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.

TASL Practice Guidance on the Clinical Assessment and Management of Patients with Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease and is significantly associated with obesity, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. NAFLD has become the most prevalent chronic liver disease in Western countries, and the proportion of NAFLD-related cirrhosis among patients on liver transplantation waiting lists has increased. In light of the accumulated data about NAFLD, and to provide a common approach with multi-disciplines dealing with the subject, it has become necessary to create new guidance for diagnosing and treating NAFLD. This guidance was prepared following an interdisciplinary study under the leadership of the Turkish Association for the Study of the Liver (TASL), Fatty Liver Special Interest Group. This new TASL Guidance is a practical application guide on NAFLD and was prepared to standardize the clinical approach to diagnosing and treating NAFLD patients. This guidance reflects many advances in the field of NAFLD. The proposals in this guidance are meant to aid decision-making in clinical practice. The guidance is primarily intended for gastroenterology, endocrinology, metabolism diseases, cardiology, internal medicine, pediatric specialists, and family medicine specialists.

Problems in Postmortem Pathology Training.

OBJECTIVE: In Turkey, autopsy performers, namely forensic medicine practitioners, are neither pathologists nor have properly received pathology training during residency in contrast to the Anglo-Saxon model of forensic medicine practices, since the current curriculum of forensic medicine residency lacks adequate training in post-mortem histopathology. Likewise, pathologists lack a specific post-mortem pathology clerkship. In this study, we intended to determine whether forensic physicians in Turkey find themselves competent in post-mortem histopathology or were adequately trained during their residencies. MATERIAL AND METHOD: Turkish forensic medicine practitioners were administered an online questionnaire whereby self-evaluations of their histopathology knowledge and their views on histopathology training during forensic medicine residency were assessed. The 151 physicians who completed the questionnaire made up the study group. RESULTS: It was found out that the majority of Turkish forensic medicine practitioners (85.4%) did not find the histopathology training during their residency adequate. Similarly, 85.4% of the participants indicated their incompetence in histopathological examination of post-mortem tissue of any kind, and showed their willingness for further training in pathology. 66.9% strongly agreed that post-mortem histopathology requires training that is distinct from surgical pathology. In case of providing post-mortem histopathology training within the scope of forensic medicine residency, topics such as microscopic morphology of post-mortem changes, histological changes related to injuries, and estimation of wound age are expected to be beneficial to 88.7% 83.4%, and 83.4% of the participants respectively. CONCLUSION: The current curriculum should be revised in a way that the surgical pathology clerkship meets forensic physicians' needs, so that they can then refer more difficult, non-routine histopathological consultations to pathologists who are also well-trained in postmortem histopathology. Consideration should also be given to establishing a subspecialty training - a master's or doctoral degree programs in forensic pathology.

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.

Assessment of 4DCT imaging findings of parathyroid adenomas in correlation with biochemical and histopathological findings.

PURPOSE: To assess polar vessel presence and enhancement 4DCT imaging and their relation with biochemical and histopathological features. METHODS: Patients with primary hyperparathyroidism and preoperative 4DCT imaging were screened retrospectively and those with histopathologically proven diagnosis of PA were included. Biochemical findings, densitometric measurements (HUprecontrast, HUarterial, HUvenous, HUwash-in, HUwash-out, HUretained) and CTvolume of PA on 4DCT, presence of a polar vessel (PV), and histopathological features were recorded. Correlations between serum PTH, calcium levels and densitometric measurements of PA on 4DCT were investigated. Differences between subgroups created according to PV presence were also evaluated. RESULTS: Thirty-nine patients were enrolled (F/M = 32/7, median age = 57, interquartile range = 50-62 years). In all patients, serum PTH levels positively correlated with CTvolume (r = 0.398, p = 0.012) but negatively correlated with HUarterial (r = - 0.366; p = 0.022), HUvenous (r = - 0.452; p = 0.004) and HUretained (r = - 0.421; p = 0.008). In PV (-) PAs, PTH levels were positively correlated with CTvolume (r = 0.608, p ≤ 0.002) and negatively with HUarterial (r = - 0.449, p ≤ 0.028), HUvenous (r = - 0.560, p = 0.004), HUwash-in (r = - 0.460, p = 0.024), and HUretained (r = - 0.539, p = 0.007). No correlation between PTH levels and densitometric measurements was found in PV (+) PAs. HUwash-in and HUwash-out were significantly higher in PV (+) PAs compared to PV (-) PAs (p = 0.021 and p = 0.033, respectively). Histopathologic features revealed no difference according to the presence of PV. CONCLUSION: PTH levels might have an association with imaging findings of PAs, especially when categorized with respect to PV presence. PTH levels were negatively correlated with degree of enhancement in PV (-) PAs. Therefore, radiologists should be aware that in patients with high serum PTH levels and without a discernible PV, PA might be difficult to localize.

Comprehensive clinicopathologic characteristics of intraabdominal neurogenic tumors: Single institution experience.

BACKGROUND: Neurogenic tumors are rare but represent an important consideration in the differential diagnosis of abdominal mesenchymal tumors. Reports on their incidence, pathological features and clinical characteristics are scarce. AIM: To advance the overall knowledge on the histologic, immunohistochemical, clinical and radiologic characteristics of neurogenic tumors through this case series. METHODS: An established database of a nationwide tertiary referral center, covering a 15-year period (2005 and 2020), was retrospectively re-evaluated. Diagnoses of neurogenic tumor cases were confirmed by two experts following review of the macroscopic, histological and immunohistochemical records along with findings from analysis of archived tissue sections for each included patient. Tissue microarrays were constructed for cases lacking necessary immunohistochemical studies. Clinical data and follow-up information were collected from the hospital records and the patients themselves, when available. RESULTS: The study included 19 cases of intraabdominal neurogenic tumors, representing 12 women and 7 men, between 18 and 86 years of age (median: 51 years). Final confirmed diagnoses were 12 schwannomas, 2 diffuse submucosal neuro-fibromatoses, 2 ganglioneuromas, 2 malignant peripheral sheath nerve tumors, and 1 mucosal Schwann cell hamartoma. Sizes of the tumors were variable, with a median diameter of 4 cm; the two largest (> 10 cm) were schwannomas. The majority of cases were asymptomatic at presentation, but the most frequent symptom was abdominal pain. Gastrointestinal tract lesions were detected with endoscopy and extra-luminal lesions were detected with cross-sectional imaging. All cases were S100-positive and CD117-negative; most cases were negative for desmin, epithelial membrane antigen, smooth muscle actin and CD34. In all but 5 cases, the Ki67 proliferation index was ≤ 1%. CONCLUSION: Re-evaluation of 19 cases of abdominal neurogenic tumors demonstrated con-siderable variability in clinicopathologic characteristics depending on location, dimension and histological features.

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.

In the presence of autoantibodies and iron overload, do not judge a book by its cover: A case report.

The presence of autoantibody positivity with an elevated ferritin level and high transferrin saturation can create a diagnostic dilemma. This report describes the challenging case of 38-year-old male patient who presented with new-onset diabetes, malaise, weight loss, dark-yellow skin discoloration, and splenomegaly. Initial laboratory tests revealed thrombocytopenia, leucopenia, an elevated unconjugated bilirubin level, and mildly elevated liver enzymes in a cholestatic pattern. Antinuclear antibody and anti-smooth muscle antibody findings were positive with titers of 1/160 and 1/320, respectively, along with hypergammaglobulinemia. The transferrin saturation value was 92% and the ferritin level was 498 µg/L. HFE gene mutation analysis revealed a C282Y heterozygote mutation, which is not diagnostic, but supported a diagnosis of hereditary hemochromatosis (HH). A liver biopsy is the most accurate way to differentiate autoimmune hepatitis from HH, and confirmed a diagnosis of HH. This case highlights the importance of paying close attention to all findings to avoid misdiagnosis and treatment which might result in dangerous outcomes. Additionally, in spite of a genetic test, a liver biopsy has great value as an important tool to determine an accurate diagnosis in patients with iron overload, especially in patients with concomitant autoantibody positivity.

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.

AttentionBoost: Learning What to Attend for Gland Segmentation in Histopathological Images by Boosting Fully Convolutional Networks.

Fully convolutional networks (FCNs) are widely used for instance segmentation. One important challenge is to sufficiently train these networks to yield good generalizations for hard-to-learn pixels, correct prediction of which may greatly affect the success. A typical group of such hard-to-learn pixels are boundaries between instances. Many studies have developed strategies to pay more attention to learning these boundary pixels. They include designing multi-task networks with an additional task of boundary prediction and increasing the weights of boundary pixels' predictions in the loss function. Such strategies require defining what to attend beforehand and incorporating this defined attention to the learning model. However, there may exist other groups of hard-to-learn pixels and manually defining and incorporating the appropriate attention for each group may not be feasible. In order to provide an adaptable solution to learn different groups of hard-to-learn pixels, this article proposes AttentionBoost, which is a new multi-attention learning model based on adaptive boosting, for the task of gland instance segmentation in histopathological images. AttentionBoost designs a multi-stage network and introduces a new loss adjustment mechanism for an FCN to adaptively learn what to attend at each stage directly on image data without necessitating any prior definition. This mechanism modulates the attention of each stage to correct the mistakes of previous stages, by adjusting the loss weight of each pixel prediction separately with respect to how accurate the previous stages are on this pixel. Working on histopathological images of colon tissues, our experiments demonstrate that the proposed AttentionBoost model improves the results of gland segmentation compared to its counterparts.

Human splenic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are strategically located immune regulatory cells in cancer.

In contrast to the mouse, functional assets of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the human spleen remain to be better elucidated. Here, we report that the spleen in gastric and pancreatic cancer adopts an immune regulatory character, harbors excessive amount of PMN-MDSC, and anatomically enables their interaction with T cells. Compared to the peripheral blood, the spleen from cancer patients contained significantly higher levels of low-density PMN-MDSC, but not early-stage MDSC (e-MDSC) and monocytic-MDSC (M-MDSC). Low-density fraction of polymorphonuclear (PMN) cells was enriched in immature myeloid cells and displayed higher levels of CD10, CD16, and ROS than their blood-derived counterparts. They were also positive for PD-L1, LOX-1, and pSTAT3. The white pulp and periarteriolar lymphoid sheath (PALS) were strategically surrounded by PMN cells that were in contact with T cells. Unlike those from the blood, both low-density and normal-density PMN cells from the human spleen suppressed T cell proliferation and IFN-γ production. Independent of clinical grade, high PMN-MDSC percentages were associated with decreased survival in gastric cancer. In summary, our results outline the immune regulatory role of the spleen in cancer where neutrophils acquire MDSC functions and feasibly interact with T cells.

Prognostic value of the 2017 World Health Organization Classification System for gastric neuroendocrine tumors: A single-center experience.

BACKGROUND/AIMS: Gastric neuroendocrine tumors (G-NETs) are rare tumors, but their incidence is gradually increasing. Despite the existence of many classification systems, determining prognosis and planning treatment in patients with G-NETs remains a clinical challenge. In this study, the prognostic value of the World Health Organization (WHO) 2017 grading system and the effect of surgery on survival in low grade neuroendocrine tumors were investigated. MATERIALS AND METHODS: G-NETs who were diagnosed between January 2000 and May 2017 were included in the study. Patients' demographic characteristics, treatment details, and survival data were obtained from medical charts. Pathological samples were re-classified according to the WHO 2017 grading system. RESULTS: Of the total 94 evaluated patients, 50 (53.2%) were classified with G1 NETs, 37(39.4%) with G2 NETs, 4(4.2%) with well-differentiated G3 NETs, and the remaining 3 patients with poorly differentiated G3 neuroendocrine carcinoma (NEC). The median follow-up time was 83.2 months. There was a statistically significant difference in 5-year progression free survival (PFS) between G1 tumors (100%) and G2 tumors (76%) (p<0.001). However, there was no statistically significant deference in 5-year overall survival rate (OS) for G1 (97%) and G2 (82%) tumors (p=0.141). When G2 and G1 NETs were compared according to their surgical approach, radical surgery was more frequently performed in patients with G2 tumors (p<0.001). However, radical surgery did not improve PFS in G1 and G2 NETs. CONCLUSION: The WHO 2017 NET classification system may have low prognostic value for determining the prognosis of patients with G1 and G2 tumors. Radical surgery for G1 and G2 NETs did not improve PFS in our study.

An immunohistochemical approach to detect oncogenic CTNNB1 mutations in primary neoplastic tissues.

The Wnt/ß-catenin signaling pathway is dysregulated in different types of neoplasms including colorectal cancer (CRC). Aberrant activation of this signaling pathway is a key early event in the development of colorectal neoplasms, and is mainly caused by loss of function mutations in Adenomatous Polyposis Coli (APC), and less frequently by ß-catenin stabilization mutations via missense or interstitial genomic deletions in CTNNB1. In this study, we have defined an immunohistochemical algorithm to dissect Wnt pathway alterations in formalin-fixed and paraffin-embedded neoplastic tissues. Basically, consecutive sections of tumor specimens were stained by immunohistochemistry with two different monoclonal antibodies against ß-catenin: one (anti-active ß-catenin antibody) recognizes hypo-phosphorylated ß-catenin and the other recognizes the total pool of ß-catenin. We validated the strategy in the HCT116 CRC cell line which has an in-frame deletion of ß-catenin serine 45, and then studied human tumor microarrays containing colon adenomas, CRCs, solid pseudopapillary neoplasms of the pancreas as well as the whole tissue sections of CRCs, desmoid fibromatosis, and pilomatrixoma of the skin. In some tumors, we found strong ß-catenin cytoplasmic and/or nuclear staining with the total ß-catenin antibody but no staining with the anti-active ß-catenin antibody. This was inferred to be an altered/mutant ß-catenin staining pattern. All six colon adenomas of the 126 total adenomas studied for the altered/mutant ß-catenin staining pattern had presumptively pathogenic point mutations or deletions in CTNNB1. Four of 10 CRCs with the alterated/mutant ß-catenin staining pattern studied in depth, from 181 total CRCs from tissue microarray, had pathogenic CTNNB1 mutations. The frequencies of CTNNB1 alterations in non-colonic tumors with altered/mutant ß-catenin staining ranged between 46 and 100%. Our results demonstrate that the immunohistochemical approach described here can detect oncogenic forms of ß-catenin in primary tissue samples and can also highlight other tumors with presumptive novel defects activating the Wnt/ß-catenin pathway.