Nodal Merkel Cell Carcinoma with Unknown Primary Site and No Distant Metastasis: A Single-Center Series.

Merkel cell carcinoma (MCC) is a very rare and aggressive neuroendocrine carcinoma originating from Merkel cells, typically with a skin nodule; however, it exceptionally presents with only a basin lymph node localization, with neither a cutaneous primary site nor distant metastases. From 1996 to 2020, among patients with histologically confirmed MCC managed at a neuroendocrine neoplasm-referral center, we selected those with an exclusive nodal basin, no distant metastasis, and an unknown primary site defined by cross-sectional and physical examination. A total of 55 out of 310 patients fulfilled the selection criteria. The median age was 64 years and the majority were males. Inguinal lymph-nodes were the most common anatomic site. With a median follow-up of 4.3 years, the 5-year relapse-free survival (RFS) rate was 56.6 (95% CI 42.0-68.8%) and the 5-year cancer specific survival (CSS) rate was 68.5 (95% CI 52.8-79.9%) for the whole population. The 36 patients (65.5%) undergoing lymphadenectomy (LND) + radiotherapy (RT) ± chemotherapy had a 5-year RFS rate of 87.2% (95% CI 65.5-95.7%) and a 5-year CSS rate of 90.5% (95% CI 67.0-97.5), which were better than those receiving LND alone. In a multivariable analysis, the survival benefit for LND + RT remained significant. Results from one of the largest single-center series of nMCC-UP suggest that a curative approach including RT can be effective, similar to what is observed for stage IIIB MCC. Multicentric studies with homogenous populations should be carried out in this controversial clinical entity, to minimize the risk of biases and provide robust data.

Neuroendocrine neoplasms of rectum: A management update.

The estimated annual incidence of R-NENs is 1.04 per 100,000 persons although the real incidence may be underestimated, as not all R-NEN are systematically reported in registers. Also the prevalence has increased substantially, reflecting the rising incidence and indolent nature of R-NENs, showing the highest prevalence increase among all site of origin of NENs. The size of the tumor reveals the behavior of R-NENs where the risk for metastatic spread increases for lesions > 10 mm. Applying the WHO 2010 grading system to whole NENs originating in the gastroenteropancreatic system, R-NENs are classified as Well-Differentiated Neuroendocrine Tumors (WD-NET), which contain NET G1 and NET G2, and Poorly-Differentiated Carcinomas (PD-NEC) enclosing only G3 neoplasms for which the term carcinoma is applied. The treatment is endoscopic resection in most cases: conventional polypectomy or endoscopic mucosal resection (EMR) for smaller lesions or endoscopic submucosal resection with a ligation device (ESMR-L), cap-assisted EMR (EMR-C) and endoscopic submucosal dissection (ESD). However it is important to know when the endoscopic treatment is not enough, and surgical treatment is indicated, or when the latter could be unnecessary. For PD-NECs, it has recently been demonstrated that chemoradiotherapy is associated with a similar long-term survival to that obtained with surgery. As well, new targeted-agents chemotherapy may be indicated for metastatic WD-NETs.

The role of multimodal treatment in patients with advanced lung neuroendocrine tumors.

Lung neuroendocrine tumors (NETs) comprise typical (TC) and atypical carcinoids (AC). They represent the well differentiated (WD) or low/intermediate grade forms of lung neuroendocrine neoplasms (NENs). Unlike the lung poorly differentiated NENs, that are usually treated with chemotherapy, lung NETs can be managed with several different therapies, making a multidisciplinary interaction a key point. We critically discussed the multimodal clinical management of patients with advanced lung NETs. Provided that no therapeutic algorithm has been validate so far, each clinical case should be discussed within a NEN-dedicated multidisciplinary team. Among the systemic therapies available for metastatic lung NETs everolimus is the only approved drug, on the basis of the results of the phase III RADIANT-4 trial. Another phase III trial, the SPINET, is ongoing comparing lanreotide with placebo. Peptide receptor radionuclide therapy and chemotherapy were not studied within phase III trials for lung NETs, and they have been reported to be active within retrospective or phase II prospective studies. Temozolomide and oxaliplatin are two interesting chemotherapeutic agents in lung NETs. While some European Institutions were certificated as Centers of Excellence for gastroenteropancreatic NENs by the European Neuroendocrine Tumor Society (ENETS), an equivalent ENETS certification for lung NENs does not exist yet. Ideally a lung NEN-dedicated multidisciplinary tumor board should include NEN-dedicated medical oncologists, thoracic medical oncologist, thoracic surgeons, pathologists, interventional radiologists, endocrinologists, radiotherapists, interventional pneumologists, nuclear physician.

Predictive Markers of Response to Everolimus and Sunitinib in Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques.

Metronomic and metronomic-like therapies in neuroendocrine tumors - Rationale and clinical perspectives.

Metronomic therapy is characterized by the administration of regular low doses of certain drugs with very low toxicity. There have been numerous debates over the empirical approach of this regimen, but fewest side effects are always something to consider in order to improve patients' quality of life. Neuroendocrine tumors (NETs) are rare malignancies relatively slow-growing; therefore their treatment is often chronic, involving several different therapies for tumor growth control. Knowing that these tumors are highly vascularized, the anti-angiogenic aspect is highly regarded as something to be targeted in all patients harboring NETs. Additionally the metronomic schedule has proved to be effective on an immunological level, rendering this approach as a multi-targeted therapy. Rationalizing that advanced NETs are in many cases a chronic disease, with which patients can live for as long as possible, a systemic therapy with regular low doses and a very low toxicity is in many cases a judicious manner of pursuing stabilization. Metronomic schedule is usually correlated with chemotherapy in oncology, but other therapies, such as radiotherapy and biotherapy can be delivered in a metronomic like manner. This review describes clinical trials and case series involving metronomic therapies alone or in combination in patients with advanced NETs. Nowadays level of evidence about metronomic therapy in NETs is quite low, therefore future prospective clinical studies are needed to validate the metronomic approach in specific clinical settings.

Risk factors of type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis. A retrospective, multicentre study.

The aim of this retrospective study was to evaluate the presence of risk factors for a type 1 gastric neuroendocrine neoplasia in a large cohort of patients with chronic atrophic gastritis. The study design consisted of an Italian multicentre, retrospective analysis. The study included all consecutive patients with chronic atrophic gastritis with or without type 1 gastric neuroendocrine neoplasias followed at the participating centres. Two hundred and twenty-nine patients with chronic atrophic gastritis were enroled at the participating centres. A total of 207 patients (154 female, 53 males, median age: 56.0 years) were included in the final analysis. One hundred and twenty-six patients had chronic atrophic gastritis without a gastric neuroendocrine neoplasia and 81 had a chronic atrophic gastritis with type 1 gastric neuroendocrine neoplasia. The median Chromogranin A level, evaluated in 141 patients, was 52.0 U/L. At upper gastrointestinal endoscopy, atrophy of the gastric mucosa was mild/moderate in 137 patients and severe in 68. Intestinal metaplasia of the corpus was present in 168 patients. At histological examination, 81 patients had a gastric neuroendocrine neoplasia (42 patients had a NET G1 and 33 a NET G2). The median Ki67 index was 2.0 %. At univariate and multivariate analysis, the risk factors for a gastric neuroendocrine neoplasia were: male gender, chromogranin A greater than 61 U/L, presence of intestinal metaplasia and age equal to or greater than 59 years. Chromogranin A greater than 61 U/L, the presence of intestinal metaplasia and male gender were independent risk factors for a type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis.

Endoscopic electrocautery dilation of benign anastomotic colonic strictures: a single-center experience.

BACKGROUND: Benign anastomotic colonic stenosis sometimes occur after surgery and usually require surgical or endoscopic dilation. Endoscopic dilation of anastomotic colonic strictures by using balloon or bougie-type dilators has been demonstrated to be safe and effective in multiple uncontrolled series. However, few data are available on safety and efficacy of endoscopic electrocautery dilation. The aim of our study was to retrospectively investigate safety and efficacy of endoscopic electrocautery dilation of postsurgical benign anastomotic colonic strictures. METHODS: Sixty patients (37 women; median age 63.6 years, range 22.6-81.7) with benign anastomotic colonic or rectal strictures treated with endoscopic electrocautery dilation between June 2001 and February 2013 were included in the study. Anastomotic stricture was defined as a narrowed anastomosis through which a standard colonoscope could not be passed. Only annular anastomotic strictures were considered suitable for electrocautery dilation which consisted of radial incisions performed with a precut sphincterotome. Treatment was considered successful if the colonic anastomosis could be passed by a standard colonoscope immediately after dilation. Recurrence was defined as anastomotic stricture reappearance during follow-up. RESULTS: The time interval between colorectal surgery and the first endoscopic evaluation or symptoms development was 7.3 months (1.3-60.7). Electrocautery dilation was successful in all the patients. There were no procedure-related complications. Median follow-up was 35.5 months (2.0-144.0). Anastomotic stricture recurrence was observed in three patients who were successfully treated with electrocautery dilation and Savary dilation. CONCLUSIONS: Endoscopic electrocautery dilation is a safe and effective treatment for annular benign anastomotic postsurgical colonic strictures.

Clinical management of patients with gastric neuroendocrine neoplasms associated with chronic atrophic gastritis: a retrospective, multicentre study.

To provide data regarding clinical presentation, pathological features, management, and response to different treatments of patients with type I gastric neuroendocrine tumors in stages 0-2A. The study design consist of an Italian multicentre, retrospective analysis of patients with type I gastric neuroendocrine tumors managed with different therapeutic approaches: surgery, endoscopic surveillance, endoscopic resection, or somatostatin analog therapy. Among the 97 patients included, 3 underwent surgery, 45 (46.4%) radical endoscopic resection of the neoplastic lesions, 13 (13.4%) follow-up with upper endoscopy, and 36 (37.1%) somatostatin analog therapy. At the end of the follow-up, all patients were alive and there was no evidence of metastatic disease. Somatostatin analog therapy resulted in a complete response in 76.0% of the patients and stable disease in 24.0%. A prolonged period of therapy, the use of a full dose of somatostatin analogs and higher gastrin levels at diagnosis were related to a complete response to the therapy. The recurrence rate was 26.3% in patients treated with somatostatin analog therapy and 26.2% in patients treated with endoscopic resection, without a statistically significant difference in terms of disease-free survival. Regarding recurrence of the disease, no statistical difference was found according to type of therapy, number of neoplastic lesions, and 2010 WHO classification. The only risk factor for tumor recurrence was a short period of medical treatment. In conclusion, our study suggested that endoscopic surveillance, endoscopic resection and somatostatin analog therapy represent valid options in the management of patients with type I gastric neuroendocrine tumors in stages 0-2A.

Small intestinal neuroendocrine tumors with liver metastases and resection of the primary: Prognostic factors for decision making.

INTRODUCTION: Patients with small intestine neuroendocrine tumors present with liver metastases in 50-75% of cases at diagnosis. The aim of the present study was to assess prognostic factors in patients with liver metastases from intestinal neuroendocrine tumor after primary tumor surgical removal with or without liver surgery or radiofrequency ablation. The primary endpoint was disease-specific survival. METHODS: Data regarding seventy-eight consecutive patients with liver metastases who undergone primary tumor surgical removal between 1996 and 2011 were extracted from the institutional tumor registry and retrospectively analyzed. RESULTS: Liver tumor burden was <25% in 43 (55.1%) 25-50% in 30 (38.5%) and >50% in 5 (6.4%) patients. For the whole cohort of patients disease-specific survival at 3, 5 and 8 years was 93.2%, 83.6% and 77.3%, respectively. Fifteen patients who underwent radical liver surgery were all alive with a median survival of 106 months (range 18-152 months). In multivariate analysis the Ki-67 index in a continuous fashion significantly correlate with prognosis (p = 0.021). Liver tumor burden (p = 0.036) and extrahepatic involvement (p = 0.03), were the most powerful prognosticators for patients who underwent only debulking surgery. CONCLUSION: The Ki-67 index, the liver tumor burden and the presence of extrahepatic metastases should be carefully considered in the selection criteria for liver debulking in asymptomatic patients.

Same-day 2-L PEG-citrate-simethicone plus bisacodyl vs split 4-L PEG: Bowel cleansing for late-morning colonoscopy.

AIM: To evaluate the efficacy, tolerability, acceptability and feasibility of bisacodyl plus low volume polyethyleneglycol-citrate-simeticone (2-L PEG-CS) taken the same day as compared with conventional split-dose 4-L PEG for late morning colonoscopy. METHODS: Randomised, observer-blind, parallel group, comparative trial carried out in 2 centres. Out patients of both sexes, aged between 18 and 85 years, undergoing colonoscopy for diagnostic investigation, colorectal cancer screening or follow-up were eligible. The PEG-CS group received 3 bisacodyl tablets (4 tablets for patients with constipation) at bedtime and 2-L PEG-CS in the morning starting 5 h before colonoscopy. The control group received a conventional 4-L PEG formulation given as split regimen; the morning dose was taken with the same schedule of the low volume preparation. The Ottawa Bowel Preparation Scale (OBPS) score was used as the main outcome measure. RESULTS: A total of 164 subjects were enrolled and 154 completed the study; 78 in the PEG-CS group and 76 in the split 4-L PEG group. The two groups were comparable at baseline. The OBPS score in the PEG-CS group (3.09 ± 2.40) and in the PEG group (2.39 ± 2.55) were equivalent (difference +0.70; 95%CI: -0.09-1.48). This was confirmed by the rate of successful bowel cleansing in the PEG-CS group (89.7%) and in the PEG group (92.1%) (difference -2.4%; 95%CI: -11.40- 6.70). PEG-CS was superior in terms of mucosa visibility compared to PEG (85.7% vs 72.4%, P = 0.042). There were no significant differences in caecum intubation rate, time to reach the caecum and withdrawal time between the two groups. The adenoma detection rate was similar (PEG-CS 43.6% vs PEG 44.7%). No serious adverse events occurred. No difference was found in tolerability of the bowel preparations. Compliance was equal in both groups: more than 90% of subjects drunk the whole solution. Willingness to repeat the same bowel preparations was about 90% for both regimes. CONCLUSION: Same-day PEG-CS is feasible, effective as split-dose 4-L PEG for late morning colonoscopy and does not interfere with work and daily activities the day before colonoscopy.

Confocal laser endomicroscopy for in vivo diagnosis of Barrett's oesophagus and associated neoplasia: a pilot study conducted in a single Italian centre.

BACKGROUND: Diagnosis and management of Barrett's oesophagus are controversial. Technical improvements in real-time recognition of intestinal metaplasia and neoplastic foci provide the chance for more effective target biopsies. Confocal laser endomicroscopy allows to analyze living cells during endoscopy. AIMS: To assess the diagnostic accuracy, inter- and intra-observer variability of endomicroscopy for detecting in vivo neoplasia (dysplasia and/or early neoplasia) in Barrett's oesophagus. METHODS: Prospective pilot study. Patients referred for known Barrett's oesophagus were screened. Endomicroscopy was carried out in a circular fashion, every 1-2 cm, on the whole columnar-lined distal oesophagus. Visible lesions, when present, were analyzed first. Targeted biopsies were taken. Confocal images were classified according to confocal Barrett classification. Endomicroscopic and histological findings were compared. RESULTS: Forty-eight out of 50 screened patients underwent endomicroscopy. Visible lesions were observed in 3 patients. In a per-biopsy analysis, Barrett's-oesophagus-associated neoplasia could be predicted with an accuracy of 98.1%. The agreement between endomicroscopic and histological results was substantial (κ=0.76). CONCLUSIONS: This study suggests that endomicroscopy can provide in vivo diagnosis of Barrett's oesophagus-associated neoplasia. Because it allows for the study of larger surface areas of the mucosa, endomicroscopy may lead to significant improvements in the in vivo screening and surveillance of Barrett's oesophagus.

Linear array ultrasonography to stage rectal neoplasias suitable for local treatment.

BACKGROUND: Because of the many therapeutic options available, a reliable staging is crucial for rectal neoplasia management. Adenomas and cancers limited to the submucosa without lymph node involvement may be treated locally. AIMS: The aim of this study is to evaluate the diagnostic accuracy of endorectal ultrasonography in the staging of neoplasias suitable for local treatment. METHODS: We considered all patients who underwent endorectal ultrasonography between 2001 and 2010. The study population consisted of 92 patients with 92 neoplasias (68 adenocarcinomas and 24 adenomas). A 5 and 7.5MHz linear array echoendoscope was used. The postoperative histopathologic result was compared with the preoperative staging defined by endorectal ultrasonography. Adenomas and cancers limited to the submucosa were considered together (pT0-1). RESULTS: The sensitivity, specificity, overall accuracy rate, positive predictive value, and negative predictive value of endorectal ultrasonography for pT0-1 were 86%, 95.6%, 91.3%, 94.9% and 88.7%. Those for nodal involvement were 45.4%, 95.5%, 83%, 76.9% and 84%, with 3 false positive results and 12 false negative. For combined pT0-1 and pN0, endorectal ultrasonography showed an 87.5% sensitivity, 95.9% specificity, 92% overall accuracy rate, 94.9% positive predictive value and 90.2% negative predictive value. CONCLUSION: Endorectal linear array ultrasonography is a reliable tool to detect rectal neoplasias suitable for local treatment.

Positron emission tomography for the detection of colorectal adenomas.

BACKGROUND: (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) has been reported to detect colorectal adenomas. AIMS: This study aimed at evaluating the sensitivity of (18)F-FDG PET with computed tomography image fusion (PET/CT) for detecting colorectal adenomas. METHODS: We retrospectively compared the results of 92 (18)F-FDG PET/CT studies followed by colonoscopy. Colonoscopy and histology were considered as the gold standard. RESULTS: One hundred fifty-seven lesions were observed. All the 12 malignancies were identified by (18)F-FDG PET/CT but only 27 out of 119 resected adenomas (sensitivity 22.7%) and none of the hyperplastic polyps were detected. At the univariate and multivariate analyses there was a significant statistical association between adenomas sized more than 10mm, presence of villous component and high-grade dysplasia and the ability of (18)F-FDG PET/CT to detect adenomas. (18)F-FDG PET/CT showed an overall sensitivity of 29.8%, a specificity of 81.1%, a positive predictive value (PPV) of 84.8% and a negative predictive value (NPV) of 24.6% for the neoplastic colorectal lesions globally considered. CONCLUSION: (18)F-FDG PET/CT has a low sensitivity for detecting adenomas. However, because of the specificity and PPV of the technique for neoplastic colorectal lesions, the presence of a focal colorectal FDG uptake justifies the patient undergoing colonoscopy.

Full robotic left colon and rectal cancer resection: technique and early outcome.

OBJECTIVE: The technique for robotic resection of the left colon and anterior resection of the rectum with total mesorectal excision is not well defined. In this study we describe a method that standardizes robot and trocar position, and allows for a complete mobilization of the left colon and the rectum, without repositioning of the surgical cart. Outcome and pathology findings are also reported. METHODS: From January 2007 to May 2008 a total of 55 consecutive patients affected by rectal and left colon cancer were operated on, with full robotic technique, using the Da Vinci robot. Data regarding outcome and pathology reports were prospectively collected in a dedicated database. RESULTS: The following procedures were performed 27 left colectomies, 17 anterior resections, 4 intersphincteric resections, 7 abdominoperineal resections. There were 21 female and 34 male patients with a mean age of 63 +/- 9.9 years. Mean operative time was 290 +/- 69 minutes, ranging from 164 to 487 min., none were converted to open surgery. The median number of lymph nodes harvested was 18.5 +/- 8.3 (range 5-45), and circumferential margin was negative in all cases. Distal margin was 25.15 +/- 12.9 mm (range 6-55) for patients with rectal cancer, and 31.6 +/- 20 mm for all the patients in this series. Anastomotic leak rate was 12.7% (7/55); in all cases conservative treatment was successful. CONCLUSIONS: Full robotic colorectal surgery is a safe and effective technique that exploits the advantages of the Da Vinci robot during the whole intervention, without the need to make use of hybrid operations. Outcome and pathology findings are comparable with those observed in open and laparoscopy procedures.

Frequency and outcomes of rectal ulcers during argon plasma coagulation for chronic radiation-induced proctopathy.

BACKGROUND: Argon plasma coagulation is suitable for treating hemorrhagic GI tract lesions. This study evaluated the frequency and clinical outcomes of complications arising during use of argon plasma coagulation to treat chronic radiation-induced proctopathy. METHODS: This uncontrolled prospective study included 27 consecutive patients. Fever and any rectal symptoms or signs were assessed by telephone with a structured questionnaire. Patients with symptoms underwent endoscopy; follow-up examination was performed when rectal complications developed. RESULTS: Fifty-nine therapeutic sessions were performed (mean 2 per patient; mean interval between sessions, 72.5 days); mean follow-up was 11.5 months. The treatment reduced the mean bleeding severity score from 2.8 to 0.5 (p < 0.001). Two patients (7%) experienced fever and anal pain, and 14 (52%) developed rectal ulcers but remained asymptomatic; ulcer detection never precluded further treatment. Ulcer healing was assessed in 7 patients after a mean of 141 days; no strictures were observed. CONCLUSIONS: The frequency of complications during argon plasma coagulation for radiation-induced proctopathy was high in the present series (59%), the most frequent untoward event being the development of rectal ulcers in asymptomatic patients. However, given the benign outcome, these lesions do not necessitate discontinuation of treatment or additional monitoring.