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.

Pushing the boundaries: circumferential endoscopic submucosal dissection in distal duodenum.

Video 1Pushing the boundaries: circumferential endoscopic submucosal dissection in distal duodenum (7.58 seconds).

Performance of CT in the locoregional staging of colon cancer: detailed radiology-pathology correlation with special emphasis on tumor deposits, extramural venous invasion and T staging.

PURPOSE: To investigate the performance of computed tomography (CT) in the local staging of colon cancer in different segments, with emphasis on parameters that have been found to be significant for rectal cancer, namely, extramural venous invasion (EMVI) and tumor deposits (TDs). METHODS: CT and pathology data from 137 patients were independently reviewed by radiology and pathology teams. The performance of CT in categorizing a given patient into good, versus poor prognostic groups was assessed for each segment, as well as the presence of lymph nodes (LNs), TDs and EMVIs. Discordant cases were re-evaluated to determine potential sources of error. Elastic stain was applied for EMVI discordance. RESULTS: The T staging accuracy was 80.2%. For T stage stratification, CT performed slightly better in the left colon, and the lowest accuracy was in the transverse colon. Under-staging was more common (in 12.4%), and most of the mis-staged cases were in sigmoid colon. According to the first comprehensive correlative analysis, the sensitivity, specificity, and accuracy of CT for detecting TDs were found to be 57.9%, 92.4%, 87.6%, respectively. These figures were 44.7%, 72.7%, and 63.5% for LN, and 58.5%, 82.1% and 73% for EMVI. The detection rate was better for multifocal EMVI. The detection rate was also comparable (although substantially underestimated) for LNs, with the half of the LNs missed by CT being < 5 mm. Four patients that were classified as TD by CT, disclosed to be LNs by pathology. Correlative analysis led to refinement of the pathology criteria, with subsequent modifications of the initial reports in 13 (9.5%) patients. CONCLUSION: Overall, CT performed well in the evaluation of colon cancer, as did TD and EMVI. It is advisable to include these parameters in CT-based staging. Radiologists should be aware of the pitfalls that occur more commonly in different segments.

Adenomyomas of the Gallbladder: An Analysis of Frequency, Clinicopathologic Associations, and Relationship to Carcinoma of a Malformative Lesion.

CONTEXT.­: The nature and associations of gallbladder (GB) "adenomyoma" (AM) remain controversial. Some studies have attributed up to 26% of GB carcinoma to AMs. OBJECTIVE.­: To examine the true frequency, clinicopathologic characteristics, and neoplastic changes in GB AM. DESIGN.­: Cholecystectomy cohorts analyzed were 1953 consecutive cases, prospectively with specific attention to AM; 2347 consecutive archival cases; 203 totally embedded GBs; 207 GBs with carcinoma; and archival search of institutions for all cases diagnosed as AM. RESULTS.­: Frequency of AM was 9.3% (19 of 203) in totally submitted cases but 3.3% (77 of 2347) in routinely sampled archival tissue. A total of 283 AMs were identified, with a female to male ratio = 1.9 (177:94) and mean size = 1.3 cm (range, 0.3-5.9). Most (96%, 203 of 210) were fundic, with formed nodular trabeculated submucosal thickening, and were difficult to appreciate from the mucosal surface. Four of 257 were multifocal (1.6%), and 3 of 257 (1.2%) were extensive ("adenomyomatosis"). Dilated glands (up to 14 mm), often radially converging to a point in the mucosa, were typical. Muscle was often minimal, confined to the upper segment. Nine of 225 (4%) revealed features of a duplication. No specific associations with inflammation, cholesterolosis, intestinal metaplasia, or thickening of the uninvolved GB wall were identified. Neoplastic change arising in AM was seen in 9.9% (28 of 283). Sixteen of 283 (5.6%) had mural intracholecystic neoplasm; 7 of 283 (2.5%) had flat-type high-grade dysplasia/carcinoma in situ. Thirteen of 283 cases had both AM and invasive carcinoma (4.6%), but in only 5 of 283 (1.8%), carcinoma arose from AM (invasion was confined to AM, and dysplasia was predominantly in AM). CONCLUSIONS.­: AMs have all the features of a malformative developmental lesion, and may not show a significant muscle component (ie, the name "adeno-myoma" is partly a misnomer). While most are innocuous, some pathologies may arise in AMs, including intracholecystic neoplasms, flat-type high-grade dysplasia or carcinoma in situ, and invasive carcinoma (1.8%, 5 of 283). It is recommended that gross examination of GBs include serial slicing of the fundus for AM detection and total submission if one is found.

Multimodal assessment after total neoadjuvant therapy versus standard neoadjuvant chemoradiotherapy in locally advanced rectal cancer accurately predicts complete responders.

PURPOSE: This study aimed to compare local regrowth rates after total neoadjuvant therapy (TNT) versus standard neoadjuvant chemoradiotherapy (SNCRT) in locally advanced rectal cancer (LARC) patients that were strictly selected and assessed with a multimodal approach. Secondary outcomes were 4-year disease-free (DFS) and overall survival (OS) rates. METHODS: Locally advanced rectal cancer patients without distant metastases treated at Koç Healthcare Group between January 2014 and January 2021 were included. Patients were assessed for complete response with a combination of digital rectal exam, endoscopy, and magnetic resonance imaging with a dedicated rectum protocol. The systemic evaluation was performed with an upper abdomen MRI using intravenous hepatobiliary contrast agent and a thorax CT. RESULTS: Of the 270 patients with LARC, 182 fulfilled the inclusion criteria. Ninety-seven (53.3%) underwent TNT, while 85 (46.7%) underwent SNCRT. A cumulative combination of pathological and sustained clinical complete response was significantly higher in the TNT group than in the SNCRT (45.4% vs. 20.0%, p < 0.0001). After a median follow-up of 48 months, seven patients in the W&W group had regrowth [TNT: 4 (10.8%) vs. SNCRT: 3 (23.1%), p = 0.357]. Based on pathological examination, complete/near complete mesorectum rates (p = 1.000) and circumferential resection margin positivity rates (p = 1.000) were similar between the groups. The 4-year DFS and OS rates were comparable. The patients with clinical or pathological complete response had significantly longer overall survival (p = 0.017) regardless of the type of neoadjuvant treatment. CONCLUSIONS: Multimodal assessment after TNT effectively detects complete responders, resulting in low local recurrence and increased cumulative complete response rates. However, these outcomes did not translate into a survival advantage.

Is there no need to discuss adjuvant chemotherapy in stage II colon cancer patients with high tumor budding and lymphovascular invasion?

PURPOSE: The aim of this study is to evaluate the clinicopathologic associations of tumor budding (Bd) as well as other potential prognosticators including lymphovascular invasion (LVI) in T3/4aN0 colon cancer patients and to investigate their impact on the outcome. METHODS: The patients were enrolled in three groups according to the number of budding as Bd1 (0-4 buds), Bd2 (5-9 buds), and Bd3 (> 10 buds). These groups were retrospectively compared in terms of demographic features, other tumor characteristics, operative outcomes, recurrences, and survival. The mean follow-up time was 58 ± 22 months. RESULTS: A total of 194 patients were divided as follows: 97 in Bd1, 41 in Bd2, and 56 in Bd3 groups. The Bd3 group was associated with significantly higher LVI and larger tumor size. The rate of recurrence increased progressively from 5.2% in Bd1 to 9.8% in Bd2 and to 17.9% in Bd3 group (p = 0.03). More importantly, the 5-year overall survival (OS: Bd1 = 92.3% vs. Bd2 = 88% vs. Bd3 = 69.5%, p = 0.03) and disease-free survival (DFS: Bd1 = 87.9% vs. Bd2 = 75.3% vs. Bd3 = 66%, p = 0.02) were significantly worse in Bd3 group. In addition, in the subgroup of patients with the presence of Bd3 and LVI together, the 5-year OS (60% vs. 92%, p = 0.001) and DFS (56.1% vs. 85.4%, p = 0.001) were significantly worse. In multivariate analysis, Bd3+LVI was significantly associated with poor OS and DFS (p < 0.001). CONCLUSION: In patients with T3/4aN0 colon cancer, high tumor budding negatively affects long-term oncological outcomes. These findings strongly suggest that adjuvant chemotherapy be considered for the patients with Bd3 and LVI together.

BRAF, NRAS, KIT, TERT, GNAQ/GNA11 Mutation Profile and Histomorphological Analysis of Anorectal Melanomas: A Clinicopathologic Study.

OBJECTIVE: Primary anorectal melanomas (AMs) are uncommon neoplasms with aggressive behavior. Molecular profile and clinicopathologic features of AMs are still not well established. In this study, we aimed to investigate BRAF, NRAS, KIT, TERT, and GNAQ/GNA11 mutation status and clinicopathologic features of AMs. MATERIAL AND METHOD: All diagnostic slides of 15 AMs were reviewed. Histopathological and follow-up information were documented. Mutations in exon 15 of the BRAF gene; exons 2 and 3 of the NRAS gene; exons 9, 11, 13, 17, and 18 of the KIT gene; and exons 4 and 5 of the GNAQ/GNA11 genes and mutations in the promoter region of the TERT gene (chr.5, 1,295,228C > T and 1,295,250C > T) were analyzed. RESULTS: BRAF(V600E) and KIT(V555I and K642E) mutations were observed in one (7%) and two cases (14%), respectively. NRAS, TERT and GNAQ/GNA11 mutations were not detected. The mean age was 65. Patients presented with rectal mass, rectal bleeding, pain, and weight loss. 73% of the lesions were macroscopically polypoid. The most common tumor cell type was epithelioid. Mean tumor thickness was 10.4 mm. One third of the cases lacked pigmentation. In situ melanoma was present in one third of the cases. Among 14 patients with follow-up data, 12 succumbed to disease. The mean overall survival was 36 months. CONCLUSION: AMs are uncommon tumors with dismal survival, usually occurring in the elderly in various gross and microscopic appearances. In terms of molecular profile, BRAF and KIT mutations are rarely detected. Profiling of larger cohorts is required to elucidate the pathogenesis and to identify potential molecular indicators that may contribute to the development of individualized targeted therapies.

Neuroendocrine Tumor of Tailgut Cyst with Unexpected Metastases.

Neuroendocrine tumors (NETs) originate from the neuroendocrine cells, which are found in various organs. NETs occur frequently in the gastrointestinal tract. NETs arising from tailgut cysts are uncommon. We herein report an interesting case of metastatic tailgut cyst NET, which was firstly diagnosed as plasmacytoma.

Optimizing the Personalized Care for the Management of Rectal Cancer: A Consensus Statement.

Colorectal cancer is the third most common cancer in Turkey. The current guidelines do not provide sufficient information to cover all aspects of the management of rectal cancer. Although treatment has been standardized in terms of the basic principles of neoadjuvant, surgical, and adjuvant therapy, uncertainties in the management of rectal cancer may lead to significant differences in clinical practice. In order to clarify these uncertainties, a consensus program was constructed with the participation of the physicians from the Acibadem Mehmet Ali Aydinlar and Koç Universities. This program included the physicians from the departments of general surgery, gastroenterology, pathology, radiology, nuclear medicine, medical oncology, radiation oncology, and medical genetics. The gray zones in the management of rectal cancer were determined by reviewing the evidence-based data and current guidelines before the meeting. Topics to be discussed consisted of diagnosis, staging, surgical treatment for the primary disease, use of neoadjuvant and adjuvant treatment, management of recurrent disease, screening, follow-up, and genetic counseling. All those topics were discussed under supervision of a presenter and a chair with active participation of related physicians. The consensus text was structured by centralizing the decisions based on the existing data.

Extramural venous invasion (EMVI) revisited: a detailed analysis of various characteristics of EMVI and their role as a predictive imaging biomarker in the neoadjuvant treatment response in rectal cancer.

PURPOSE: To assess whether size, diameter, and large vein involvement of MR-detected extramural venous invasion (MR-EMVI) have an impact on neoadjuvant therapy response in rectal adenocarcinoma. METHODS: 57 patients with locally advanced rectal adenocarcinoma scanned with MRI before and after neoadjuvant therapy were included. Two abdominal radiologists evaluated the images with special emphasis on EMVI, on initial staging and after neoadjuvant treatment. The sensitivity and specificity of MRI for detection of rest EMVI were determined. The association of various MR-EMVI characteristics including number, size, and main vein involvement with treatment response was investigated. In subjects with discordance of radiology and pathology, elastin stain was performed, and images and slides were re-evaluated on site with a multidisciplinary approach. RESULTS: At initial evaluation, 17 patients were MR-EMVI negative (29.8%) and 40 were MR-EMVI positive (70.2%). Complete/near-complete responders had less number (mean 1.45) and smaller diameter of MR-EMVI (mean 1.8 mm), when compared with partial responders (2.54 and 3.3 mm; p < 0.005). The sensitivity of MRI for rest EMVI detection was high, specificity was moderate, and in one patient elastin stain changed the final decision. In five patients with rest MR-EMVI positivity, carcinoma histopathologically had a distinctive serpiginous perivascular spread, growing along the track of vascular bundle, although it did not appear in intravascular spaces. CONCLUSION: This study demonstrates that not only the presence, but also size and number of EMVI that may be significant clinically and thus these parameters also ought to be incorporated to the MRI evaluation and prognostication of treatment response. From pathology perspective, tumors growing alongside major vessels may also reflect EMVI even if they are not demonstrably "intravascular."

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.

Recommendations for Clinical Decision-making in Children with Type 1 Diabetes and Celiac Disease: Type 1 Diabetes and Celiac Disease Joint Working Group Report

It is well-known that in children with type 1 diabetes (T1D), the frequency of Celiac disease (CD) is increased due to mechanisms which are not fully elucidated but include autoimmune injury as well as shared genetic predisposition. Although histopathologic examination is the gold standard for diagnosis, avoiding unnecessary endoscopy is crucial. Therefore, for both clinicians and patients' families, the diagnosis of CD remains challenging. In light of this, a joint working group, the Type 1 Diabetes and Celiac Disease Joint Working Group, was convened, with the aim of reporting institutional data and reviewing current international guidelines, in order to provide a framework for clinicians. Several controversial issues were discussed: For CD screening in children with T1D, regardless of age, it is recommended to measure tissue transglutaminase-immunoglobulin A (tTG-IgA) and/or endomysial-IgA antibody due to their high sensitivity and specificity. However, the decision-making process based on tTG-IgA titer in children with T1D is still debated, since tTG-IgA titers may fluctuate in children with T1D. Moreover, seronegativity may occur spontaneously. The authors' own data showed that most of the cases who have biopsy-proven CD had tTG-IgA levels 7-10 times above the upper limit. The decision for endoscopy based solely on tTG-IgA levels should be avoided, except in cases where tTG-IgA levels are seven times and above the upper limit. A closer collaboration should be built between divisions of pediatric endocrinology and gastroenterology in terms of screening, diagnosis and follow-up of children with T1D and suspicious CD.

An intrathyroidal nodule consisting of papillary thyroid cancer and ectopic hyperechoic parathyroid adenoma: a case report.

A 53-year-old woman with fatigue lasting for 6 weeks and increased parathormone level underwent a neck ultrasound. It revealed a large, lobulated, solid intrathyroidal nodule consisting of hypoechoic component with microcalcifications and hy-perechoic component with vascularity on Doppler mode. There were also subcentimetric intrathyroidal hypo- and hyperechoic nodules. Upon the diagnosis of papillary thyroid cancer on fine-needle aspiration biopsy, a total thyroidectomy procedure was performed. In the histopathologic evaluation, the hypoechoic component was diagnosed as papillary thyroid cancer, while the hyperechoic component was diagnosed as ectopic parathyroid adenoma. Subcentimetric nodules were demonstrated as multi-foci of papillary thyroid cancer.

Intrathyroidal Ectopic Thymus and Sonoelastographic Findings.

BACKGROUND: Intrathyroidal ectopic thymus (IET) can be misdiagnosed as thyroid nodules. PURPOSE: The purpose of this study is to evaluate the sonoelastographic findings of IET in pediatric population. METHODS: Twelve children who had been examined with ultrasound (US) and strain elastography between December 2012 and December 2019 were included in this retrospective study. The patients' demographics and ultrasonographic findings, including the location, margin, shape, diameters, volume, structure, vascularity, and elastography values of the lesions were evaluated. RESULTS: Twelve lesions were detected in 12 asymptomatic patients (3 females and 9 males) with a mean age of 4.67 ± 2.27 years. The most common location of the IET was in posterior part and middle third of thyroid, and the most common appearance on US was a well-defined, ovoid-shaped, and predominantly hypoechoic solid lesion with punctate/linear branching hyperechogenities. The lesions were mostly hypovascular on Doppler US. The mean strain ratio on elastography was found to be 1.10 ± 0.04. In the follow-up of 7 patients with available information, there was no significant change in size or appearance of IET on US. CONCLUSION: IET should be considered in the differential diagnosis of the lesions within the thyroid. The first step to accurately diagnose an IET is to consider it in the differential diagnosis. In addition to US, strain elastography findings can be used to distinguish IETs from papillary thyroid cancers which can have similar US appearance, and help avoid unnecessary biopsies.

Löwenstein-Buschke: Clinicopathologic Analysis of 78 Cases of Large and Giant Condyloma Acuminata of the Anus.

OBJECTIVE: The nature and clinicopathologic associations of Löwenstein-Buschke disease are unclear. MATERIALS AND METHODS: 78 anal condylomatous lesions (≥2 cm) were analyzed. Cases were classified based on size as "medium-large"(2-5 cm, n=59), "large" (5-10 cm, n=13) and "giant" ( > 10 cm, n=6). RESULTS: Patients were predominantly males (male/female=70/8). The mean age was 38 years (range:20-66). Two distinct lining types were recognized: 1) Epidermal type, typically lacking overt koilocytotic change, with associated invasive carcinoma in 8%; 2) Mucosal type, often manifesting koilocytotic change, with associated invasive carcinoma in 21%. Three types of high-grade dysplasia were discerned: 1) Basaloid, 8/9 showing high-grade dysplasia/carcinoma in-situ but non-invasive lesions; 2) Keratinizing, innocuous-appearing, but 5/6 was associated with invasion; 3) Giant cell, showing scattered individual bizarre cells, with 3/5 showing invasive carcinoma. Overall, invasion was found in 14% of the cases. The bulbous, broad-based destructive pattern characterizing verrucous carcinomas of the upper aerodigestive tract was not observed. A statistically significant trend existed between the incidence of invasion and size: 8.5% for medium-large, 23% for large, and 50% for giant (p=0.02). There was no discernable trend in the depth of invasion relative to condyloma size. CONCLUSIONS: Our findings suggest that Löwenstein-Buschke lesions are mega versions of conventional condyloma. Being verrucoid, large and minimally invasive, they can be conceptually regarded as a form of verrucous carcinoma, but they do not display the histologic characteristics of verrucous carcinoma defined in the aerodigestive tract. They exhibit two types of linings: the mucosal type that often shows koilocytotic changes, and the epidermal type that can be difficult to recognize in biopsies. These lesions may be associated with invasive carcinoma, albeit limited in amount.

The use of focused, radioguided parathyroidectomy in geriatric patients with a history of thyroid surgery.

OBJECTIVE: Geriatric patients are often reluctant to undergo parathyroid surgery under general anesthesia because of the major comorbidities. The use of minimally invasive techniques for parathyroid lesions under local anesthesia have been published. Radioguided lesion localization has been known to decrease operative time and reduce the occurrence of positive margins in breast cancer surgery. We hypothesize that it could also be effectively used in focused parathyroid surgery in geriatric patients with in history of thyroid surgery. MATERIALS AND METHODS: Our study group consists of geriatric patients with a history of thyroid surgery who underwent focused parathyroid surgery between February 2017 and October 2019. Group-1 included 18 patients who had parathyroidectomy under radioguidance. Group-2, 22 patients who had surgery without it. Patient demographics, operative time, number of frozen sections and length of hospital stay were analyzed. RESULTS: Analyzed data were similar between groups. The mean age of the patients was 72.56±12.65 years (range: 65-88). The operative times for group-1 and group-2, were 65.42±7.78 and 74.63±15.98 minutes, respectively (P=0.002). All patients were discharged uneventfully on postoperative day-2. CONCLUSION: Radioguidance parathyroidectomy positively affected the operative time and also decreased the need for additional frozen section.