Analysis of KRAS Mutations in Gastrointestinal Tract Adenocarcinomas Reveals Site-Specific Mutational Signatures.

Adenocarcinomas of the luminal gastrointestinal tract and pancreatobiliary system often show histologic and immunohistochemical overlap, making delineation of the primary site in a metastatic setting difficult. Previous studies have shown that site-specific missense mutations in the oncogene KRAS could be used in conjunction with immunohistochemistry to differentiate metastatic pancreatic adenocarcinoma from primary lung adenocarcinoma. In this study, we assessed the patterning of KRAS mutations across sites in the gastrointestinal and pancreatobiliary system. By integrating sequencing data from 44 separate studies, we assessed 2523 KRAS mutations in 7382 distinct cases of adenocarcinoma, including those from the esophagus, stomach, ampulla, biliary system, pancreas, and colon. We found that gastrointestinal adenocarcinomas demonstrate a marked regional variation in the frequency of KRAS mutations, with the most frequent KRAS mutation observed in pancreatic adenocarcinoma (up to 94.9%), whereas the frequency is much lower in adenocarcinomas from the esophagus and stomach (5.4% and 8.7%, respectively). Intriguingly, the pattern of missense mutations showed site specificity as well, with c.35G>T (p.G12V) and c.34G>C (p.G12R) mutations enriched in pancreatic primaries and codon 13 and non-codon 12/13 alterations enriched in gastric primaries (specificity of 98.9% and 93.2%, respectively, with a negative predictive value of 93.6% and 92.93% against pancreatic adenocarcinoma). Furthermore, we found that esophageal and gastric adenocarcinomas show an enrichment in transitional mutations, whereas other sites showed an equal distribution. Importantly, the examination of a validation cohort from our own institution revealed similar trends. These findings indicate that, in addition to providing therapeutic and diagnostic information, KRAS mutational analysis may also prove useful in delineating the site of origin in gastrointestinal adenocarcinomas that share morphologic and immunohistochemical overlap. Moreover, transitional mutations are more frequent in esophageal and gastric adenocarcinomas, reiterating the role of chronic inflammation in the pathogenesis of foregut adenocarcinomas.

Histologic Variants of Kaposi Sarcoma in the Gastrointestinal Tract: A Contemporary Multi-institutional Clinicopathologic Analysis of 46 Cases.

Kaposi sarcoma (KS) can pose diagnostic challenges in biopsy specimens. Multiple histologic variants of cutaneous KS have been described; however, the histomorphologic spectrum of gastrointestinal (GI) KS has not been systematically studied. This large series comprehensively evaluated 46 cases of KS involving the GI tract and identified 7 histomorphologic variants, some that have not been previously described. Five of them are inconspicuous but have unique morphologic patterns, including lymphangioma/lymphangiectatic-like (n=17), mucosal hemorrhage/telangiectatic-like (n=17), mucosal inflammation-like (n=15), granulation tissue-like (n=13), and mucosal prolapse-like (n=4) variants. These variants can be easily misdiagnosed or misinterpreted on routine examination if KS is not considered, and if the immunohistochemical stain for human herpesvirus-8 is not performed. The other 2 morphologic variants present as spindle cell proliferations and are the GI stromal tumor-like (n=8) and inflammatory myofibroblastic tumor-like (n=2). These variants raise a broad differential diagnosis of spindle cell tumors of the GI tract and could pose diagnostic challenges. In summary, GI KS lesions exhibit variable, often unconventional histomorphologic patterns. KS should be included in the differential diagnosis even if features of conventional KS are not seen, particularly in limited biopsies in immunocompromised patients, such as those with human immunodeficiency virus infection. Although the clinical significance of these morphologic variants is yet to be determined, they are nonetheless important from a diagnostic standpoint. Misdiagnosis and delay in appropriate management can be avoided by recognizing the morphologic diversity of GI KS and appropriately utilizing the human herpesvirus-8 immunohistochemical stain.

Pathologic Examination of Pancreatic Specimens Resected for Treated Pancreatic Ductal Adenocarcinoma: Recommendations From the Pancreatobiliary Pathology Society.

Currently, there are no internationally accepted consensus guidelines for pathologic evaluation of posttherapy pancreatectomy specimens. The Neoadjuvant Therapy Working Group of Pancreatobiliary Pathology Society was formed in 2018 to review grossing protocols, literature, and major issues and to develop recommendations for pathologic evaluation of posttherapy pancreatectomy specimens. The working group generated the following recommendations: (1) Systematic and standardized grossing and sampling protocols should be adopted for pancreatectomy specimens for treated pancreatic ductal adenocarcinoma (PDAC). (2) Consecutive mapping sections along the largest gross tumor dimension are recommended to validate tumor size by histology as required by the College of American Pathologists (CAP) cancer protocol. (3) Tumor size of treated PDACs should be measured microscopically as the largest dimension of tumor outer limits that is bound by viable tumor cells, including intervening stroma. (4) The MD Anderson grading system for tumor response has a better correlation with prognosis and better interobserver concordance among pathologists than does the CAP system. (5) A case should not be classified as a complete response unless the entire pancreas, peripancreatic tissues, ampulla of Vater, common bile duct, and duodenum adjacent to the pancreas are submitted for microscopic examination. (6) Future studies on tumor response of lymph node metastases, molecular and/or immunohistochemical markers, as well as application of artificial intelligence in grading tumor response of treated PDAC are needed. In summary, systematic, standardized pathologic evaluation, accurate tumor size measurement, and reproducible tumor response grading to neoadjuvant therapy are needed for optimal patient care. The criteria and discussions provided here may provide guidance towards these goals.

Dataset for the reporting of carcinoma of the exocrine pancreas: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: Current guidelines for pathology reporting on pancreatic cancer differ in certain aspects, resulting in divergent reporting practices and a lack of comparability of data. Here, we report on a new international dataset for pathology reporting on resection specimens with cancer of the exocrine pancreas (ductal adenocarcinoma and acinar cell carcinoma). The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), which is a global alliance of major (inter)national pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's rigorous process for dataset development, an international expert panel consisting of pancreatic pathologists, a pancreatic surgeon and an oncologist produced a set of core and non-core data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or non-core element and its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalised and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for cancer of the exocrine pancreas is intended to promote high-quality, standardised pathology reporting. Its widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance the comparability of data, all of which will help to improve the management of pancreatic cancer patients.

Amsterdam International Consensus Meeting: tumor response scoring in the pathology assessment of resected pancreatic cancer after neoadjuvant therapy.

Histopathologically scoring the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant treatment can guide the selection of adjuvant therapy and improve prognostic stratification. However, several tumor response scoring (TRS) systems exist, and consensus is lacking as to which system represents best practice. An international consensus meeting on TRS took place in November 2019 in Amsterdam, The Netherlands. Here, we provide an overview of the outcomes and consensus statements that originated from this meeting. Consensus (≥80% agreement) was reached on a total of seven statements: (1) TRS is important because it provides information about the effect of neoadjuvant treatment that is not provided by other histopathology-based descriptors. (2) TRS for resected PDAC following neoadjuvant therapy should assess residual (viable) tumor burden instead of tumor regression. (3) The CAP scoring system is considered the most adequate scoring system to date because it is based on the presence and amount of residual cancer cells instead of tumor regression. (4) The defining criteria of the categories in the CAP scoring system should be improved by replacing subjective terms including "minimal" or "extensive" with objective criteria to evaluate the extent of viable tumor. (5) The improved, consensus-based system should be validated retrospectively and prospectively. (6) Prospective studies should determine the extent of tissue sampling that is required to ensure adequate assessment of the residual cancer burden, taking into account the heterogeneity of tumor response. (7) In future scientific publications, the extent of tissue sampling should be described in detail in the "Materials and methods" section.

Rosai-Dorfman disease of the pancreas: Cytologic analysis of three cases presenting as pancreatic masses.

Rosai-Dorfman Disease (RDD), or sinus histiocytosis with massive lymphadenopathy, is a rare entity characterized by proliferating S100-positive histiocytes. It is most commonly found in lymph nodes with extranodal involvement usually occurring in the head and neck. Pancreatic involvement is extremely rare. The pathology department archives were searched for fine needle aspirations and pancreatic resections showing evidence of RDD. Clinicopathologic features, cytologic smears, cell blocks, immunocytochemical stains and surgical resections were reviewed. Three cases were identified. They were all females, aged 65, 69 and 75, with involvement of the pancreatic tail or head by solid masses of median size 2.3 cm (range 2.1-4.5 cm). Cytologic findings on smears included multiple histiocyte clusters resembling loosely cohesive epithelioid granulomas, singly dispersed histiocytes with moderate to marked nuclear atypia and characteristic emperipolesis. These atypical histiocytes stained positively for CD68, CD163 and S100. Smear background contained variable mixed inflammatory cells, necrotic debris and stromal fragments. The RDD diagnosis was further confirmed on pancreatic resection in two patients and core biopsy in one. The latter patient required three separate procedures before a definitive diagnosis was made. RDD of pancreas is a rare benign inflammatory condition that is diagnostically challenging on cytology. This can cause delays in cytologic diagnosis and/or misdiagnosis. Identification of characteristic cytologic features, primarily histiocytes with emperipolesis, and matching immunocytochemical profile can ensure accurate diagnosis and distinction from mimics.

Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvß3 Targeting Protein for Pancreatic Cancer Treatment.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapeutics owing to dense fibrotic stroma orchestrated by cancer-associated pancreatic stellate cells (CAPaSC). CAPaSC also support cancer cell growth, metastasis, and resistance to apoptosis. Currently, there is no effective therapy for PDAC that specifically targets CAPaSC. We previously reported a rationally designed protein, ProAgio, that targets integrin αvß3 at a novel site and induces apoptosis in integrin αvß3-expressing cells. Because both CAPaSC and angiogenic endothelial cells express high levels of integrin αvß3, we aimed to analyze the effects of ProAgio in PDAC tumor. METHODS: Expression of integrin αvß3 was examined in both patient tissue and cultured cells. The effects of ProAgio on CAPaSC were analyzed using an apoptosis assay kit. The effects of ProAgio in PDAC tumor were studied in 3 murine tumor models: subcutaneous xenograft, genetic engineered (KrasG12D; p53R172H; Pdx1-Cre, GEM-KPC) mice, and an orthotopic KrasG12D; p53R172H; Pdx1-Cre (KPC) model. RESULTS: ProAgio induces apoptosis in CAPaSC. ProAgio treatment significantly prolonged survival of a genetically engineered mouse-KPC and orthotopic KPC mice alone or in combination with gemcitabine (Gem). ProAgio specifically induced apoptosis in CAPaSC, resorbed collagen, and opened collapsed tumor vessels without an increase in angiogenesis in PDAC tumor, enabling drug delivery into the tumor. ProAgio decreased intratumoral insulin-like growth factor 1 levels as a result of depletion of CAPaSC and consequently decreased cytidine deaminase, a Gem metabolism enzyme in cancer cells, and thereby reduced resistance to Gem-induced apoptosis. CONCLUSIONS: Our study suggests that ProAgio is an effective PDAC treatment agent because it specifically depletes CAPaSC and eliminates tumor angiogenesis, thereby enhancing drug delivery and Gem efficacy in PDAC tumors.

A Subset of Intrahepatic Cholangiocarcinomas Express Albumin RNA as Detected by In Situ Hybridization.

Intrahepatic cholangiocarcinomas (ICCs) show morphologic diversity, ranging from tumors composed of nonmucinous small ducts to mucin-producing large duct tumors to tumors with mixed hepatocellular carcinoma features. Diagnosing ICCs can be difficult, especially on biopsy, not only because of the morphologic diversity, but also because metastatic tumors are often in the differential diagnosis. Recently, branched DNA-based albumin RNA in situ hybridization (ISH) has been shown to be a potential sensitive and specific marker for ICC with 99% sensitivity. Using a different RNA ISH technology, we evaluated the expression of albumin RNA ISH in ICC. We performed RNA ISH for albumin using RNAscope on 43 ICCs in a triplicate tissue microarray. Albumin RNA ISH was positive in 18 of 43 (42%) ICCs. Five of the 6 (83%) combined hepatocellular carcinoma-CC were positive in the CC component. None of the tumors with mucin production were positive (0/9). In our cohort, albumin RNA ISH showed a sensitivity of 42% in ICCs, supporting the morphologic diversity of ICCs. Albumin RNA ISH does not appear to be a highly sensitive marker for ICC and hence cannot be used as a stand-alone marker for ICC.

HSP90 expression and early recurrence in gastroenteropancreatic neuroendocrine tumors: Potential for a novel therapeutic target.

BACKGROUND: Heat shock protein (HSP)-90 promotes tumor growth and is overexpressed in many malignancies. HSP90 expression profile and its potential as a therapeutic target in primary and metastatic neuroendocrine tumors (NETs) are not known. METHODS: HSP90 cytoplasmic expression and Ki-67 index were re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables for patients who underwent resection of primary and metastatic gastroenteropancreatic (GEP) neuroendocrine tumors at a single institution (2000-2013). Primary outcome was recurrence-free survival (RFS). RESULTS: Of 263 tumors reviewed, 73% (n = 191) were primary GEP NETs, and 12% (n = 31) were NET liver metastases. Of the primary GEP-NETs, mean age was 56 years, 42% were male; 53% (n = 103) were pancreatic and 23% (n = 44) were small bowel. HSP90 expression was high in 34% (n = 64) and low in 66% (n = 127). Compared to low expression, high HSP90 was associated with advanced T-stage (T3/T4) (47 vs 27%; p = 0.02). Among patients who underwent curative-intent resections for primary, non-metastatic NETs (n = 145), high HSP90 was independently associated with worse RFS (HR 5.09, 95% CI 1.65-15.74; p = 0.005), after accounting for positive margin, LN involvement, increased tumor size, site of primary tumor, and Ki-67. When assessing NET liver metastases, 13% (n = 4) had high HSP90 expression and 87% (n = 26) had low expression. Patients with liver metastases with high HSP90 tended to have worse 1- and 3-year progression-free survival (25%, 25%) compared to those with low HSP90 (69%, 49%; p = 0.059). CONCLUSION: HSP90 exhibits differential expression in resected GEP-NETs and liver metastases. High cytoplasmic expression is associated with early disease recurrence, even after accounting for other adverse pathologic factors. HSP90 inhibition may be a potential therapeutic target for neuroendocrine tumors.

Suppressive myeloid cells are expanded by biliary tract cancer-derived cytokines in vitro and associate with aggressive disease.

BACKGROUND: BTC is an aggressive disease exacerbated by inflammation and immune suppression. Expansion of immunosuppressive cells occurs in biliary tract cancer (BTC), yet the role of BTC-derived cytokines in this process is unclear. METHODS: Activated signalling pathways and cytokine production were evaluated in a panel of human BTC cell lines. Human peripheral blood mononuclear cells (PBMCs) were cultured with BTC supernatants, with and without cytokine neutralising antibodies, and analysed by flow cytometry or immunoblot. A human BTC tissue microarray (TMA, n = 69) was stained for IL-6, GM-CSF, and CD33+S100a9+ cells and correlated with clinical outcomes. RESULTS: Immunomodulatory factors (IL-6, GM-CSF, MCP-1) were present in BTC supernatants. BTC supernatants expanded CD33dimCD11b+HLA-DRlow/- myeloid-derived suppressor cells (MDSCs) from human PBMCs. Neutralisation of IL-6 and GM-CSF in BTC supernatants inhibited activation of STAT3/5, respectively, in PBMCs, with heterogeneous effects on MDSC expansion in vitro. Staining of a BTC TMA revealed a positive correlation between IL-6 and GM-CSF, with each cytokine and more CD33+S100a9+ cells. Increased CD33+S100a9+ staining positively correlated with higher tumour grade, differentiation and the presence of satellite lesions. CONCLUSION: BTC-derived factors promote suppressive myeloid cell expansion, and higher numbers of CD33+S100a9+ cells in resectable BTC tumours correlates with more aggressive disease.

STAT3 Inhibition for Gastroenteropancreatic Neuroendocrine Tumors: Potential for a New Therapeutic Target?

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascular neoplasms treated similarly, irrespective of tumor location. The expression of pro-angiogenic factors (STAT3, VEGF, and HIF-1α) and their association with adverse pathologic factors and disease recurrence following resection remains unclear. METHODS: All patients with non-metastatic GEP-NETs who underwent curative-intent resection from 2000 to 2013 were included. Immunohistochemistry was performed for pro-angiogenic factors, Ki-67 index, and CD31 using tissue microarrays made in triplicate by a pathologist blinded to other clinicopathologic variables. Primary outcome was a 3-year recurrence-free survival (3-yrRFS); secondary outcomes were correlation of pro-angiogenic factors with Ki-67 index, adverse pathologic factors, and CD31 expression, a marker of microvascular density. RESULTS: Of 144 GEP-NETs resected, STAT3 expression was high in 12 (8%) and low in 132 (92%) pts. High STAT3 expression was associated with worse 3-yrRFS compared to low expression (55% vs 84%; p = 0.003). High VEGF expression had a 3-yrRFS of 76% vs 82% for low expression (p = 0.09). HIF-1α expression was not associated with RFS. Ki-67 ≥ 3% was associated with worse 3-yrRFS (≥ 3%: 51% vs < 3%: 84%; p < 0.001), as was the presence of increased microvascular density (CD31 > median: 75% vs CD31 < median: 86%; p = 0.04). High STAT3 expressing tumors were more likely to have a Ki-67 ≥ 3% (42% vs 7%; p < 0.001). LVI was present in 82% of high STAT3 tumors compared to only 50% with low STAT3 (p = 0.058). CD31 expression was similar between groups (58% vs 49%; p = 0.5). CONCLUSIONS: In resected GEP-NETs, high STAT3 expression is associated with an increased Ki-67 index, presence of lymphovascular invasion and worse 3-yr RFS. STAT3 may be a novel therapeutic target for patients undergoing resection of high-risk tumors.

Immunologic alterations in the pancreatic cancer microenvironment of patients treated with neoadjuvant chemotherapy and radiotherapy.

Pancreatic ductal adenocarcinoma (PDAC) has dismal 5-year survival (<9%). We hypothesize that exposure of tumors to conventional therapies may preferentially modulate immune biomarkers in the tumor microenvironment in PDAC. PDAC patients who underwent upfront surgical resection or who received neoadjuvant FOLFIRINOX with or without neoadjuvant radiotherapy followed by surgical resection were selected for study. Total expression of immunologically relevant transcripts and spatially resolved expression of immunologically relevant proteins was quantitated using multiplexed methods (NanoString nCounter and GeoMX platforms). This analysis identified numerous differentially expressed transcripts associated with the type of neoadjuvant therapy received. Moreover, we identified significant alterations in the expression and/or spatial distribution of immunologically relevant proteins in different regions (tumor cell rich, immune cell rich, stromal cell rich) of the tumor microenvironment. These data provide insight into the immunological effects of clinically relevant neoadjuvant therapy for resectable/borderline-resectable PDAC by describing significant differences in the expression of key immunologic biomarkers within the PDAC microenvironment that were associated with the type of treatment patients received prior to surgical resection. This represents a comprehensive analysis of numerous biomarkers conducted on the PDAC microenvironment. This work may guide strategic new combination therapies for pancreatic cancer.

Development of a Plasma Screening Panel for Pediatric Nonalcoholic Fatty Liver Disease Using Metabolomics.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children, but diagnosis is challenging due to limited availability of noninvasive biomarkers. Machine learning applied to high-resolution metabolomics and clinical phenotype data offers a novel framework for developing a NAFLD screening panel in youth. Here, untargeted metabolomics by liquid chromatography-mass spectrometry was performed on plasma samples from a combined cross-sectional sample of children and adolescents ages 2-25 years old with NAFLD (n = 222) and without NAFLD (n = 337), confirmed by liver biopsy or magnetic resonance imaging. Anthropometrics, blood lipids, liver enzymes, and glucose and insulin metabolism were also assessed. A machine learning approach was applied to the metabolomics and clinical phenotype data sets, which were split into training and test sets, and included dimension reduction, feature selection, and classification model development. The selected metabolite features were the amino acids serine, leucine/isoleucine, and tryptophan; three putatively annotated compounds (dihydrothymine and two phospholipids); and two unknowns. The selected clinical phenotype variables were waist circumference, whole-body insulin sensitivity index (WBISI) based on the oral glucose tolerance test, and blood triglycerides. The highest performing classification model was random forest, which had an area under the receiver operating characteristic curve (AUROC) of 0.94, sensitivity of 73%, and specificity of 97% for detecting NAFLD cases. A second classification model was developed using the homeostasis model assessment of insulin resistance substituted for the WBISI. Similarly, the highest performing classification model was random forest, which had an AUROC of 0.92, sensitivity of 73%, and specificity of 94%. Conclusion: The identified screening panel consisting of both metabolomics and clinical features has promising potential for screening for NAFLD in youth. Further development of this panel and independent validation testing in other cohorts are warranted.

Bile duct involvement by hepatocellular carcinoma: A rare occurrence and poor prognostic indicator in bile duct brushing samples.

BACKGROUND: Hepatocellular carcinoma (HCC) rarely involves the biliary tree and may be inadvertently sampled on bile duct brushings (BDBs). METHODS: The pathology archives of 5 institutions were searched for BDBs with HCC involvement. RESULTS: A total of 17 BDBs from 14 patients were obtained. There was a male:female ratio of 6:1; the median age of the patients was 59.5 years (range, 22-80 years). The median hepatic tumor size was 6.2 cm (range, 2.2-13.0 cm). HCC risk factors included viral hepatitis (5 patients), cirrhosis (5 patients), hemochromatosis (1 patient), and alcoholic steatohepatitis (1 patient). Jaundice with elevated bilirubin, liver enzymes, and α-fetoprotein was common. Endoscopic retrograde cholangiopancreatography demonstrated bile duct dilatation, polypoid intraductal masses (5 samples), clots/debris (2 samples), or strictures (4 samples). All BDBs had single and clustered large cells with naked atypical nuclei, granular cytoplasm, high nuclear/cytoplasmic ratios, and nuclei with prominent macronucleoli. Less common findings included clear/microvesicular cytoplasm (35%), papillae (29%), and anisonucleosis (35%). Classic HCC features (widened trabeculae [35%], endothelial wrapping [24%], multinucleation [24%], and cytoplasmic bile pigment [35%]) were uncommon. A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two-thirds were found to have polysomy on fluorescence in situ hybridization. Approximately 71% of patients died of disease at a median of 3.5 months. CONCLUSIONS: HCC may extend into the intrahepatic and/or extrahepatic biliary tree, causing masses and/or strictures that may be sampled on BDB. Although cytologically malignant, the classic features of HCC are uncommon, which can cause misdiagnosis. Cytopathologists should be mindful of this differential when evaluating BDBs, particularly when concomitant liver masses and/or HCC risk factors are present. Because of the associated high mortality and rapid rate of death, its presence should be conveyed clearly in pathology reports.

Rosai-Dorfman Disease of the Pancreas Shows Significant Histologic Overlap With IgG4-related Disease.

Rosai-Dorfman disease (RDD) is a rare entity characterized by proliferating S100-positive histiocytes. Originally described in lymph nodes, it can involve extranodal sites. Pancreatic involvement is rare, with <10 cases previously reported. Recent studies demonstrate a possible overlap between RDD and the more common IgG4-related disease (IRD), which could further complicate pathologic diagnosis. We describe distinct morphologic characteristics as well as overlapping histologic features of IRD in 5 cases of pancreatic RDD at our institution and compare these to a cohort of nonpancreatic extranodal RDD cases. All pancreatic cases were mass forming and had spindled patterns of elongated histiocytes with smaller areas of more classical appearing RDD; all cases had areas of storiform fibrosis and dense lymphoplasmacytic infiltrates with no increase in IgG4-positive plasma cells, and all cases had some degree of vasculitis (4 cases had obliterative vasculitis). Thirteen nonpancreatic extranodal RDD cases had dense lymphoplasmacytic infiltrates; most (85%) had some fibrosis with 46% showing storiform fibrosis, 85% had vasculitis with 31% demonstrating obliterative vasculitis and 2 cases had increased IgG4 staining. Extranodal (pancreatic and nonpancreatic) RDD often shows overlapping morphologic features with IRD, including lymphoplasmacytic inflammation, storiform fibrosis with elongated histiocytes and vasculitis. This can create a diagnostic challenge in the pancreas where IRD is more commonly encountered. Pathologists need to be aware that RDD can occur in the pancreas and should include RDD in the differential of any mass forming pancreatic lesion in which morphologic features of IRD are present.

Serous Cystadenoma of the Pancreas With Complex Florid Papillary Architecture: A Case Report and Review of the Literature.

Serous cystadenoma (SCA) is a relatively rare benign pancreatic neoplasm. It has a very distinctive gross and microscopic appearance including pure and mixed microcystic and macrocystic patterns as well as rare solid architectural pattern. In this article, we present a rare case of SCA with a complex florid papillary architecture. A 40-year-old man was diagnosed with a 3.5 cm SCA of the uncinate process of the pancreas based on abdominal computed tomography scan. The tumor was monitored radiographically until recent magnetic resonance imaging showed a new 1.0-cm eccentric mural nodule within the tumor with multiple arterial enhancing septations and features suspicious for a neuroendocrine tumor. A pylorus-preserving Whipple procedure was subsequently performed and the mass was resected. Gross examination confirmed the radiological findings of a well-demarcated, 3.5 cm multicystic pancreatic lesion with a 1.0 cm circumscribed, tan solid nodule at its periphery. Microscopic evaluation revealed a predominantly microcystic pattern classical of SCA with occasional macrocysts. The 1.0 cm discrete nodule was also a SCA, but showed unusually exuberant complex papillary growth. To our knowledge, this is the first reported case describing this morphologic variant. Recognition of this rare and unusual pattern is important to avoid misdiagnosis, especially on small biopsy specimens.

Phase IB Study of Induction Chemotherapy With XELOX, Followed by Radiation Therapy, Carboplatin, and Everolimus in Patients With Locally Advanced Esophageal Cancer.

PURPOSE: Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation. MATERIALS AND METHODS: Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used. RESULTS: Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively. CONCLUSIONS: The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.

Intrasinusoidal Spread of Hepatic Epithelioid Hemangioendothelioma: Implications for the Diagnosis in Minimal Samples.

Epithelioid hemangioendothelioma (EHE) is an angiocentric tumor that, when arising in liver, is centered around hepatic/portal veins. However, EHE cells can also track along sinusoids, which is not well recognized or studied. We identified 18 cases of hepatic EHE and 6 nonhepatic EHEs. For all cases, we recorded EHE multifocality and maximum size. When tumor cells were identified apart from the main mass, we recorded their location, maximum distance from the main tumor, density per high-power field, and cytomorphology. Immunohistochemical staining for CAMTA1, ERG, and CAM5.2 was performed on all cases. Lesional cells were present apart from the main mass in 17 of 18 (94%) liver cases, always within sinusoids and occasionally (4/17, 24%) in central veins. They appeared intensely hyperchromatic with vaguely cerebriform nuclei and multinucleation in 6 (35%) of cases. CAMTA1 and ERG positivity was seen in all 17 cases. Two cases (12%) demonstrated focal CAM5.2 positivity. Sinusoidal EHE cells ranged from 0.1 to 0.8 cm away from the main tumor. There were no statistically significant associations between histologic findings and patient outcome. In the 6 nonhepatic cases, tumor cells did not extend beyond the main EHE. Lesional cells in hepatic EHE often extend beyond the main lesion into sinusoids, where they demonstrate an unusual, somewhat distinctive morphology. Care should be taken to identify such cells in limited biopsies; immunohistochemistry for CAMTA1, a specific and sensitive marker for EHE, can be confirmatory.

Orthotropic Liver Transplantation for Acute Intrahepatic Cholestasis in Sickle Cell Disease: Clinical and Histopathologic Features of a Rare Case.

Sickle cell disease has a wide range of hepatic manifestations, with acute intrahepatic cholestasis being one of the rarest and most fatal, often resulting in acute fulminant hepatic failure. Liver transplantation is an emerging but rarely utilized treatment for hepatic failure in the setting of sickle cell disease. Few such cases have been reported in the literature, with little emphasis on histopathologic correlation. We report a case of acute intrahepatic cholestasis in a patient with sickle cell disease who underwent orthotropic liver transplantation and describe novel correlating histopathologic features. The patient is a 29-year-old man who presented with hyperbilirubinemia, acute kidney injury, and coagulopathy. He was diagnosed clinically with acute intrahepatic cholestasis and received an orthotropic liver transplant. The explanted liver demonstrated marked sinusoidal expansion by sickled erythrocytes, hyperplastic Kupffer cells, and extramedullary hematopoiesis. There was extensive sinusoidal and centrizonal fibrosis with occlusion of central veins reminiscent of chronic sinusoidal obstructive syndrome, a previously undescribed pattern of injury. This case represents one of the few reported cases of sickle cell intrahepatic cholestasis treated by transplantation and demonstrates the rarely reported histopathologic features and gives insight to a potentially new mechanism of injury in these patients. Familiarity with the morphologic features of sickle cell hepatopathy and its clinical manifestations is important as transplantation in sickle cell-related liver injury increases in frequency.