Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols.

BACKGROUND: Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach. METHODS: Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed. RESULTS: In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001). CONCLUSIONS: G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up.

Can endocan serve as a molecular "hepatostat" in liver regeneration?

BACKGROUND: Intriguingly, liver regeneration after injury does not induce uncontrolled growth and the underlying mechanisms of such a "hepatostat" are still not clear. Endocan, a proteoglycan, was implicated in liver regeneration. It can support the function of hepatocyte growth factor/scatter factor in tissue repair after injury. Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, may modulate the cessation of liver regeneration. eEF2K, a protein kinase that regulates protein synthesis, can regulate angiogenesis. Thus, we investigated the role of endocan, endostatin and eEF2K during normal liver regeneration. METHODS: Serum samples and regenerating remnant liver tissues were obtained on various days after partial hepatectomy in rats. mRNA expression levels of Vegf and Pcna were analyzed in addition to immunohistochemical evaluations. Liver tissue protein levels of endostatin, endocan and p-eEF2K/eEF2K were determined with Western blot. Serum levels of endostatin and endocan were assessed with ELISA. RESULTS: Pcna expression level in residual liver tissues peaked on day-1, while Vegf expression reached its highest level on days 1-3 after partial hepatectomy (70%). Endocan activity declined gradually on days 1-7. The decrease in liver endocan expression was accompanied by an increase in serum endocan levels. Partial hepatectomy induced a rapid increase in liver endostatin levels. Following its surge on day-1, endostatin expression gradually declined, which was accompanied by a peak in serum endostatin. Finally, partial hepatectomy was shown to regulate eEF2K; thus, increasing protein translation. CONCLUSIONS: We revealed possible mechanistic insights into liver regeneration by examining the associations of Pcna, Vegf, endocan, endostatin, eEF2K with hepatic regeneration after partial hepatectomy. Indeed, endocan might serve as a useful biomarker to monitor clinical prognosis in a plethora of conditions such as recovery of donor's remaining liver after living-donor liver transplant. Whether endocan might represent a strategy to optimize liver regeneration when given therapeutically needs to be investigated in future studies.

Infiltration pattern predicts metastasis and progression better than the T-stage and grade in pancreatic neuroendocrine tumors: a proposal for a novel infiltration-based morphologic grading.

The advancing edge profile is a powerful determinant of tumor behavior in many organs. In this study, a grading system assessing the tumor-host interface was developed and tested in 181 pancreatic neuroendocrine tumors (PanNETs), 63 of which were <=2 cm. Three tumor slides representative of the spectrum (least, medium, and most) of invasiveness at the advancing edge of the tumor were selected, and then each slide was scored as follows. Well-demarcated/encapsulated, 1 point; Mildly irregular borders and/or minimal infiltration into adjacent tissue, 2 points; Infiltrative edges with several clusters beyond the main tumor but still relatively close, and/or satellite demarcated nodules, 3 points; No demarcation, several cellular clusters away from the tumor, 4 points; Exuberantly infiltrative pattern, scirrhous growth, dissecting the normal parenchymal elements, 5 points. The sum of the rankings on the three slides was obtained. Cases with scores of 3-6 were defined as "non/minimally infiltrative" (NI; n = 77), 7-9 as "moderately infiltrative" (MI; n = 68), and 10-15 as "highly infiltrative" (HI; n = 36). In addition to showing a statistically significant correlation with all the established signs of aggressiveness (grade, size, T-stage), this grading system was found to be the most significant predictor of adverse outcomes (metastasis, progression, and death) on multivariate analysis, more strongly than T-stage, while Ki-67 index did not stand the multivariate test. As importantly, cases <=2 cm were also stratified by this grading system rendering it applicable also to this group that is currently placed in "watchful waiting" protocols. In conclusion, the proposed grading system has a strong, independent prognostic value and therefore should be considered for integration into routine pathology practice after being evaluated in validation studies with larger series.

Everolimus and/or Nivolumab-Associated Cytomegalovirus Colitis in a Patient with Metastatic Renal Cell Carcinoma.

Everolimus-associated cytomegalovirus colitis is very rare in cancer patients. We present a case of cytomegalovirus colitis that occurred on using everolimus in a 64-year-old male with metastatic renal cell carcinoma who received pazopanib, nivolumab, and everolimus treatments, respectively. Although an increasing number of nivolumab-related cytomegalovirus colitis cases are reported recently, its mechanism of development is still unknown. Our study highlights that clinicians should remember cytomegalovirus reactivation in the presence of diarrhea or colitis in patients receiving everolimus and/or nivolumab. Further studies are needed to elucidate the relationship between immune checkpoint inhibitors and cytomegalovirus reactivation, and these will also be a guide to prevent other possible viral infections.

Can we differentiate neoplastic and non-neoplastic spontaneous adrenal bleeding? Imaging findings with radiopathologic correlation.

Spontaneous adrenal bleeding is a rare clinical event with non-specific clinical features. Life-threatening bleeding in the adrenal glands may be promptly diagnosed with imaging. Computed tomography (CT) is generally the first imaging modality to be used in these patients. However, in the acute phase of bleeding, it may be difficult to detect the underlying mass from the large hematoma. In these patients, additional imaging studies such as magnetic resonance imaging or positron emission tomography/CT may be utilized to rule out a neoplastic mass as the source of bleeding. In patients where an underlying neoplastic mass could not be identified at the time of initial diagnosis, follow-up imaging may be helpful after the acute phase subsides.

Cross-sectional imaging features of unusual adrenal lesions: a radiopathological correlation.

The detection rates of adrenal masses are increasing with the common and widespread use of cross-sectional imaging. Adrenal adenomas, myelolipomas, metastases, pheochromocytomas, and adrenocortical tumors are well-known and relatively common adrenal tumors. However, there are many less-known neoplastic and nonneoplastic adrenal diseases that might affect the adrenal glands in addition to these common lesions. These rare entities include, but are not limited to, hydatid cysts, congenital adrenal hyperplasia, Wolman disease, adrenal tuberculosis, primary adrenal lymphoma. This article aims to present imaging findings of these unusual lesions in accordance with their pathologic characteristics. We think that the simultaneous presentation of the pathological findings with the imaging features may facilitate the learning process and may potentially enhance the recognition of these entities.

Immunoglobulin G4-related systemic disease: mesenteric and peritoneal involvement with radiopathological correlation and differential diagnoses.

Since its first introduction in 2003 by Kamisawa et al., IgG4-related disease has gained wide interest in the imaging community, and several manuscripts have been published regarding its imaging features. In addition to initial observations in the pancreaticobiliary system, it is now well known that the disease may involve every organ system in the body. There is not much information in the imaging literature about the involvement of mesentery, omentum, and peritoneum in this disease. This article aims to provide more information about the imaging findings of IgG4-related disease regarding these areas by making radiopathological correlations and discussing the possible differential diagnoses.