Jin-Ping Lai

Primary Angiosarcoma of the Pancreas

The pancreas is a glandular organ located in the retroperitoneum composed of an exocrine component, which includes acini and ducts and an endocrine component, the islets of Langerhans. Stroma is scant in a normal pancreas [1]. Pancreatic cancer continues to be one of the deadliest cancers, with only a 6 % 5-year survival rate [2]. The most common primary neoplasms of the pancreas are ductal adenocarcinomas, which comprise 85 % of all pancreatic tumors [1]. Mesenchymal tumors are neoplasms of mesoderm-derived connective tissue (stroma) and can be benign or malignant. Primary mesenchymal tumors of the pancreas are rare with only 221 cases reported in the English literature to date [3]. Of these, only 76 are primary malignant mesenchymal tumors (sarcomas) [3–5]. The most frequently reported sarcomas of the pancreas are leiomyosarcomas and Ewing sarcoma/ primitive neuroectodermal tumor (PNET) [6]. Angiosarcomas (AS) are highly malignant neoplasms with endothelial cell differentiation that arise from blood or lymphatic vessels. AS represent 1% of all soft tissue sarcomas [7], which in turn represent 1 % of all adult solid malignancies [8]. AS can arise from any site on the body, most commonly from the cutaneous tissue of the breast and scalp [9]. So far, only three cases of primary angiosarcoma of the pancreas have been reported in the literature [4, 10, 11]. Herein, we report the fourth case of primary angiosarcoma of the pancreas.

Metastatic signet ring cell carcinoma of unknown primary origin: a case report and review of the literature

In spite of the increasingly sophisticated diagnostic workup, detailed investigations fail to reveal a primary site of origin for about 3-5% of metastatic tumors. The most commonly reported subtype in cancer of unknown primary origin is adenocarcinoma. Signet ring cell carcinoma (SRCC) is a rare poorly differentiated aggressive subtype of adenocarcinoma that most commonly arise from the gastrointestinal tract. It usually presents late and is associated with poor prognosis. Treatment options remain limited to anecdotal reports. However, immunohistochemical studies can be useful in suggesting an origin and therefore may help guide investigations and treatment options. Here we present an unusual case of metastatic SRCC of unknown primary origin presenting as peritoneal carcinomatosis in a 73-year-old man. We also review the literature on metastatic SRCC of unknown primary origin and discuss the relevant findings. This work highlights the importance of collaboration between clinicians and pathologists as well as detailed histopathological, immunohistochemical, and molecular analyses which can help guide investigations and management options.

Gastrointestinal: Pyogenic granuloma of the duodenum

A 59-year-old African American man presented to the emergency declinical entity that is characterized by the same histopathological features partment with episodic melena, generalized fatigue, and dyspnea on exertion of 4-month duration. Medical history was significant for chronic hepatitis C, coronary artery disease, and atrial fibrillation treated with rivaroxaban. He denied weight loss or anorexia. Clinical examination revealed marked conjunctival pallor. Laboratory studies showed a normal platelet count and were consistent with iron deficiency anemia, including a hemoglobin of 9.1 g/dL and mean corpuscular volume of 82.7 fL. A colonoscopy did not reveal any bleeding lesions. An esophagogastroduodenoscopy revealed an actively oozing duodenal polypoid lesion that was resected and then clipped (Fig. 1). Histological examination of the duodenal lesion showed a benignappearing vascular proliferation of multiple capillaries with nonspecific granulation tissue (Fig. 2a–d). Based on the endoscopic and histological findings of this lesion, a differential diagnosis of pyogenic granuloma (PG), bacillary angiomatosis, Kaposi sarcoma, and inflammatory polyp was formed. These four lesions are characterized by a histological pattern of endothelial cells and granulation tissue. However, Kaposi sarcoma and bacillary angiomatosis can be distinguished from PG by immunohistochemistry of human herpesvirus-8 and Warthin–Starry stain, respectively. PG can be distinguished from inflammatory polyps by the presence of a characteristic capillary lobular arrangement (Fig. 2d). Pyogenic granuloma is a benign lesion that usually occurs on the skin and oral mucosa. PG of the gastrointestinal tract is a rarely reported

Oncocytoma of the Submandibular Gland: Diagnosis and Treatment Based on Clinicopathology.

Background. Submandibular oncocytomas are rare benign salivary gland neoplasms. They are typically found in Caucasian patients aged 50–70 years with no gender preference. Due to the overlapping histological and clinical features of head and neck tumors, they are often misdiagnosed. Methods. We report a case of unilateral submandibular gland oncocytoma in a 63-year-old Caucasian man. Results. The patient underwent unilateral submandibular gland resection and histopathologic analysis of the tumor specimen. On follow-up at 2 weeks and 1 year, no recurrence was identified. Conclusion. Submandibular oncocytomas are best diagnosed with preoperative FNA and CT imaging and have distinctive findings on cytology and histology. CT followed by fine-needle aspiration cytology would be the preferred diagnostic modalities. Due to its low rate of malignant transformation and recurrence, the best treatment is local resection with follow-up as necessary.

Gastrointestinal Pyogenic Granuloma (Lobular Capillary Hemangioma): An Underrecognized Entity Causing Iron Deficiency Anemia

Pyogenic granuloma (PG), more accurately known as lobular capillary hemangioma, is a benign vascular tumor that usually occurs in the skin or oral mucosa. This lesion is rarely reported in the gastrointestinal tract but is known to bleed if not resected. We herein describe a case series with the clinical, endoscopic, and histologic findings of four cases of gastrointestinal PG at our institution. In addition, we provide a review of the literature and summation of all reported cases of PG specific to the gastrointestinal tract. Based on our experience, we suggest that the actual incidence of gastrointestinal PG may in fact be higher than reported because PG can be unrecognized or improperly diagnosed. It is important for the clinician to properly recognize this lesion as a source of anemia and its propensity to bleed during biopsy or resection.

Vasodilator-stimulated phosphoprotein promotes liver metastasis of gastrointestinal cancer by activating a β1-integrin-FAK-YAP1/TAZ signaling pathway

Extracellular matrix (ECM)-induced β1-integrin-FAK signaling promotes cell attachment, survival, and migration of cancer cells in a distant organ so as to enable cancer metastasis. However, mechanisms governing activation of the β1-integrin-FAK signaling remain incompletely understood. Here, we report that vasodilator-stimulated phosphoprotein (VASP), an actin binding protein, is required for ECM–mediated β1-integrin-FAK-YAP1/TAZ signaling in gastrointestinal (GI) cancer cells and their liver metastasis. In patient-derived samples, VASP is upregulated in 53 of 63 colorectal cancers and 43 of 53 pancreatic ductal adenocarcinomas and high VASP levels correlate with liver metastasis and reduced patient survival. In a Matrigel-based 3-dimensional (3D) culture model, short hairpin RNA (shRNA)–mediated VASP knockdown in colorectal cancer cells (KM12L4, HCT116, and HT29) and pancreatic cancer cells (L3.6 and MIA PaCa-1) suppresses the growth of 3D cancer spheroids. Mechanistic studies reveal that VASP knockdown suppresses FAK phosphorylation and YAP1/TAZ protein levels, but not Akt or Erk-related pathways and that YAP1/TAZ proteins are enhanced by the β1-integrin-FAK signaling. Additionally, VASP regulates the β1-integrin-FAK-YAP1/TAZ signaling by at least two mechanisms: (1) promoting ECM-mediated β1-integrin activation and (2) regulating YAP1/TAZ dephosphorylation at downstream of RhoA to enhance the stability of YAP1/TAZ proteins. In agreement with these, preclinical studies with two experimental liver metastasis mouse models demonstrate that VASP knockdown suppresses GI cancer liver metastasis, β1-integrin activation, and YAP1/TAZ levels of metastatic cancer cells. Together, our data support VASP as a treatment target for liver metastasis of colorectal and pancreatic cancers.Liver metastasis: Protein that drives tumor spread offers therapeutic targetA protein involved in cytoskeleton regulation and cell motility control offers a new drug target for cancer spreading to the liver. Ningling Kang Ph.D. from the Hormel Institute in Austin, Minnesota, USA, and colleagues showed that levels of this actin-binding protein, known as vasodilator-stimulated phosphoprotein (VASP), are elevated in most patients with advanced colon and pancreatic cancers and that higher VASP expression levels are linked to liver metastasis and poorer patients’ outcomes. To explore the reasons why, the researchers studied three-dimensional tumor spheroids and mouse metastasis models of these cancers, and identified the signaling pathway by which VASP promotes the survival of cancer cells in distant organs, such as the liver. What’s more, they showed that knocking down VASP of cancer cells in metastasis mouse models suppressed cancer metastatic growth in the liver, suggesting that the same might be true in patients as well.

Expression of RNA-binding protein LIN28 in classic gastric hepatoid carcinomas, gastric fetal type gastrointestinal adenocarcinomas, and hepatocellular carcinomas: An immunohistochemical study with comparison to SALL4, alpha-fetoprotein, glypican-3, and Hep Par1

INTRODUCTION Gastric hepatoid carcinomas (GHCs) include type I (classic) and type II (fetal type gastrointestinal adenocarcinoma). The classic type shows overlapping morphologic features with those of hepatocellular carcinoma (HCC). The aim of this study is to investigate expression of LIN28 in GHCs and explore its utility to distinguish classic GHC from HCC. METHODS We investigated immunohistochemical expression of LIN28 in 93 primary GHCs (47 type I, 46 type II) and 60 HCCs with comparison to SALL4, AFP, glypican-3, Hep Par1, p-CEA and CK7. We also stained LIN28 and SALL4 in 52 conventional gastric adenocarcinomas to assess their specificity in gastric carcinomas. RESULTS Classic GHCs and fetal type gastrointestinal adenocarcinomas showed positive LIN28 in 21/47 (45%) and 10/46 (22%), SALL4 in 41/47 (87%) and 36/46 (78%), AFP in 30/46 (65%) and 33/46 (72%), glypican-3 in 31/41 (76%) and 24/38 (63%), Hep Par1 in 27/41 (66%) and 28/37 (76%), and CK7 in 15/40 (38%) and 25/38 (66%), respectively. p-CEA staining was seen in 19/44 (43%) classic GHCs. Among HCCs, LIN28, SALL4, AFP, glypican-3, Hep Par1, p-CEA and CK7 was seen in 1/60 (2%), 0/60 (0%), 6/30 (20%), 23/30 (77%), 29/30 (97%), 28/30 (93%) and 21/30 (70%) cases, respectively. LIN28 and SALL4 staining was seen in 2/52 (4%) and 14/52 (27%) gastric conventional adenocarcinomas, respectively. The sensitivity and specificity of distinguishing classic GHCs from HCCs was 45% and 98% for LIN28, 87% and 100% for SALL4, 65% and 80% for AFP, 76% and 30% for glypican-3, 66% and 3% for Hep Par1, 43% and 7% for p-CEA, and 38% and 30% for CK7, respectively. Combining LIN28 and SALL4 increased the sensitivity to 96% with 98% specificity to distinguish classic GHCs from HCCs. CONCLUSIONS LIN28 is a very specific marker (98% specificity) for distinguishing classic GHCs from HCCs though it is not as sensitive as SALL4. AFP, glypican-3, Hep Par1 and p-CEA are not useful in distinguishing classic GHCs from HCCs. Combining LIN28 and SALL4 increased the sensitivity to distinguish classic PHCs from HCCs.

Hepatic Collision Tumor of Metastatic Pancreatic Adenocarcinoma and Chronic Lymphocytic Leukemia: A Case Report.

A 70-year-old man with a past medical history of osteoarthritis and a long history of smoking and alcohol use presented to the emergency room after sustaining a fall at home and landing on his right hip. Vital signs on the presentation were notable for tachycardia. Laboratory testing revealed anemia (hemoglobin 11.9 g/dL, reference range: 13.5–17.5 g/dL) as well as leukocytosis (white blood cell count 53,600/μL, reference range 3500–10,500/μL) with lymphocyte predominance (an absolute lymphocyte count of 45,000/μL with 1% atypical lymphocytes). X-ray of the right hip revealed a right intertrochanteric fracture for which he underwent a successful operative repair on the next day. Workup for lymphocytosis and atypical lymphocytes included testing for infectious mononucleosis, CMV, HIV, and hepatitis B and C viruses with either enzyme-linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR), all of which was unrevealing. Flow cytometry was performed on peripheral blood and confirmed the diagnosis of chronic lymphocytic leukemia (CLL). It demonstrated that 80% of the cells were in the small lymphocyte region. Within the small lymphocyte region, there was a monoclonal population of B-cells that co-expressed CD5, CD19, CD20, CD23, CD45, HLA-DR, and surface kappa light chain. In addition, ATM gene deletion was detected by fluorescence in situ hybridization (FISH) and was found in 23% of the cells. Workup for anemia revealed iron deficiency without any evidence of hemolysis. While awaiting flow cytometry results, abdominal ultrasonography (Fig. 1) was performed to assess splenic size and revealed a cystic lesion near the splenic hilum without any evidence of splenomegaly. Abdominal computed tomography with IV contrast (Fig. 2) was obtained and revealed a 5.0 × 3.5 cm multiloculated thick-walled cystic structure arising from the tail of the pancreas with an adjacent occlusion of the splenic vein and resultant gastric varices. Low-attenuation wedge-shaped lesions in the spleen l ike ly rep re sen ted sp len ic in fa rc t s were a l so demonstrated. Esophagogastroduodenoscopy with endoscopic ultrasonography revealed a 2 × 1 cm cyst-like structure in the pancreatic tail; the endosonographic appearance of which was highly suspicious for benign inflammatory changes likely representing a resolving pseudocyst. Pancreatic abnormalities were also suggestive of chronic pancreatitis in the setting of a long history of alcohol and tobacco use. Testing for vitamins A, D, E, K, and B12 levels as well as hemoglobin A1c was unremarkable. Fecal elastase was within normal limits but split qualitative fecal fat was elevated, so the patient started on pancreatic enzyme replacement. The hip fracture was thought to be mechanical although a pathologic fracture could not be ruled out. * Bassel Jallad jalladbm@slu.edu

Cytoreductive Surgery and Normothermic Intraperitoneal Chemotherapy for Signet Ring Cell Appendiceal Adenocarcinoma With Peritoneal Metastases in the Setting of Cirrhosis

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are combined to treat peritoneal surface malignancies (PSM). The objective of cytoreduction is to eradicate macroscopic disease, while HIPEC addresses residual microscopic disease. Currently, there are no protocols guiding treatment of cirrhotic patients with PSM. We report the case of a cirrhotic patient with signet ring cell (SRC) appendiceal adenocarcinoma who underwent normothermic, as opposed to hyperthermic intraperitoneal chemotherapy (IPC). A 50-year-old woman with compensated class A cirrhosis and chronic hepatitis B and C underwent a right hemicolectomy in 2007 and adjuvant chemotherapy in 2008 for appendiceal SRC adenocarcinoma. In 2011, she was found to have peritoneal disease after a laparotomy. She subsequently experienced intolerance to chemotherapy, with stable disease on serial restaging. In light of her cirrhosis, the decision was made to perform CRS and IPC without hyperthermia to treat her residual disease. In 2012, she underwent CRS (omentectomy, total abdominal hysterectomy, left salpingo-oophorectomy) and IPC with mitomycin C. Thirty-day postoperative morbidity included delayed abdominal closure (Clavien-Dindo Grade IIIb), prolonged ventilator support (IIIa), vasopressor requirements (II), and confusion (II). The patient’s liver function remained stable. Eight months later, she had evidence of recurrence on computed tomography. Twenty-two months later, she developed an extrinsic compression secondary to evolving disease, requiring a palliative endoscopic stent. The patient expired from her disease 29 months after her CRS and IPC. The criteria guiding selection of suitable candidates for CRS continues to evolve. Concomitant compensated cirrhosis in patients with PSM should not constitute a reason independently to exclude CRS with intraperitoneal chemotherapy, given the oncologic benefits of the procedure.

Foamy Histiocyte-Like Hepatocellular Carcinoma (HCC): A New Variant of HCC?

Intrahepatic cholestasis of pregnancy (ICP) is a severe liver disease uniquely occurring during pregnancy. In this study we aimed to identify novel biomarker for the diagnosis of ICP in Chinese population. 50 healthy pregnant women, 50 mild ICP patients and 48 severe ICP patients were enrolled for this study. Liver function tests, including serum total bilirubin, direct bilirubin, alanine transami-nase, aspartate aminotransferase and cholyglycine, were performed in all participants. After an overnight fast serum levels of total bile acids (TBA), matrix metalloproteinase (MMP)-2 and MMP-9 were measured, and their correlation with liver function tests were analyzed. The observed increase in serum TBA in ICP patients was not statistically significant which made it unreliable for diagnosis of ICP in Chinese population. On the other hand, both MMP-2 and MMP-9 serum levels exhibited a progressive and significant elevation in mild and severe ICP patients compared with healthy pregnant women, which also positively correlated with liver function tests. Serum levels of both MMP-2 and MMP-9 could be reliably used as laboratory abnormalities for accurate diagnosis and sensitive grading of ICP in Chinese population.* Department of Pathology, Saint Louis University School of Medicine, St. Louis, USA. ** Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, USA. *** University College, Washington University in St. Louis, St. Louis, USA. **** Department of Radiology, Saint Louis University School of Medicine, St. Louis, USA. March-April, Vol. 16 No. 2, 2017: 304-307 IMAGES IN HEPATOLOGY