Neuroendocrine carcinoma arising in a hepatitis C virus-infected liver: mechanism of the tumor development may be similar to that of development of pancreatic neuroendocrine cells.

We experienced a case of neuroendocrine carcinoma (NC). The tumor developed in the cirrhotic liver of a 62-year-old Japanese man who had been infected with hepatitis C virus. The tumor cells showed high N/C ratio, formed many rosettes, and expressed CD56, synaptophysin, HepPar1 and pancreatic and duodenal homeobox 1. MIB1 expression was 65%. Because both liver and pancreas are derived from a common endodermal layer during fetal development, we speculated that the tumor may have formed via the interaction of neurogenin 3, insulinoma-associated 1 gene and NeuroD/beta2, which are involved in the stage at which some pancreatic cells commit to becoming endocrine cells. Molecular analysis revealed that the NC had higher relative expression levels of mRNA of the three molecules than did the nontumorous liver. The results indicate that the NC in this patient may have formed via the same mechanism that acts in the development of pancreatic neuroendocrine cells.

Oncolytic Vaccinia Virus Gene Modification and Cytokine Expression Effects on Tumor Infection, Immune Response, and Killing.

Oncolytic vaccinia viruses have promising efficacy and safety profiles in cancer therapy. Although antitumor activity can be increased by manipulating viral genes, the relative efficacy of individual modifications has been difficult to assess without side-by-side comparisons. This study sought to compare the initial antitumor activity after intravenous administration of five vaccinia virus variants of the same Western Reserve backbone and thymidine kinase gene deletion in RIP-Tag2 transgenic mice with spontaneous pancreatic neuroendocrine tumors. Tumors had focal regions of infection at 5 days after all viruses. Natural killer (NK) cells were restricted to these sites of infection, but CD8+ T cells and tumor cell apoptosis were widespread and varied among the viruses. Antitumor activity of virus VV-A34, bearing amino acid substitution A34K151E to increase viral spreading, and virus VV-IL2v, expressing a mouse IL2 variant (mIL2v) with attenuated IL2 receptor alpha subunit binding, was similar to control virus VV-GFP. However, antitumor activity was significantly greater after virus VV-A34/IL2v, which expressed mIL2v together with A34K151E mutation and viral B18R gene deletion, and virus VV-GMCSF that expressed mouse GM-CSF. Both viruses greatly increased expression of CD8 antigens Cd8a/Cd8b1 and cytotoxicity genes granzyme A, granzyme B, Fas ligand, and perforin-1 in tumors. VV-A34/IL2v led to higher serum IL2 and greater tumor expression of death receptor ligand TRAIL, but VV-GMCSF led to higher serum GM-CSF, greater expression of leukocyte chemokines and adhesion molecules, and more neutrophil recruitment. Together, the results show that antitumor activity is similarly increased by viral expression of GM-CSF or IL2v combined with additional genetic modifications.

Large cell neuroendocrine tumor of the cervix and human papillomavirus 16: a case report.

BACKGROUND: Large cell neuroendocrine cancer of the cervix is a rare entity. Most cervical cancers are high-risk human papillomavirus (HPV)-related neoplasms. CASE: A 31-year-old woman presented with pelvic pain and daily vaginal bleeding for 6 months. Uterine curettage revealed an undifferentiated malignancy. A total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic, common iliac, and periaortic lymphadenectomy and peritoneal cytology were performed. The pathological findings revealed a poorly differentiated large cell neuroendocrine carcinoma of the cervix with metastasis to 1 right obturator lymph node. Nonisotopic in situ hybridization stains were positive for high-risk HPV in the cervical tumor and in the lymph node metastasis in virtually every tumor cell indicative of viral integration into the host genome. Specific HPV typing by polymerase chain reaction was positive for HPV-16. CONCLUSIONS: Integration of high-risk HPV, in particular type 16, is associated with this uncommon variant of cervical carcinoma.

Contribution of Human papillomavirus in neuroendocrine tumors from a series of 10,575 invasive cervical cancer cases.

AIMS: Neuroendocrine tumors (NET) of the cervix are rare tumors with a very aggressive course. The human papillomavirus (HPV) has been linked to its etiology. The objective of this study is to describe HPV prevalence and genotype distribution of NET. METHODS AND RESULTS: Forty-nine tumors with histological neuroendocrine features were identified among 10,575 invasive cervical cancer (ICC) cases from an international study. HPV DNA detection was done using SPF10/DEIA /LiPA25 system. Immunohistochemical (IHC) staining for neuroendocrine markers (chromogranin A, synaptophysin, CD56) and for p16INK4a as a surrogate for HPV transforming infection was performed. In 13 samples with negative IHC for all 3 neuroendocrine markers studied, it was possible to conduct electron microscopy (EM). NET represented 0.5% of the total ICC series and HPV was detected in 42 out of 49 samples (85.7%, 95%CI:72.8%,94.1%). HPV16 was the predominant type (54.8%), followed by HPV18 (40.5%). p16INK4a overexpression was observed in 38/44 cases (86.4%). Neuroendocrine IHC markers could be demonstrated in 24/37 (64.9%) cases. EM identified neuroendocrine granules in 8 samples with negative IHC markers. CONCLUSIONS: Our data confirms the association of cervical NET with HPV and p16INK4a overexpression. Specifically, HPV16 and 18 accounted together for over 95% of the HPV positive cases. Current HPV vaccines could largely prevent these aggressive tumors.

AGA clinical practice update on the diagnosis and management of Atrophic Gastritis: expert review

The purpose of this Clinical Practice Update Expert Review is to provide clinicians with guidance on the diagnosis and management of atrophic gastritis, a common preneoplastic condition of the stomach, with a primary focus on atrophic gastritis due to chronic Helicobacter pylori infection-the most common etiology-or due to autoimmunity. To date, clinical guidance for best practices related to the diagnosis and management of atrophic gastritis remains very limited in the United States, which leads to poor recognition of this preneoplastic condition and suboptimal risk stratification. In addition, there is heterogeneity in the definitions of atrophic gastritis, autoimmune gastritis, pernicious anemia, and gastric neoplasia in the literature, which has led to confusion in clinical practice and research. Accordingly, the primary objective of this Clinical Practice Update is to provide clinicians with a framework for the diagnosis and management of atrophic gastritis. By focusing on atrophic gastritis, this Clinical Practice Update is intended to complement the 2020 American Gastroenterological Association Institute guidelines on the management of gastric intestinal metaplasia. These recent guidelines did not specifically discuss the diagnosis and management of atrophic gastritis. Providers should recognize, however, that a diagnosis of intestinal metaplasia on gastric histopathology implies the diagnosis of atrophic gastritis because intestinal metaplasia occurs in underlying atrophic mucosa, although this is often not distinctly noted on histopathologic reports. Nevertheless, atrophic gastritis represents an important stage with distinct histopathologic alterations in the multistep cascade of gastric cancer pathogenesis. The Best Practice Advice statements presented herein were developed from a combination of available evidence from published literature and consensus-based expert opinion. No formal rating of the strength or quality of the evidence was carried out. These statements are meant to provide practical advice to clinicians practicing in the United States. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Atrophic gastritis is defined as the loss of gastric glands, with or without metaplasia, in the setting of chronic inflammation mainly due to Helicobacter pylori infection or autoimmunity. Regardless of the etiology, the diagnosis of atrophic gastritis should be confirmed by histopathology. BEST PRACTICE ADVICE 2: Providers should be aware that the presence of intestinal metaplasia on gastric histology almost invariably implies the diagnosis of atrophic gastritis. There should be a coordinated effort between gastroenterologists and pathologists to improve the consistency of documenting the extent and severity of atrophic gastritis, particularly if marked atrophy is present. BEST PRACTICE ADVICE 3: Providers should recognize typical endoscopic features of atrophic gastritis, which include pale appearance of gastric mucosa, increased visibility of vasculature due to thinning of the gastric mucosa, and loss of gastric folds, and, if with concomitant intestinal metaplasia, light blue crests and white opaque fields. Because these mucosal changes are often subtle, techniques to optimize evaluation of the gastric mucosa should be performed. BEST PRACTICE ADVICE 4: When endoscopic features of atrophic gastritis are present, providers should assess the extent endoscopically. Providers should obtain biopsies from the suspected atrophic/metaplastic areas for histopathological confirmation and risk stratification; at a minimum, biopsies from the body and antrum/incisura should be obtained and placed in separately labeled jars. Targeted biopsies should additionally be obtained from any other mucosal abnormalities. BEST PRACTICE ADVICE 5: In patients with histology compatible with autoimmune gastritis, providers should consider checking antiparietal cell antibodies and anti-intrinsic factor antibodies to assist with the diagnosis. Providers should also evaluate for anemia due to vitamin B-12 and iron deficiencies. BEST PRACTICE ADVICE 6: All individuals with atrophic gastritis should be assessed for H pylori infection. If positive, treatment of H pylori should be administered and successful eradication should be confirmed using nonserological testing modalities. BEST PRACTICE ADVICE 7: The optimal endoscopic surveillance interval for patients with atrophic gastritis is not well-defined and should be decided based on individual risk assessment and shared decision making. A surveillance endoscopy every 3 years should be considered in individuals with advanced atrophic gastritis, defined based on anatomic extent and histologic grade. BEST PRACTICE ADVICE 8: The optimal surveillance interval for individuals with autoimmune gastritis is unclear. Interval endoscopic surveillance should be considered based on individualized assessment and shared decision making. BEST PRACTICE ADVICE 9: Providers should recognize pernicious anemia as a late-stage manifestation of autoimmune gastritis that is characterized by vitamin B-12 deficiency and macrocytic anemia. Patients with a new diagnosis of pernicious anemia who have not had a recent endoscopy should undergo endoscopy with topographical biopsies to confirm corpus-predominant atrophic gastritis for risk stratification and to rule out prevalent gastric neoplasia, including neuroendocrine tumors. BEST PRACTICE ADVICE 10: Individuals with autoimmune gastritis should be screened for type 1 gastric neuroendocrine tumors with upper endoscopy. Small neuroendocrine tumors should be removed endoscopically, followed by surveillance endoscopy every 1-2 years, depending on the burden of neuroendocrine tumors. BEST PRACTICE ADVICE 11: Providers should evaluate for iron and vitamin B-12 deficiencies in patients with atrophic gastritis irrespective of etiology, especially if corpus-predominant. Likewise, in patients with unexplained iron or vitamin B-12 deficiency, atrophic gastritis should be considered in the differential diagnosis and appropriate diagnostic evaluation pursued. BEST PRACTICE ADVICE 12: In patients with autoimmune gastritis, providers should recognize that concomitant autoimmune disorders, particularly autoimmune thyroid disease, are common. Screening for autoimmune thyroid disease should be performed.

Human polyomaviruses and other human viruses in neuroendocrine tumors.

BACKGROUND: While the association of the Merkel cell polyomavirus (MCV) with the neuroendocrine Merkel cell carcinomas (MCC) has been shown recently, it is unknown whether other human polyomaviruses (HPyV) may be associated with neuroendocrine tumours (NETs) of distinct entities. METHODS: Using novel, highly sensitive polyomavirus genotyping assays, we evaluated the prevalence of eight distinct HPyVs in a selection of 51 NETs from different entities. In addition, we analyzed these NETs for the presence of DNA from 12 adeno-associated virus (AAV) genotypes, adeno virus-5, 27 mucosal human papillomavirus (HPV) genotypes, hepatitis B (HBV), 8 human herpes viruses (HHV), and xenotropic murine leukemia virus-related virus (XMRV). RESULTS: 43 of the 50 (86%) NETs were positive for the DNA integrity control. Of these, 2 of 3 MCCs (67%) were positive for MCV. NETs from other entities, however, were negative for all HPyVs. Only a small subset of lung and appendix NETs were positive for EBV, HHV-6, and -7. CONCLUSION: While the association of MCV with MCC was confirmed, other human viruses could not be identified as potentially causative agents of other NETs. IMPACT: Our findings suggest that the human viruses tested for in this study do not play a comparable role in NETs like the polyomavirus MCV in MCC.

Long-term high-dose proton pump inhibitor administration to Helicobacter pylori-infected Mongolian gerbils enhances neuroendocrine tumor development in the glandular stomach.

Proton pump inhibitors (PPIs) are routinely used for control of upper gastrointestinal disorders, often with long-term application. However, there has been some concern about the long-term safety and the possibility of cancer induction and development of neuroendocrine tumors (NET) in the stomach. We therefore analyzed the influence of PPI use on tumor development histologically, immunohistochemically, and serologically in the glandular stomachs of Helicobacter pylori (Hp)-infected and uninfected Mongolian gerbils (MGs). 53 MGs were divided into 6 groups: Hp+25PPI, Hp+5PPI, Hp, 25PPI, 5PPI, and controls. The high-dose Hp+25PPI and 25PPI groups received the PPI (lansoprazole) at 25mg/kg/day, and the low-dose Hp+5PPI and 5PPI groups were given 5mg/kg/day. After 50 or 100 weeks, animals were sacrificed humanely, and the glandular stomach samples were evaluated histologically and phenotypically, using antibodies against chromogranin A (CgA), gastrin and gastric inhibitory polypeptide (GIP). Serum gastrin levels were also examined. NETs occurred in the Hp+25PPI, Hp+5PPI, Hp, and 25PPI groups, but there was no synergistic effect between Hp-infection and high-dose PPI administration. Serum gastrin was increased statistically by Hp infection and high-dose PPI administration, but not influenced by the low-dose. The NETs featured expression of CgA, but not gastrin or GIP. In conclusions, PPI at low dose had no influence on development of carcinomas and NETs in the Hp-infected and uninfected glandular MG stomach, suggesting clinical safety. However, PPI at high dose increased NET development and serum gastrin in the MG model.

Merkel cell polyomavirus: a specific marker for Merkel cell carcinoma in histologically similar tumors.

The recently described Merkel cell polyomavirus (MCPyV) is reportedly present in 50% to 80% of Merkel cell carcinomas (MCC). Although the virus has been shown to be absent from other cutaneous neoplasms, its association with malignancies that are histologically similar to MCC, specifically small cell carcinoma of the lung and other high-grade neuroendocrine tumors, has yet to be thoroughly investigated. To address this issue, we identified a set of 74 cases of visceral high-grade neuroendocrine tumors from a variety of anatomic sites, including 32 cases from the lung, 16 cases from the gastrointestinal tract, 20 cases from the female reproductive system, 3 cases from soft tissue, 2 cases from the head and neck region, and 1 case from the bladder. Using a set of primers optimized to detect MCPyV in formalin-fixed tissue, polymerase chain reaction (PCR)-based testing showed evidence of MCPyV DNA in only 1 of the 74 tumors; however, clinicopathologic review of the positive case (a neuroendocrine tumor of the small intestine) disclosed that the patient had a history of primary MCC of the buttock. PCR-based testing also showed no evidence of the related WU and KI polyomaviruses in the set of 74 cases. We conclude that, when evaluated by PCR-based testing, MCPyV is a specific marker for MCC that can be helpful in distinguishing cases of metastatic MCC from other high-grade neuroendocrine tumors. Our results also suggest that MCPyV does not have a role in the oncogenesis of visceral high-grade neuroendocrine tumors.

Endocrine tumors of the cervix: morphologic assessment, expression of human papillomavirus, and evaluation for loss of heterozygosity on 1p,3p, 11q, and 17p.

BACKGROUND: Cervical endocrine tumors are rare lesions, with a varied diagnostic nomenclature. A recent consensus meeting proposed a standardized terminology. This study evaluated: 1) applicability of histopathologic guidelines; 2) evidence of loss of heterozygosity (LOH) at selected sites; and 3) the presence of human papillomavirus (HPV) detected by nonisotopic in situ hybridization (ISH). METHODS: Thirty-eight cases (patient age range, 19-88 years; mean, 48 years) were retrieved. Outcome data were available for 32 patients. Classification was based on architectural and cytologic features. Tissue was available from 15 cases for LOH analysis with D3S1234(3p14), D3S1289(3p21), THRB(3p24), TP53(17p13), D1S468(1p36), and INT-2(11q13). In ten cases, tissue was analyzed by nonisotopic ISH with HPV probes for types 6/11, 16/18, and 31/33. RESULTS: Tumors were divided into four groups: small cell carcinoma (SCC) (n=25); large cell neuroendocrine carcinoma (LCNC) (n=5); SCC with focal LCNC differentiation (n=3), and carcinoid tumor (n=5). Tumors defined as exclusively or predominantly SCC had a particularly poor prognosis, with 20 patients dead of disease (<6 years after diagnosis) and 6 alive with disease (after <3 years of follow-up). LOH at various 3p loci (3p14, 3p21, and 3p24) was observed in eight cases. One patient demonstrated LOH on 17p(TP53). Eight of ten cases assessed by ISH showed nuclear staining using a combined HPV-16/18 probe. CONCLUSIONS: Cervical endocrine tumors are highly aggressive and can be subdivided into definable categories. LOH at 3p loci is a frequent finding, as is nuclear staining with a combined HPV-16/18 probe. LOH at 17p(TP53 locus) appears to be relatively uncommon, suggesting that p53 mutations may not be developmentally significant.