Genetic and Epigenetic Characteristics in Isolated Pancreatic Metastases of Clear-Cell Renal Cell Carcinoma.

Isolated pancreatic metastases of renal cell carcinoma (IsPMRCC) are a rare manifestation of metastatic, clear-cell renal cell carcinoma (RCC) in which distant metastases occur exclusively in the pancreas. In addition to the main symptom of the isolated occurrence of pancreatic metastases, the entity surprises with additional clinical peculiarities: (a) the unusually long interval of about 9 years between the primary RCC and the onset of pancreatic metastases; (b) multiple pancreatic metastases occurring in 36% of cases; (c) favourable treatment outcomes with a 75% 5-year survival rate; and (d) volume and growth-rate dependent risk factors generally accepted to be relevant for overall survival in metastatic surgery are insignificant in isPMRCC. The genetic and epigenetic causes of exclusive pancreatic involvement have not yet been investigated and are currently unknown. Conversely, according to the few available data in the literature, the following genetic and epigenetic peculiarities can already be identified as the cause of the protracted course: 1. high genetic stability of the tumour cell clones in both the primary tumour and the pancreatic metastases; 2. a low frequency of copy number variants associated with aggressiveness, such as 9p, 14q and 4q loss; 3. in the chromatin-modifying genes, a decreased rate of PAB1 (3%) and an increased rate of PBRM1 (77%) defects are seen, a profile associated with a favourable course; 4. an increased incidence of KDM5C mutations, which, in common with increased PBRM1 alterations, is also associated with a favourable outcome; and 5. angiogenetic biomarkers are increased in tumour tissue, while inflammatory biomarkers are decreased, which explains the good response to TKI therapy and lack of sensitivity to IT.

Isolated Pancreatic Metastases of Renal Cell Carcinoma-Clinical Particularities and Seed and Soil Hypothesis.

A meta-analysis of 1470 isolated pancreatic metastases of renal cell carcinoma revealed, that, in addition to the unusual exclusive occurrence of pancreatic metastases and the favourable treatment results, the isPMRCC is characterised by further peculiarities of the clinical course: The lack of prognostic significance of volume and growth rate dependent risk factors and the independence of treatment results from standard or local resections. As an explanation for all these peculiarities, according to today's knowledge, a strong acting seed and soil mechanism can serve, which allows embolized tumour cells to grow to metastases only in the pancreas, and prevents them definitively or for years in all other organs. The good prognosis affects not only isolated PM, but also multi-organ metastases of the RCC, in which the additional occurrence of PM is also associated with a better prognosis. Genetic studies revealed specific changes in cases of PM of RCC: Lack of loss of 9p21.3 and 14q31.2, which are otherwise specific gene mutations at the onset of generalization, a low weight genome instability index, i.e., high genetic stability, and a low rate of PAB1 and a high rate of BPRM1 alterations, which signal a more favourable course. The cause of pancreatic organotropism in isPMRCC is still unclear, so only those factors that have been identified as promoting organotropism in other, more frequent tumour entities can be presented: Formation of the pre-metastatic niche, chemokine receptor-ligand mechanism, ability to metabolic adaptation, and immune surveillance.

Isolated Pancreatic Metastases of Renal Cell Cancer: Genetics and Epigenetics of an Unusual Tumour Entity.

Isolated pancreatic metastases of renal cell carcinoma (isPMRCC) are a rare manifestation of metastatic renal cell carcinoma (mRCC) characterized by two peculiarities: (1). The definite or at least long-term exclusive occurrence of metastases in the pancreas and (2). an unusual low tumour aggressiveness with slow tumour progression and consecutive, good treatment results. According to current knowledge, the exclusive occurrence of pancreatic metastases is due to a highly specific and highly selective seed and soil mechanism, which does not allow metastases settlement outside the pancreas, and whose detailed genetic/epigenetic causes are not yet elucidated. Recent studies have shed light on some of the pathways involved for the protracted course of the disease and highlighted a special genetic profile (lack of loss of 9p, lower weight genome instability index, low frequency of BAP1 alterations, and a high frequency of PBRM1 loss), which deviates from the conventional mRCC profile. Finally, the question of the reasons for the long-term relative genetic stability of the involved cell clones, which is an essential prerequisite for a favourable prognosis, remains unanswered.

Tumour Evolution and Seed and Soil Mechanism in Pancreatic Metastases of Renal Cell Carcinoma.

In metastatic renal cell carcinoma, pancreatic metastases can appear in two clinical manifestations: (a) very rarely as isolated pancreatic metastases and (b) in the context with multi-organ metastatic disease. Both courses are characterised by rare, unusual clinical features. For isolated pancreatic metastases, the literature shows no effect on survival in all 11 publications that examined the effect of singular versus multiple pancreatic metastases; a lack of effect on survival time was also present in all 8 studies on pancreatic metastases size, in 7 of 8 studies on the influence of disease-free interval (DFI), and in 6 of 7 studies on the influence of synchronous versus metachronous metastases. In multi-organ site metastases observations, on the other hand, all five available references showed significantly better results in patients with concurrent pancreatic metastases compared to those without pancreatic metastases, although the total number of affected organs in the pancreatic metastases cohort was larger. Tumour volume-dependent risk factors thus remain surprisingly ineffective in both groups, which contradicts the usual behaviour of solid tumours. The reasons for this unusual behaviour and possible relations to tumour evolution and the hypothesis of an influence of a seed and soil mechanism in the occurrence of pancreatic metastases in metastatic renal cell carcinoma are discussed.

Isolated Pancreatic Metastases of Renal Cell Carcinoma-A Paradigm of a Seed and Soil Mechanism: A Literature Analysis of 1,034 Observations.

Previously documented arguments, in favor of the suspected impact of a seed and soil mechanism, in the development and progression of isolated pancreatic metastasis of renal cell carcinomas (isPM) are: (1) uniform and independent from the side of the primary tumor distribution of isPM within the pancreas and, (2) the similar survival rates for singular and multiple isPM. In addition, the present study adds new arguments that further confirm the importance of an seed and soil mechanism in isPM: (1) Within the singular isPM, the size of the metastasis does not affect the overall survival; (2) Within the group of multiple isPMs, the overall survival does not depend on the number of metastases; (3) For synchronous and metachronous isPM, survival rates are also not different, and (4) Within the group of metachronous isPM there is also no correlation between the overall survival and interval until metastases occurs. This unusual ineffectiveness of otherwise known risk factors of solid cancers can be explained plausibly by the hypothesis of a very selective seed and soil mechanism in isPM. It only allows embolized renal carcinoma cells in the pancreas to complete all steps required to grow into clinically manifest metastases. In all other organs, on the other hand, the body is able to eliminate the embolized tumor cells or at least put them into a dormant state for many years. This minimizes the risk of occult micrometastases in distant organs, which could later-after isPM treatment-grow into clinically manifest metastases, so that the prognosis of the isPM is only determined by an adequate therapy of the pancreatic foci, and prognostic factors, such as total tumor burden or interval until the occurrence of the isPM remain ineffective.

A Preoperative Clinical Risk Score Including C-Reactive Protein Predicts Histological Tumor Characteristics and Patient Survival after Surgery for Sporadic Non-Functional Pancreatic Neuroendocrine Neoplasms: An International Multicenter Cohort Study.

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients >60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off ≥0.2mg/dL; hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size ≥3.0cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p < 0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival.

Observations on Solitary Versus Multiple Isolated Pancreatic Metastases of Renal Cell Carcinoma: Another Indication of a Seed and Soil Mechanism?

Isolated pancreas metastases are a rare type of metastasis of renal cell carcinoma, characterized by the presence of pancreatic metastases, while all other organs remain unaffected. In a previous study, we determined arguments from the literature which (a) indicate a systemic-haematogenic metastasis route (uniform distribution of the metastases across the pancreas and independence of the metastatic localization in the pancreas of the side of the renal carcinoma); and (b) postulate a high impact of a seed and soil mechanism (SSM) on isolated pancreatic metastasis of renal cell carcinoma (isPM) as an explanation for exclusive pancreatic metastases, despite a systemic haematogenous tumor cell embolization. The objective of the study presented was to search for further arguments in favor of an SSM with isPM. For that purpose, the factor's histology, grading, and singular/multiple pancreas metastases were analyzed on the basis of 814 observations published up to 2018. While histology and grading allowed for no conclusions regarding the importance of an SSM, the comparison of singular/multiple pancreas metastases produced arguments in favor of an SSM: 1. The multiple pancreas metastases observed in 38.1% prove that multiple tumor cell embolisms occur with isPM, the exclusive "maturation" of which in the pancreas requires an SSM; 2. The survival rates (SVR), which are consistent with singular and multiple pancreas metastases (despite the higher total tumor load with the latter), prove that the metastasized tumor cells are not able to survive in all other organs because of an SSM, which results in identical SVR when the pancreatic foci are treated adequately.

Exploring the surgical landscape of pancreatic neuroendocrine neoplasia in Austria: Results from the ASSO pNEN study group.

INTRODUCTION: Pancreatic neuroendocrine neoplasia (pNEN) show increasing incidence and management is complex due to biological heterogeneity. Most publications report isolated high-volume single-centre data. This Austrian multi-centre study on surgical management of pNENs provides a comprehensive real-life picture of quality indicators, recurrence-patterns, survival factors and systemic treatments. METHODS: Retrospective, national cohort-study from 7 medium-/high-volume centres in Austria, coordinated under the auspices of the Austrian Society of Surgical Oncology (ASSO). RESULTS: Two-hundred patients underwent resection for pNEN, 177 had non-functioning tumours and 31 showed stage 4 disease. Participating centres were responsible for 2/3 of pNEN resections in Austria within the last years. The mean rate of completeness of variables was 98.6%. Ninety-days mortality was 3.5%, overall rate of complications was 42.5%. Morbidity did not influence long-term survival. The 5-year overall-survival (OS) was 81.3%, 10-year-OS 52.5% and 5-year recurrence-free-survival (RFS) 69.8%. Recurrence was most common in the liver (68.1%). Four out of five patients with recurrence underwent further treatment, most commonly with medical therapy or chemotherapy. Multivariable analysis revealed grading (HR:2.7) and metastasis (HR:2.5) as significant factors for relapse. Tumours-size ≥2 cm (HR:5.9), age ≥60 years (HR:3.1), metastasis (HR:2.3) and grading (HR:2.0) were associated with OS. Tumours <2 cm showed 93.9% 10-year-OS, but 33% had G2/G3 grading, 12.5% positive lymph-nodes and 4.7% metastasis at diagnosis, each associated with significant worse survival. CONCLUSION: Resection of pNENs in Austria is performed with internationally comparable safety. Analysed factors allow for risk-stratification in clinical treatment and future prospective trials. A watch-and-wait strategy purely based on tumour-size cannot be recommended.

Isolated pancreatic metastases from renal cell carcinoma: an outcome of a special metastatic pathway or of specific tumor cell selection?

Isolated pancreatic metastases (isPM) are a rare metastasizing pattern in the natural history of renal cell cancer. Their clinical hallmark is that they are confined to a single organ, the pancreas, while all other organs are unaffected for a long time. Almost all workers in the field suggested that mechanical tumor cell propagation to the pancreas may be the mechanism underlying this metastasizing pattern. In 2006 our group, by contrast, proposed an alternative mechanism, i.e. a special affinity of the tumor cells for the pancreas. In the present study an attempt was made to shed more light on the settlement of isPM by reviewing recent literature data. 666 observations of isPM reported in the literature were reviewed. The analyses showed that local lymphatic spread does not play a major role because the lymphatic system is, in general, rarely involved in isPM. This also applies to a local venous spread, because the site of pancreatic metastases is independent of the side affected by the primary renal cancer. But the results are compatible with a systemic metastatic pathway. That metastases in other organs, which would be expected given a systemic spread, are absent can plausibly be explained by a seed and soil mechanism: only the pancreas offers the tumor cell emboli an environment which is conducive to the growth of clinically manifest metastases, while settlement of metastatic tumor cells is prevented in all other organs.

Tumor and Patient Characteristics of Individuals with Mismatch Repair Deficient Colorectal Cancer.

AIMS: To investigate tumor and patient characteristics of individuals with mismatch repair (MMR)-deficient colorectal carcinomas. METHODS: We immunhistochemically investigated tissue samples of 307 consecutive patients with colorectal cancer for defects in DNA MMR proteins (hMLH1, hMSH2, hMSH6, hPMS2) and those with mutations further for microsatellite instability (MSI) and BRAF V600E mutations. RESULTS: 32/308 (10.4%) tumors showed MMR deficiency. Seventy five percent (n = 24) had loss of hMLH1 and hPMS2 expression, 3% (n = 1) of hPMS2 alone, 18.8% (n = 6) of hMSH6 and hMSH2, 3% (n = 1) of hMSH2 alone. All MMR-deficient tumors showed high MSI. These tumors occurred preferably in the right-sided colon, in women and showed specific histological features. We obtained the family history of 18/32 patients; 2 (11.1%) met Amsterdam Criteria, 5 (27.8%) Bethesda Guidelines and 6 (33.3%) revised Bethesda Guidelines. BRAF V600E mutations were found in 16 (67%) of hMLH1 and none of the hMSH2 deficient tumors. CONCLUSION: We suggest using immunhistochemical testing of tumor tissues with subsequent MSI analysis, which may be justified as a screening method for MMR deficiency in colorectal cancer, since it identifies patients with possibly hereditary defects and unalike response to chemotherapy.

The analysis of organic anion transporting polypeptide (OATP) mRNA and protein patterns in primary and metastatic liver cancer.

Organic anion transporting polypeptides (OATP, SLCO genes) mediate the uptake of endobiotics and drugs. Thus, their expression levels and pattern could be of relevance for cancer therapy. This prompted us to investigate the expression of poorly characterized OATPs, namely OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in hepatic cancer of different origin. First, mRNA levels of all eleven OATPs were determined in paired (cancerous and adjacent non-cancerous) specimens from 43 patients with primary liver cancer (hepatocellular carcinoma, HCC; cholangiocellular carcinoma, CCC) and liver metastases from colon tumors (MLT). Real-time RT-PCR analysis revealed that all OATPs, except OATP1C1 and OATP6A1, are extensively expressed in nearly all samples. In contrast to downregulated OATP1B1, OATP1B3, OATP1A2 and OATP2B1 in cancerous vs. non-cancerous samples, an increase in OATP2A1, OATP3A1, OATP4A1 and OATP5A1 mRNA levels was seen in tumors (up to 40-fold for OATP5A1 in the MLT group). Therefore, OATP2A1, OATP3A1, OATP4A1 and OATP5A1 were further investigated by immunofluorescence microscopy on paraffin-embedded cancerous and non-cancerous sections (seven per group). OATP-derived immunoreactivity was observed in plasma membranes and cytosol of hepatic tumor cells, and additionally, in various cytokeratin 19 positive bile ducts. An increased percentage of immunoreactive cells and a higher staining intensity in cancerous vs. non-cancerous paraffin sections paralleled higher mRNA levels of OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in cancerous tissues of HCC, CCC and MLT patients. The extensive expression of OATP2A1, OATP3A1, OATP4A1 and OATP5A1 in hepatic tumors of different origin suggests that these transporters might be further exploited for the discovery of novel anticancer agents.

TNM stage and grade in predicting the prognosis of operated, non-functioning neuroendocrine carcinoma of the pancreas--a single-institution experience.

OBJECTIVE: To evaluate the prognostic significance of TNM and grading categories in curatively resected non-functioning neuroendocrine pancreatic carcinoma (nfnepC). METHOD: Eighteen nfnepC were retrospectively analyzed for differences in survival. RESULTS: (1) There was a correlation between pT (P = 0.026), respectively pM categories (P = 0.016) and survival. (2) G categories and length of survival were closely correlated (P = 0.0036). (3) Disease stages I-IV had a significant effect on survival (P = 0.051). (4) The WHO classification in well and poorly differentiated carcinomas proved to be the most conclusive predictive factor (P = 0.0009). (5) Subgroups with significantly different prognoses determined by histological grade were present within disease stage II. CONCLUSIONS: The retrospective analysis showed a good correlation between survival and pT, pM, tumor stage, G categories, and WHO classification in well and poorly differentiated carcinomas. Including histological differentiation in the staging system or carrying it out separately in well and poorly differentiated carcinomas, could enhance the predictive potential of TNM-based disease stages.

Altered expression of organic anion transporter polypeptide (OATP) genes in human breast carcinoma.

Organic anion transporter polypeptides (OATPs) mediate the transmembrane uptake of endogenous compounds and clinically important drugs in various tissues thereby effecting drug disposition and tissue penetration. OATPs have also been identified in gastric, pancreatic and colon carcinomas but little is known about their expression in breast carcinoma. We therefore analyzed the expression pattern of all 11 known OATPs in three breast cancer cell lines (MCF-7, ZR-75-1, MDA-MB-231) and one immortalized breast epithelial cell line (MCF-10A) using quantitative real-time RT-PCR. Transcripts of 7/11 OATP genes with heterogeneity in their expression profile were detected in control and/or cancer cell lines. Of these seven OATPs, five were also expressed in breast tumor and adjacent non-tumorous specimens from 13 patients. OATP2B1, not found in the analyzed cell lines, was verified in the tissue samples. Interestingly, mRNA expression of OATP2B1, OPATP3A1 and OATP4A1 was significantly higher (p < 0.022) in non-malignant specimens as compared to tumor tissue samples.

Expression of estrogen-metabolizing enzymes and estrogen receptors in cholelithiasis gallbladder.

BACKGROUND: Estrogen exposure is a risk factor for gallstone disease (cholelithiasis), which often leads to chronic inflammation (cholecystitis). Studies in various estrogen-sensitive tissues showed that key enzymes involved in the inactivation and activation of estrogens as well as expression of estrogen receptors alpha and beta determine the amount of active estrogen. In estrogen-sensitive tissues, e.g. the female breast, estrone sulfate (E1S), present at high concentrations in the circulation, is converted into the biologically active estrone (E1) by steroid sulfatase (STS) and again reverted into E1S by estrogen sulfotransferase (SULT1E1) providing a local estrogen storage. AIMS: To assess whether this might also apply for gallbladder epithelia, we determined expression of these two enzymes and of ERalpha and ERbeta in 15 cholelithiasis specimens from tissues with/or without inflammation. METHODS: Quantitative (Real-time) PCR and immunofluorescence were used as methods. RESULTS: We demonstrate mRNA expression of SULT1E1, STS, and ERalpha in all specimens with mean enrichment of 3.53- vs. 1.72-fold (n.s.), 3.5- vs. 0.91-fold (n.s.), and 3.04- vs. 1.6-fold (n.s.) in the inflammatory and non-inflammatory groups, respectively. Although high expression levels were seen in many specimens (means 4.88-fold vs. 5.77-fold), ERbeta mRNA was below the detection limit in two specimens from cholecystitis patients. To further investigate this varying expression pattern of ERbeta, immunohistological studies were performed, which indeed showed low expression levels of ERbeta in the damaged mucosa, while in specimens with well preserved mucosa, high ERbeta levels were seen in the cytosol and in the nucleus. CONCLUSION: The data show expression of an estrogen network of activating STS and inactivating SULT1E1. Together with ERalpha and ERbeta, these enzymes could regulate estrogen concentrations in human gallbladder.

Intermittent hepatic portal vein gas complicating diverticulitis--a case report and literature review.

CASE REPORT: This report describes a case of intermittent hepatic portal venous gas (HPVG) because of colonic diverticulitis in a 48-year-old man, who was successfully treated by surgery. CONCLUSION: Based on an extensive literature search, which produced 21 observations, the etiology, symptoms, imaging features, clinical significance, treatment strategy, and outcome of HPVG because of colonic diverticulitis are evaluated: While observations with an underlying intramesocolic abscess carry a favorable prognosis, the prognosis of observations because of septic thrombophlebitis with gas forming germs is poor.

Solitary and multiple isolated metastases of clear cell renal carcinoma to the pancreas: an indication for pancreatic surgery.

BACKGROUND: Isolated pancreatic metastases (isPMs) of clear cell renal carcinoma are rare. Most of them are solitary; some are multiple. The reported rates and the clinical implications of multiple isPMs from clear cell renal cancer vary. Therefore, the available literature was analyzed to shed light on the clinical significance of these extremely rare metastatic lesions. METHODS: A literature search brought to light 236 cases of isPMs (both solitary and multiple) from renal cell carcinoma. These were analyzed. RESULTS: A total of 12% of the metastases were synchronous with the primary tumor, and 88% were metachronous, occurring 10.0 +/- 6.5 years (mean +/- SD) after nephrectomy. A predilection for a specific part of the pancreas was not identifiable. The localization of the renal cell cancer (left or right kidney) did not have any effect on the site of the metastases. Seventy-four (39%) of the metastases to the pancreas were multiple (3.2 +/- 1.5). Their epidemiology did not differ from that of solitary metastatic lesions. Actuarial 3- and 5-year survival rates after radical resection were 78% and 78%, respectively, for multiple versus 75% and 64% for solitary metastases. CONCLUSIONS: The epidemiological data do not support a direct local lymphogenous or venous spread from the primary tumor to the pancreas. They rather suggest a systemic spread. Because of the positive outcome, radical removal of both solitary and multiple metastases should be attempted in eligible patients.

2-18fluoro-deoxy-D-glucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: an update of the prospective multicentric SEMPET trial.

PURPOSE: To define the clinical value of 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG PET) as a predictor for viable residual tumor in postchemotherapy seminoma residuals in a prospective multicentric trial. PATIENTS AND METHODS: FDG PET studies in patients with metastatic pure seminoma who had radiographically defined postchemotherapy residual masses were correlated with either the histology of the resected lesion or the clinical outcome documented by computer tomography (CT), tumor markers, and/or physical examination during follow-up. The size of the residual lesions on CT, either >3 cm or < or =3 cm, was correlated with the presence or absence of viable residual tumor. RESULTS: Fifty-six FDG PET scans of 51 patients were assessable. All 19 cases with residual lesions >3 cm and 35 (95%) of 37 with residual lesions < or =3 cm were correctly predicted by FDG PET. The specificity, sensitivity, positive predictive value, and negative predictive value of FDG PET were 100% (95% CI, 92% to 100%), 80% (95% CI, 44% to 95%), 100%, and 96%, respectively, versus 74% (95% CI, 58% to 85%), 70% (95% CI, 34% to 90%), 37%, and 92%, respectively, for CT discrimination of the residual tumor by size (>3 cm/< or =3 cm). CONCLUSION: This investigation confirms that FDG PET is the best predictor of viable residual tumor in postchemotherapy seminoma residuals and should be used as a standard tool for clinical decision making in this patient group.