Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018.

The NCCN Guidelines for Neuroendocrine and Adrenal Tumors provide recommendations for the management of adult patients with neuroendocrine tumors (NETs), adrenal gland tumors, pheochromocytomas, and paragangliomas. Management of NETs relies heavily on the site of the primary NET. These NCCN Guidelines Insights summarize the management options and the 2018 updates to the guidelines for locoregional advanced disease, and/or distant metastasis originating from gastrointestinal tract, bronchopulmonary, and thymus primary NETs.

Does adjuvant therapy improve overall survival for stage IA/B pancreatic adenocarcinoma?

BACKGROUND: Current guidelines recommend adjuvant chemotherapy for resected pancreatic adenocarcinoma (PDAC). However, no studies have addressed its survival benefit for stage I patients as they comprise <10% of PDAC. METHODS: Using the NCDB 2006-2012, resected PDAC patients with stage I disease who received adjuvant therapy (chemotherapy or chemoradiation) were analyzed. Factors associated with overall survival (OS) were identified. RESULTS: 3909 patients with resected stage IA or IB PDAC were identified. Median OS was 60.3 months (mo) for stage IA and 36.9 mo for IB. 45.5% received adjuvant chemotherapy; 19.9% received adjuvant chemoradiation. There was OS benefit for both stage IA/IB patients with adjuvant chemotherapy (HR = 0.73 and 0.76 for IA and IB, respectively, p = 0.002 and <0.001). For patients with Stage IA disease (n = 1,477, 37.8%), age ≥70 (p < 0.001), higher grade (p < 0.001), ≤10 lymph nodes examined (p = 0.008), positive margins (p < 0.001), and receipt of adjuvant chemoradiation (p = 0.002) were associated with worse OS. For stage IB patients (n = 2,432, 62.2%), similar associations were observed with the exception of adjuvant chemoradiation whereby there was no significant association (p = 0.35). CONCLUSION: Adjuvant chemotherapy was associated with an OS benefit for patients with stage I PDAC; adjuvant chemoradiation was either of no benefit or associated with worse OS.

Neuroendocrine tumors, version 1.2015.

Neuroendocrine tumors (NETs) comprise a broad family of tumors that may or may not be associated with symptoms attributable to hormonal hypersecretion. The NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine Tumors discuss the diagnosis and management of both sporadic and hereditary NETs. This selection from the guidelines focuses on sporadic NETs of the pancreas, gastrointestinal tract, lung, and thymus.

Neuroendocrine tumors.

Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.

Analysis of clinical and dosimetric factors associated with change in renal function in patients with gastrointestinal malignancies after chemoradiation to the abdomen.

PURPOSE: To analyze clinical and dosimetric factors associated with change in renal function in patients with gastrointestinal malignancies after chemoradiation to the abdomen. METHODS AND MATERIALS: A retrospective review of 164 patients with gastrointestinal malignancies treated between 2002 and 2007 was conducted to evaluate change in renal function after concurrent chemotherapy and three-dimensional conformal abdominal radiotherapy (RT). Laboratory and biochemical endpoints were determined before RT and after RT at 6-month intervals. Factors assessed included smoking, diabetes, hypertension, blood urea nitrogen, creatinine, creatinine clearance (CrCl), chemotherapy, and dose-volume parameters. Renal toxicity was assessed by decrease in CrCl and scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring schema. RESULTS: Of 164 patients, 63 had clinical and dosimetric data available. Median follow-up was 17.5 months. Creatinine clearance declined from 98.46 mL/min before RT to 74.20 mL/min one year after chemoradiation (p < 0.0001). Mean decrease in CrCl was 21.37%. Pre-RT CrCl, percentage of bilateral renal volume receiving at least 10 Gy (V(10)), and mean kidney dose were significantly associated with development of Grade > or =2 renal complications at 1 year after chemoradiation (p = 0.0025, 0.0170, and 0.0095, respectively). CONCLUSIONS: We observed correlation between pre-RT CrCl, V(10), and mean kidney dose and decline in CrCl 1 year after chemoradiation. These observations can assist in treatment planning and renal dose constraints in patients receiving chemotherapy and abdominal RT and may help identify patients at increased risk for renal complications.

CD24 expression is an independent prognostic marker in cholangiocarcinoma.

CD24 has been described as an adverse prognostic marker in several malignancies. This study evaluates CD24 expression in cholangiocarcinoma and correlates the findings with clinicopathologic data and patient survival. Between 1996 and 2002, 22 consecutive patients with cholangiocarcinoma were treated at our institution. Demographic data, SEER stage, pathologic data, treatment, expression of CD24, mitogen-activated protein kinase (MAPK), phosphorylated MAPK, and survival were analyzed. The majority of the tumors demonstrated CD24 (81.8%) and p-MAPK (87%) expression. A negative association was noted between the expression of CD24 and p-MAPK. Median survival for patients with low expression of CD24 was 36 months and high expression was 8 months. Median survival for patients who received chemotherapy with low CD24 expression was 163 months, and for seven patients with high CD24 expression, it was 17 months (p=0.04). With the addition of radiation therapy, median survival for patients with low expression of CD24 was 52 months and high expression was 17 months (p=0.08). On multivariate analysis, the use of chemotherapy (p=0.0014, hazard ratio 0.069) and the CD24 overexpression (p=0.02, hazard ratio 7.528) were predictive of survival. CD24 is commonly expressed in cholangiocarcinoma, and overexpression is predictive of poor survival and possibly of lack of response to chemotherapy and radiation therapy. These findings may improve selection of patients for the appropriate treatment modality and the development of CD24-targeted therapy.

Impact of robotics and laparoscopy on surgical skills: A comparative study.

BACKGROUND: This study objectively surveyed and compared the ability of participants to perform laparoscopic and robotic tasks, and attempted to determine the key advantages of each modality. STUDY DESIGN: A task-based training course was developed that included laparoscopic and robotic task modules. Twenty-two participants (6 faculty members, 6 fellows, and 10 residents) completed a pretask and posttask questionnaire concerning 3 tasks, using both laparoscopy trainer and the daVinci robotic system (Intuitive Surgical, Inc). All tasks were timed and values were recorded. The surveys were completed by each participant to assess both pre- and posttask experiences. RESULTS: In the pretask survey, 55% of subjects reported participating in more than 20 laparoscopic cases, and only 27% had ever worked at a robotic console. The median number of beads threaded in 5 minutes was similar for the 2 methods, but the median time to complete 5 beads was 98 seconds for the laparoscope compared with 160 seconds using the robot (p = 0.001). The median number of loops completed in 5 minutes was greater (p < 0.001) using the robot (7.5 versus 2). Only 9% of subjects completed 9 loops in 5 minutes using the laparoscope; 50% did so using the robot (p < 0.05). The percentage of subjects completing 3 knots in 5 minutes was similar when using the laparoscope (45%) and robot (68%). Familiarity and tactile feedback were the primary advantages with laparoscopy, and EndoWrist (Intuitive Surgical, Inc) and stereoscopic visualization were perceived as advantages of the robot. CONCLUSIONS: As with any new technology, skills must be mastered to use robotic technology for the most benefit. The EndoWrist action and stereoscopic visualization were the most valued advantages of the robot. Most fellows and residents would seek additional training in robotics if given the opportunity.

Akt expression may predict favorable prognosis in cholangiocarcinoma.

BACKGROUND: Overexpression of signaling proteins including epidermal growth factor receptor (EGFR), Akt, mitogen activated protein kinase (MAPK) and cyclooxygenase-2 (COX-2) occurs in cholangiocarcinoma cell lines. However, the prognostic value of these markers is unknown. No prior study correlated the expression of these signaling proteins with clinical outcome. Further, co-expression of these proteins has not been reported. Co-expression may reflect cross-talk between signaling pathways. The aim of this clinicopathological study was to investigate the overexpression and co-expression of EGFR and related signaling proteins in cholangiocarcinoma and explore their relationship to clinical outcome. METHODS: Twenty-four consecutive cases of cholangiocarcinoma treated from 1996 to 2002 at Roswell Park Cancer Institute were included. Immunohistochemical staining of paraffin-embedded tissue sections was performed using antibodies against Akt, p-Akt, MAPK, p-MAPK, COX-2, EGFR and p-EGFR. Two pathologists independently scored the protein expression. RESULTS: Cyclooxygenase-2, Akt, and p-MAPK were commonly expressed in biliary cancers (100%, 96% and 87% of malignant cells, respectively). EGFR (60%) and p-EGFR (22%) overexpression was also detected. There was a significant association between EGFR and p-EGFR (P = 0.027) and between Akt and p-Akt (P = 0.017) expression in tumor tissue. A noteworthy association was shown between MAPK and p-Akt (P = 0.054). Multivariate analysis using the Cox proportional hazard model identified the use of chemotherapy (hazard ratio [HR] = 0.039, P = 0.0002), radiation (HR = 0.176, P = 0.0441) and Akt expression (HR = 0.139, P = 0.006) as the best predictors of overall prognosis. CONCLUSION: Epidermal growth factor receptor signaling intermediates are commonly expressed in cholangiocarcinoma. Expression of Akt and use of systemic chemotherapy or radiation may correlate with improved survival.

Activated Akt and Erk expression and survival after surgery in pancreatic carcinoma.

BACKGROUND: Long-term survival of surgically resectable pancreatic cancer patients is uncommon. The epidermal growth factor receptor (EGFR) and the phosphoinositol-3-kinase pathways are often activated in pancreatic cancer, and an understanding of their role in resected cases may help refine adjuvant therapy. METHODS: We investigated the expression of EGFR, Erk, Akt, and their phosphoforms (p-) in pancreatectomy specimens and correlated these with survival. Thirty-nine consecutive surgically resected pancreatic adenocarcinoma cases were included. Immunohistochemical staining of paraffin-embedded blocks was performed by using monoclonal antibodies against EGFR, Erk, p-Erk, Akt, and p-Akt. A standard immunoperoxidase technique was used to detect the avidin-biotin peroxidase complex. Immunostaining was visually scored with the histoscore method by two surgical pathologists. RESULTS: Patient characteristics were as follows: 17 men and 22 women; median age, 66 years; and American Joint Committee on Cancer stage I, 5 patients; stage II, 4 patients; stage III, 27 patients; and stage IV, 3 patients. The tumor was World Health Organization grade 1 in 4, grade 2 in 17, and grade 3 in 18 cases. Adjuvant therapies were chemotherapy (n = 6), radiotherapy (n = 1), and chemoradiotherapy (n = 17). Immunohistochemistry revealed positive expression of EGFR in 30.8%, Erk in 92.3%, p-Erk in 45.9%, Akt in 71.8%, and p-Akt in 20.5% of cases. On univariate analyses, tumor grade (P = .0098), p-Akt (P = .0003), and p-Erk (P = .0052) expression correlated with survival. On multivariate analyses, age (P = .0002; hazard ratio [HR], 1.8), grade (P = .00318; HR, 3.0), Akt (P = .0433; HR, .4), p-Akt (P = .0002; HR, .2), and p-Erk (P = .0003; HR, 3.5) expression correlated significantly with survival. CONCLUSIONS: p-Erk and p-Akt expression may have prognostic and therapeutic implications in pancreatic cancer.

Diagnosing regenerative nodular hyperplasia, the "great masquerader" of liver tumors.

Distinguishing benign tumors and pseudotumors of the liver from malignant tumors is a common clinical problem. Regenerative nodular hyperplasia (RNH) represents one of the more challenging pseudotumors to diagnose, because they can appear clinically indistinguishable from either a primary or a secondary liver malignancy. Even after comprehensive radiologic evaluation and image-guided percutaneous biopsy, the diagnosis of RNH can remain elusive. We reviewed the pathophysiology of RNH and present five cases illustrating the limitations of percutaneous biopsy and the utility of laparoscopic wedge biopsy in establishing the diagnosis. All patients underwent a complete workup that included percutaneous biopsy. Patients with a nondiagnostic percutaneous biopsy underwent a laparoscopic wedge biopsy or anatomical resection. H&E, vimentin, trichrome, and reticulin staining as well as CD34 immunostaining were performed. Five patients were diagnosed with RNH between May 2002 and April 2004. Three had focal nodular disease, whereas the other two had a diffuse multinodular presentation. Percutaneous biopsy definitively made the diagnosis in only one out of the five cases. Laparoscopic wedge biopsy was necessary to accurately make the diagnosis in three cases, whereas the fifth diagnosis was established after an anatomical resection. RNH is a unique pseudotumor of the liver that can present either as a solitary nodule or as a multinodular process. Percutaneous biopsy is associated with limitations in diagnosing RNH, and a more definitive surgical biopsy may be required. When RNH is considered, laparoscopic wedge biopsy is a safe and efficient way to obtain enough tissue to preserve the hepatic architecture required for diagnosis, while avoiding the morbidity of an unnecessary open resection.

Neoadjuvant therapy for gastric cancer.

Gastric cancer is a global health issue. Most cases are diagnosed at an advanced stage with poor prognosis. Current therapies have a modest impact on survival. Surgery remains the only potentially curative treatment, but is associated with a high rate of locoregional recurrence and distant metastases. Total gastrectomy for proximal cancers is complicated by postoperative morbidity and quality-of-life impairment. Combined-modality therapy may improve outcomes in this disease. Adjuvant therapy for gastric cancer has now become the standard in the Western world. However, adjuvant therapy improves survival by only a few months and is associated with high morbidity. Neoadjuvant therapy is commonly used for esophageal and gastroesophageal junction cancers, but is still regarded as investigational in gastric cancer. Several small phase II studies indicate the feasibility of neoadjuvant strategies. The incorporation of novel, targeted agents into neoadjuvant programs and an assessment of biologic changes within the tumor may refine therapy. This article provides a concise review of the literature on neoadjuvant therapy for gastric cancer and suggests avenues for further investigation.

Postoperative computed tomography scan surveillance for patients with stage II and III colorectal cancer: worthy of further study?

The use of computed tomography scan (CT) of the abdomen and pelvis for surveillance of colorectal cancer (CRC) after primary curative therapy (PCT) remains controversial. Surveillance guidelines at Roswell Park Cancer Institute have included annual CT for the first 2 years after PCT. Isolated metastases from CRC may be amenable to surgical resection, potentially leading to a survival advantage. To assess this, a retrospective chart review of all 203 patients diagnosed with stage II or III CRC between January 1, 1990, and December 31, 1995, was conducted. First-year surveillance CT (CT-1) was performed for 146 of 203 patients and 81 of 146 patients had second-year surveillance CT (CT-2). CT was considered "directed" when at least 1 of the following prompted evaluation: suspicious symptoms or signs, rising carcinoembryonic antigen, findings from colonoscopies, chest x-rays, or laboratory tests. Otherwise, CT was considered "nondirected." Of 121 of 146 CT-1 and 63 of 81 CT-2 with nondirected CT, 7 of 121(5.8%) and 4 of 63 (6.4%) had proven recurrence, respectively. During 2 years of follow up, the estimated lower bound for detection of recurrence by nondirected CT was 11 of 121(9.1%). There were no apparent differences between the 2 groups in demographics, clinical presentation, surgical margins, treatment, tumor site, grade, or TNM stage. Surgical resectability of the metastases for directed and nondirected groups was 10 of 28 (36%) and 6 of 11 (54%), respectively. The median survival for the patients with recurrence in the directed and nondirected groups was 35 and 50 months, respectively. In conclusion, this retrospective study generates the hypothesis that CT surveillance may be of value. A prospective study, properly sized for power, is needed to answer this question.

Risk factors associated with earlier age of onset in familial pancreatic carcinoma.

BACKGROUND: An estimated 5-10% of all pancreatic adenocarcinomas have a hereditary association. The objective of the current study was to characterize the clinical and pathologic features of familial pancreatic carcinoma and to determine potential differences in demographics, risk factors, and outcomes between familial and sporadic pancreatic carcinoma populations. METHODS: A retrospective review was performed to identify patients diagnosed with pancreatic carcinoma who had an associated familial disposition. Demographic analyses and assessment of clinical features and treatment outcomes were performed for the familial subgroup, and the results were compared with observations made in the nonfamilial, or 'sporadic', population. RESULTS: Thirty of 826 patients (3.6%) had familial pancreatic carcinoma. Baseline demographics, resectability, and metastases were similar in both the familial cohort and the sporadic cohort. The mean age of onset was slightly lower in the familial cohort (57.6 years, compared with 61 years in the sporadic cohort). However, the familial population had a significantly greater proportion of patients who were diagnosed at age <50 years compared with the sporadic population (36.7% vs. 18.3%; P=0.017). A positive smoking history was more commonly associated with familial pancreatic carcinoma (87% vs. 66%; P=0.06). The overall median survival durations were 7 months and 6 months for the familial group and the sporadic group, respectively. CONCLUSIONS: Patients with familial pancreatic carcinoma present at an earlier age compared with their counterparts who have nonfamilial disease. Smoking may play a significant role in the risk or promotion of pancreatic carcinoma in patients with an inherited predisposition.

Nuclear survivin expression predicts poor outcome in cholangiocarcinoma.

BACKGROUND/AIMS: Survivin is an anti-apoptotic protein expressed in cancer and may have prognostic value. Our study examined the prognostic role of survivin in biliary cancer. METHODOLOGY: Twenty-four consecutive cases of cholangiocarcinoma were studied. Immunohistochemistry was performed using a monoclonal antibody to survivin. Survivin expression was described as absent or weak and strong. RESULTS: Median age was 68 years (range 40 to 77). There were 16 females and 8 males. SEER (Surveillance, Epidemiology and End Results) staging was local in 2, regional in 15 and distant in 7. Treatments included chemotherapy (n=3), surgery (n=9), combined modality (n=10) or no therapy (n=2). Cytoplasmic and nuclear survivin expression was seen in 13 and 11 patients respectively. Strong cytoplasmic survivin expression was seen in 6 cases and strong nuclear survivin in 4. Patients with strong nuclear survivin had a median survival of 11 months, significantly lower than for patients with weak nuclear survivin expression (20 months, p=0.033). Multivariate analysis using the Cox-proportional hazards model identified 4 important prognostic predictors: nuclear survivin (P=0.022), presence of metastasis (P=0.025), age (P=0.019) and use of combined modality therapy (P=0.006). CONCLUSIONS: Nuclear survivin expression in cholangiocarcinoma may identify those with a poor prognosis.

Solitary liver mass causing diagnostic dilemma in a case of lupus nephritis.

Diffuse proliferative lupus nephritis requires aggressive therapy. Patients with lupus nephritis may have concomitant hepatic involvement in the form of lesions that may be inflammatory or neoplastic in nature. In such situations, initiation of immuno-suppressive therapy may prove difficult without defining the nature of the lesion. This report describes the diagnostic dilemma that we encountered in a young patient with lupus nephritis who was discovered to have an incidental solitary liver mass on abdominal ultrasound. The literature of hepatic involvement in lupus is reviewed and discussed.

Radiofrequency ablation of liver tumors: influence of technique and tumor size.

BACKGROUND: Radiofrequency thermal ablation (RFA) of liver tumors is done by both radiologists and surgeons by using various techniques for a variety of indications. This report describes our initial experience with RFA in 45 patients with hepatic malignancies. METHODS: Patients with primary or secondary hepatic malignancies who were not candidates for resection underwent ultrasound-guided RFA under general anesthesia. End points were recurrence within or adjacent to the ablation zone or new hepatic or extrahepatic lesions. Product limit survival estimates for both ablation site recurrence-free survival and disease-free survival were calculated and compared for tumor size (less than 4 cm or 4 cm or greater), operative approach (percutaneous, laparoscopy, or open), and tumor type (hepatocellular cancer, colorectal cancer, or other metastatic disease). RESULTS: Patients with hepatocellular cancer (n = 11) and with secondary hepatic malignancies (n = 34) had 84 lesions ablated with a median follow-up of 12 months. Largest ablated tumor size of 4 cm or greater (P <.001) and the percutaneous approach (P <.02) were associated with worse ablation site recurrence-free survival but not overall disease-free survival (P =.06). The 15 patients with colorectal cancer had worse disease-free survival compared with other tumor types (P <.01). CONCLUSIONS: RFA of hepatic malignancies can be done by using a percutaneous, laparoscopic, or open approach. Local control appears superior for tumors less than 4 cm and when an open surgical approach is used. The difficulty in achieving prolonged disease-free survival, especially in colorectal cancer, underscores the need to investigate multimodality approaches that include local ablative techniques. Future RFA studies should consider tumor size, operative technique, and tumor type in trial design.