Management of Pancreatic Neuroendocrine Tumors (PNETs): Surgical strategies and controversies.

OBJECTIVE: Pancreatic neuroendocrine tumors (PNETs) are uncommon tumors which are increasing in incidence. The management of these tumors continues to evolve. This review examines the current role of surgery in the treatment of these tumors METHODS: Studies published over the past 10 years were identified using several databases including PubMed, MEDLINE, and Science Direct. Search terms included pancreatic neuroendocrine tumors, treatment, and surgery. Clinical practice guidelines and updates from several major groups were reviewed. RESULTS: Surgery continues to have a major role in the treatment of sporadic functional and Felibert non-functional PNETs. Pancreas-sparing approaches are increasingly accepted as alternatives to formal pancreatic resection in selected patients. Options such as watch and wait or endoscopic ablation may be reasonable alternatives to surgery for NF-PNETs < 2cm in size. Surgical decision-making in MEN-1 patients remains complex and in some situations such as gastrinoma quite controversial. The role of surgery has significantly diminished in patients with advanced disease due to the advent of more effective systemic and liver-directed therapies. However, the optimal treatments and sequencing in advanced disease remain poorly defined, and it has been suggested that surgery is underutilized in these patients. CONCLUSIONS: Surgery remains a major treatment modality for PNETs. Given the plethora of available treatments, ongoing controversies and the changing landscape, management has become increasingly complex. An experienced multidisciplinary team which includes surgery in essential to manage these patients.

A Rare Adrenal Incidentaloma That Mimics Adrenocortical Carcinoma.

OBJECTIVE: We present a case of an adrenal hemangioma, an uncommon cause of an adrenal mass, and review the clinical presentation, work-up, and management of adrenal incidentalomas. BACKGROUND: A 64-year-old male was found to have a right adrenal incidentaloma during work-up for elevated liver transaminase levels, later found to be from hepatitis C. The mass was suspicious for adrenocortical carcinoma on CT imaging. Biochemical evaluation revealed no evidence of function. He underwent an open right adrenalectomy. The mass was found to be an adrenal hemangioma on histopathologic analysis. METHODS: This is a case report with pertinent review of the diagnosis and management of adrenal incidentalomas. RESULTS: Adrenal hemangiomas are rare, benign, nonfunctional tumors typically found during imaging for other reasons. As illustrated by this case, they appear similar to adrenocortical carcinoma on CT imaging. The diagnosis is usually not made prior to surgical resection. CONCLUSION: Adrenal hemangioma is a rare nonfunctional adrenal incidentaloma that displays atypical features on CT imaging. The suspicion for adrenocortical carcinoma usually prompts adrenalectomy.

SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer.

BACKGROUND: Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS "pathway" activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. METHODS: In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. FINDINGS: SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. INTERPRETATION: The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. FUNDING: This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).

RAS pathway biomarkers for breast cancer prognosis.

Metastatic breast cancer is a highly heterogeneous, rapidly evolving and devastating disease that challenges our ability to find curative therapies. RAS pathway activation is an understudied research area in breast cancer. EGFR/RAS pathway activation is prevalent in breast cancer with poor prognosis. The prognostic RAS pathway biomarkers can be used to identify resistant tumour clones, stratify patients and guide therapies.

Merkel cell carcinoma: high recurrence rate despite aggressive treatment.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine cancer of the skin whose incidence has been increasing. The objective of the study was to evaluate current treatment modalities, including sentinel lymph node (SLN) biopsy and outcomes and identify prognostic factors in patients with MCC. METHODS: A retrospective chart review of patients with MCC. Clinical, pathologic, treatment characteristics, disease status, and survival were collected. All slides were reviewed by a single pathologist, and additional pathologic elements were evaluated for prognosis. RESULTS: Twenty-six patients were identified in the study period. All patients were Caucasian with an average age of 71.3 y. Twenty-one patients had tumors in sun-exposed locations, and 13 had a prior history of skin cancer. All nonmetastatic patients underwent wide excision. SLN biopsy was successful in 19 patients. The SLN was positive in 21% of patients. Radiation therapy was used in 13 patients. Average follow-up was 26 mo, and median survival was 29 mo. Recurrence occurred in eight patients: four locoregional, two distant, one combined, and one unknown. Recurrence occurred in five patients with stage I disease. Five patients with negative SLN later developed recurrence. The presence of metastasis to the nodes was significant for recurrence. No other pathologic factor was found to have prognostic significance. CONCLUSIONS: Despite aggressive surgical and radiation treatment, MCC has a high rate of locoregional recurrence, even in early stage disease. SNLB is useful for the staging and management of patients. Further research is needed to identify better prognostic markers.

Serum proteomic biomarker discovery reflective of stage and obesity in breast cancer patients.

BACKGROUND: Currently no standardized blood test exists for breast cancer screening or staging purposes. The goals of this study were to use proteomic mass spectrometry approaches for profiling, fractionation, and identification of serum proteins from breast cancer patients for discovery of new biomarkers of stage and nodal status. STUDY DESIGN: Samples from 150 patients were collected preoperatively for patients undergoing breast biopsy. Serum was processed using weak cation exchange (WCX) fractionation and analyzed with matrix-assisted laser desorption ionization time of flight mass spectrometry. Spectra were processed and group profiles, peak statistics, and cross-validation scores were determined using a k-nearest neighbor genetic algorithm. Pools of subgroups based on stage, race, and obesity were processed with WCX fractionation followed by trypsin digestion. Differentially expressed proteins and peptides were identified by tandem mass spectrometry. RESULTS: Matrix-assisted laser desorption ionization time of flight proteomic profiling using WCX capture of serum proteins resulted in correct cancer stage classifications ranging from 72% to 84%. Nodal status was classified correctly with 88% cross-validation scores. Levels of endogenous low mass peptide fragments derived from kininogen, fibrinogen, plasminogen, and inter-alpha-trypsin inhibitor heavy chain 4 protein were increased in cancer stage III and stage IV samples. Adding trypsin digestions with WCX capture indicated increased levels of alpha-2-HS-glycoprotein, prothrombin, and serum amyloid A in stage IV samples. Obesity, but not race, was a factor in the relative levels of detected proteins/peptides. CONCLUSIONS: WCX fractionation alone or with trypsin digestion of serum suggest it can be possible to use a panel of proteins to predict breast cancer stage and nodal status. Additional study is required on the role of inflammatory molecules in breast cancer development.

Cutaneous melanoma in Asian-Americans.

BACKGROUND: There is little information available on melanoma in non-white populations. Our objective was to characterize melanoma in Asian-Americans (AsA) and compare patient demographics and tumor characteristics with the non-Hispanic White (NHW) population. METHODS: 483,050 cutaneous melanoma patients diagnosed between 1986 and 2005 were identified using the National Cancer Data Base (NCDB); 1,237 were AsA, and 409,564 were NHW. Age, gender, site, histologic type, tumor thickness, AJCC stage, and survival were compared. RESULTS: AsA were more likely to be diagnosed with acral lentiginous tumors (6.7%) than NHW (0.8%, P < 0.001). A greater proportion of AsA were diagnosed with T4 tumors (15.6%) than NHW (8.5%, P < 0.001). AsA presented with fewer early stage I-II tumors and more late stage III-IV tumors than NHW (P < 0.001). Survival was similar for AsA and NHW. CONCLUSIONS: This is the largest study to date on melanoma in AsA. Compared to NHW, AsA are more likely to have acral lentinginous tumors, thick tumors, and higher stage. Despite this, their survival is similar to the NHW population.

Serum biomarkers to differentiate benign and malignant mammographic lesions.

BACKGROUND: Mammographic screening has increased detection of earlier-stage breast cancers and has decreased mortality from breast cancer. A Breast Imaging-Reporting and Data System (BIRADS) 4 classification prompts a biopsy that most often reveals benign disease. Our objective was to determine if serum protein-expression profiles could be used to differentiate between benign and malignant mammographic lesions. STUDY DESIGN: After IRB approval, women undergoing an image-guided biopsy for a BIRADS category 4 lesion were recruited. Serum was collected prebiopsy and labeled retrospectively after final pathology was reviewed. Serum was incubated with weak cation exchange magnetic beads and assayed in duplicate for analysis on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) instrumentation (Bruker Daltonics). Spectra were analyzed using ClinProTools 2.0 software (Bruker Daltonics), and classifications determined using a genetic-clustering algorithm. RESULTS: In a 14-month period, 260 subjects were recruited into this study. Sera from 92 subjects were randomly selected to form benign (n = 46) and cancer (n = 46) cohorts. The MALDI-TOF spectra analysis yielded 273 peaks, with 14 peaks expressed differentially (p < 0.05) between the cancer and benign cohorts. A genetic algorithm model was generated, yielding a sensitivity of 88.3% and specificity of 85.8%. CONCLUSIONS: MALDI-TOF protein-expression profiles generated from BIRADS 4 sera could be used to distinguish between benign and malignant mammographic lesions.

Micrometastasis in the sentinel lymph node of breast cancer does not mandate completion axillary dissection.

OBJECTIVE: To determine if micrometastatic disease in the sentinel lymph node is a predictor of non-sentinel lymph node (non-SLN) involvement in breast cancer. SUMMARY BACKGROUND DATA: Sentinel lymph node biopsy (SLN) is an accepted alternative to axillary dissection in staging breast cancer. If the SLN contains metastatic foci, the standard recommendation is completion axillary node dissection (CAD). However, a large subset of patients with metastasis limited to the SLN is unnecessarily subjected to the morbidity of CAD. METHODS: A retrospective review of prospectively gathered breast cancer patients having SLN was conducted. Patients with metastasis to the SLN were selected for analysis. Various clinicopathologic features were analyzed for association with metastasis to the non-SLN. RESULTS: A total of 194 women underwent successful SLN dissection. Metastasis to the SLN was found in 48 patients (21 had micrometastases, 27 had macrometastases). Of those with micrometastases, 16 underwent CAD with 1 patient having metastasis to the non-SLN. In patients with macrometastases, 26 had CAD with 14 patients having non-SLN metastasis. Multivariable logistic regression identified only macrometastatic disease in the SLN as significantly associated with involvement of the non-SLN (P = 0.03). None of the patients with micrometastases, including those without CAD, has evidence of local recurrence to date (3-30 months). CONCLUSION: This study demonstrates that the incidence of non-SLN involvement is low in SLN that contains only micrometastatic foci and is within the accepted range of the false-negative rate of SLN. This suggests that a CAD may be omitted in patients with micrometastatic disease.

Obesity and lymphatic mapping with sentinel lymph node biopsy in breast cancer.

BACKGROUND: With increasing sentinel lymph node experience, patient subsets associated with lower success rates are being identified. Obesity may be one such subset. METHODS: A retrospective review was conducted of breast cancer patients who underwent sentinel lymph node biopsy from March 1997 to September 2002. Factors examined included demographics, body mass index (BMI), breast size, tumor characteristics, lymphoscintigraphy drainage, and success of mapping. Chi-square and exact P values were used for statistical analysis. RESULTS: One hundred seventy-four breast cancer patients had sentinel lymph node biopsy. Sixty-seven patients were normal weight (BMI <25.1); 56 patients were overweight (BMI 25.1 to 29.9); and 51 patients were obese (BMI >29.9). Failure to identify a sentinel lymph node and the false negative rate were not statistically different (P = 0.7783 and P = 0.9290, respectively) among the three groups. CONCLUSIONS: Obesity has no significant effect on sentinel node identification rate or false negative rate.

A novel approach toward development of a rapid blood test for breast cancer.

Mammography remains the diagnostic test of choice for breast cancer, but 20% of cancers still go undetected. Many serum biomarkers have been reported for breast cancer but none have proven to represent effective diagnostic strategies. ProteinChip mass spectrometry is an innovative technology that searches the proteome for differentially expressed proteins, allowing for the creation of a panel or profile of biomarkers. The objective of this study was to construct unique cancer-associated serum profiles that, combined with a classification algorithm, would enhance the detection of breast cancer Pretreatment serum samples from 134 female patients (45 with cancer, 42 with benign disease, 47 normal) were procured prospectively following institutional review board-approved protocols. Proteins were denatured, applied onto ProteinChip affinity surfaces, and subjected to surface enhanced laser desorption/ionization (SELDI) time-of-flight mass spectrometry. The SELDI output was analyzed using Biomarker Pattern Software to develop a classification tree based on group-specific protein profiles. The cross-validation analysis of cancer versus normal revealed sensitivity and specificity rates of 80% and 79%, and for cancer versus benign disease, 78% and 83%, respectively. When 2 different chip surfaces were combined the sensitivity and specificity increased to 90% and 93%, respectively. The sensitivity and specificity of this technique are comparable to those of mammography and, if confirmed in a larger study, this technique could provide the means toward development of a simple blood test to aid in the early detection of breast cancer. The combination of SELDI ProteinChip mass spectrometry and a classification- and regression-tree algorithm has the potential to use serum protein expression profiles for detection and diagnosis of breast cancer.

SELDI-TOF serum profiling for prognostic and diagnostic classification of breast cancers.

Surface enhanced laser desorption/ionization (SELDI) time-of-flight mass spectrometry has emerged as a successful tool for serum based detection and differentiation of many cancer types, including breast cancers. In this study, we have applied the SELDI technology to evaluate three potential applications that could extend the effectiveness of established procedures and biomarkers used for prognostication of breast cancers. Paired serum samples obtained from women with breast cancers prior to surgery and post-surgery (6-9 mos.) were examined. In 14/16 post-treatment patients, serum protein profiles could be used to distinguish these samples from the pre-treatment cancer samples. When compared to serum samples from normal healthy women, 11 of these post-treatment samples retained global protein profiles not found in healthy women, including five low-mass proteins that remained elevated in both pre-treatment and post-treatment serum groups. In another pilot study, serum profiles were compared for a group of 30 women who were known BRCA-1 mutation carriers, half of whom subsequently developed breast cancer within three years of the sample procurement. SELDI protein profiling accurately classified 13/15 women with BRCA-1 breast cancers from the 15 non-cancer BRCA-1 carriers. Additionally, the ability of SELDI to distinguish between the serum profiles from sentinel lymph node positive and sentinel lymph node negative patients was evaluated. In sentinel lymph node positive samples, 22/27 samples were correctly classified, in comparison to the correct classification of 55/71 sentinel lymph node negative samples. These initial results indicate the utility of protein profiling approaches for developing new diagnostic and prognostic assays for breast cancers.