Colonic Neuroendocrine Carcinoma Research Articles

P373 An Unusual Occurrence of Right-sided Colonic Neuroendocrine Carcinoma in Ulcerative Colitis – A case report

Abstract Background It's estimated that inflammatory bowel disease (IBD) accounts for 1-2% of all colorectal cancer (CRC) cases. However, the mere presence of IBD increases the risk by 2 folds compared with the general population. It's been established that the most prevalent epithelial colonic malignancy linked to IBD is adenocarcinoma. Neuroendocrine neoplasms arising in the large intestines are extremely rare (rate <1%), even less common in association with IBD.(1) Herein, we report a 49 years-old male with a longstanding history of ulcerative pancolitis, who was found to have a metastatic right-sided colorectal neuroendocrine carcinoma (NEC). Methods Case Presentation A 49-years-old male patient, with a 13-years history of ulcerative pancolitis underwent a colonoscopy. It revealed a large ulcerated mass extending from the ileocecal valve into the proximal ascending colon highly suspicious for malignancy. Biopsy showed a large cell poorly differentiated NEC in the ascending colon. Tumor cells were positive for Synaptophysin and cytokeratin AE1/3, and a high Ki67. Serum Chromogranin A (CgA) and urine 5-hydroxyindoleacetic acid were high. Imaging was evident for a short segment circumferential wall thickening at the ascending colon and hepatic metastasis. The patient was planned to receive chemotherapy, but died before treatment. Results Discussion Risk of CRC increments linearly approximately 7 years following diagnosis of IBD. After 30 years of colitis, the incidence is estimated to be around 18%. NECs in particular are not frequently encountered in association with IBD, much less right-sided.(1) Colonic NECs are usually aggressive with a Ki67 typically greater than 20%, often present with metastasis with absence of a characteristic hormonal secretion picture.(2, 3) The incidence of NECs in association with Ulcerative Colitis (UC) is twice more frequent in males, with a mean age of 49.36, and development after a median of 15 years of UC first diagnosis. Majority of NECs were found in the left side of the colon, in the contrary to our patient. Prognosis was dismal in most cases, as most demonstrated a higher malignant potential compared to adenocarcinomas.(3) Early diagnosis of gastrointestinal NECs poses a challenge since it lacks a specific clinical presentation. Serum CgA level correlates with the tumor burden and overall survival. Additionally, studies demonstrating the role of endoscopic surveillance in colonic NECs early detection is scarce.(1,4) Conclusion Thorough understanding of the condition and its risk factors is crucial for a timely diagnosis, which maximizes the likelihood of a favorable prognosis. By reporting this case, we emphasize the importance of considering NEC as a differential diagnosis of CRC in IBD, particularly in UC patients.

S2010 Colonic Carcinoma With Neuroendocrine Features Diagnosed in the Setting of Enterococcus faecalis Bacteremia, Endocarditis and Embolic Phenomenon

Introduction: A 77-year-old man with a history of hypertension, hyperlipidemia, prior ischemic stroke, and chronic back pain presented with fever and confusion 3 days after undergoing a lumbar epidural steroid injection. Case Description/Methods: A 77-year-old man with a history of hypertension, hyperlipidemia, prior ischemic stroke, and chronic back pain presented with fever and confusion 3 days after undergoing a lumbar epidural steroid injection. Multiple sets of blood cultures grew Enterococcus faecalis. His CRP was elevated at 86. An MRI scan of the spine was negative for epidural abscess. Brain MRI revealed multiple acute embolic infarcts. Transthoracic echocardiography revealed a mobile 8mm vegetation, and transesophageal echocardiography confirmed mitral valve endocarditis. CT of the abdomen and pelvis revealed colonic wall thickening at the hepatic flexure with coexistent fat stranding and lymphadenopathy. Subsequent colonoscopy revealed a 1 cm solitary cratered ulcer with heaped up borders at the hepatic flexure (Figure A). Histopathology demonstrated a high-grade carcinoma immunophenotypically positive for colonic (CDX2+, SATB2+, CK20+, CK7-) and neuroendocrine differentiation (chromogranin+, synaptophysin+) (Figure C, D). The favored diagnosis was colonic high-grade neuroendocrine carcinoma, large cell type. PET/CT Dotatate scan was negative for uptake at the hepatic flexure reflecting poor differentiation of the carcinoma and lack of somatostatin receptors expression. Subsequent PET/CT FDG scan was positive reflecting high FDG avidity in the identified hepatic flexure hypermetabolic lesion, surrounding lymph nodes, and numerous hepatic lesions (Figure B). The patient was treated with antibiotics for endocarditis and started on carboplatin and etoposide. Discussion: Classically, Streptococcus bovis bacteremia and endocarditis are associated with colorectal cancer. Evidence is accumulating for a link between Enterococcus faecalis, a component of gut flora, and colorectal adenocarcinoma. The biopsies of the ulcerated mass at the hepatic flexure, in our patient with Enterococcus faecalis bacteremia and endocarditis, suggested a primary colonic neuroendocrine carcinoma, large cell type. Neuroendocrine tumors of the colon arise from enterochromaffin cells in the crypts of Lieberkuhn. Colon carcinoid tumors are rare, with an annual incidence of approximately 0.2 per 100,000. Most neuroendocrine tumors are asymptomatic at the time of diagnosis and often present with metastatic disease.Figure 1.: A: Colonoscopy revealing a 1 cm solitary cratered ulcer at the hepatic flexure. B: PET/CT FDG scan showing high FDG avidity at hepatic flexure. C: Histopathology H&E stain showing poorly differentiated carcinoma. D: Histopathology chromogranin stain positivity confirming neuroendocrine differentiation.

Effects of transplantation-related immunosuppression on co-existent neuroendocrine tumours.

Here we detail our experience of managing patients found to have a neuroendocrine neoplasm (NEN) whilst on immunosuppression for a transplanted organ. We aimed to quantify the behaviour of NENs under solid-organ transplant-related immunosuppression. This was an observational, retrospective case series. Ten patients were identified from a prospectively kept database. Three were excluded. Four patients received a liver, two a kidney, and one a heart transplant. All but one received calcineurin-based immunosuppression. NENs were found in five patients post-transplant: one had surgery for transverse colonic neuroendocrine carcinoma NEC (pT4N1M0, Ki67 60%), was cancer-free after four years; one had cold biopsy of duodenal NEN (pT1N0M0, Ki67 2%), cancer-free at four months; one 7 mm pancreatic NEN (pT1N0M0), untreated and stable for seven years; one small-bowel NEN with mesenteric metastasis (pTxNxM1), alive four years after diagnosis; and one untreated small-bowel NEN with mesenteric metastasis, stable at 1 year after liver transplantation. Two NENs were discovered pre-transplant, one pancreatic NEN (pT1N0M0, Ki67 5%), remains untreated and stable at three years. One gastric NEN (type 3, pT1bN0M0, Ki67 2%) remains stable without treatment for two years. NENs demonstrate indolent behaviour in the presence of transplant-related immunosuppression.

Correlation between marker profiles of tumor tissue and circulating tumor cells in a Grade 3 colonic neuroendocrine carcinoma: Case study and review

Correlation between marker profiles of tumor tissue and circulating tumor cells in a Grade 3 colonic neuroendocrine carcinoma: Case study and review

An Uncommon Case of Colonic Neuroendocrine Carcinoma with Scalp Metastasis

Abstract Introduction/Objective Neuroendocrine neoplasms of the colon account for <1% of all colorectal malignancies. While visceral metastasis of neuroendocrine neoplasms is commonly observed, cutaneous distant metastasis has infrequently been reported and correlates with an advance stage and progression of disease. To our knowledge, there have been only 10 cases of neuroendocrine neoplasms with metastasis to the scalp reported in the literature. Herein, we report an unusual case of colonic neuroendocrine carcinoma with scalp metastasis, that can be microscopically indistinguishable from the highly aggressive cutaneous neuroendocrine carcinoma, Merkel Cell Carcinoma. Methods/Case Report A 47-year-old female with a history of ileocecal neuroendocrine carcinoma and status post right hemicolectomy had developed liver metastasis and subsequently had an orthotopic liver transplant. PET scan later revealed multiple areas of increased activity involving the ribs, scalp and cervical lymph node that were concerning for malignancy. The scalp lesion consisted of a 7mm non-tender, mobile, violaceous, erythematous dermal nodule that was clinically concerning for cutaneous metastasis. A skin punch biopsy microscopically revealed a subcutaneous infiltrate of nests composed of neoplastic monotonous blue cells with the classic nuclear “salt and pepper” chromatin and scant eosinophilic cytoplasm. The lesional cells showed positive immunoreactivity for synaptophysin and chromogranin. With the given patient’s clinical history and presentation, the observed histological findings and immunophenotypic expression of the tumor cells supported a diagnosis of metastatic neuroendocrine carcinoma. Results (if a Case Study enter NA) N/A Conclusion Metastatic neuroendocrine carcinoma to the scalp is a rare entity and is infrequently encountered in dermatopathology. Given the location and the gross appearance of the scalp lesion, a wide differential diagnosis would include both benign and malignant tumors. In particular, Merkel Cell Carcinoma can grossly and histologically mimic metastatic colonic neuroendocrine carcinoma. Both entities would show synaptophysin and chromogranin uptake. However, metastatic tumors originating from the colon will demontrate CDX2 and SATB2 nuclear staining. We share this rare case of metastatic colonic neuroendocrine carcinoma as it is an important differential diagnosis for primary cutaneous Merkel Cell Carcinoma.

Primary tumor location (right versus left side of the colon) and resection affect the survival of patients with liver metastases from colonic neuroendocrine carcinoma: a population-based study.

Background:Colonic neuroendocrine carcinomas (co-NECs) are heterogeneous and aggressive, especially with regard to metastasis. Whether co-NECs on the right and left sides of the colon have different characteristics from colon adenocarcinoma is unknown.Methods:The co-NEC patients were selected from the 2010–2017 Surveillance, Epidemiology, and End Results Program (SEER) database. The right and left sides of the colon were separated by the splenic flexure. Coarsened exact matching (CEM) was performed to adjust for relevant factors before regression models were constructed.Results:A total of 669 pathologically diagnosed co-NEC patients with sufficient baseline data were identified from the SEER database. A total of 80.72% of the patients had co-NEC that originated from the right side of the colon, and their mean overall survival (mOS) was similar to that of the patients with left-sided co-NECs (right versus left: 22.30 m versus 22.55 m). A total of 44.84% of the patients were diagnosed with liver metastasis (46.68% right side versus 37.98% left side). In patients with liver metastasis, those with right-sided co-NECs had better survival than those with left-sided co-NECs (mOS right versus left: 15.37 m versus 9.62 m; adjusted hazard ratio (HR) = 0.69, 95% confidence interval (CI): 0.49–0.98, p = 0.035). To further investigate the survival benefits of primary site resection, we separated the patients who had liver metastasis according to the primary site and performed CEM to balance the groups (no patients underwent liver metastasis resection or intervention). The results suggested that primary surgery could benefit patients with both left- and right-sided co-NECs (adjusted HR = 0.50, 95% CI: 0.33–0.77, p = 0.001 on the right side; HR = 0.38, 95% CI: 0.16–0.89, p = 0.026 on the left side).Conclusions:Co-NECs frequently originate on the right side and commonly develop liver metastasis. Right-sided co-NECs are associated with better survival than left-sided co-NECs after liver metastasis has occurred. Primary site resection is associated with prolonged survival in co-NEC patients with liver metastasis, regardless of the side from which the co-NEC has originated.

Clinicopathological features and prognostic validity of the European Neuroendocrine Tumor Society (ENETS) and American Joint Committee on Cancer (AJCC) 8th staging systems in colonic neuroendocrine neoplasms.

PurposeThis study aimed to investigate the characteristics of colonic neuroendocrine neoplasms (NENs) and to validate the prognostic value of the European Neuroendocrine Tumor Society (ENETS) and American Joint Committee on Cancer (AJCC) 8th staging systems.MethodsA total of 167 and 1248 patients with colonic NENs from 12 medical centers across China and from the Surveillance, Epidemiology, and End Results (SEER) cancer registry in the United States, respectively, were reviewed. Patients were staged according to the ENETS and AJCC 8th staging systems.ResultsClinicopathological features of colonic NENs in the Chinese cohort and SEER cohort were significantly distinct. In both the Chinese cohort and the SEER cohort, colonic neuroendocrine carcinoma (NEC) and mixed adeno‐neuroendocrine carcinoma (MANEC) were more frequent in the midgut than in the hindgut. Tumors originating from the midgut tended to be larger and at a more advanced stage than those from the hindgut. The AJCC 8th staging system and the ENETS system appeared to have similar prognostic ability for colonic NEC/MANEC.ConclusionsOur study revealed that tumors originating from the midgut and the hindgut shared different clinicopathological features. The AJCC 8th staging system and the ENETS system appeared to have similar prognostic ability for colonic NEC/MANEC.

Frequent BRAF mutations suggest a novel oncogenic driver in colonic neuroendocrine carcinoma.

The World Health Organization (WHO) 2010 has classified GI neuroendocrine neoplasms into neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). The genetic underpinnings of NEC are poorly understood. The aim of the study was to perform genomic profiling of NEC to better characterize this aggressive disease. We identified nine patients with colonic NEC between January 1, 2005 and June 30, 2013. Whole exome sequencing (WES) was performed on tumor DNA from two patients with ≥80% tumor cellularity and matched normal tissue available. Focused BRAF mutational analysis was performed on an additional seven patients via sanger sequencing of BRAF exons 11 and 15. We identified BRAF exon 15 mutations (c.A1781G: p.D594G and c.T1799A: p.V600E) by WES in two patients. Upon additional screening of seven colonic NECs for BRAF exon 11 and 15 mutations, we identified BRAF V600E mutations in two of seven specimens (29%). Overall, BRAF exon 15 mutations were present in four of nine colonic NECs. Colonic NEC is a rare but aggressive tumor with high frequency (44%) of BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients.

Colonic Neuroendocrine Carcinoma in the Setting of Ulcerative Colitis and PSC: Coincidence or Colitis-Associated?

Introduction: Ulcerative colitis (UC) patients are at increased risk of developing colorectal cancer. The risk is increased significantly in patients with concomitant primary sclerosing cholangitis (PSC). Adenocarcinoma is the most common GI cancer among IBD patients, and other types of malignancies are rarely reported. We describe a patient with IBD and PSC who was found to have an invasive adenocarcinoma with neuroendocrine features. Case Description: A 68 year-old woman with prior appendectomy and a 40-year history of UC and PSC was in long-standing stable clinical remission on sulfasalazine and undergoing annual surveillance colonoscopies by her local physician. Both parents had advanced age colorectal cancer and her older sister had recently died of gastric adenocarcinoma. During her recent surveillance colonoscopy, biopsy of an abnormal mucosal area in the cecum was interpreted as a neuroendocrine tumor. In order to define the tumor and identify synchronous lesions, a pre-operative chromoendoscopy was performed. The previously seen lesion was identified, and there was no additional dysplasia found. At the time of surgery, thickening of the ascending colon wall was noted (Image 1); histologic review of the colectomy specimen confirmed an invasive poorly differentiated adenocarcinoma with signet ring cells and neuroendocrine features (image 2), as well as other areas of multifocal low-grade dysplasia. 14/31 lymph nodes were involved with tumor. CT scan did not identify additional metastatic disease. She is currently receiving chemotherapy. Discussion: Neuroendocrine cancers are rare, often well-differentiated and clinically indolent, with the most common locations being appendiceal and rectal. These tumors are not commonly described in the setting of colitis, but neuroendocrine differentiation has been described as a possible early event in the UC neoplasia pathway, or a feature or poorly differentiated and more aggressive tumors. This patient's tumor was in an atypical location and accompanied by multi-focal low-grade dysplasia, suggesting that this was likely a colitis-associated tumor which was poorly differentiated and not the more indolent type of primary neuroendocrine tumor, like a carcinoid. The invasive nature of this tumor and advanced staging at the time of diagnosis despite her annual surveillance is a cautionary note for both clinicians and pathologists, who might otherwise be reassured by the neuroendocrine features.Figure 1Figure 2

BRAF mutations in colonic high-grade neuroendocrine carcinoma.

612 Background: The WHO 2010 has classified GI neuroendocrine neoplasms into well-differentiated neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). NEC is more aggressive than NET. Whole genome sequencing (WGS) has provided insight into the genetic underpinnings of NET but little is known about NEC. The aim of this study is to perform genomic profiling of NEC to better characterize the underlying mutations in this aggressive disease. Methods: We identified 9 patients who underwent biopsy or resection for NEC between 1/2005 - 6/2013 with histological blocks available. WGS was performed on DNA extracted from tissue from 2 patients with ≥80% tumor cellularity using the Illumina HiSeq 2500 platform. Validation and mutational analysis of the BRAF gene was performed on 2 WGS patients and an additional 7 patients via Sanger Sequencing of exon 11 and 15. Results: 7 of 9 patients (78%) presented with metastasis at initial diagnosis (Table). 8 patients died of disease within 25 months. In 2 NECs, we identified BRAF mutations on exon 15 by WGS. Patient S1 presented with cecal NEC and had an A1781G:p.D594G mutation on exon 15. Patient S2 presented with a descending colon NEC and had a c.1799T>A: p.V600E mutation on exon 15. An additional 7 colonic NECs were analyzed with Sanger Sequencing of exons 11 and 15. 2 had BRAFV600E mutations. Overall, BRAF mutations were present in 4 of 9 (44%) colonic NECs. The 3 cases with V600E mutations were large cell NECs, whereas the case with a D594G mutation was a small cell NEC. Conclusions: High grade colonic NEC is an aggressive tumor with high frequency (44%) of activating BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients. [Table: see text]

Clinical Outcome in Colonic Neuroendocrine Neoplasms

Introduction: Colonic Neuroendocrine Neoplasms (NEN) is classified of Neuroendocrine Tumor (NET) G1, NET G2, Neuroendocrine Carcinoma (NEC) in according with the 2010 WHO Classification. Herein we report the clinical outcome of colonic NEN. Methods: 52 patients treated in our hospital between 2004 and 2014 were reviewed, which were defined pathologically as colonic NEN. Results: The mean follow-up time was 37 months. 36 patients were male and 16 patients were female. Median age of 52 patients were 61.2 years (30-85 years). 46 tumors (88.5%) were NET. The tumor localization of NET is lower rectum: upper rectum: recto-sigmoid = 40:5:1. 98% of NET (n=45) were diagnosed stage I. 28 cases were underwent endoscopic resection. The mean tumor size was 5.8mm (2-11mm) in these cases, and had no recurrence. In other cases, transanal partial excision, transsacral partial excision or rectum excision with regional lymph node dissection were performed. Liver metastases and local recurrence were identified in 1 case at Stage I after surgery. Without this 1 case, no recurrences were not identified. 6 tumors (11.5%) were NEC including 5 MANEC (Mixed Adenoneuroendocrine Caricinoma). Tumors were located at the cecum, ascending colon and transverse colon. The mean tumor size was 58.3mm (25-80mm). Right hemicolectomy with regional lymph node dissection was performed in all cases. These were diagnosed at stage IIb (n=2), stage IIIb (n=2) and stage IV (n=2). Two cases had recurrence and were administered chemotherapy. However, because of limited therapeutic effect the disease progressed. Conclusion: In colonic NET G1 and G2, which located mostly in rectum, and good overall survival is expected by resection. In tumor size≤10mm cases, endoscopic resection can be useful. In tumor size>10mm and lower rectum location cases, careful selection of operation such as transanal partial excision or rectum excision is needed from the perspective for conservating anus. In colonic NEC, the most frequent location is ascending colon and these have highly malignancy. When these are diagnosed as NEC, the disease already progress and its prognosis is poor. It is difficult to treat colonic NEC by only surgical resection. No effective chemotherapy has been established. It is thus important to gather more evidence on this disease. The optimal strategy and strong chemotherapy for the management of NEN.

Multiple scalp metastases from colonic neuroendocrine carcinoma: case report and literature review.

BackgroundColonic neuroendocrine neoplasms (NENs) are relatively rare tumors with an incidence rate of 0.11–0.21/100,000. NENs account for approximately 0.4% of colorectal neoplasms. Cutaneous metastases of colonic neuroendocrine carcinomas (NECs) are very infrequent, while cases of scalp metastasis are even fewer. Cutaneous metastases are more rare than visceral metastases and usually develop later; therefore, cutaneous metastases as initial distant metastases can be easily overlooked. This is the second case report of a colonic NEC with scalp metastasis. Compared with the previous case, in this instance scalp metastasis developed before visceral metastasis, and the cutaneous lesions were confined to the scalp alone.Case presentationA 62-year-old Chinese man, who had undergone radical surgery for a “locoregional” colonic NEC one and half months before, came to our hospital for adjuvant chemotherapy. We found multiple scalp nodules during physical examination. Moreover, these nodules had occurred and had not been detected prior to the patient undergoing radical surgery. The scalp nodules proved to be metastases from colonic NEC as determined using pathological and immunohistochemical examinations following lumpectomy. After one and half months, visceral metastases were detected in this patient. Ultimately, the patient died two months later.ConclusionsIn this report an unusual case of a colonic NEC with initial distant metastasis confined to the scalp is presented. This case is unusual because of the development of cutaneous metastasis before visceral metastasis. The scalp metastasis were initially overlooked, leading to inaccurate staging and radical surgery that was not curative. This demonstrates that distant metastasis can occur during the early phase of tumor growth in these aggressive lesions. Thus, the possibility of distant metastases should be assessed in the initial work up to avoid mistaken clinical staging especially when distant metastases occur only in skin.

Colonic neuroendocrine carcinoma in a child

A 10-year-old boy with congenital immunodeficiency (X-linked agammaglobulinaemia) presented with loss of appetite and weight, right-sided abdominal pain, diarrhoea and low-grade fever. Radiological investigations with barium follow-through, CT, PET and octreotide scans revealed a primary caecal/ascending proximal colonic mass with liver and bony metastases. Urine screen for 5HIAA was positive. Percutaneous liver biopsy confirmed the diagnosis of neuroendocrine carcinoma. The radiological work-up and the usefulness of various imaging modalities in the diagnosis of this rare paediatric tumour are discussed. The PET scan demonstrated the primary tumour and the metastatic locations more vividly than the octreotide scan, which is currently considered to be the most specific imaging modality for neuroendocrine masses.