Ethiopian woman presented with a six-month history of non-foul-smelling whitish vaginal discharge. She also reported a one-year history of postcoital bleeding. A pelvic examination revealed a nodular, hard, and fragile cervical mass. In addition, there were nontender, firm nodules in the epigastric, periumbilical, gluteal areas, and thyroid gland. Investigations, including abdominopelvic ultrasound, magnetic resonance imaging, fine-needle aspiration cytology, and immunohistochemistry, confirmed mixed neuroendocrine carcinoma of the cervix with metastasis to the abdominal wall, gluteal area, lumbar vertebrae, and thyroid gland. The patient was started on palliative chemotherapy. Metastatic adenocarcinoma admixed with neuroendocrine carcinoma of the cervix presents a formidable disease phenotype, characterized by complex diagnostic and therapeutic obstacles. Multidisciplinary cooperation among oncologists, radiologists, pathologists, and surgeons is required to refine treatment approaches and improve patient prognoses for this uncommon and intricate malignancy.

Retroperitoneal mixed neuroendocrine non-neuroendocrine neoplasm: A case report and review of literature.

The existence of both neuroendocrine and non-neuroendocrine histology in variable proportion in a lesion has been described by the World Health Organisation (WHO) as mixed neuroendocrine and non-neuroendocrine neoplasm (MiNEN). The pathogenesis of this tumour remains controversial but molecular studies point towards a common monoclonal origin. Tumours are classified as functioning and nonfunctioning based on substances secreted. The nonfunctioning tumours may be discovered due to its local effect. Presented is a 66-year-old male with an intra-abdominal mass, underwent laparotomy and excision biopsy with transient right lower limb lymphoedema. Histology confirmed retroperitoneal MiNEN with no evidence of tumour recurrence 12 months following surgery. MiNENs should be considered as a differential diagnosis in patients with intra-abdominal mass. Surgical resection is recommended as this may offer the best treatment option.

[Mixed adenoneuroendocrine carcinoma: case report]. / Carcinoma adenoneuroendocrino mixto: reporte de caso.

Introducción: Mixed adenoneuroendocrine carcinoma is a rare tumor of the gastrointestinal tract with double differentiation into adenomatous and neuroendocrine carcinoma, each component with at least 30%. Case report: A 60-year-old female with acute abdominal pain. Surgical treatment was decided, finding a tumor at the level of the cecum and ascending colon, a right hemicolectomy and ileostomy were performed. Discussion: Mixed adenoneuroendocrine carcinoma can appear in various organs. They are highly malignant tumors, with a high risk of metastasis. Conclusions: These tumors do not present symptoms or specific radiological or laboratory findings; diagnosis depends on postoperative histopathological and immunohistochemical studies.

Introducción: El carcinoma adenoneuroendocrino mixto es un tumor raro del tracto gastrointestinal con doble diferenciación en carcinoma adenomatoso y neuroendocrino, cada componente con al menos el 30%. Caso clínico: Mujer de 60 años con cuadro de dolor abdominal agudo. Se decide tratamiento quirúrgico, encontrando un tumor a nivel de ciego y colon ascendente, y se realizan hemicolectomía derecha e ileostomía. Discusión: El carcinoma adenoneuroendocrino mixto puede aparecer en diversos órganos. Son tumores muy malignos, con alto riesgo de metástasis. Conclusiones: Estos tumores no presentan síntomas ni hallazgos radiológicos o de laboratorio específicos; el diagnóstico depende de estudios histopatológicos e inmunohistoquímicos posoperatorios.

Mixed mucinous adenocarcinoma/large cell neuroendocrine carcinoma of the uterine cervix: case report and molecular characterization of a rare entity.

Mixed neuroendocrine-non-neuroendocrine carcinomas of the cervix are rare and generally aggressive diseases. They often present at an advanced stage with hematogenous or lymphatic metastases. The prognosis is poor, mostly influenced by the neuroendocrine component. Unfortunately, the rarity of the disease caused a lack of information about its pathogenesis and molecular landscape. The latest guidelines recommend a multimodal approach that usually includes radical surgery, platinum/etoposide-based chemotherapy, or chemoradiation. Here, we are presenting a case of metastatic mixed adenocarcinoma-large cell neuroendocrine carcinoma of the cervix in a 49-year-old female patient. The molecular characterization of the lesion highlighted the ubiquitous presence of human papillomavirus-18 DNA both in the adenocarcinomatous and the neuroendocrine components, suggesting a role for the virus in the pathogenesis. Moreover, a different set of mutations was detected in the two parts, thus ruling out a possible clonal evolution of the neuroendocrine component from the adenocarcinoma one. More studies are needed to clarify the molecular landscape of these rare lesions and identify putative targets for therapy.

Comparison of survival outcomes and survival prediction in patients with primary colorectal MANEC and primary colorectal SRCC: a population-based propensity-score matching study.

PURPOSE: Primary mixed adeno-neuroendocrine carcinoma (MANEC) and primary signet-ring cell cancer (SRCC) are two rare but highly malignant tumors in colorectal cancer. Therefore, we attempted to compare the tumors' survival outcomes, identify risk factors, and ultimately evaluate the prognosis by developing a nomogram. METHODS: We identified 755 MANEC and 5836 SRCC patients of colorectal cancer. PSM was used to balance the influence of baseline clinical and pathological differences. Kaplan-Meier method was used to compare the prognosis of different pathological grades and AJCC stages. Cox proportional hazards model was used to identify potential prognostic factors for the two groups. Finally, we developed a nomogram and evaluated the feasibility of the model. RESULTS: After PSM, the median OS and CSS of MANEC patients were significantly better than those of SRCC patients in stage III-IV (P < 0.001) but similar in stage I-II. The median OS and CSS of MANEC patients in each pathological grade were also greater than those of SRCC patients. Patients with MANEC and SRCC who underwent lymph node dissection in more than four areas had longer survival time. MANEC patients benefited from postoperative chemotherapy and radiotherapy; among SRCC patients, those who received preoperative and postoperative comprehensive chemotherapy and radiotherapy had benefits in OS and CSS. CONCLUSION: Both MANEC and SRCC are often diagnosed in advanced stages, highlighting the importance of early screening. Despite the better prognosis of MANEC compared to SRCC, both types of patients require the formulation of personalized treatment strategies based on different risk factors combined with column charts.

Precise microdissection of gastric mixed adeno-neuroendocrine carcinoma dissects its genomic landscape and evolutionary clonal origins.

Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.

Mixed adenoneuroendocrine carcinoma originating from the appendix and colorectum: a comparative analysis of a large population-based database.

PURPOSE: As a rare gastrointestinal neoplasm, the demographic, clinicopathological, and prognostic characteristics of mixed adenoneuroendocrine carcinoma (MANEC) remain unclear. The purpose of this study was to evaluate its biological features, survival outcome, and prognostic factors. METHODS: From the Surveillance, Epidemiology, and End Results (SEER) database, we retrospectively reviewed clinicopathological and survival data of 513 patients who were histopathologically diagnosed with MANEC of the appendix and colorectum bettween 2004 and 2015. The clinicopathological features and survival outcomes of MANEC located at different anatomical locations were compared, and predictive factors for cancer-specific survival (CSS) and overall survival (OS) were assessed. RESULTS: In terms of anatomical distribution of MANEC, the appendix (64.5%, 331/513) was more frequently involved, followed by colon (28.1%, 144/513) and rectum (7.4%, 38/513). The MANEC at different anatomical locations had a distinct clinicopathological characteristic, and colorectal MANEC was significantly associated with more aggressive biological features. The survival outcomes of appendiceal MANEC were significantly better than that of colorectal MANEC (3-year CSS rate 73.8% vs 59.4%, P = 0.010; 3-year OS 69.2% vs 48.3%, P < 0.001). In addition, hemicolectomy had a better survival benefit than appendicectomy for patients with appendiceal MANEC, regardless of lymph node metastasis (P < 0.05). Tumor location, histology grade III, tumor size > 2 cm, T3-T4 stage, lymph node metastasis, and distant metastasis were independent prognostic factors for patients with MANEC. CONCLUSIONS: Tumor location had an important prognostic significance for MANEC. As an uncommon clinical entity, colorectal MANEC had more aggressive biological features and worse prognosis than its appendiceal counterpart. The standard surgical procedure and clinical management strategy for MANEC need to be established.

Mixed Adenoneuroendocrine Carcinoma in the Ampulla of Vater: Case Report

A mixed non-neuroendocrine neuroendocrine neoplasm is a mixed neoplasm with a neuroendocrine component combined with a non-neuroendocrine component. It has a low incidence and limited studies, but with evidence of being an aggressive entity associated with poor survival. We present the case of a 58-year-old woman admitted with clinical symptoms of abdominal pain in the left hypochondrium associated with generalized jaundice and feverish spikes with an imaging diagnosis of bile duct dilation secondary to distal choledocholithiasis. Endoscopic retrograde cholangiopancreatography (ERCP) was performed, finding a significant papilla with a neoplastic appearance, which was biopsied and histopathologically analyzed. The diagnosis of mixed carcinoma with a component of high-grade poorly differentiated neuroendocrine carcinoma and a component of mucinous carcinoma was confirmed. Therefore, we decided to schedule a pancreaticoduodenectomy.

La neoplasia neuroendocrina no neuroendocrina mixta es una neoplasia mixta con un componente neuroendocrino combinado con un componente no neuroendocrino. Esta presenta una incidencia baja y estudios limitados, pero con evidencia de ser una entidad agresiva asociada a una pobre supervivencia. Presentamos el caso de una mujer de 58 años que ingresó por un cuadro clínico de dolor abdominal en el hipocondrio izquierdo asociado a ictericia generalizada y picos febriles con diagnóstico imagenológico de dilatación de la vía biliar secundaria a coledocolitiasis distal, por lo que se realizó una colangiopancreatografía retrógrada endoscópica (CPRE) en la que se encontró una papila mayor de aspecto neoplásico a la cual se le realizó una biopsia analizada histopatológicamente y se confirmó el diagnóstico de carcinoma mixto con componente de carcinoma neuroendocrino pobremente diferenciado de alto grado y componente de carcinoma mucinoso, por lo cual se decidió programar una pancreatoduodenectomía.

Management and outcomes of mixed adenoneuroendocrine carcinoma of the ampulla of Vater: A systematic review and pooled analysis of 56 patients.

BACKGROUND: Tumors of mixed neuroendocrine and nonneuroendocrine histology are classified as collision, combined, or amphicrine and can occur in most organs, including the hepato-pancreato-biliary tract. Given the rarity of mixed adenoneuroendocrine carcinoma (MANEC) of the ampulla of Vater, the patient characteristics, management, and outcomes remain unclear. We sought to systematically review the worldwide literature on ampullary MANECs. METHODS: Eligible studies were identified through a systematic search of the MEDLINE (via PubMed), Scopus, and Cochrane Library databases (end-of-search-date: January 5th, 2022), according to the PRISMA 2020 statement. RESULTS: A total of 39 studies reporting on 56 patients with ampullary MANEC were included. The median age was 63.0 (interquartile range [IQR]: 51.0-69.0) years and 55.6% were male (n = 25/45). Most had combined tumors (64.4%; n = 29/45), followed by collision (24.4%; n = 11/45), and amphicrine tumors (11.1%; n = 5/45). More than half had lymph node metastasis (56.8%; n = 25/44), yet only 7.9% had distant metastasis (n = 3/38). Tumor resection (i.e., mostly pancreaticoduodenectomy) was performed in 96.3% (n = 52/54), followed by adjuvant chemotherapy in 61.8% (n = 21/34). Nearly half experienced disease recurrence (47.2%; n = 17/36) over a median follow-up of 12.0 (IQR: 3.0-16.0) months, and 42.1% (n = 16/38) died over a median follow-up of 12.0 (IQR: 4.0-18.0) months. The most common cause of death was disease progression/recurrence in 81.3% (n = 13/16). CONCLUSION: Early diagnosis and management of ampullary MANEC is challenging yet crucial to improve outcomes since many patients are diagnosed at an advanced disease stage and have unfavorable outcomes. Multicenter granular data are warranted to further understand and improve outcomes in these patients.

Mixed Adeno-Neuroendocrine Neoplasms: Two Cases, One Institution.

Epithelial tumors with neuroendocrine and nonendocrine components constitute the rare yet aggressive entity of neoplasms of the gastro-entero-pancreatic tract. These tumors were first named "mixed adeno-neuroendocrine carcinomas" (MANECs) by the World Health Organization in 2010 and in 2017 renamed "mixed neuroendocrine non-neuroendocrine neoplasms" (MiNENs). Combined adenocarcinoma and neuroendocrine carcinoma neoplasms are a rare occurrence within the gastrointestinal tract. In this report, we describe two separate cases of mixed rectal adeno-neuroendocrine carcinomas and their treatment. We describe two cases at one institution of mixed neuroendocrine non-neuroendocrine rectal neoplasms. Given the rarity of diagnosis and inconsistencies in both nomenclature and treatment recommendations in the literature, mixed adeno-neuroendocrine carcinoma epidemiology and prognosis are not yet fully understood. Future prospective trials with a focus in management of MiNENs will offer valuable insight into these rare mixed carcinomas.

Clinicopathological and immunological profiles of prostate adenocarcinoma and neuroendocrine prostate cancer.

BACKGROUND: Biomarkers of DNA damage repair deficiency provide opportunities for personalized treatment with immunotherapy. However, there is limited research on the immune microenvironment of adeno-neuroendocrine prostate cancer (NEPC). In this study, we aimed to assess and describe the comprehensive clinicopathological manifestations of NEPC to improve diagnosis and predict prognosis. METHODS: A retrospective medical record review of 66 patients with prostate cancer (PCa) was performed. PCa samples from the 66 patients were analyzed using immunohistochemical staining for the detection of chromogranin, neural cell adhesion molecule 1, and synaptophysin. For tumor-associated immune microenvironment analysis, PD-L1, CD3, and CD8 were labeled in tissue slides. The effect of clinicopathological factors on the survival of patients with Adeno-NEPC was analyzed. RESULTS: Twenty patients presented with adeno-NEPC, whereas 46 presented with adeno-PCa. The median age of patients at PCa diagnosis was 67.86 ± 7.05 years (68.65 ± 7.23 years, adeno-NEPC; 67.52 ± 7.02 years, adeno-PCa). Eleven patients with adeno-NEPC underwent prostatectomy, whereas nine received primary androgen deprivation therapy (ADT). Additionally, 30 patients with adeno-PCa underwent prostatectomy, whereas 16 (34.8%) received primary ADT. There was a significant difference in overall survival between patients with adeno-NEPC and those with adeno-PCa (46.0 months vs. 65.0 months). There was also a significant difference in time from prostatectomy to biochemical recurrence between the groups of patients who underwent prostatectomy. Prostatectomy and normal lactate dehydrogenase levels were clinical factors that were significantly associated with better outcomes in patients with adeno-NEPC. Metastatic adeno-NEPC was associated with a higher programmed death ligand 1 (PD-L1) score (2-4) than localized PCa. The data showed that PD-L1 expression in adeno-NEPC may be negatively associated with that in CD8+ T cells. CONCLUSIONS: Our study revealed clinicopathological manifestations of adeno-NEPC and some possible predictive factors significantly associated with better outcomes in patients with adeno-NEPC. These findings might be beneficial in the development of diagnostic strategies and customized treatment plans.

Peritoneal metastatic mixed adenoneuroendocrine carcinoma treated with cytoreduction surgery and hyperthermic intraperitoneal chemotherapy: a case report.

A 61-year-old man presented with abdominal distension without any symptoms. On colonoscopy and computed tomography findings, it was clinically diagnosed as peritoneal metastasis of sigmoid colon cancer, and diagnostic laparoscopy was performed. Only the peritoneum was partially resected, and the pathology was signet ring cell carcinoma with predominantly local mucinous carcinoma component. However, the patient complained of persistent symptoms and, despite the progress of chemotherapy, the peritoneal dissemination worsened, and additional cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) was performed. Mixed adenoneuroendocrine carcinomas (MANECs) were reported in the appendix with perforated visceral peritoneum. After additional chemotherapy, the patient was discharged. Patients with advanced MANEC with peritoneal spreading may benefit from aggressive treatment by cytoreduction surgery with HIPEC, followed by intravenous chemotherapy.

Mixed neuroendocrine-non-neuroendocrine neoplasm arising from long-segment Barrett's esophagus showing exceptionally aggressive clinical behavior.

BACKGROUND: There is only one report of Barrett's esophagus (BE) with mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). Herein, for the first time, we present a case with an aggressive esophageal MiNEN, as well as with both primary MiNEN and conventional adenocarcinoma, arising in BE. CASE: A 68-year-old woman had been diagnosed with 0-IIa type adenocarcinoma in the background of long-segment BE, 45 months earlier. She underwent endoscopic submucosal dissection (ESD) and the pathological diagnosis was tubular adenocarcinoma, well-differentiated, with slight submucosal invasion. There was no lymphovascular invasion and the margins were intact. The upper esophagogastroduodenoscopy conducted the year after ESD showed no residual or recurrent cancer. However, she was subsequently followed up at another hospital, and endoscopy was not performed after the second year. She was urgently transported to our hospital due to buttock pain in the ninth month of the fourth year. A computed tomography (CT) of the head showed multiple cerebral metastases and positron emission tomography-CT revealed numerous osseous and nodal involvements. We performed upper endoscopy and detected type 3 esophageal tumor. Multiple biopsy specimens histopathologically contained invasive neoplasm composed of neuroendocrine carcinoma (NEC) and adenocarcinoma, moderately to poorly differentiated. The NEC element showed diffuse proliferation of primitive cancer cells possessing fine-granular cytoplasm and nuclei with prominent nucleoli, whereas the adenocarcinoma component had tubules or nested growth of basophilic cells. Immunohistochemically, the NEC cells were diffusely positive for synaptophysin, with focal expressions of INSM1, chromogranin A and NCAM, whereas the adenocarcinoma cells were mostly negative for these NE markers. The Ki67 index was 90% at the hot spots in both types. The patient died 3.5 months after the biopsy-based histological diagnosis. CONCLUSION: Appropriate therapy according to the guidelines and/or meticulous clinical follow-up based on periodic endoscopy as well as a full physical examination are essential, from a proactive perspective, for early diagnosis of secondary aggressive cancers after ESD.

Metastasis of Mixed Adenoneuroendocrine Carcinoma of the Uterine Cervix to Thyroid Gland.

The thyroid metastasis from cervical cancer is extremely rare compared to other organs. It is sometimes difficult to distinguish primary tumors from metastases, as most metastatic thyroid nodules are asymptomatic. In this case, a 54-year-old woman had undergone radical hysterectomy due to cervical tumor of stage IB1 mixed adenoneuroendocrine carcinoma (MANEC) 5 years ago. After 3 years, ultrasound examination revealed a suspicious malignant nodule in the left lobe of thyroid gland at regular postoperative follow-up. This patient had no obvious clinical symptoms. The ultrasonography (US)-guided core needle biopsy (CNB) of the thyroid nodule was performed on the patient. The immunohistochemistry analyses revealed that it was poorly differentiated small-cell neuroendocrine carcinoma (SCNEC). Subsequently, the patient underwent left hemithyroidectomy plus isthmusectomy. The postoperative pathology and immunohistochemistry, combining with clinical history, confirmed that the thyroid nodule was a metastasis from cervical MANEC. Conventional chemotherapy and regular follow-up were carried out after the operation. The patient was readmitted 1 year later for pancreatic metastatic lesions and died 1 month after surgery. Early detection of metastatic cancer is potentially helpful, and when necessary, ultrasound-guided puncture biopsy can be utilized to further diagnose metastatic thyroid cancer.

Mixed adenoneuroendocrine carcinoma of the non-ampullary duodenum with mismatch repair deficiency: a rare case report.

A non-ampullary duodenal mixed adenoneuroendocrine carcinoma (MANEC), consisting of a conventional adenocarcinoma and a neuroendocrine carcinoma (NEC), is exceedingly rare. Moreover, mismatch repair (MMR) deficient tumors have recently attracted attention. The patient, a 75-year-old woman with epigastric pain and nausea, was found to have a type 2 tumor of the duodenum, which was diagnosed on biopsy as a poorly differentiated carcinoma. A pancreaticoduodenectomy specimen showed a well-defined 50 × 48 mm tumor in the duodenal bulb, which was morphologically composed of glandular, sheet-like, and pleomorphic components. The glandular component was a tubular adenocarcinoma, showing a MUC5AC-positive gastric type. The sheet-like component consisted of homogenous tumor cells, with chromogranin A and synaptophysin diffusely positive, and a Ki-67 index of 72.8%. The pleomorphic component was diverse and prominent atypical tumor cells proliferated, focally positive for chromogranin A, diffusely positive for synaptophysin, and the Ki-67 index was 67.1%. The sheet-like and pleomorphic components were considered NEC, showing aberrant expression of p53, retinoblastoma, and p16. Notably, all three components were deficient in MLH1 and PMS2. We diagnosed a non-ampullary duodenal MANEC with MMR deficiency. This tumor has a unique morphology and immunohistochemical profile, and is valuable for clarifying the tumorigenesis mechanism of a non-ampullary duodenal MANEC.