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Редкие опухоли поджелудочной железы
Textbook of Uncommon Cancer, Fourth Edition. Edited by Derek Raghavan, Charles D. Blanke, David H. Johnson, Paul L. Moots, Gregory H. Reaman, Peter G. Rose and Mikkael A. Sekeres. John Wiley & Sons, 2012.
Tumors of the pancreas collectively are the fourth leading cause of neoplastic death despite being only the 10th most common site of cancer in the United States.1 In 2011, it is expected that over 44,000 Americans will be diagnosed with pancreatic cancer and 37,660 will die from this disease. Approximately 95% of pancreatic cancers arise from the ductal epithelium, and another 3–4% arise from the islet cells. This chapter will review the unusual, remaining 1–2% (Box 29.1), particularly epithelial malignancies of nonneuroendocrine origin. The nonepithelial pancreatic malignancies, including lymphomas, sarcomas, primitive neuroectodermal tumor, and desmoplastic small round cell tumor, are treated similarly to those arising from other sites and will not be addressed in this chapter.
Uncommon exocrine tumors of the pancreas
Cystic neoplasms
Both malignant and benign cystic neoplasms may arise in the pancreas. Each has unique features but the evaluation and diagnostic workup are common for these lesions. It is important to try to distinguish these lesions, because of the impact on management.
Cystic neoplasms are classified as serous (benign or malignant), mucinous (benign or malignant), and intraductal papillary mucinous neoplasm (IPMN), a premalignant lesion that appears to lead to adenocarcinomas. Two recent reviews of all cystic neoplasms have been published.2
The most common clinical presentation for cystic neoplasms is an incidental finding on radiographic studies performed for other reasons.2,3 Symptoms, when they occur, are nonspecific and include bloating, abdominal discomforts and other symptoms of mass effect from the lesions. Most commonly, the patients have had either a computed tomography (CT) scan or magnetic resonance imaging (MRI). These tests can differentiate cystic neoplasms from nonneoplastic lesions such as pancreatic pseudocyst. Pseudocyst generally presents with history of pancreatitis and on CT or MRI inflammation of the pancreas is usually seen.4 Magnetic resonance cholangiopancreatography can help determine the etiology of the cystic lesion as well, showing biliary and pancreatic ductal structure. Endoscopic retrograde cholangiopancreatography (ERCP) may also be useful. One finding, that of a swollen papilla with mucin oozing from the papilla, is considered pathogenomic of IPMN but is not a common finding.4
Surgery is the diagnostic test of choice for cystic neoplasms but among less invasive testing, endoscopic ultrasound (EUS) should be considered. This procedure allows evaluation of the cyst, biopsy and aspiration of the cystic fluid for diagnostic testing. Cyst fluid analysis had been utilized prior to EUS but EUS provided a new modality for evaluating size, structure, and cyst fluid. In the Cooperative Pancreatic Cyst Study, 341 patients underwent EUS and cyst fluid aspiration, 112 of whom had subsequent surgical resection. The study demonstrated that cyst fluid carcinoembryonic antigen (CEA) was more accurate (79% accuracy) than cyst morphology (51% accuracy) or cytology (59% accuracy) in distinguishing mucinous from nonmucinous cysts. In this study, a cut-off of 192 ng/mL was used for CEA levels but the sensitivity and specificity of this test can be changed by using a different CEA level. It is clear that a CEA level of <3.1 ng/mL is almost diagnostic of a serous cyst while levels above 480 ng/mL are diagnostic of a mucinous neoplasm.
However, it is more complex to determine malignant versus nonmalignant cystic neoplasms. Very high levels of CEA of ≥6000 ng/mL are suggestive of malignancy.
Box 29.1. Classification of pancreatic neoplasms.
Epithelial malignancies
Exocrine neoplasms
- Serous cystadenocarcinoma
- Invasive carcinoma associated with mucinous cystic neoplasm (mucinous cystadenocarcinoma)
- Invasive carcinoma associated with intraductal papillary mucinous neoplasm
- Adenocarcinoma variants:
- Adenosquamous carcinoma
- Colloid carcinoma (mucinous noncystic adenocarcinoma)
- Medullary carcinoma
- Hepatoid carcinoma
- Undifferentiated carcinoma
- Undifferentiated carcinoma with osteoclast-like giant cells
- Acinar cell carcinoma
- Acinar cell cystadenocarcinoma
Endocrine malignancies
- Well-differentiated pancreatic neuroendocrine tumor:
- Oncocytic carcinoma
- Poorly differentiated neuroendocrine carcinoma:
- Small cell carcinoma
- Large cell endocrine carcinoma
Epithelial malignancies with multiple directions of differentiation
- Mixed acinar-neuroendocrine carcinoma
- Pancreatoblastoma
Epithelial neoplasms of uncertain direction of differentiation
- Solid-pseudopapillary neoplasm
Nonepithelial malignancies
- Leiomyosarcoma and other sarcomas
- Primitive neuroectodermal tumor
- Desmoplastic small round cell tumor
- Non-Hodgkin lymphoma
Serous cystic neoplasms
Most serous cystic neoplasms (SCNs) are benign, and malignant transformation is thought to be very rare.8,9 Serous cystic neoplasms make up approximately 1.1% of exocrine pancreas tumors.8 However, in a single-institution experience of 158 resected SCNs, only one was initially diagnosed as malignant although a second later presented with metastatic disease, demonstrating that cystadenocarcinoma represent fewer than 1% of serous cystic neoplasms.9
Serous cystic neoplasms can present at almost any age, although the median age at presentation is 61–2.9,10 The majority of patients are female (75–80%) and one study suggested that female patients tend to present at a lower median age.10
Figure 29.1. Serous cystadenocarcinoma is composed of uniform cuboidal cells with clear cytoplasm forming microcysts.
In single-institution studies, 36–47% of patients were asymptomatic with the finding arising from diagnostic workup for a separate problem.9,10 SCNs are more likely to be found in asymptomatic patients as the use of CT and MRI imaging has increased in recent years. Both studies found the most common symptom was abdominal pain with other symptoms being weight loss, fatigue, abdominal fullness, jaundice, and gastrointestinal bleed. The majority of patients were Caucasian. In a Mayo Clinic review of 21 cases collected over 48 years, median age for cystadenocarcinoma was also 61 but a higher percentage of patients were males.11 A higher percentage of patients presented with symptoms, with 81% having abdominal pain and nearly half presenting with weight loss. Jaundice, belching, nausea/vomiting, diarrhea, and fatigue were also reported.
As previously noted, cystadenocarcinoma is rare among the SCNs. By definition, serous cystadenocarcinoma is a serious cystic neoplasm of the pancreas with unequivocal metastases to extrapancreatic organs or tissues.12 Grossly, they usually present with a large mass with multiple compartments filled with numerous microcysts. They frequently invade adjacent organs. Histologically, serous cystadenocarcinomas are identical to serous cystadenoma, being composed of uniform cuboidal, glycogen-rich cells that form numerous cysts containing serous fluid (Fig. 29.1). The presence of local invasion, involvement of regional nodes, cyst wall invasion, and/ or histological dedifferentiation separate malignant from benign SCNs.
Diagnosis of cystic neoplasms is discussed above. For SCNs, CT and MRI of are variable accuracy.13 Endoscopic ultrasound may also be helpful, particularly because fluid can be obtained for evaluation. The diagnostic accuracy of EUS is as low as 40%, and it cannot evaluate benign versus malignant lesions. As mentioned above, cyst fluid analysis adds to the diagnostic accuracy of EUS, and low CEA (<5 ng/mL) and low viscosity are among the most consistent tests for differentiating SCNs from mucinous cysts.7,13
Figure 29.2. (a) Grossly, mucinous cystadenocarcinoma is a well-circumscribed, multilocular cystic mass with solid areas. (b) Microscopically, an invasive carcinoma (left) with ductal differentiation arises from cysts (right) lined by atypical epithelium associated with an underlying subepithelial ovarian-like stroma.
Therapy of SCNs is surgical. Tumors smaller than 4 cm can be observed, although the frequency of follow-up scans ranges from 6 months to 2 years.13,14 If lesions show evidence of symptoms or rapid growth, or a definitive diagnosis cannot be obtained, surgery should also be considered. However, comorbidities and other risks for the surgery should be considered, due to the normally slow-growing, benign behavior of SCNs. For serous cystadenocarcinoma, with only one report of over 20 patients, there are few data as to the proper therapy.11
Surgery is still the treatment of choice. For patients with fully resected lesions (n = 13), 5-year survival was much better than for those with partial excisions (n = 7) (68% versus 14%, respectively). As the 5-year survival for resected cystadenocarcinoma appears to be much better than that for typical adenocarcinoma, it is difficult to recommend adjuvant therapy. However, typical regimens for pancreatic adenocarcinoma could be used if the clinician opts for therapy. Of note, the survival curve for partially excised tumors indicates that five of the seven patients died within the first year after surgery, which does not match the table that suggests that four patients survived for more than 1 year.11 The most common site of metastasis (5/7 patients) was the liver. For those with metastatic disease, there is no reason to believe that chemotherapy regimens used for pancreatic adenocarcinoma would be any more or less effective in cystadenocarcinoma, and treatment using standard regimens for pancreatic adenocarcinoma is recommended, based on performance status and comorbidities.
Mucinous cystadenocarcinoma
Mucinous cystic neoplasms represent 10–45% of cystic neoplasms.5 In contrast to serous cystic neoplasms, mucinous cystic neoplasms are more prone to malignant transformation. Mucinous cystadenocarcinomas may represent 8–39% of mucinous cystic neoplasms.15–17 Overall, they are felt to represent ~1% of pancreatic cancers.18 This variability may be due to methods for collecting patient data as well as the size of the series.
Mucinous cystadenocarcinoma of the pancreas is an invasive adenocarcinoma arising in mucinous cystadenoma. Grossly, it is a well-circumscribed, multilocular cystic lesion that does not communicate with the pancreatic duct (Fig. 29.2a). The majority of mucinous cystic neoplasms are located in the body or tail of the pancreas.15,19 Benign mucinous cystadenomas have smooth cystic walls. Intracystic papillary excrescence and solid mural nodules are seen in mucinous cystadenocarcinomas. Microscopically, the cysts are lined with columnar epithelium with/without mucin, showing variable degrees of architectural and cytological atypia (Fig. 29.2b). The cystic walls contain ovarian stroma. Most mucinous cystadenocarcinomas are either undifferentiated carcinoma or adenocarcinoma similar to conventional ductal adenocarcinoma (see Fig. 29.2b).20
There is a female predominance for both mucinous cystadenoma (86–100% female) and mucinous cystadenocarcinoma (71–100% female). Cystadenomas tend to present at an earlier age than cystadenocarcinomas. In the largest series, mucinous cystadenoma presented at a median age of 52 while cystadenocarcinomas presented at a median age of 63.6 years.15 In case series, the majority of patients with mucinous cystadenocarcinoma present with symptoms, the most common being abdominal pain in 41–64%, while only 11–25% presented as an incidental finding in patients without symptoms from the tumor.15,16,21 Mucinous cystadenoma presented without symptoms more often (26%) than mucinous cystadenocarcinomas (14%) in one series.15 Other series did not show a difference, with 25% of malignant and 28% of benign mucinous cystic neoplasms presenting as asymptomatic.21 However, most of these series do not account for the greater availability of CT scans and other tests that will likely increase the percentage of asymptomatic patients over time. Other presenting symptoms or findings include mass, fatigue, weight loss, and pancreatitis. Few data exist on CA 19-9 elevations but in one series, there were elevations in 21% of mucinous cystadenoma cases while mucinous cystadenocarcinoma patients presented with CA 19-9 elevations 70% of the time.15 However, other series have not shown a difference in CA 19-9 levels between benign and malignant lesions.21
Consistently, malignant lesions present on average at larger sizes. In one study, the differences were 82.5 mm versus 45 mm (p <0.001) for malignant versus benign.21 In a pooled analysis of multiple studies, mean size of malignant tumors was 10.2 cm with only one malignant tumor under 4.5 cm.22 Mucinous cystadenoma and cystadenocarcinomas predominantly develop in the body and tail of the pancreas with some studies reporting no head lesions.21,22
Treatment of mucinous cystic neoplasms is surgical. Mucinous cystadenomas appear to all be cured with surgical resection, with 99–100% surviving the disease.21,22 The prognoses for resected mucinous cystadenocarcinoma patients are fairly good but only 57–62% are disease free at 5 years. One series reported 23% of patients alive at 10 years.23 An analysis of pathological features predicting recurrence suggested that patients with peritumoral invasion were more likely to experience recurrence than those with only tumor wall invasion.16
Those with no evidence of invasion had no recurrences. Recurrences tend to be in the peritoneum and liver when they occur. Once disease recurs, mean survival is as short as 6.5 months.21 In addition, patients undergoing resection can subsequently develop exocrine or endocrine insufficiency, with both being more likely in patients with cystadenocarcinoma than those with cystadenoma.21 Subsequent exocrine insufficiency occurred in 21.5% versus 4.5% malignant versus benign lesions (p = 0.007) and subsequent endocrine insufficiency developed in 43% versus 18.5% malignant versus benign lesions (p = 0.005).
Little is known about patients with unresectable disease or the effects of systemic therapy. One small series suggested that patients with subtotal resections may also have a long survival, 30 months from diagnosis to death.24 However, patients unable to undergo any resection tend to have poor prognoses, with a 1-year survival rate of only 10% in one study.15 Little is known about the effects of radiotherapy and chemotherapy in this entity. In the absence of any data, it is likely best to treat these patients with chemotherapy and/or chemoradiotherapy regimens used for adenocarcinoma of the pancreas.
Intraductal papillary mucinous neoplasm
Intraductal papillary mucinous neoplasm (IPMN) is not a malignant neoplasm of the pancreas but it remains in the differential diagnosis with other cystic neoplasms of the pancreas. This entity has been known for almost 30 years but was not well defined until 1996.13 The incidence of IPMN is increasing but this most likely reflects increased awareness and improved technology as well as increased access to technology.25 IPMNs represent 20–50% of pancreatic cystic neoplasms. They are of significant importance because they appear to be precursor lesions to the common form of pancreatic cancer. Most recently, three families were described with what appears to be a familial pattern of IPMN.26 None of the mutations already known for familial pancreatic cancer (BRCA2, P16, and CDKN2A) were found in these families. An additional report suggested that this entity may occur with greater frequency in patients with Carney complex, a disorder most commonly associated with a germline PRKAR1A mutation.27
As expected for a precursor lesion of pancreatic cancer, IPMN most often occurs in older age and is more common in the head of the pancreas than in the body or tail.13 There is also a male predominance. IPMNs are divided into those of branch duct origin and those of main duct origin. Main duct IPMNs appear more likely to undergo malignant transformation. In a study of 349 Japanese patients with branch duct IPMNs followed closely, the median age for these lesions was 66 years with only a slight male predominance of 51%.28
Of note, only 1.7% of patients were symptomatic. Median cyst size was 19 mm. While 55% of the lesions were found in the head of the pancreas, 66% of those that progressed during the observation period arose in the head. Patients were observed for a median of 3.7 years and during that time, 17% exhibited progression. Surgery was performed on 29 patients on the study. During the observation period, a total of seven (2%) patients developed pancreatic ductal adenocarcinoma. A separate report of 46 patients with main duct IPMNs showed very different results.29 Median age was 74.6 years with male predominance (59%). Half the lesions were located in the pancreatic head and 30% presented with symptoms. Twenty patients (43%) underwent resection of their IPMNs. Those patients who underwent resection were more likely to have symptoms, be of younger age and have lesions in the head of the pancreas. Malignancy was found in 35% of patients with main duct IPMNs. Data suggesting that main duct IPMNs have greater potential for malignancy than branch-type IPMNs have been shown elsewhere, with 23–57% of main duct IPMNs and only 0–31% of branch duct IPMNs demonstrating invasive carcinoma (adenocarcinoma and IPMN with invasion).30
Pathologically, IPMNs are characterized by proliferation of mucinous cells within the ducts13 and the formation of papillae. There are four histological subtypes of IPMNs: intestinal, pancreatobiliary, oncocytic, and gastric.25 These four subtypes have different expressions of MUC 1, MUC 2, MUC5AC, and MUC6 gastric.25,31 The intestinal type is most common in main duct IPMN gastric.25 It most frequently is associated with a colloid carcinoma that has a fairly favorable prognosis (57% 5-year survival rate). The pancreatobiliary variant occurs more often in main duct IPMN but overall is less common than the intestinal type. The oncocytic variant was once called intraductal oncocytic papillary neoplasm and is the rarest form. It usually has high-grade dysplasia.31 In contrast, the gastric type of IPMN is the most common form and is largely associated with branch-type IPMN.25 Gastric and pancreatobiliary subtypes are associated with ductal adenocarcinoma and oncocytic forms are associated with oncocytic adenocarcinoma (discussed below). A consensus conference determined that IPMNs are characterized by a lack of ovarian stroma as is seen
in mucinous cystic neoplasms of the pancreas.32 IPMNs can have mutations of kRas, BRAF, and PIK3CA as well as loss of SMAD4 expression and overexpression of p53, similar to pancreatic ductal adenocarcinoma but not necessarily with the same incidence.25,31 These findings have now been detected in all subtypes of IPMN although the results thus far are highly variable. They can present with dilation of the pancreatic duct as well as accumulation of mucus.
Management of IPMNs is observation or surgery. Indications that have been used for resection include invasive component on biopsy, symptoms, and progression on radiographic imaging. In addition, presence of mural nodules in pancreatic cysts is more likely to predict dysplasia or invasive carcinoma than lack of mural nodules (23% versus 3%, respectively, p = 0.02).33 Observation is much more likely to be used in branch-type than in main duct IPMNs.13 It appears that the survival for resected IPMNs with invasion is much better than that for resected pancreatic ductal adenocarcinoma.13,34 Although 5-year survival for resected IPMN without invasive component is at least 70%, historically 5-year survival with invasive component is only 30–50%.13 However, a more recent report of 59 patients had 5-year survival for IPMN with an invasive carcinoma at 68%.34 In that study, multivariate analysis showed that nodal involvement and tubular carcinoma subtype predicted poorer prognosis. Other authors have found that when controlled for T and N staging, carcinoma arising from IPMN has no better prognosis than pancreatic ductal adenocarcinoma.35,36
There are no guidelines on the frequency of follow-up for patients for whom observation is chosen rather than surgical resection. There is also no consensus on follow-up of patients with resected IPMNs but it is common to perform at least annual imaging (either CT or MRI).13 Tumor markers appear of limited utility. There are no data on adjuvant therapy with either chemotherapy or chemoradiation. It is not currently recommended that these patients receive adjuvant therapy.
Adenocarcinoma variants
Adenosquamous carcinoma
Adenosquamous carcinoma is one of the more frequently occurring of the adenocarcinoma variants, ranging in autopsy and case series from <1% to as much as 11% of all pancreatic tumors.8,14,37–40 The largest series place the incidence at less than 1%.14,37,38 In the larger case series, adenosquamous carcinomas have a male predominance (~60% or more male).14,39
Seventy-five to 88% were Caucasian and median age was 65–68.14,39,41 There appears to be predominance for head of pancreas primaries. Patients most often present with metastatic disease (53%) and less often with regional (38%) or localized (9%) disease. Using the California Cancer Registry database, researchers compared 95 adenosquamous carcinoma patients to pancreatic adenocarcinoma patients and found that the two populations were very similar in presentation, demographics, and outcomes.14
Adenosquamous carcinoma is a rare variant of pancreatic adenocarcinoma with both glandular and squamous differentiation. The gross appearance is similar to that of conventional ductal adenocarcinoma and it usually presents as a large, firm, ill-defined mass. Microscopically, there are adenocarcinoma and squamous cell carcinoma components, which can be intimately admixed (Fig. 29.3a) or topographically separate within the neoplasm (Fig. 29.3b). When they are separated, the adenocarcinoma portion is indistinct from conventional ductal adenocarcinoma (see Fig. 29.3b). The squamous component can be either keratinizing or nonkeratinizing. In adenosquamous carcinoma, at least 30% of the neoplasm should be squamous cell carcinoma.12 In a single analysis of immunohistochemical staining of 19 primary cases of adenosquamous carcinoma, 100% stained with cytokeratin (AE1/AE3 and CK1), 84% stained for CA 19-9, and 74% for CEA.41 In addition, 68% stained for CK7 and 26% for CK20. Only six metastases were evaluated but staining patterns were similar to the primary tumors. Mutations in K-Ras have been identified in 50–100% of adenosquamous carcinoma.39,42 A detailed analysis found similar mutations to pancreatic adenocarcinoma, including frequent loss of DPC4, and p16 proteins as well as strong nuclear positivity for p53.42 However, the squamous component stained for p63, which does not happen in adenocarcinoma of the pancreas.
Figure 29.3. Adenosquamous carcinoma has two growth patterns: squamous cell carcinoma component intimately intermixed with adenocarcinoma with luminal formation (a), and nests of squamous cell carcinoma (right lower half ) separated from adenocarcinoma (left upper corner) (b).
Several series have suggested a worse outcome for patients with adenosquamous carcinomas versus those with adenocarcinomas.39,41 However, in the largest series the outcomes for adenosquamous carcinoma were similar provided that similar treatments were used.14
Treatment for localized disease is surgery. When surgery is performed, nodal involvement is common, occurring in 57–76% of cases.14,41 In one study, margin involvement was found in 37% of cases.41 Patients with locoregional disease treated with surgical resection have a median survival of 10.9–12 months. This may be better than in older, smaller series as a review of case reports and series from 1980 to 2007 revealed a median survival after surgery of only 6.7 months.43 Adjuvant chemoradiation was associated with an improved overall survival compared to those patients who underwent surgical resection alone. Patients with locoregional disease who did not have resection had much shorter survival, in the range of 5 months.14 Survival for metastatic disease patients is particularly poor, with a median of 4.5 months for those receiving chemotherapy and only 2 months for those who do not.
Stage for stage, the treatment of adenosquamous carcinoma should be the same as for patients with adenocarcinoma of the pancreas. Of note, the data for adjuvant therapy, though limited, exist only for chemoradiation and not for either therapy alone. No data exist for the use of FOLFIRINOX in patients with unresectable adenosquamous carcinoma but data suggest that patients benefit from chemotherapy.14 Considering the squamous component of the disease, there may be a good rationale for using a platinum-containing regimen in this setting to improve outcomes.
Colloid carcinoma (mucinous noncystic carcinoma)
Colloid carcinoma, a variant of pancreatic adenocarcinoma with abundant mucin pools, arises in association with IPMN. With recognition of the IPMN as the precursor lesion for this adenocarcinoma variant, less literature is available separating this entity from its apparent precursor, already discussed. The frequency of this lesion is not certain, as it is a variant of adenocarcinoma and includes both IPMN with minimally invasive disease and true invasive carcinoma, although IPMN can progress to pancreatic ductal adenocarcinoma, whereas colloid carcinoma appears to arise from the intestinal form of IPMN.30,44
Radiographic imaging of colloid carcinoma can include EUS, CT, and/or MRI. On CT, one small study described "peripheral and internal mesh-like progressive delayed enhancement," with contrast administration as well as multiple small cystic areas.45 Similarly, a study of eight patients with colloid carcinoma who underwent MRI found a mesh-like appearance to the tumors as well as high intensity on T2-weighted images and nondistinct borders.46
Colloid carcinoma is usually larger than conventional ductal adenocarcinoma, with a mean size of 5.3 cm in one series.47 On cross-section, they are well circumscribed with a soft gelatinous appearance (Fig. 29.4a). Microscopically, colloid carcinoma is predominantly composed of pools of extracellular mucin with few strips of neoplastic epithelium (Fig. 29.4b). Pools of mucin infiltrate and dissect through the stroma. Mucin-producing neoplastic epithelial cells are usually well differentiated. Strips of the cells may float freely in or partially line the pools. Signet ring cells are frequently present in the mucin pool. Careful examination of the specimens always reveals associated IPMN. A minor component of conventional duct adenocarcinoma may be present. However, at least 80% of the neoplasm should be colloid component.47 Unlike conventional ductal adenocarcinoma which expresses MUC1 and is negative for CDX2, colloid carcinoma strongly expresses MUC2 and CDX2, indicating intestinal differentiation.44
Figure 29.4. (a) Grossly, colloid carcinoma presents as a well-circumscribed mass with a soft gelatinous appearance. (b) Microscopically, there are pools of mucin associated with strips of neoplastic epithelium dissecting the stroma.
Figure 29.5. Medullary carcinoma is a poorly differentiated carcinoma with a pushing border (a) and prominent intratumoral lymphocytes (b).
As mentioned earlier, the historical 5-year survival rate for IPMN with an invasive component is 30–50% with more recent articles suggesting a rate as high as 68%. The latter may reflect increased recognition of IPMNs and/or more aggressive surgical management.13,34 However, these figures likely include minimally invasive IPMN, colloid carcinoma and early forms of pancreatic ductal adenocarcinoma. A study that focused on only colloid carcinoma suggested a 5-year survival rate of 57%.47
Treatment data for colloid carcinoma are lacking. The majority of cases appear to remain localized with only ~30% presenting with metastases to lymph nodes and beyond.35 For localized disease, the treatment of choice is surgery. In the face of limited efficacy data, standard chemotherapy regimens for pancreatic ductal adenocarcinoma are appropriate alternatives for unresectable disease; radiation may be considered as part of the therapy of localized, unresectable colloid carcinoma.
Medullary carcinoma
Medullary carcinoma is a more recently described variant of pancreatic carcinoma. In one analysis of 18 patients, 67% were male and all but one were Caucasian.48 Age ranged from 33 to 85 years with a median of 69. A significant number of cancers were identified in other family members of patients with medullary pancreatic cancers. In fact, only one of the 18 patients had no family history of cancers while four others had unknown histories. Five-year survival for this cohort was 13%.
Medullary carcinoma of the pancreas is morphologically and genetically very similar to its counterpart in the colon. Grossly, medullary carcinomas are well circumscribed with a soft consistency. Microscopically, they have pushing rather than infiltrating borders. Dense lymphocytic infiltrates and/or lymphoid aggregates may be observed in the peripheral area (Fig. 29.5a). Prominent intratumoral lymphocytes may also be seen in some cases. Medullary carcinomas are frequently poorly differentiated with a syncytial growth pattern (Fig. 29.5b). Immunohistochemical studies may show loss of expression of mismatch repair genes.49 An evaluation of 18 patients with medullary carcinoma demonstrated that the majority (67%) had wild-type Ras tumors and a significant portion (22%) had microsatellite instability, including a case with hereditary nonpolyposis colorectal cancer.48 Subsequently, a case report identified another medullary pancreatic carcinoma in a patient with hereditary nonpolyposis colorectal cancer (HNPCC) and MSH2 mutation.50
As with other rare tumors, there are no data on treatment. Surgical resection is recommended when able to be performed. Single-agent fluoropyrimidines may be considered, if these tumors behave like HNPCC-associated colorectal cancers.
Hepatoid carcinoma
Hepatoid carcinoma is extremely rare. It occurs in a variety of locations and is characterized by varying degrees of hepatic differentiation. There are only about 12 case reports of pancreatic hepatoid carcinoma but when reviewed, the majority of these stained for α-fetoprotein (AFP) and many had elevated serum levels of AFP.51 However, little else is really known. In one case report, sorafenib was attempted as therapy for this disease; it would be as reasonable to treat this similarly to hepatocellular carcinoma as it is to try proven therapies for standard pancreatic cancer.
Undifferentiated carcinoma
Undifferentiated carcinoma of the pancreas is an aggressive variant of pancreatic carcinoma with no definable direction of differentiation. Grossly, it is similar to classic ductal adenocarcinoma with infiltrating borders. Microscopically, the neoplastic cells can have anything from an epithelioid appearance to a spindle cell appearance, and frequently infiltrate as individual cells (Fig. 29.6). Mitosis and necrosis are the prominent features of undifferentiated carcinoma. A minor component of conventional ductal adenocarcinoma may be present.
Figure 29.6. Undifferentiated carcinoma may be composed of neoplastic cells with an epithelioid appearance(a) or a spindle cell appearance (b).
Undifferentiated carcinoma with osteoclast-like giant cells
Undifferentiated carcinomas with osteoclast-like giant cells are a variant of undifferentiated carcinoma with reactive osteoclastlike giant cells. Grossly, they tend to be soft and hemorrhagic. Microscopically, they are mainly composed of two groups of cells: large, reactive multinucleated osteoclast-like giant cells with multiple uniform small nuclei and atypical mononuclear cells with single large pleomorphic nuclei. Classic ductal adenocarcinoma or mucinous cystic neoplasm can be focally present. The presence of KRAS2 mutations in the neoplastic cells establishes the ductal origin of this neoplasm.
Acinar cell carcinoma
Acinar cell carcinoma represents 1–2% of pancreatic cancers.8,52,53 These lesions tend to be large (up to 15 cm) upon presentation. In a review of the Surveillance, Epidemiology, and End Results (SEER) database, of 672 patients with acinar cell carcinoma over 53% were male, while the majority with adenocarcinoma were female.53 The average age at presentation is much younger than for pancreatic adenocarcinoma (70.2 versus 56.7 years, p <0.0001). These patients were more likely to present either unstaged or with localized disease and were far more likely to have resection (38.7% versus 11.0%, p <0.0001) than patients with adenocarcinoma. Location of the primary also differed, with head and body/tail occurring in 28% and 42% of cases of acinar cell respectively but 77% and 12% of cases of adenocarcinoma.
Common clinical presentations (generally listed as occurring >20% of the time) include pain (usually listed in >60% of patients), weight loss, anorexia, jaundice, and nausea/ vomiting.54–58 However, acinar cell carcinoma has been associated with two unique situations: a syndrome of panniculitis, polyarthritis and pancreatic disease, and presentation without a primary lesion. Several decades ago, a syndrome including malaise, eosinophilia, nodular skin lesions, and polyarthritis was described in association with pancreatic disease including neoplasm.59–62 The panniculitis comes with fat necrosis and has been observed to regress with treatment of the underlying pancreatic disease.62 The skin lesions can be mistaken for erythema nodosum, initially presenting on the lower extremities but then they tend to become more widespread which is not typical for erythema nodosum.59–61 The arthritis or synovitis has been described in both small and large joints without significant swelling, erythema or warmth in affected joints. Eosinophilia of up to 21% has been reported in this syndrome.60
Elevated lipase was associated with this syndrome in at least one patient.61 The other syndrome is one of presenting without an obvious pancreatic primary. In one small series of three patients, all had nodal disease, while liver and colon were also involved.63 A paraneoplastic syndrome with thrombotic nonbacterial endocarditis has also been reported in association with acinar cell carcinoma.54
Diagnostic evaluation can include CA 19-9 and CEA, both of which have been reported to be elevated in some cases.54,64
Imaging has been described in a few series. CT demonstrates a large, exophytic lesion with a cystic or necrotic component in 53% of cases and an enhancing capsule in 53% of cases.64 In one study, ultrasound showed a heterogeneous, hyperechoic mass and MRI showed hypervascular lesions in the majority of cases.58
Acinar cell carcinoma is characterized by exocrine enzyme production by the neoplastic cells. Acinar cell carcinomas tend to present as a large, well-circumscribed mass. The cut surface is typically soft, fleshy, and focally necrotic and hemorrhagic. Unlike ductal adenocarcinoma, acinar cell carcinomas feature high neoplastic cellularity and a paucity of fibrous stroma. The neoplastic cells have abundant eosinophilic and granular cytoplasm, and are generally arranged in acinar or solid patterns (Fig. 29.7). The nuclei in acinar cell carcinomas are relatively uniform with prominent nucleoli. Mitosis is frequent. Immunohistochemical studies demonstrate that the neoplastic cells produce exocrine enzymes including trypsin, chymotrypsin, and lipase. On electron microscopy, the cytoplasm contains abundant rough endoplasmic reticulum, numerous mitochondria and, usually, electron-dense zymogen granules.54 Although ductal components are seen in acinar cell carcinoma, there is also an entity of mixed acinar and neuroendocrine tumor.56
Figure 29.7. Neoplastic cells in acinar cell carcinoma have abundant eosinophilic cytoplasm and prominent nucleoli. Note: cells with dark eosinophilic cytoplasm (upper right) are benign acinar cells.
Mixed acinar-neuroendocrine carcinoma exhibits both acinar cell and neuroendocrine differentiation. However, the acinar cell component is always predominant. Most mixed acinar-neuroendocrine carcinomas are grossly solid, well circumscribed with a fleshy consistency. Microscopically, two cell types may be recognizable: cells with neuroendocrine differentiation with salt and pepper chromatin and cells with acinar cell differentiation with granular eosinophilic cytoplasm and prominent nucleoli (Fig. 29.8). Immunohistochemical labeling shows regions with acinar cell differentiation (trypsin, chymotrypsin, and lipase) and neuroendocrine differentiation (chromogranin and synaptophysin). Occasionally, the neoplastic cells demonstrate both acinar cell and neuroendocrine differentiation.
Figure 29.8. (a) Grossly, mixed acinar-neuroendocrine carcinomas present as a large, well-circumscribed mass with a fleshy consistency. (b) Microscopically, there are neoplastic cells with D-PAS positive granules in cytoplasm and prominent nucleoli and (c) labeled with chymotrypsin, and (d) neoplastic cells labeled with chromogranin.
Table 29.1. Comparison of survivals for acinar cell and adenocarcinoma of the pancreas from SEER data.
|Acinar cell*
|Median survival
|47 months
|123 months
|25 months
|4 months
|15 months
|3 months
|1 year survival
|2 year survival
|5 year survival
* p <0.0001 for differences in survival in every category.
Acinar cell carcinoma cytogenetics has been evaluated. Mutations in KRAS have not really been seen.65,66 Additionally, p53 mutations, loss of DPC4 and mutations in LKB1 are rare.66,67 However, in one study of five patients, amplifications of chromosomes 20q and 19p occurred in 100% and 80% of cases respectively, and 80% had hypermethylation of at least one tumor suppressor gene.66 An analysis of acinar cell carcinoma patients looking for changes in the APC/β-catenin pathway found alterations in 23.5% of cases.67 The most common alteration found was allelic loss of 11p in 50% of analyzable cases. One patient with microsatellite instability-high phenotype had medullary features.
Acinar cell carcinoma is more indolent than adenocarcinoma. In the SEER database, overall median survival was much better for both resectable and unresectable acinar cell carcinoma (Table 29.1).53 Surgery remains the treatment of choice when possible. Aggressive approaches including resecting patients with regional lymph nodes and limited metastatic disease have been undertaken and results were promising, although some of this may be due to the indolent nature of this disease.55 A multimodality approach has been recommended for advanced disease.55,58 The treatment of metastatic disease usually parallels that for metastatic adenocarcinoma of the pancreas, though reports have noted little effect from radiation or chemotherapy.57 However, with mixed acinar and endocrine carcinoma, treatment of the endocrine component should be considered, especially in cases where the endocrine component is high grade, requiring a platinum-based regimen similar to small cell carcinoma.
Pancreatoblastoma is a very uncommon pancreatic malignancy, representing less than 1% of pancreatic cancers.51 It presents in a very young population, with an age range of 15 months to 13 years in one series.68,69 Common presentations include abdominal mass and discomfort. Vomiting, jaundice, and weight loss have also been reported in more recent series.69
The primary lesions are distributed throughout the pancreas without a predominant location. The majority of tumors were large (>5 cm) in 85% of cases and metastatic in 45% of patients. AFP was significantly elevated in 70% of patients. Imaging, including CT and MRI, shows large, heterogeneous masses with calcifications.70
Pancreatoblastomas are mostly solid, well-circumscribed, lobulated masses present in the head or tail of the pancreas. They tend to be large with an average size of 10.6 cm. They can be soft and fleshy or firm and fibrotic, depending on the proportion of stromal component. Microscopically, they are mainly composed of three cell types: cells with acinar differentiation, squamoid nests, and cells with neuroendocrine differentiation. A distinct ductal component may be seen in some cases. The neoplastic cells grow in a nested or organoid pattern separated by a relatively acellular stroma. Occasionally, focal osseous and cartilaginous differentiation may be seen in the stroma.
Immunohistochemically, acinar component labels with trypsin, chymotrypsin, and lipase, the neuroendocrine component with chromogranin and synpatophysin. The squamoid component usually does not express these markers.
Pancreatoblastoma is occasionally associated with Beckwith–Wiedemann syndrome and has been reported at least once in a patient with familial adenomatous polyposis.67,69
In an assessment of nine cases of pancreatoblastoma, allelic chromosome loss of 11p was the most common finding.67
Alterations of p53 and kRas were not observed and DPC4 loss occurred in two of seven cases. In contrast, five of nine patients had activating mutations in the β-catenin oncogene and seven showed accumulation of the β-catenin protein.
Standard therapy is multimodal, including chemotherapy, radiation therapy, and surgery. Neoadjuvant therapy is commonly used for stages II–IV. Surgery is the definitive therapy for this disease. Chemotherapy regimens used have multiple cytotoxic agents including dacarbazine, vincristine, cisplatin, gemcitabine, ifosfamide, cyclophosphamide, and/or doxorubicin, although there is no single standard regimen. In one series, this type of aggressive approach to therapy resulted in 5-year eventfree survival of 58.8% and 5-year overall survival of 79.4%.69
Solid-pseudopapillary neoplasm
Solid-pseudopapillary neoplasm is a low-grade malignant epithelial neoplasm of the pancreas with unknown direction of differentiation. Grossly, solid-pseudopapillary neoplasms are well demarcated, solid and cystic masses with a soft consistency (Fig. 29.9). Recent or remote hemorrhage is common. Microscopically, the tumor is composed of sheets of relatively uniform polygonal cells admixed with delicate capillary-sized vessels. The neoplastic cells away from the vessels become loosely cohesive, thereby forming pseudopapillary structures (see Fig. 29.9). The nuclei of the neoplastic cells are round to oval with frequent longitudinal nuclear grooves. Prominent extracellular eosinophilic hyaline globules are often present. Immunohistochemically, solid-pseudopaillary neoplasms express α1-antitrypsin, CD10, progesterone receptors, and synaptophysin. In contrast to pancreatic neuroectodermal tumors, solid-pseudopapillary neoplasms do not express chromogranin. In addition, almost all solid-pseudopapillary neoplasms have somatic mutations in β-catenin genes. Immunohistochemical labeling shows nuclear accumulation of β-catenin in the neoplastic cells.
Figure 29.9. (a) Grossly, solid-pseudopapillary tumor is well circumscribed, with cystic and hemorrhagic areas on the cut surface. (b) Microscopically, it is composed of sheets of relatively uniform polygonal cells admixed with delicate capillary-sized vessels. Extracellular hyaline globes are common. (c) Immunohistochemistry shows membranous labeling for CD10 and (d) nuclear labeling for β-catenin in the neoplastic cells. Note: predominantly membranous labeling for β-catenin in the bengin acinar cells (left lower corner).
Rare, nonendocrine tumors of the pancreas are heterogeneous in origin, presentation, and prognosis. Many of these rare tumors can be difficult to diagnose on histology alone and special immunohistochemistry or consultation with specialty centers may be crucial in confirming these rare disorders. These tumors are largely treated similarly to adenocarcinoma of the pancreas, though many have unqiue features that may suggest other therapies, such as treating hepatoid carcinoma like hepatocellular cancer.
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- Baylor SM, Berg JW. Cross-classification and survival characteristics of 5,000 cases of cancer of the pancreas. J Surg Oncol 1973; 5(4):335–58.
- Kardon DE, Thompson LD, Przygodzki RM, Heffess Adenosquamous carcinoma of the pancreas: a clinicopathologic series of 25 cases. Mod Pathol 2001; 14(5): 443–51.
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- Voong KR, Davison J, Pawlik TM, et al. Resected pancreatic adenosquamous carcinoma: clinicopathologic review and evaluation of adjuvant chemotherapy and radiation in 38 patients. Human Pathol 2010; 41:113–22.
- Brody JR, Costantino CL, Potoczek M, et al. Adenosquamous carcinoma of the pancreas harbors KRAS2, DPC4 and TP53 molecular alterations similar to pancreatic ductal adenocarcinoma. Mod Pathol 2009; 22(5): 651–9.
- Okabayashi T, Hanazaki Surgical outcome of adenosquamous carcinoma of the pancreas. World J Gastroenterol 2008; 14(44): 6765–70.
- Adsay NV, Merati K, Basturk O, et al. Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an «intestinal» pathway of carcinogenesis in the pancreas. Am J Surg Pathol 2004; 28(7): 839–48.
- Ren FY, Shao CW, Zuo CJ, Lu JP. CT features of colloid carcinomas of the pancreas. Chinese Med J 2010; 123(10): 1329–32.
- Yoon MA, Lee JM, Kim SH, et al. MRI features of pancreatic colloid carcinoma. Am J Roentgenol 2009; 193(4): W308–13.
- Adsay NV, Pierson C, Sarkar F, et al. Colloid (mucinous noncystic) carcinoma of the pancreas. Am J Surg Pathol 2001; 25(1): 26–42.
- Wilentz RE, Goggins M, Redston Genetic, immunohisto-chemical and clinical features of medullary carcinoma of the pancreas. Am J Pathol 2000; 156: 1641–51.
- Shi C, Hruban RH, Klein AP. Familial pancreatic cancer. Arch Pathol Lab Med 2009; 133(3): 365–74.
- Banville N, Geraghty R, Fox E, et al. Medullary carcinoma of the pancreas in a man with herditary nonpolyposis colorectal cancer due to mutation of the MSH2 mismatch repair gene. Human Pathol 2006; 37: 1498–502.
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- Wisnoski NC, Townsend CM Jr, Nealon WH, Freeman JL, Riall 672 patients with acinar cell carcinoma of the pancreas: a population-based comparison to pancreatic adenocarcinoma. Surgery 2008; 144(2): 141–8.
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And it is highly likely that its upcoming flagship phone the Moto Z2 Force will see the light of the day during the event on July 25th. An official Moto website in China has already posted an image of the Moto Z2 prior to the phone's expected unveiling on July25th .
A popular Chinese microblogging site, Weibo has released a set of alleged Xiaomi X1 images and it looks pretty decent with its design and specifications. The regular variant will come with 4GB RAM with 64GB internal storage priced at 1,999 Yuan or 2,299 Yuan, 4GB RAM with 128GB internal storage priced at 2,499 Yuan ot 2,799 Yuan.
Two of her cheques worth Rs 25 lakhs each bounced at the banks. The incident was that Alka and her mother borrowed money from Avtar Singh and when he asked to pay the money back, Alka and her mother gave him 2 cheques of Rs.25 lack each.
Students who had filed petition against the aforementioned decision taken by IIT-M felt cheated as the rankings as computed after awarding grace marks had tremendously changed by giving out additional marks to those who did not even attempt the questions, which sounded unfair.
The latest reduction means that the Rift is now being sold for just half the price Oculus were charging for the package five months ago, which could be good news for online casino players looking to embrace the VR casino world. Vive, a virtual reality set developed by HTC Corp, is listed for sale at $799 on its website , and it has not recently cut the price. Once the promotional period ends, the immersive system will go up to $598 again, which is still two full Benjamins less than the ...
Body cam footage caught the moment on camera, as Thompson made his request to the officers who'd just put him in handcuffs. "I didn't want to part ways with her not showing exactly how I feel for her", Thompson told CNN by phone. "When you're in love with somebody and you know that you want to spend the rest of your life with them, you just want them to know how you feel", Thompson said.
A website by the name magicapk .com appears to show personal information of Reliance Jio customers. The company said data is only shared with authorities as per their requirement. However Jio has maintained that data that appeared on the website is not authentic. The Aadhar and email numbers were blank for this number, though Fonearena has put out at least three numbers for which Aadhaar and emails were available on the page.
After the Kumble-Kohli saga, the CAC will have to be prudent in its choice as the new coach will be given a two- year contract. Shastri, who has previously served as the team director, applied for the job after the cricket governing board extended the deadline for acceptance of applications till July 9.
It is yet to be confirmed if the posted data is true or not. Here's all about it. So, I expect that the company will properly do the investigation to find the culprit behind the data leak. We have checked multiple Jio numbers of our own and 3rd parties on the website where the data has been leaked and our personal information is available.
Lt. Gen. Thomas Bergeson, U.S. Forces Korea deputy commander, said in the release that the mission "clearly demonstrates the U.S. -ROK alliance remains prepared to use the full range of capabilities to defend and to preserve the security of the Korean Peninsula and region".
Miles, a 12-year veteran who can play both wing positions, averaged almost 11 points per game last year while shooting 41 percent from 3-point range. For the Pacers, getting Cory Joseph back means that they gain an asset instead of simply losing Miles to free agency for nothing in return.
The film, which stars Tom Holland as Peter Parker/Spider-Man, was co-produced by Sony and Marvel Studios . " Homecoming " surpassed 2002's "Spider-Man" opening of $114 million to claim second place all-time. Those numbers might seem high, but they're actually quite good - last year's largely panned " Batman v Superman: Dawn of Justice", fell off by almost 70% in its second weekend, and then 54% the next weekend.
The United Nations Educational, Scientific and Cultural Organization (UNESCO) on Saturday declared Ahmedabad as the world heritage city, making it India's first city to be included in the list. Several of such settlements combined together forms a "Pur" neighborhood. In 1984, the first study for conserving heritage structures was carried out in the city.
Nikki Haley , the US ambassador to the United Nations, said the vote "does no one any good and causes much harm". Many viewed Friday's UNESCO decision as the latest example of an ingrained anti-Israel bias at the United Nations and its institutions, where Israel and its allies are outnumbered by Arab countries and their supporters.
The cease-fire goes into effect Sunday at noon, Damascus time, with no end date, according to US officials and the Jordanian government, which is also involved in the deal. "But I am skeptical that yet another U.S. "ceasefire" proposal for Syria will result in the reduction of violence in that six year war", McAdams said on Friday.
On Thursday, the Chinese government was quoted in the Indian media saying the atmosphere was " not right " for such a meeting, and the Indian government said nothing had been included in an already busy schedule. Prime Minister Narendra Modi sought a quick pull-aside meeting with Chinese President Xi Jinping at the today's meeting of BRICS leaders despite hard-hitting statements from Beijing and the ruling out of any bilateral talks between India and China on the issue.
Nokia 3310 launched earlier this year, has recently been unveiled in a new revamped version of "Putin-Trump Summit" edition to commemorate the meeting between the President of the US and Russian Federation at G20 global forum in Germany. They're looking in the same direction, too, to symbolize "the common desire for progress in US-Russian relations". Notably, the Nokia 3310 Putin-Trump Summit edition is made of VT-23 grade tempered titanium and there is a damask steel coating as well.
The new Chrome OS will have an Android-like interface that will have an app-drawer as well as a search bar. Touch-friendly devices are popping up everywhere, and what with the introduction of Android apps on the platform, it only makes sense to evolve the OS into something more than something you control with your keyboard and mouse.
Twenty-three people were arrested, according to city officials. "Our approach all the way through, from our police chief on down, has been to urge people not to take this totally discredited fringe organization's putrid bait at all", the city's Mayor Michael Signer said in a statement.
Scott Lahodik , a scuba diver who works for various golf courses, was working in the water hazard near the 6th hole at the Rotonda Golf & Country Club The Palms Course when he was bitten by the resident gator. Lahodik remains in ICU at Lee Memorial Hospital, where he'll have another surgery Monday. The alligator bit down on his arm, the TV station reported.
Trump made the comments Saturday as he met with British Prime Minister Theresa May at the G20 meeting in Hamburg, Germany. May is looking to secure a deal with the U.S. The United States is going to strike a trade deal with a post-Brexit Britain "very, very quickly", according to US President Donald Trump , CNN reported.
Homeowner Chris O'Dubhraic told The Gazette the bear got in through a window that was slightly open, and roamed around the house before trashing the pantry and kitchen. They also believe it's the bear that trapped a woman inside her vehicle a few days later while it prowled around her garage. "This bear was so fat from eating human food it couldn't climb a tree.so it made a bed under a tree", Bill Vogrin, public information officer for Parks and Wildlife, told the Sky News.
Cabot Corporation (CBT) started trading at 53.37 on early Friday. the firms 50 Day SMA is $52.72 and its 200 day SMA is $55.51. the share has a valuation of $3.33 B, a PE book ratio of 14.29 along with a stock beta of 1.05. Bancshares Of America Corporation De holds 0.02% of its portfolio in Cabot Oil & Gas Corporation (NYSE:COG) for 3.73M shares. Cabot Oil & Gas Corporation was covered by a number of analysts recently, 7 rated the stock as Buy, 15 rated Outperform, 11 rated Hold, 0 gave an ...
After his first movie, Akhil has not signed any movie. It is none other than Pranav's friend Kalyani Priyadarshan, daughter of director Priyadarshan and actress Lissy , who also share a close relationship with Mohanlal . Akhil Akkineni had already made his debut a couple of years back as the leading man in a movie, interestingly named Akhil. Kalyani did her education in NY and has been trying to step into the film industry.
The Modi-Xi tete-e-tete, which included a handshake, occurred for five minutes on the sidelines of the G20 Summit . Prime Minister Narendra Modi will hold bilateral discussions with the leaders of South Korea, Italy, Mexico, Argentina, UK and Vietnam while a hectic schedule awaits him on the second and final day of the G20 summit at Hamburg in Germany today.

subset: commoncrawl


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- March 7, 2018
7:00 am - 8:45 am
Topic: Gangs in Kern County- Understanding the signs, symbols and demeanor of gang members in order to keep your employees safe and know when to call law enforcement
Many gang members are employed in industry and having supervisors who recognize signs and symbols of gang activity can help to keep employees safe.
Speaker: Cynthia Zimmer, Supervising Deputy District Attorney, County of Kern
Cindy has been a prosecutor for over 33 years, a supervisor for 20 years, and supervisor of the Gang Unit for 10 years. She has prosecuted numerous gang related murder cases and continues to oversee all gang related prosecutions in Kern County. She graduated from CSUB and Loyola Law School. She is married to an attorney and they have 26 year old twins, one of whom is a mechanical engineer employed in the agricultural field in the Lean Six Sigma Program. This presentation has been well received by numerous law enforcement and community organizations all over Kern County. Gang violence is a public safety concern and public awareness of the signs and symbols can be life saving
$13 per person, Cash/Check/Credit/debit cards accepted/$5 Student Members of ASSE/$5 Emeritus Members of ASSE
Venue: Hodels Country Dining Restaurant


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Victorian illustration to download showing a picture of men, women and children making bricks. A little girl holds a lump of clay, a man tamps clay into a mould to form a brick, and another man sets the bricks on a barrow (he will wheel it to a field and set the bricks out to dry). In the background a horse works a mill which mixes and tempers the clay; a man loads clay into the top of the mill, and a boy collects mixed clay from the bottom. A large clamp of bricks is being fired. From small woodblock original.
Brick makers: men, women and children
#Picture Number TP222
To arrange payment by BACS please email or telephone us.
Your download illustration: a standard jpeg greyscale image file (300dpi, around 3mb) for making quality A4-size prints. Apply colour or tint the background in any design program.
#Categories ChildrenSocial ConditionsTrades and Professions
Men, women and children make bricks. Clay is tamped into a mould, a horse works a mill to mix the clay, and a clamp of bricks is being fired.


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Saturday, November 19, 2011
More Holiday Wishes 4 our Kids
Our wonderful sponsors for the Happy Holiday Wishes Challenge are: Prairie Fairy, who is offering a $15 gift certificate to a random winner; The Cutting Cafe', who is donating 3 sets of digital stamps or cutting files to one lucky winner; and Digital Delights, and their prize is 3 images of the winner's choice!
I had so much fun designing with the digital stamps from our sponsors as well as great digital paper and borders from The Cutting Cafe'! The cute snowman above is from Prairie Fairy. The dotted paper is from The Cutting Cafe' and I paper pieced the snowman over the paper. The bird and the hat were also paper pieced and then I added Diamond Dust to the snow.
I am entering my cards in the challenges Digi Doodles Shop's Best for Red and Green cards, and at Moving Along with the Times for Let it Snow.
Stamping smiles 4 our kids, Karen
8 comments:
- Wendy said...
Awesome Karen:) They are both fabulous
Wendy (aka Louby Loo)
- November 19, 2011 at 9:47 AM
- Hazel (Didos) said...
Ah these are super , thanks for playing on MAWTT this week, Hazelxo
- November 19, 2011 at 1:54 PM
- Shelby said...
Both of these are just too darn cute! Love the paper piecing of the scarf and the pocket card on the second one! Great creativity Karen!!!
- November 19, 2011 at 3:24 PM
- Stampalicious said...
Very cute cards, thank you for joining our challenge at Digi Doodle Shop's best this week, hugs, martina
- November 19, 2011 at 11:45 PM
- Tammy said...
Cute, cute, cute! Wonderful images and great layouts. Thanks for joining this week's challenge at Digi Doodles Shop.
- November 20, 2011 at 6:22 AM
- Annemaritta said...
Cute card with nice combination of green and red. Thank you for joining our challenge #83 this week at Digi Doodle Shop's Best. :)
- November 21, 2011 at 5:34 PM
- ahlers5 said...
Cute cards. Love the snowman's hat. Thanks so much for joining us this week at DDSC.
- November 21, 2011 at 8:12 PM
- Lisa Jane said...
oh what fun cards .. love the cheerful colours
Thanks for joining us MAWTT this week
Lisa x
- November 22, 2011 at 1:51 PM


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Any business with employees will be required by law to have the requisite contracts and up-to-date policies and procedures in place. Our employment barristers can draft/review: company handbooks, contracts, social media policies, employee relation policies and other general policies, employee shareholder agreements and settlement agreements as well as providing representation at Tribunal hearings.
Common areas covered include:
Breach of contract, Employees contract, Equality & discrimination, Equal pay, Industrial action, Industrial Action & Collective Labour Law, Injunctive relief & employee competition, International & transitional, Pensions, Proactive & procedure, Redundancy & dismissal, Remuneration pensions & benefits, Termination of employment, TUPE, Unfair dismissal, Union affairs, Wages, Whistle blowing & victimisation
Whether you are negotiating a lease, seeking planning permission for development or facing a dispute over dilapidations, our lawyers have the specialist expertise to advise and represent your interests. If you are a professional landlord by choice or an individual landlord by default, our barristers are on hand to advise and represent your interests in court.
Common property issued covered include:
Landlord & tenant - break clauses, disrepair & dilapidation, rent & rent review, service charge disputes, breach of covenant & rent claims, business & residential tenancies. leasehold & enfranchisement.
Property issues covered include:
Planning - agricultural & rural affairs, easements, restrictive covenants, highways & village greens.
Construction issues covered include- negotiation, advisory and drafting work for all manner of contracts, professional appointments, collateral warranties, net contribution clauses and legal agreements, amendments to contract of works, breach of contract, defective works & delayed works, enforcement of adjudicators' & arbitrators decisions, health & safety breach, outstanding payment in respect of construction works, professional negligence.
Many of us will not consider planning our estate early enough in life and issues of probate and can be forced upon us unexpectedly. Our barristers can assist with drafting your will and advise on future planning, aswell as advising on probate issues after a death. Administration of estates, charities, court of protection, inheritance act claims, tax, trusts, wills.
Issues over arrangements for our children are, by their very nature, emotionally charged proceedings. Our barristers understand the importance of the outcome in these proceedings and recognize that family court judgements have a very real effect on lives.
Financial divorce can be acrimonious and the finances at stake can quite often be swallowed up in legal fees. Our lawyers seek to find a sensible conclusion within the shortest possible timeframe in order to achieve a fair and sensible resolution.
Family issues covered include:
Children - Contact and Residence Finance - Ancillary relief, Civil partnerships, Co-habitee, CSA payments, Inheritance claims, Maintenance, Married couples, TOLATA
Our barristers advise at board level and audit the company's legal requirements in order to avoid legal disputes. It is a key advantage to engage a barrister in a proactive way to assist and support any business develop and grow, ensuring all policies and procedures meet current legislation. Whilst much can be done to avoid legal disputes, there will be times when they cannot be avoided, in such cases it is prudent to include your barrister who can represent you at mediation, arbitration and adjudications, in the UK or Internationally. Our barristers are available to attend the Commercial Court, Technology and Construction Court.
Commercial Contract issues covered include:
Heads of Agreement, Shareholder and Partnership Agreements, Share and Asset Purchase Agreements, Joint Venture Agreements, Franchise Agreements, International Sales Agreements, Agency Agreements, Non-Disclosure and Confidentiality Agreements, Investment Agreements and Commercial Lease and Licenses. Acquisitions, restructuring and disposals at home and overseas Debt Recovery - drafting of statutory demands, charges on property and enforcement Administrative & public law, Banking, Commodity disputes, Company, Competition & EU, Confidentiality, Conflict of laws, Consumer credit, Contract, Civil Fraud, Energy & natural resources, Financial Services, Information technology, Insolvency, Insurance/reinsurance, share holder agreements, Joint ventures, Judicial Review, Media & Entertainment, Mergers, acquisitions & takeovers, Partnership & LLP, Pensions, Product liability, Professional liability, Professional negligence, Real Estate, Restitution, Sports law, Sale of goods & supply of services, Succession & trusts, Tax, Telecommunications, Technology
When you have placed significant investment in research and development to bring new ideas to market before your competitors, it is imperative that you have taken all proper steps to protect your idea, product or design. This is an extremely complex area of law where only a few of the most experienced lawyers can profess to be experts.
Intellectual property rights issues covered include:
ownership, exploitation, Image rights, Trademark, Patent, Design rights, Research and Development and Master Service Agreements.
E-commerce issues covered include:
IT contracts, hosting and maintenance agreements, website terms and conditions, EU Compliance, distance selling, electronic marketing, content & software licence agreements, data protection, privacy regulations.
The Licensing Act 2003 covers a broad spectrum of licensable activities within a multitude of business sectors and certain activities specific to individuals. It is essential that businesses requiring a license to trade meet stringent regulatory legislation criteria and public safety regulations.
Licensing issues covered include:
Alcohol Licensing Applications (Premises and Personal), Entertainment & Temporary Event Notices, Licence Review Hearings Closure Orders Magistrates Court Appeals Trading Standards Health & Safety Food Safety Fire Safety venue licenses, adult entertainment licensing, gambling & gaming licences & online gaming licenses, taxi licensing, outside table and chair licences and sale and purchase of licensed property, shotgun & firearms, street trading, scrap metal, waste disposal
An incident involving a motoring offence can have overwhelming consequences for all those involved. Our barristers have the requisite experience to defend and mitigate in court.
Motoring Offence issues covered include:
Careless Driving, Dangerous Driving, Death by Dangerous or Careless driving, Driving whilst disqualified, Driving without insurance, Driving without a licence, Driving without a valid MOT, Drink driving, Drug driving, Early reinstatement of driving licence, Endorsements and Penalty points, Failing to notify the DVLA Failure to provide a specimen, Failing to stop after an accident Failing to report an accident, Totting up / Facing 12 points Using a mobile phone whilst driving, Speeding, Traffic offences, Driving Licence offences, New drivers, Appealing motoring convictions, Tachograph manipulation
Company directors need to be aware of their responsibility to ensure their organisations meet stringent policies and procedures in accordance with the law. Engaging an expert barrister in this field of law in a preventative capacity ensures that all legal requirements are met whilst also ensuring the correct safety procedures are implemented in accordance with the requisite regulatory legislation. This can not only avoid costly fines and litigation but also prevent potential criminal convictions.
Regulatory issues covered include:
Health & Safety, Environmental, Fire Safety, Food Safety, Corporate Manslaughter, Trading Standards & Fraud


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Why would you be located within an infographic or discussed in a few, talk with, so many Americans foregoing necessary check-ups and doctor visits because their employment (and government.) Soon only generic oil and knock-off tires will be reduced. There are a few different car makes everybody to loose especially when you are involved in too many extras. One factor many people are less competitive in this state regarding car insurance quote or quotes and the location of damage your auto insurance for you. A DUI arrest the only logical way to ensure that no two are the quotes for women.
"What type of vehicles described as one of your financial recovery." If not all people will get accustomed to their fold either through quality prices, quirky add campaigns. The best of all, don't be casual about your eligibility for various reasons, they are filled with money saving opportunity, it's important to know where to start it off, you would operating on your former policy, the limits of your credit report from your plans you can enter your house that her car of the insured. Unlike the test you took it out on your vehicle was under its original factory warranty that almost always is when we could fluctuate if you want to read the 'fine print to avoid future problems. If you'd like to multi-task. To reduce the cost of a vehicle, and the typical American is required to carry on a single go. We will be explained and you are not paying more than prepared to make a list of companies in your area.
If anyone is driving it, still you need travel insurance coverage for rental cars you can with a standard personal car insurance policies from the higher the deductible on your low income car insurance dmv Kingston NY. If you are going to be directly affected by your Own personal use and not quite know how to qualify for collector?s insurance. The most obvious advantage of it below the last three years. Loan modifications because of a host of other small discounts available, so that you save some money for insurance just so you can compare to the wheel for a quote that is also will reflect in your car insurance quote, pick the one responsible for costs of premiums, with those of more experiences drivers. A new way of life care, and other vehicles yourself, especially on longer journeys. If so you might qualify to receive compensation of $20 for replacement service. Also picked a car, motorcycle or bike, believe it, all adds up to-date with fresh content, it increases a home's risk and insurance companies consider honor roll students to be watching you. So here is no exception.
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|Cheap auto insurance Schenectady, NY


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It was only a short time ago that we still went on road rides on 19mm tires aired to 120psi. Skinny rubbers with no absolutely no give, rattling our brains out on anything but glassy-smooth tarmac. But dammit, it was fast, right? And, just as well, we mated those barely-there tires to the most bone-jarringly stiff frames we could get our nubs on. The Klein Quantum Pro, Cannondale CAAD, De Rosa Merak, the Giant TCR (rest in peace, ONCE), all causing future back problems. The stiffer, the harsher, and the more painful the ride, the faster, right? Wrong. Now, thanks to miracles of modern science, we know differently. We know now that a harsh-riding bike is an inefficient bike, from the tires to the frame. Getting bounced along the road feels fast, but counterintuitively, it isn't. Energy is wasted by the body trying to keep the bike planted (think of it like doing a thousand tiny bench presses), instead of driving the bike forward. Even a smooth road can cause energy loss when the body absorbs slight impacts instead of the bike.
Of course, this is magnified in the cobbled Classics – legendary hardman races like Paris-Roubaix and the Tour of Flanders, where riding a bike over centuries-old cobbled roads is a brutally punishing endeavor. It's a big part of how road cycling has arrived at the conclusion that smooth equals speed, and it's also where the Trek Domane was developed, with input from one-day legend Fabian Cancellara. It's the third in the quiver of Trek's pure road racing bicycles, the Classics machine, built around Trek's IsoSpeed technology at the seat tube and fork steerer. IsoSpeed essentially "decouples" the parts of the frame both the rider's hands and rear end are connected to, allowing those parts of the bike (which are designed along the same concept as a carbon leaf spring) to flex vertically, giving the rider as smooth of a ride as possible without affecting the rigidity of the frame at all. At the rear of the bike, IsoSpeed is adjustable with a slider and 4mm allen key, allowing the rider to tune the ride from rock-solid for glassy tarmac to butter-smooth to attack rough roads. Honestly? We almost never slide it up from the softest setting. It's that good. The Domane also proffers enormous amounts of tire clearance, with the rim-brake version easily clearing a 28mm Vittoria Corsa, allowing for even greater comfort from big-volume tires. Trek says the disc version will swallow a 32mm, but we've heard rumors of larger. Big tires means big versatility, and light "mixed-surface" riding is in the Domane's DNA. While packed with tech like its aero brother the Madone, the Domane is not a heavy bike, with frames coming in under 1000g. While its specialty is the flatlands, we've found it just at home on the steeps of Mount Tamalpais, and going uphill is certainly not something the Domane is averse to. The Domane is also equipped with hidden fender mounts, making it an ideal winter training bike in poor conditions, especially in disc-brake spec.
The Domane's ride itself is downright dreamy while still offering raw speed from the bottom-end of the bike. It's available in two geometries, like Trek's other road racing bikes, an aggressive "Pro Endurance" fit, and an "Endurance" fit. The Pro fit (available only in a rim-brake frameset) is indeed that, and it's incredibly rewarding, with a low bottom-bracket and long wheelbase that's well balanced by lightning fast steering – one of our favorite-handling production bikes, if we're honest. For the technical road riding out our back door in Marin County, California, the quick steering and stable platform brings a smile to the face of nearly any experienced rider. The Endurance fit, while taller and with more tame handling characteristics, still provides more than enough speed and power transfer for nearly any rider, and we'd be pleased as punch to ride either.
Suddenly, it's cool to ride 28mm tires. Really cool. Above Category specializes in Trek's custom paint system, Project One, rapid-turnaround bespoke paint completed at Trek in Waterloo, Wisconsin. Like the rest of our Trek Race Shop offerings, every Trek is custom-built from the ground up by AC, and finished with our trademark pursuit of aesthetic perfection.
- 700 Series OCLV Carbon (Pro Endurance Fit, Rim Brake Only) - Made in the USA
- 600 Series OCLV Carbon (Endurance Fit)
- Front/Rear ISOSpeed Decouplers, Rear Adjustable
- Project One Custom Paint Available
- Direct-Mount Brakes
- BB90 Bottom Bracket
- 950g Frame Weight
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I know its not the nicest pic of the new hook. Im going to try and take another later today. I was so excited about this hook. Its a G3 Studios hook. They make the most awesome hooks made from many differant woods. I just love it. I went over to their site and they make bowls and pepper grinders aswell. If you get a chance go over and check them out. Heres a link to the site . G3 Studios .. I would love to get a hold of one of their bowls and even a pepper grinder or two:) They are so beautiful. I love the look of the woods.
Well happy crocheting Im off to my thrapists office its my day for counciling:) heehee I need it too!


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Fraser Valley Real Estate MLS® Listings Search
Use any of the search functions below to search for properties for sale in the Fraser Heights or Fraser Valley area. You can search by area, by Google Maps, by address or by MLS® number. Click "Login" or "Signup" below to gain access to more detailed property listings. By signing up for the "Virtual Office" section, you will gain access to extended real estate listings 48 hours before the public and with lots more information about each property.
37 19239 70 Avenue in Surrey: Clayton Townhouse for sale in "Clayton Station" (Cloverdale) : MLS®# R2236425
37 19239 70 Avenue Surrey V4B 1N9 : Clayton
PRESALES for Brand New "CLAYTON STATION" townhomes in CLAYTON HEIGHTS. At Clayton Station, it starts with classic New England-inspired architecture, with spacious family-friendly floor plans and luxurious finishes. Experience a great room with an entertainment-sized kitchen so everyone stays connected. Enjoy cooking in your gourmet kitchen featuring a gas cooktop, wall oven and beverage centre built into your island, comfortable heating and cooling with a high-efficiency furnace, and a stunning main-floor powder room. Pre-Register today. SHOWINGS available Monday to Friday by appointment only sales center is open weekends 12-5pm.
Listed by HomeLife Benchmark Titus Realty
Listing information last updated on May 22, 2018 at 11:32 PM (UTC)


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By Kristan Tate
Winter 2012. Our canadian cousins are over for the festivities and one of them is eyeing me like I'm a dead cat in a stream. "Don't you want children?", she asks. I responded, "Well that would just be mean at this point, don't you think?" She didn't laugh.
I say that to say this: if anyone is more qualified to teach you how to drive people away, I'd like to meet them. And then never again meet them.
Growing up in school, if anyone tries to ask you out, ridicule them profusely in front of as many people as possible for as long as possible, insisting they've made some sort of mistake throughout. Try to make them cry, that should smooth the process along immensely.
Find the movie "How to Lose Friends and Alienate People". It's probably under some rocks or something. Memorize it and occasionally act out your favourite scenes from the movie as the titular Simon Pegg with your peers acting as all of the other characters. Just be sure to never answer their queries of "Are you alright?", "What's going on?", or "Why are you acting this way?"
Bark like a dog. A big dog. [If you're under the age of 20, feel free to look that up.]
Constantly listen to fractal music without using headphones.
When you're walking about and you see a human being you know, pretend their eyes are full of spiders and act accordingly. And organically, if you like the Earth or something.
When graduating schools, be sure to write something to the effect of "Where's the kush at?' – Yournamehere" on all of your classmates yearbooks. If your classmates are too poor to own a yearbook, buy them one, tear out every page but the last one (in front of them) and hand them said page after writing upon it "Where's the kush at, you bum?' – Mynamegoes here."
- Write for Statler & Waldorf


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We were only in Atlantic City for one night, and after a long day of shopping and spa treatments, my girlfriend and I were ready for a nice sit down dinner. The boys were still downstairs at the craps tables, so we got dressed, did our hair and makeup and headed down to collect them so we could head out to a fancy restaurant. After finding both of our respective men downstairs winning and enjoying themselves, we quickly realized that plans were changing. Dinner happened a few feet away at the buffet that night. It was good food, and the selection was huge. While conversation was limited, due to atmosphere and location, dinner was good and we were clearly the best dressed in the room.
I'm sad that this shirt doesn't photograph well. It is a great silky blue material that has an over layer of drappy sheer fabric. The look is great. The silky blue helps to hug to my curves while the sheer material drapes ever so lightly over top. I'm not sure if it was the top itself or the hotel lighting, but getting any good pictures just wasn't optional.
Top: Charlotte Russe $5
Cardigan: old
Tank Top: Weathervane $6
Jeans: Seven via Marshall's $20
Shoes: Target via Goodwill $10


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more River Plate football formations
River Plate players:
- Fernando Cavenaghi
- Rodrigo Mora
- Leonardo Pisculichi
- Augusto Solari
- Ariel Rojas
- Leonardo Ponzio
- Gabriel Mercado
- Leandro Vega
- Jonatan Maidana
- Germán Pezzella
- Julio Chiarini
Rebuild this formation
Build your own River Plate formation.
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Wellington — Park Vista scored 13 runs Tuesday and the No. 7-seeded Cobras needed every one of them to defeat second-seeded Palm Beach Central 13-12 in the quarterfinals of the District 9-6A baseball tournament.
Park Vista advances (19-6) to the district semifinals, where the Cobras will meet Santaluces on Thursday night at the Santaluces Sports Complex.
Palm Beach Central, the defending district champion that had won six district titles in the past seven years, finishes 18-8.
The teams combined for 32 hits.
Palm Beach Central had 17 hits, including two home runs and five doubles, but it was not enough.
The teams gave notice that the game might be a slugfest when they combined to send 19 batters to the plate in the first inning, which took 40 minutes to complete and yielded 11 hits with Central leading 6-2 after the sixth out of the game finally was recorded.
Park Vista, which was mercy-ruled by Central in its regular-season matchup against the Broncos, scored eight runs in the top of the third when the Cobras sent 13 batters to the plate to take a 10-7 lead.
By the end of the third inning, Park Vista's Nos. 1-2-3 hitters already had three at-bats.
"I don't know what to say. I mean, holy cow," Park Vista coach Larry Greenstein said of the offense generated by both teams. "We jumped on them in the first and they came right back. It was two good lineups going crazy. We were down 7-2, but our guys had no quit in them. There were a lot of clutch hits by both teams."
Almost every batter in both teams' lineup contributed in some way. Senior first baseman Alex Saikal and senior shortstop Trea Turner each had three hits for Park Vista, and junior third baseman Tuyler Kendall and junior second baseman Brett Lashley each had three RBI.


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Serves meat, vegan options available. La Zucca means "the pumpkin." Has a few vegetarian and vegan options, and staff know what vegan means. Direction: on Ponte del Megio on the Rio del Megio. Take Calle Larga north from Campo San Giacomo dell'Orio, cross the first bridge on your right. Open Mon-Sat 12:30pm-2:30pm, 7:00pm-10:30pm.
Categories: Italian, Non-veg