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Risk stratification of gastrointestinal stromal tumors (GISTs) is based on experience with tumors of the stomach, small bowel, and rectum, which are far more common than GISTs of other sites. In this study from 47 institutions, we analyzed GISTs of the esophagus (n = 102), colon (n = 136), and appendix (n = 27) for their size, mitotic rate, morphology, and outcome to determine which criteria predict their behavior. Esophageal GISTs were small (median: 2.5 cm) with spindle cell morphology and a low mitotic rate (mean: 3.6/5 mm2). Twelve (12%) tumors progressed, including 11 with a mitotic rate >5/5 mm2 and one large (6.8 cm) GIST with a mitotic rate of 2/5 mm2. Colonic GISTs were smaller (median: 1.4 cm) and presented with abdominal pain or bleeding in 29% of cases. Most (92%) were composed of spindle cells with a mean mitotic rate of 4.6/5 mm2. Sixteen (12%) tumors progressed: 14 had mitotic rates >5/5 mm2, and two were >5.0 cm with a mitotic rate 5/5 mm2) and size >5.0 cm. These findings support the use of size and mitotic rate for prognostication of GISTs in these locations, similar to tumors of the stomach, small bowel, and rectum.

Supplementary Figure 5 from Interaction of MLL Amino Terminal Sequences with Menin Is Required for Transformation

Rearrangements of the mixed lineage leukemia gene MLL are associated with aggressive lymphoid and myeloid leukemias. The resulting MLL fusion proteins enforce high-level expression of HOX genes and the HOX cofactor MEIS1, which is pivotal for leukemogenesis. Both wild-type MLL and MLL fusion proteins interact with the tumor suppressor menin and with the Hoxa9 locus in vivo. Here, we show that MLL sequences between amino acids 5 and 44 are required for interaction with menin and for the transformation of hematopoietic progenitors. Blocking the MLL-menin interaction by the expression of a dominant negative inhibitor composed of amino terminal MLL sequences down-regulates Meis1 expression and inhibits cell proliferation, suggesting that targeting this interaction may be an effective therapeutic strategy for leukemias with MLL rearrangements. [Cancer Res 2007;67(15):7275–83]

Supplementary Figure 2 from Interaction of MLL Amino Terminal Sequences with Menin Is Required for Transformation

Supplementary Figure 4 from Interaction of MLL Amino Terminal Sequences with Menin Is Required for Transformation

Supplementary Figure 3 from Interaction of MLL Amino Terminal Sequences with Menin Is Required for Transformation

Supplementary Figure 1 from Interaction of MLL Amino Terminal Sequences with Menin Is Required for Transformation

3D patient-derived organoids (PDOs) have been utilized to evaluate potential therapies for patients with different cancers. However, the use of PDOs created from treatment-naive patient biopsies for prediction of clinical outcomes in patients with esophageal cancer has not yet been reported. Herein we describe a pilot prospective observational study with the goal of determining whether esophageal cancer PDOs created from treatment naive patients can model or predict clinical outcomes. Endoscopic biopsies of treatment-naive patients at a single tertiary care center were used to generate esophageal cancer PDOs, which were treated with standard-of-care chemotherapy, gamma-irradiation, and newer non-standard approaches, such as proton beam therapy or two small molecule inhibitors. Clinical outcomes of patients following neoadjuvant treatment were compared to their in vitro PDO responses, demonstrating the PDO’s ability to mirror clinical response, suggesting the value of PDOs in prediction of clinical response to new therapeutic approaches. Future prospective clinical trials should test the use of pre-treatment PDOs to identify specific, targeted therapies for individual patients with esophageal adenocarcinoma.

Most pancreatic neuroendocrine neoplasms are slow-growing, and the patients may survive for many years, even after distant metastasis. The tumors usually display characteristic organoid growth patterns with typical neuroendocrine morphology. A smaller portion of the tumors follows a more precipitous clinical course. The classification has evolved from morphologic patterns to the current World Health Organization classification, with better-defined grading and prognostic criteria. Recent advances in molecular pathology have further improved our understanding of the pathogenesis of these tumors. Various issues and challenges remain, including the correct recognition of a neuroendocrine neoplasm, accurate classification and grading of the tumor, and differentiation from mimickers. This review focuses on the practical aspects during the workup of pancreatic neuroendocrine neoplasms and attempts to provide a general framework to help achieve an accurate diagnosis, classification, and grading.

Type I gastric neuroendocrine tumors (GNETs) are typically managed either expectantly or endoscopically. In contrast, locoregional surgery has been recommended for patients with type III GNETs because of the risk of metastasis. This study aimed to identify predictors of outcome independent of type in a contemporary cohort of GNET patients. A single-institution retrospective cohort study of 121 patients with a pathologic diagnosis of primary GNET between January 2009 and June 2019 was performed. GNETs were designated as type 1 (n = 74) if atrophic gastritis was present, or as type III (n = 47) in the absence of atrophic gastritis. Demographic, clinical, and histopathologic factors were examined using Kaplan–Meier and multivariable Cox regression to assess the impact of various factors on recurrence and overall survival. Median follow-up for the entire cohort was 62.7 months. While there was no difference in OS in patients with different GNET types (p = 0.10), higher tumor grade (p = 0.02) and presence of nodal or distant metastases (p = 0.02) predicted worse survival on multivariable analysis. Among type III GNET patients, those with small (< 0.5 cm), grade 1 lesions (“low-risk”) were less likely to develop metastases (0% versus 33%, p < 0.01) and more likely to survive (100% versus 67%, p < 0.01) at 5 years. Size and tumor grade predict recurrence and survival in patients with GNETs irrespective of type. Small, low-grade type III GNETs are associated with minimal risk of progression and may be managed accordingly.

The present article pertains to the assessment of thermoelastic damping (TED) in rectangular nanoplates by incorporation of size effect within the constitutive and heat conduction relations. With t...

Context.— Squamous lesions of the esophagus encompass a spectrum of disorders ranging from reactive changes and benign papilloma to squamous dysplasia and squamous cell carcinoma, which may pose diagnostic challenges especially in superficial biopsies. Objective.— To provide a review on the typical features of squamous neoplasia in the esophagus, with an emphasis on the key diagnostic features as well as differential diagnosis from mimicking lesions. Data Sources.— Data sources include published peer-reviewed literature and personal experiences of the authors. Conclusions.— Accurate diagnosis of squamous neoplasia requires adherence to established diagnostic criteria, attention to subtle histologic features, and correlation with clinical and imaging findings. In difficult cases, multiple biopsies may be necessary to reach a definitive diagnosis.

Myofibroblastoma is a rare benign mesenchymal tumor first described in the breast. It is also known as mammary-type myofibroblastoma outside of the breast, more frequently located along the embryonic milk line. Exceptionally, myofibroblastoma can occur at visceral locations. We present a case of myofibroblastoma detected incidentally in the liver. A well-circumscribed mass, grossly measuring 6.2 cm in the liver parenchyma, was found on imaging studies. Histologically, the lesion is characterized by benign spindle cells in a hyalinized collagenous stroma, with positive staining for SMA and ER, focal positivity for CD34, negative for desmin, and loss of RB1. This rare tumor at such an unusual location makes it diagnostically challenging, especially on core biopsy of the lesion. To our knowledge, this is the second case of myofibroblastoma in the liver reported in the English literature and the first such case with a detailed pathology description.

Challenges exist with standardized colorectal cancer reporting despite adoption of the American Joint Committee on Cancer-Staging Manual 8th edition. We performed this study to gauge current practice patterns among a diverse group of surgical pathologists. A web-based questionnaire depicting problematic issues and images related to colorectal carcinoma staging was circulated among 118 surgical pathologists and their responses were correlated with their geographic location (North America vs. Europe vs. others), nature of practice (academic vs. community), the sign-out model (gastrointestinal subspecialty vs. general surgical pathology), and years of professional experience. We found that a substantial number of practicing pathologists ignore recommended-staging criteria in specific settings, particularly with respect to assessment of advanced T stage. Tumors that communicated with the serosa through inflammatory foci were staged as pT3 (49%) or pT4a (51%) by nearly equal numbers of pathologists regardless of level of experience, the sign-out model, or geographic location. Only 65% assigned T stage and margin status based on extent of viable tumor in the neoadjuvant setting. One-third of pathologists, particularly those in Europe (p = 0.015), classified acellular mucin deposits as N1 disease when detected in treatment-naive cases. Nearly 50% of pathologists classified isolated tumor cells (i.e., deposits

Context Core biopsy (CB) is a main tool for diagnosis of liver mass lesions. When CB is performed with fine needle aspiration (FNA), the CB may be interpreted by a cytopathologist or gastrointestinal pathologist. Objective This study compares interpretation of liver mass biopsy between cytopathologist and gastrointestinal pathologist in the era of subspecialty practice. Design 349 liver mass lesions with FNA and CB performed during a 5-year period were retrieved. All cases were initially interpreted by a cytopathologist and retrospectively reviewed by a gastrointestinal pathologist. Results The overall agreement was 95.1% (332/349 cases). There was agreement on 57/65 non-neoplastic cases (87.7%) with 8 (12.3%) discordant cases including 4 steatosis (steatohepatitis missed in 3 cases, 1 re-interpreted as focal nodular hyperplasia [FNH]); 3 inflammation (1 necrotizing granulomatous inflammation, 1 massive necrosis instead of fibrosing cholestatic hepatitis, and 1 hepatocellular carcinoma [HCC] was missed); and 1 initially deemed normal re-interpreted as FNH. There was agreement on 275/284 neoplastic cases (96.8%), with 9 (3.2%) discordant cases including: 2 initially interpreted as HCC (1 metastatic adrenal cortical carcinoma, 1 cholangiocarcinoma); 3 adenocarcinomas (2 further defined as prostatic primary, 1 well-differentiated neuroendocrine tumor [WDNET]); 2 metastatic carcinomas (1 tumor-induced fibrosis instead of cirrhosis, 1 LCNEC re-interpreted as WDNET); 1 poorly differentiated carcinoma (re-interpreted as LCNEC); and 1 sarcomatoid carcinoma (re-interpreted as leiomyosarcoma). Conclusion Cytopathologist and gastrointestinal pathologist are highly concordant in the interpretation of neoplastic liver mass CB. Consultation may improve accuracy in certain non-neoplastic biopsies and neuroendocrine neoplasms.

Background Uterine artery embolization in the treatment of uterine leiomyoma has been rarely associated with dislodgement and expulsion of infarcted uterine fibroids through the vagina, peritoneum, or bowel wall, predominantly occurring within 6 months of uterine artery embolization. Case presentation We present the case of a 54-year-old African American woman who underwent uterine artery embolization 11 years prior and developed mechanical small bowel obstruction from the migration of fibroid through a uteroenteric fistula with ultimate impaction within the distal small bowel lumen. Small bowel resection and hysterectomy were curative. Conclusions Uteroenteric fistula with small bowel obstruction due to fibroid expulsion may present as a delayed finding after uterine artery embolization and requires heightened awareness.

Neuroendocrine neoplasms (NENs) can arise from various organs such as the esophagus, stomach, small intestine, colon, rectum, appendix, and pancreas. Some of them are functional as defined by associated clinically evident hormonal syndromes due to inappropriate secretion of excess hormonal peptides, while others are nonfunctional. NENs of the digestive system show common morphological features; however, the behavior of the tumors can be unpredictable. Now there is a uniform classification and grading scheme that separates NENs into two major types: well-differentiated neuroendocrine tumor and poorly differentiated neuroendocrine carcinoma. The former often grows slowly, and the patients can live for many years even after liver metastasis, while the latter has a much precipitous clinical course and worse outcome. NENs of certain organs also display unique clinico-pathological features, which will be covered in this chapter.

Although axillary lymphadenopathy is a common clinical encounter, systemic evaluation of non-sentinel lymph node biopsy is sparse. We reviewed our institution's 15-year experience to delineate the spectrum of diagnoses in non-sentinel axillary lymph nodes. 1165 non-sentinel axillary lymph node biopsies were retrieved and the diagnosis and relevant clinical information was reviewed. This spectrum of diagnoses was further stratified by gender, age, and oncologic history. The spectrum of diagnoses included: breast carcinoma (27.6%), lymphoma (29.2%), melanoma (3.5%), other carcinoma (2.9%), sarcoma (0.4%), and benign changes (36.3%). The most common diagnoses in men were lymphoma (61.8%) and benign changes (23.6%); while in women they were benign change (41.2%), breast carcinoma (37.8%) and lymphoma (16.7%). Besides benign changes, lymphoma and breast carcinoma were most common in women younger and older than 30 years, respectively. In patients with a history of malignancy, the most common diagnoses were metastasis from the known tumor and benign change; while in patients with a negative oncologic history and female patients without a history of breast cancer, the diagnosis was generally either lymphoma or benign change. Anaplastic large cell lymphoma was rare but may be mistaken as metastatic carcinoma thus a high index of suspicion is warranted. Thus through retrospective review of a large cohort of non-sentinel axillary lymph node biopsies, we described the spectrum of pathological entities based on the gender, age, and clinical history, which could provide valuable information for further work-up of axillary lymph node biopsy.

The expression profile of immunohistochemical markers of origin in poorly differentiated neuroendocrine carcinoma (PDNEC) is not well studied.Seventy-four PDNECs from gastroenteropancreatic (GEP) organs and the lung, including 48 large cell NEC (LCNEC) and 26 small cell carcinomas (SmCC), were subject to immunohistochemical staining for CDX2, TTF1 and ISL1. The staining intensity (1 to 3) and percentage of positive tumor cells [0 (negative), 1 (50%) and 2 (≥50%)] were assessed. The multiplicative index (maximum 6) was calculated and the average total score (aTS) was determined for each primary site and histologic subtype.In the 38 GEP and 36 lung PDNECs, CDX2, TTF1 and ISL1 staining was observed in 71% (aTS 2.8), 16% (aTS 0.4), 63% (aTS 1.9), and 22% (aTS 0.6), 72% (aTS 2.9) and 92% (aTS 3.8), respectively. GEP PDNECs showed a higher aTS for CDX2 and lower aTS for TTF1 and ISL1, compared to that of lung PDNECs (Student's t-test, p 0.001). SmCC had a higher aTS for TTF1 and ISL1 (p 0.001) and lower aTS for CDX2 (p 0.002) than that of LCNEC.CDX2 and TTF1 demonstrate potential utility in suggesting the primary site of PDNEC. In addition, CDX2 may be useful in supporting the diagnosis of LCNEC in cases with overlapping or borderline morphology. Utility of ISL1 as an adjunctive diagnostic marker of SmCC remains to be studied.

We aimed to report autopsy findings in patients with acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) in the modern era, and also to focus on lung pathology in the subgroup of patients with acute respiratory failure (ARF) of unknown etiology, which is associated with especially high mortality rates. Charts and autopsy reports of 107 patients (59 AML and 48 NHL) autopsied between 2003 and 2018 were reviewed. More than 50% of patients had missed major diagnoses found at autopsy with 95% of lungs displaying abnormal findings. Malignant infiltration in at least one organ was observed in about 70% of patients with either no complete remission or relapse at the time of death (n = 92) versus 20% in patients without signs of active malignancy (n = 15) (p = 0.001). In patients with ARF of unknown etiology (n = 59), the proportion of malignant lung infiltration was 27% and equilibrated with bacterial pneumonias (29%), fungal pneumonias represented 8%, and isolated alveolar damage or pulmonary edema were the only findings in 32% of patients. Overall, 85% of patients with ARF of unknown etiology had either relapsed or not achieved remission at time of death and 80% of patients with malignant lung infiltration had ARF of unknown etiology. Ninety percent of malignant infiltration and fungal infections were observed in patients with no complete remission or relapse. Autopsy remains valuable in AML and NHL patients; besides infections, malignant infiltration is a significant contributor to ARF of unknown etiology and is rarely diagnosed ante mortem.

This work discloses a novel and efficient protocol for the construction of functionalized chromeno[3,4-c]pyridine derivatives from the Blaise reaction intermediates and 3-cyanocoumarins through a CuCl2-catalyzed sequential Michael addition/intramolecular cyclization/oxidative aromatization reaction. This new method shows the advantages of mild reaction conditions, easy workup, nonchromatographic purification technique, good functional group tolerance, and moderate to good yields.

Metastatic neoplasms of unknown primary site pose a major challenge to patient management. As targeted therapies are now being tailored to neuroendocrine tumors (NETs) of different primary sites, identifying the origin of metastatic NETs has become increasingly important. Compared with more extensive efforts on metastatic adenocarcinomas of unknown primary, the literature on metastatic NETs (often to the liver) is relatively sparse and most studies are based on primary tumors. We sought to study metastatic well-differentiated NETs to the liver to identify markers that predict the site of origin. Eighty-five metastatic NETs to the liver were retrieved from the pathology archive. The primary sites were determined based on either pathologic review of the primary tumors (in most cases) or radiologic/clinical findings. Immunohistochemical labeling for TTF1, CDX2, ISL1, NKX2.2, and PDX1 was performed on either tissue microarrays or whole sections. The primary sites of the NETs in the study cohort included: pancreas (35%), small intestine (32%), rectum (8%), stomach (2%), bile duct (1%), lung (9%), and unknown primary (12%). We found predominant expression of TTF1 in lung carcinoid (63%), CDX2 in small intestinal (89%) and ISL1 in pancreatic NETs (77%), respectively. NKX2.2 was mainly expressed in NETs of the digestive organs. PDX1 was detected in a small percentage of pancreatic, small intestinal and the single bile duct NET. There was no statistically significant association between tumor grade (World Health Organization G1 vs. G2) and the expression of any of the above markers. The 3-marker panel (TTF1, CDX2, and ISL1) had sensitivities of 81%, 89%, and 63%, specificities of 100%, 94%, and 100%, positive predictive values of 100%, 89%, and 100%, and negative predictive values of 84%, 94%, and 96% in separating metastatic NETs into 3 major primary sites: pancreas/rectum, small intestine, and lung, respectively, with an overall accuracy of 82%. Furthermore, this panel predicted a primary site for 6 of the 10 NETs of unknown primary, which reduced the NETs of unknown primary from 12% to 5%. Thus, through immunohistochemical study of a large series of metastatic NETs to the liver, we have demonstrated the utility of a 3-marker panel for the identification of one or more potential primary sites of most metastatic NETs, which could provide practical guidance in patient management.

Background and aims Individuals with familial adenomatous polyposis (FAP) may undergo a total proctocolectomy with ileal pouch-anal anastomosis (IPAA) to surgically treat their disease. Inflammation of the ileal pouch, termed pouchitis, is uncommon in FAP patients but prevalent in patients who received IPAA for ulcerative colitis, a type of inflammatory bowel disease (IBD). Methods and results We report on two FAP siblings, living in the same household, who underwent IPAA surgery within one week of each other. Their mother also had an IPAA for FAP. One sibling developed pouchitis while his brother and mother have remained pouchitis-free. We investigated the genetic and microbial factors that might explain the development of pouchitis in the one sibling. We surveyed DNA isolated from the two brothers and their parents for NOD2 IBD risk variants by Sanger sequencing. The composition of mucosa-associated bacteria was analyzed by 16S rRNA gene sequencing on terminal ileum and rectal tissue collected at the time of surgical resection from the two brothers. The sibling with pouchitis inherited the IBD-associated risk alleles for NOD2 (rs17221417 and rs2076756) from his healthy father. Both the mother and unaffected brother lacked these variants. Microbiome sequencing of the terminal ileum and rectum found reduced levels of potentially 'beneficial' bacteria (Faecalibacterium prausnitzii, Bacteroides, and Ruminococcaceae) in the sibling with pouchitis relative to his brother. Conclusion These findings suggest that the NOD2 signaling pathway may contribute to intrinsic bacterial dysbiosis which is pre-existing and which may then predispose individuals to pouchitis after IPAA surgery.

Introduction/Objective Variable histologic findings that may be seen in porto-sinusoidal vascular disease (PSVD) liver biopsies are subject to high interobserver variability, requiring correlation with clinical history of portal hypertension (traditionally interpreted as non-cirrhotic portal hypertension NCPH). We investigated which histologic features are reproducible in PSVD biopsies. Methods Archived liver biopsies (n=38) from patients with NCPH (n=14) and without NCPH (n=21) were reviewed. Static H&E images of lobules (L, x100, NCPH=27, non-NCPH=23) and portal tracts (P, x200, NCPH=23, non- NCPH=27) were distributed among 9 gastrointestinal pathologists blinded to clinical history. Each pathologist answered multiple choice questions based on the presence (Q2) or absence (Q1) of portal hypertension clinically. The choice selected by 6 pathologists or more was considered consensus answer for the image. The interpretation of the image was considered reproducible when consensus was reached on both Q1 and Q2. Results The interpretations of 27 (54%; 17L, 10P) images from NCPH and 21 (42%; 10L, 11P) from non-NCPH were reproducible. In NCPH, the interpretations of normal (n=10, 4L, 6P), sinusoidal dilatation (n=7), and increased parenchymal draining vessels (n=3) were reproducible, while there was no consensus on the diagnoses of nodular regeneration and increased number of portal vessels. In non-NCPH, the interpretations of normal (n=8, 2L, 6P), sinusoidal dilatation (n=6), and paraportal shunting vessel(s) (n=4) were reproducible, whereas no consensus was reached on the diagnoses of nodular regeneration, incomplete fibrous septa, and increased number of portal vessels. Conclusion Histologic assessment of normal L and P as well as sinusoidal dilatation appears to be reproducible independent of clinical history. The findings of increased parenchymal draining vessels in NCPH group and paraportal shunting vessels in non-NCPH group may be consistently diagnosed to a certain extent. The assessment for nodular regeneration without reticulin stain, incomplete fibrous septa, or increased number of portal vessels appears to be unreliable.

Aims CDH1 germline mutation is associated with high penetrance of hereditary diffuse gastric cancer (HDGC). Due to the lack of endoscopically identifiable lesions, routine surveillance is ineffective in the early detection of gastric cancer, and risk-reduction gastrectomy is often recommended. Many academic pathology departments elect to submit the entire gastrectomy specimen for histological examination, which is associated with significantly increased cost, technical and professional time, and turnaround time. Methods We present our experience with 5 completely submitted and 2 representatively submitted prophylactic total gastrectomy cases in HDGC patients. Results Multifocal intramucosal signet ring cell carcinoma was identified in all cases except one, in which only in situ carcinoma was identified. The tumoral foci (2 to 35 per case; average 14.4) were concentrated in proximal stomach. No submucosal invasion or nodal metastases was seen in any case. The final stage was either stage 0 (pTisN0cM0) or stage 1a (pT1aN0cM0). Conclusions Our findings are in line with that reported in the literature. Considering that deeply invasive carcinoma is very rare in this situation, and no further treatment is indicated for the vast majority of those patients, complete submission and pathologic examination of the entire stomach provides little additional value for routine clinical management. We propose a two-step approach with targeted submission of the proximal stomach, and subsequent entire submission of the remaining stomach if no intramucosal carcinoma is identified during the initial targeted examination.

Specific histologic lesions of Porto-sinusoidal vascular disease (PSVD) in idiopathic noncirrhotic portal hypertension (INCPH) and non-INCPH. All INCPH patients had portal hypertension. OPV, obliterative portal venopathy; NRH, nodular regenerative hyperplasia; ISC, incomplete septal cirrhosis. (DOCX 14.3 kb)