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Aims: Criteria for the interpretation of digestive system neuroendocrine neoplasms (NENs) continue to evolve. Although there are some literature recommendations regarding workup and diagnosis of these lesions, different practice patterns exist among pathologists when signing out these specimens. The aim of this study was to assess practice trends among pathologists worldwide when reporting these neoplasms., Methods and Results: We created an online survey with multiple questions pertaining to digestive NENs. The results were analysed based on type of practice setting, years of sign-out experience, and practice location. Respondents included 384 practicing pathologists: 70% academic, 30% private practice; 63% gastrointestinal (GI) pathology-subspecialised, 37% not; 39% North American, 42% European, 19% others; 45% with ≤10 years in practice; 55% with >10 years. Some question responses were chosen by the majority (e.g. 85% use both mitotic count and Ki67 index for grading NENs, 82% complete a synoptic, and Ki67 stain even for small incidental appendiceal neuroendocrine tumours [NETs], and 96% utilize the diagnosis of grade 3 NET). However, some questions showed varying responses, including counting mitotic figures, Ki67 stain interpretation, and pancreatic grade 3 NEN workup. Pathologists also had some variability in interpreting regional metastatic foci of small bowel NETs and in choosing blocks for Ki67 staining in multifocal lesions., Conclusion: There existed scenarios wherein practice patterns varied despite recommendations in the literature, and there were also scenarios lacking clear guidelines wherein pathologists used varying judgement. This survey highlights current key grey areas in digestive system NEN evaluation, leading to variation in practice patterns., (© 2022 John Wiley & Sons Ltd.)

Background: Chitinase 3-Like 1 (CHI3L1) has been used as an inflammatory biomarker for a variety of diseases, but its expression in acute appendicitis and appendix carcinomas remains unclear., Methods: Sixty cases of patients were studied, including 46 acute appendicitis and 14 appendix carcinomas. We divided the acute appendicitis group into acute uncomplicated appendicitis (AUA), suppurative appendicitis (SA), and gangrenous appendicitis (GA). The appendix carcinoma group was divided into appendiceal neuroendocrine neoplasms (ANENs) and appendiceal mucinous neoplasms (AMN). Controls were 32 healthy donors. Blood neutrophil to lymphocyte ratio (NLR), CHI3L1, C-reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A (SAA) were measured in the patients. Meanwhile, immunohistochemistry and immunofluorescence were used to identify the expression level and location of CHI3L1 in different cell types in appendix tissues., Results: Compared with the controls, CHI3L1 serum levels were up-regulated in SA, GA, and AMN groups, while no significant difference was observed in the AUA and ANEN groups. Immunofluorescence revealed that CHI3L1 expression was high in macrophages and adenocarcinoma cells of appendix tissues but not in the neuroendocrine carcinoma tissues. Moreover, levels of NLR and CRP in the SA and GA groups were considerably higher than in the control group. IL-6 and SAA in SA, GA, ANENs, and AMN groups were also increased compared with the control group. In addition, CHI3L1 displayed good performance in predicting appendicitis, with an AUC of 0.862., Conclusion: CHI3L1 was highly expressed in acute appendicitis and appendiceal mucinous neoplasms, which can be used as a novel biomarker predicting appendicitis., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Mesothelin is a cell surface glycoprotein overexpressed in 28%-58% of colorectal cancer (CRC). We hypothesized that CRC mesothelin expression contributes to peritoneal spread and that it is selectively overexpressed in those with peritoneal metastasis versus distant metastasis., Methods: This case-controlled study involved mesothelin immunohistochemistry staining of tumor specimens from patients with metastatic CRC/appendiceal cancers between 2017 and 2019. Staining reactivity was graded from trace to 4+ (low ≤1+; high >1+). Staining patterns were characterized on global (focal/patchy/diffuse) and cellular (apical/cytoplasmic) levels. Immunostaining of normal mesothelial cells served as internal control., Results: Thirty-one patients were identified: 11 peritoneal (study) and 20 distant metastasis (control). The control group did not include appendiceal cancers. The study group had greater proportion of high staining reactivity (55% vs. 5%; odds ratio [OR] = 20.4, 95% confidence interval [CI] 1.96-211.8). The study group had more diffuse (36% vs. 0%; OR = 22.2, 95% CI 1.1-465.3) and cytoplasmic staining patterns (73% vs. 28%; OR = 6.9, 95% CI 1.3-37.2)., Conclusion: Mesothelin expression is higher in CRC/appendiceal cancers with peritoneal metastasis than those with distant metastasis. Immunohistochemistry staining patterns suggestive of propensity towards peritoneal metastasis include diffuse and cytoplasmic staining. Mesothelin may be a potential target for novel treatments of CRC/appendiceal carcinoma with peritoneal involvement., (© 2021 Wiley Periodicals LLC.)

Introduction: Neuroendocrine neoplasms (NEN) of the appendix are often incidentally discovered after appendectomy. Appropriate management is debated. The purpose was to characterize a cohort of 335 appendix NEN and evaluate the risk of recurrence., Methods: Retrospective collection of data from 335 patients referred to the Neuroendocrine Tumor Center at Rigshospitalet 2000-2019. Appendix goblet cell carcinoids and mixed neuroendocrine non-neuroendocrine neoplasms were excluded. Patients were followed until December 31st, 2019. No patients were lost to follow-up., Results: Sixty-three percent of the patients were female. The median (range) age at diagnosis was 34 (9-92) years. Median follow-up was 66 (1-250) months. Median tumor size was 7 (1-45) mm with 10 (3%) tumors >20 mm. In 18 specimens (5%) resection margins were positive. Mesoappendiceal invasion was found in 113 (35%). Sixty-three (19%) patients underwent right-sided completion hemicolectomy (RHC) after appendectomy according to ENETS guidelines. Among these, 11 (17%) had lymph node metastases in the resected tissue. Further, one patient who underwent initial RHC due to colonic adenocarcinoma had lymph node metastases. All lymph node metastases were detected in patients with serotonin positive tumors. No patients with glucagon positive tumors (n = 85) had lymph node metastases. Mesoappendiceal invasion >3 mm and positive resection margins were associated with presence of lymph node metastases. No recurrences were recorded., Conclusion: Following ENETS guidelines may lead to overtreatment of patients with respect to completion RHC. The risk of over- and undertreatment needs to be further evaluated., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objectives: INSM1 has been described as a sensitive and specific neuroendocrine marker. This study aims to compare INSM1 with traditional neuroendocrine markers in gastrointestinal neuroendocrine neoplasms., Methods: Retrospective review (2008-2018) was used to retrieve paraffin-embedded tissue from 110 gastrointestinal neuroendocrine neoplasms and controls that was subsequently stained with INSM1, synaptophysin, chromogranin, CD56, and Ki-67., Results: INSM1 was positive in 16 of 17 (94.1%) gastric, 17 of 18 (94.4%) pancreatic, 13 of 18 (72.2%) small bowel, 17 of 21 (81.0%) colonic, and 26 of 36 (72.2%) appendiceal tumors. INSM1 was positive in 58 of 70 (82.9%) well-differentiated neuroendocrine tumors, 17 of 20 (85.0%) poorly differentiated neuroendocrine carcinomas, 8 of 11 (72.7%) low-grade goblet cell adenocarcinomas (grade 1), and 6 of 9 (66.7%) high-grade goblet cell adenocarcinomas (grade 2/3). INSM1 sensitivity for neuroendocrine neoplasms (80.9%) was less than that of synaptophysin (99.1%), chromogranin (88%), and CD56 (95.3%); specificity was higher (95.7% vs 86.0%, 87.3%, and 86.0%, respectively)., Conclusions: INSM1 is a useful marker of neuroendocrine differentiation in gastrointestinal neuroendocrine and mixed neuroendocrine neoplasms. Compared with traditional neuroendocrine markers, INSM1 is less sensitive but more specific., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims . The proximal colon derives from the midgut endoderm, the distal one third derives from the hindgut endoderm, and the distal anal canal is of ectodermal origin. At least 5 molecular subtypes of colorectal carcinomas (CRC) have been identified, and some have a marked preferential right-sided location. Histologically, some CRC are much more common in the appendix. We hypothesized that these findings suggest the existence of diverse molecular genetic colonic subregions and compared the expression of classic and recently discovered colorectal markers in tumors at various locations to determine if a site-specific immunophenotypic signature could be identified. Methods and Results . Immunostains for CK7, CK20, MUC2, MUC5AC, MUC6, SATB2, DCR3/TNF6B, CDX2, Ki-67, and MMR proteins were performed on 17 appendiceal low-grade mucinous neoplasms and 6 crypt cell adenocarcinomas of the appendix, 15 right-sided and 15 left-sided mucinous adenocarcinomas, 17 right-sided and 15 left-sided conventional adenocarcinomas, and 5 signet ring cell adenocarcinomas (SRCCA). Statistically significant differences in the expression of MUC2, MUC5AC, MUC6, CK7, and SATB2 by site and/or histologic type were documented. MMR deficiency showed a significant correlation with MUC5AC and MUC6 expression. DCR3, CDX2, and CK20 expression was consistent throughout the colon. A CK7+/CK20+ phenotype was most common in appendiceal tumors and SRCCA. Conclusions . Statistically significant differences in the expression of some markers by histologic type and site were documented, supporting the existence of regional molecular genetic heterogeneity in the colon that result in site-specific epigenetic susceptibilities, tumor phenotypes, and immunophenotypes.

The pathological features of the appendix tumors fundamentally recall those of the more frequent colorectal neoplasms, although with a higher relative incidence of carcinoids, due to the abundant presence of enteroendocrine cells in the appendix wall. Moreover, different types of lymphomas, Hodgkin and non-Hodgkin, arising from the extra-nodal mucosal-associated lymphatic tissue, can be encountered. The appendix tumor microenvironment (TME) consists of a cellular component and of a noncellular component: the former includes the immunocompetent cells, while the latter represents the support stroma. Particularly in carcinoids, the immune cell reaction can be explicated by tumor-infiltrating lymphocytes, which, in some circumstances, may arrange around and inside the tumor in a brisk fashion influencing favorably the prognosis. This active reaction has to be distinguished from any preexisting inflammatory condition of the appendix and from superimposed tumor complications, such as infection or ischemia. In practice, we consider the appendix TME a complex framework with immunological, mechanic, and metabolic functions, all supported by a marked neo-lymphoangiogenesis.

Objectives: It is challenging to distinguish between primary ovarian mucinous tumors and metastatic mucinous neoplasms from the lower gastrointestinal tract, including appendiceal tumors. A combination of PAX8 and SATB2 immunohistochemical stains can be used as a diagnostic tool to distinguish between these cases., Results: Immunostaining for SATB2, PAX8, CK7, CK20 and CDX2 was performed on 50 ovarian mucinous neoplasms (OMN) (39 cystadenomas, 4 borderline and 7 adenocarcinomas), 63 mucinous colorectal carcinoma (CRC), and 9 appendiceal mucinous neoplasms (AMN) [8 low grade appendiceal mucinous neoplasms (LAMN) and 1 adenocarcinoma]. PAX8 was positive in 32% of OMN and negative in all CRC and AMN cases. SATB2 was expressed in 2.0% of OMN, 77.8% of AMN, and 49.2% of CRC cases. CK7 was positive in 78.0% of OMN, 33.3% of AMN, and 9.5% of CRC cases. CK20 was expressed in 24.0% of OMN, 88.9% of OMN, and 87.3% of CRC cases. CDX2 was positive in 14.0% of OMN, 100% of AMN, and 90.5% of CRC cases. PAX8 can differentiate between OMN and AMN with high specificity but low sensitivity. CDX2 is the most sensitive marker for CRC and AMN, whereas SATB2 has better specificity.

Objective: The aim of this study was to investigate the clinicopathological characteristics of appendiceal mucinous neoplasm that had been preoperatively misdiagnosed as a mucinous ovarian tumor and to discuss the clinical impacts of misdiagnosis., Methods: Seventy-eight patients with a final pathologic diagnosis of appendiceal mucinous neoplasm during a 10-year period were retrospectively reviewed. All patients were diagnosed with ovarian tumor before treatment. A univariate analysis was performed to evaluate predictors of the diagnostic accuracy of a frozen section., Results: The patients' median age was 61 years (range, 21-82 years), and most were diagnosed as low-grade appendiceal mucinous neoplasm (LAMN) (84.62%). The diagnostic concordance between the frozen section and the final pathology was 56.92%. The most consistent diagnosis was LAMN (64.14%). Univariate analysis indicated that maximal diameter of the ovarian tumor (unilateral), laterality of the ovarian tumors (unilateral or bilateral), and frozen section site (appendix or extra-appendix) significantly correlated with the accuracy of frozen section diagnosis (all p < 0.05). Although the diagnostic discordance between the frozen section and the final pathology was 43.08%, only one patient was clinically impacted because of suboptimal surgery., Conclusion: Appendiceal mucinous neoplasm should be considered as a differential diagnosis of pelvic mass in women. For patients who do not require fertility-sparing surgery, excision and frozen section of the bilateral ovaries and appendix regardless of the appearance of the appendix might improve the diagnosis. For older patients with peritoneal dissemination, appropriate cytoreductive surgery is recommended to reduce the clinical impact of misdiagnosis., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Goblet cell carcinoid (GCC) is a rare appendiceal tumor with unique morphologic features that shows glandular and neuroendocrine differentiation on immunohistochemistry. An additional component of adenocarcinoma (AC) can be present (GCC-AC). Both GCC and GCC-AC are staged and treated like AC. The histogenesis and genetic alterations underlying GCC and GCC-AC are unclear. Capture-based next-generation DNA sequencing targeting 479 cancer genes was performed on 19 appendiceal tumors: 4 GCC, 9 GCC-AC, 3 neuroendocrine tumors (NET), and 3 AC (2 conventional, 1 mucinous). Somatic coding mutations were not seen in any NET. Pathogenic (P)/likely pathogenic (LP) mutations were present in 1 GCC, 8 GCC-AC and all 3 AC cases. P/LP mutations in chromatin remodeling genes were seen in 4 (44.4%) GCC-AC cases, but not in NET, GCC or AC. In GCC-AC, P/LP mutations in ARID1A and RHOA were each present in 3 cases, and KDM6A and SOX9 mutations were each seen in 2 cases. APC and KRAS mutations were present in 1 conventional AC case, but were not observed in any GCC or GCC-AC. This limited series reveals mutations in SOX9, RHOA, and chromatin-modifier genes in goblet cell tumors, and shows that the mutational profile of GCC/GCC-AC is distinct from NET and conventional appendiceal AC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The appendix gives rise to goblet cell carcinoids, which represent special carcinomas with distinct biological and histological features. Their genetic background and molecular relationship to colorectal adenocarcinoma is largely unknown. We therefore performed a next-generation sequencing analysis of 25 appendiceal carcinomas including 11 goblet cell carcinoids, 7 adenocarcinomas ex-goblet cell carcinoid, and 7 primary colorectal-type adenocarcinomas, using a modified Colorectal Cancer specific Panel comprising 32 genes linked to colorectal and neuroendocrine tumorigenesis. The mutational profiles of these neoplasms were compared with those of conventional adenocarcinomas, mixed adenoneuroendocrine carcinomas, and neuroendocrine carcinomas of the colorectum. In addition, a large-scale pan-cancer sequencing panel covering 409 genes was applied to selected cases of goblet cell carcinoid/adenocarcinoma ex-goblet cell carcinoid (n=2, respectively). Mutations in colorectal cancer-related genes (eg, TP53, KRAS, APC) were rare to absent in both, goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid, but frequent in primary colorectal-type adenocarcinomas of the appendix. Additional large-scale sequencing of selected goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid revealed mutations in Wnt-signaling-associated genes (USP9X, NOTCH1, CTNNA1, CTNNB1, TRRAP). These data suggest that appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid constitute a morphomolecular entity, histologically and genetically distinct from appendiceal colorectal-type adenocarcinomas and its colorectal counterparts. Altered Wnt-signaling associated genes, apart from APC, may act as potential drivers of these neoplasms. The absence of KRAS/NRAS mutations might render some of these tumors eligible for anti-EGFR directed therapy regimens.

The differentiation between a primary mucinous ovarian neoplasm and an extra-ovarian metastasis in the ovary is often challenging in the histopathologic practice. Among various ovarian metastases from the gastro-intestinal tract the low-grade appendiceal mucinous neoplasm (LAMN) is an important differential diagnosis to consider particularly in case of pseudomyxoma peritonei. A newly recognized marker in the routine diagnostic of a mucinous neoplasm in the ovary is SATB2 (Special AT-rich sequence-binding protein 2). The expression of SATB2 is, within cells of epithelial lineages, mainly restricted to the lower gastro-intestinal tract, indicating colorectal or appendiceal cancer origin. We report seven cases of LAMN, which clinically became apparent due to ovarian metastases in context of pseudomyxoma peritonei or at least small foci of peritoneal tumor spread. An immunohistochemical marker-panel including SATB2, CDX2, CK20, CK7, PAX8, ER and PR revealed a strong expression of SATB2 in all seven cases. On the contrary SATB2-negativity could be demonstrated in the 40 cases of mucinous borderline tumors and primary mucinous carcinomas of the ovary. The histopathologic tentative diagnosis of an ovarian metastasis of LAMN could be confirmed in the findings of the Appendix in six of seven cases. This report supports SATB2 as an additional diagnostic marker for the diagnosis of an ovarian manifestation of LAMN., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Background: Elevated BNP is associated with adverse cardiac outcomes after noncardiac surgery. We assessed BNP values as markers of perioperative fluid status and their correlation with major/cardiopulmonary (CP) complications following CRS + HIPEC., Methods: Fluid balance, BNP levels, and morbidity data were collected for all patients undergoing CRS + HIPEC between 6/2014 and 2/2016., Results: One hundred and twenty-nine patients underwent CRS + HIPEC for appendiceal adenocarcinoma (n = 99), mesothelioma (n = 16), and colon cancer (n = 14). Less than 10% had CP comorbidities. The median PCI was 14 (range 4-39); 89% underwent CC0/1 resection (n = 115). Median blood loss (EBL) was 497 mL (50-2700). Major complications (Clavien III-V) occurred in 16 (12%), CP in 17 (13%), and major/CP in 24 (18%). Thirty-day mortality occurred in 2 (1.5%). Elevated BNP on POD1 correlated with increased risk of major/CP complications (OR 2.2, P = 0.052). This was most pronounced in the 25 patients receiving cisplatin: for each 100 unit increase in POD1 BNP the OR for major/CP complication was 7.4 versus 1.2 for the remaining patients, P = 0.083. Multivariate analysis identified increased EBL (OR 4.1 P = 0.011) and a trend toward increased BNP on POD1 (OR for each 100 unit increase 2.0, P = 0.10) as risk factors for major/CP complications., Conclusions: Postoperative BNP measurement after CRS + HIPEC may guide postoperative fluid resuscitation and facilitate identification of patients at risk for major and/or cardiopulmonary complications., (© 2017 Wiley Periodicals, Inc.)

Background: Synchronous ovarian/appendiceal mucinous neoplasms sometimes occur in the absence of clinical pseudomyxoma peritonei (PMP), which raises a question about whether the 2 tumors could be independent., Methods: We identified 11 cases of synchronous ovarian/appendiceal mucinous neoplasms without PMP and subclassified them into groups 1 and 2 based on the presence or absence of microscopic peritoneal/ovarian surface mucin deposits. A 7-marker panel (CK7, CK20, CDX2, PAX8, MUC1, MUC2, and MUC5AC) immunohistochemistry was performed on both tumors., Results: Between the 2 groups, there were no significant differences in age, laterality, size, and histology of ovarian/appendiceal tumors. In group 1, 2 of 4 cases developed PMP later, and both had ovarian surface and contralateral ovarian involvement and appendiceal perforation with microscopic mucin deposits on the peritoneum. No patients in group 2 developed PMP. All group 1 cases showed a high degree of concordance of immunoprofile between the synchronous tumors, with an identical expression of appendiceal pattern in greater than 90% of the markers. In group 2, only 1 of 7 cases showed concordance in all markers., Conclusions: If peritoneal mucin deposits present, even microscopic and acellular, the synchronous tumors are most likely of a single appendiceal origin. Otherwise, they are more heterogeneous, and some may be truly dual primaries.

Background: Tumours of appendix, including classic carcinoid tumour (CCT), goblet cell carcinoid (GCC), low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm/mucinous carcinoma (MCA) and non-mucinous adenocarcinoma (NMA), show different and sometimes mixed morphological features. It was hypothesised that these tumours originate from common tumour stem cell(s) with potential of various cell lineage differentiation. In normal intestinal epithelium, absorptive lineage (enterocytes) differentiation is driven by Notch-Hes1 pathway, while secretory lineage is driven by Wnt-Math1 pathway and further separated by different downstream signallings into three sublineages (Gfi1-Klf4/Elf3 for goblet cells, Gfi1-Sox9 for Paneth cells and Ngn3-Pdx1/Beta2/Pax4 for enteroendocrine cells)., Methods: The expressions of various signalling proteins in different appendiceal tumours were detected by immunohistochemistry on tumour tissue microarray., Results: CCT showed reduced Hes1/Elf3 and Sox9/Klf4 coupled with elevated Math1, in keeping with endocrine phenotype. As compared with CCT, GCC showed higher Klf4 and similar Ngn3/Pax4, indicative of a shift of differentiation towards goblet cells as well as endocrine cells. GCC displayed a Notch signalling similar to adenocarcinoma. Mucinous tumours showed lower Elf3 than normal appendiceal epithelium and higher Math1/Gfi1/Klf4, suggestive of a differentiation towards less enterocytes but more goblet cells. NMA showed Notch signalling similar to other glandular tumours, but lower Klf4. However, some seemingly paradoxical changes were also observed, probably suggesting gene mutations and/or our incomplete understanding of the intestinal cell differentiation., Conclusions: Wnt/secretory lineage protein and Notch/absorptive lineage protein expression profiles are generally associated with the tumour cell differentiation and morphological diversity of common appendiceal tumours., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) are used to treat peritoneal carcinomatosis from a variety of primary tumor sites. Little is known about the in vivo effects of CRS and HIPEC., Methods: We examined tumor and non-neoplastic peritoneal tissue samples from 38 patients undergoing CRS and HIPEC for appendiceal or colorectal carcinomatosis, using conventional histologic analysis and immunohistochemical analysis for markers of early DNA damage (phosphorylated H2AX, γH2AX) and early necrosis (extracellular HMGB1). Findings were correlated with clinicopathologic features and oncologic outcome., Results: Histologic findings corresponding with CRS and HIPEC included extensive submesothelial inflammatory infiltrate, endothelial activation, mesothelial karyolysis and surface fibrin deposition. Endothelial activation in submesothelial vessels exhibited high specificity for samples obtained following HIPEC relative to samples obtained following CRS but prior to HIPEC. Mesothelial nuclear γH2AX staining and submesothelial extracellular HMGB1 staining increased progressively following CRS and HIPEC, consistent with DNA damage and necrosis. No significant increase in tumor staining for markers was seen with CRS or HIPEC. Submesothelial HMGB1 staining was associated with increased progression-free survival on univariate analysis., Conclusions: The immediate histologic effects of CRS and HIPEC are defined and provide evidence that DNA damage and early steps of necrosis are underway in mesothelial tissues at the conclusion of the procedure. Further research will be necessary to investigate the impact of these findings on long-term oncologic outcome, and may provide insight into the downstream effects of CRS and HIPEC that could facilitate refinement of regional therapeutic regimens for carcinomatosis.

Low-grade appendiceal mucinous neoplasms (LAMNs) are commonly associated with deposition of mucin, with or without admixed low-grade epithelium, on peritoneal surfaces (pseudomyxoma peritonei). We describe a very rare presentation of LAMN as extensive mucin deposition in the endometrium of a 43-yr-old woman initially mistaken for a primary uterine myxoid neoplasm. The patient underwent endometrial curettage that demonstrated abundant myxoid/mucoid material interspersed with small vessels, bland eosinophilic spindled cells, scattered foci of typical endometrial stroma, and occasional endometrioid glands. The endometrial stroma was positive for CD10, and the eosinophilic spindled cells were positive for actin. The lesion was interpreted as "myxoid/mucinous neoplasm, most likely of smooth muscle/endometrial stromal origin." Subsequent laparotomy revealed peritoneal mucin in the anterior cul-de-sac and a dilated appendix. Pathologic review confirmed appendiceal LAMN and multifocal peritoneal mucinosis. The uterus contained scant residual mucoid material. On review of all pathologic material at our institution, the endometrial lesion was consistent with organizing mucin derived from the LAMN with entrapped benign endometrium. "Pseudomyxoma endometrii" is readily mistaken for a primary uterine myxoid neoplasm, particularly myxoid endometrial stromal tumor. A key to diagnosis is recognition that the material is mucin rather than myxoid stroma. This is evidenced by the absence of embedded stromal cells and presence of myofibroblastic, vascular, and macrophage infiltration associated with organization. Epithelium containing goblet cells is an important clue if present. The presence of rare endometrial glands within the endometrial stroma suggests that the latter is entrapped rather than neoplastic.

The clear cell/lipid-rich change has been described in neuroendocine tumors in several organs, but rarely observed in the appendix. In this study, we describe the morphologic, immunohistochemical features of incidentally discovered appendiceal carcinoids entirely represented by clear cells in a 22-year-old man and a 52-year-old woman. Ultrastructual examination demonstrated abundant lipid droplets and dense core granules. The mechanism leading to lipid accumulation in the cytoplasm has not been discovered, but degenerative processes following recurrent inflammatory change might be considered. This uncommon variant of appendiceal classic carcinoid tumors may bear a superficial resemblance to goblet carcinoid and/or appendiceal metastases from clear cell carcinoma. Awareness of clear cell carcinoid of the appendix will prevent incorrect diagnosis and unnecessary aggressive management., (© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Background: Mucins are implicated in survival in various cancers, but there have been no report addressed on survival in appendiceal carcinoma, an uncommon disease with different clinical and pathological features from those of other colon cancers. We aimed to investigate the clinical implications of expression of mucins in appendiceal carcinoma., Methods: Expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6, MUC16 and MUC17 in cancer tissue were examined by immunohistochemistry in 108 cases of surgically resected appendiceal carcinoma., Results: The following relationships of mucins with clinicopathologic factors were identified: MUC1 with positive lymphatic invasion (p = 0.036); MUC2 with histological type (mucinous carcinoma, p<0.001), superficial invasion depth (p = 0.007), negative venous invasion (p = 0.003), and curative resection (p = 0.019); MUC3 with non-curative resection (p = 0.017); MUC5AC with histological type (mucinous carcinoma, p = 0.002), negative lymphatic invasion (p = 0.021), and negative venous invasion (p = 0.022); and MUC16 with positive lymph node metastasis (p = 0.035), positive venous invasion (p<0.05), and non-curative resection (p = 0.035). A poor prognosis was related to positive lymph node metastasis (p = 0.04), positive lymphatic invasion (p = 0.02), positive venous invasion (p<0.001), non-curative resection (p<0.001), and positive expression of MUC3 (p = 0.004). In multivariate analysis, positive venous invasion (HR: 6.93, 95% CI: 1.93-24.96, p = 0.003), non-curative resection (HR: 10.19, 95% CI: 3.05-34.07, p<0.001) and positive MUC3 expression (HR: 3.37, 95% CI: 1.13-10.03, p = 0.03) were identified as significant independent prognostic factors in patients with appendiceal carcinoma., Conclusions: Expression of MUC3 in appendiceal carcinoma is an independent factor for poor prognosis and a useful predictor of outcome in patients with appendiceal carcinoma after surgery.

Background: Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2., Methods: Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer., Results: A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes., Conclusions: Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts have identified mutational spectra in several subtypes of these tumors that may suggest a phenotypic heterogeneity showing mutations that are relevant for targeted therapies., (© 2014 The American Association for Clinical Chemistry.)

The distinction between low-grade and high-grade disseminated appendiceal mucinous neoplasms is of critical importance in assessing prognosis and guiding patient therapy. SMAD4 encodes a protein that is a central component of the TGFβ signal transduction pathway, and loss of SMAD4 expression has been associated with poor prognosis in carcinomas of the gastrointestinal tract. We reviewed the clinicopathologic and molecular features of 109 disseminated appendiceal mucinous neoplasms identified over an 8-year period at our institution in an attempt to: (1) correlate SMAD4 immunohistochemical expression with tumor grade; and (2) assess the prognostic significance of SMAD4 expression in predicting overall survival. Compared with tumors demonstrating preserved SMAD4 expression, tumors with loss of SMAD4 expression more frequently exhibited high cytologic grade (85% vs. 50%, P=0.035), high cellularity (100% vs. 45%, P<0.001), and destructive invasion (100% vs. 55%, P=0.001). SMAD4 expression significantly correlated with overall tumor grade (P=0.003): all 13 tumors with loss of SMAD4 expression were high grade, whereas all 42 low-grade tumors displayed preserved SMAD4 expression. A significantly higher proportion of tumors with loss of SMAD4 immunohistochemical expression demonstrated loss of heterozygosity at chromosome 18q (38%) compared with tumors with preserved SMAD4 expression (11%) (P=0.049), suggesting that loss of SMAD4 expression is due to genomic deletion in a high proportion of cases. Patients with SMAD4-negative tumors had significantly worse overall survival in comparison with patients with preserved SMAD4 expression (log rank P=0.023). However, our multivariable analysis found that SMAD4 expression was not independent of overall tumor grade in predicting overall survival. Our results indicate that loss of SMAD4 immunohistochemical expression is associated with loss of heterozygosity at chromosome 18q and is always associated with aggressive histologic features in disseminated appendiceal mucinous neoplasms. SMAD4 immunohistochemistry may be a useful ancillary study in select cases of disseminated appendiceal neoplasia, in which the distinction between low-grade and high-grade tumors is difficult.

Background: Cytoreductive surgery (CRS) combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is the optimal treatment for Pseudomyxoma Peritonei (PMP). Despite treatment, disease often recurs and may not be amenable to further CRS. Clinical experience suggests a spectrum of disease which may correlate with tumour marker levels. The aim of this study was to analyse the influence of markers on recurrence and survival., Methods: The details of all patients undergoing surgery for PMP of appendiceal origin at a national centre for peritoneal malignancy were recorded in a dedicated prospective database. The data on all patients who had CRS and HIPEC between March 1994 and January 2012 was analysed and recurrence and survival correlated with pre-operative levels of CEA, CA-125 and CA19-9., Results: Overall, 519 (69%) of 752 consecutive patients, underwent complete CRS and HIPEC. The median (range) age was 56 (20-82) years with 342/519 (66%) females. The mean overall (OS) and disease free survival (DFS) in the 131/519 patients who had normal preoperative tumour markers was 168 (128-207) and 125 (114-136) months respectively, significantly higher when compared with the 109/519 (21%) who had all three tumour markers elevated (OS of 65 (42-88) and DFS of 55 (41-70) months respectively) (P = 0.002)., Conclusions: Elevated tumour markers predict an increased risk of recurrence and reduced survival after complete CRS. This may reflect cell biology in low grade tumours and is an independent prognostic feature. Further analysis may help to select patients for post-operative chemotherapy, second look procedures or stratification of follow up., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Pseudomyxoma peritonei (PMP) cases can be classified into the prognosis-related subtypes of disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). To investigate the mechanisms of mucinous invasion and the differing prognoses of these two subtypes, we examined the expression levels of proteins involved in cellular adhesion and invasion, including E-cadherin, vimentin, β-catenin, and S100A4, in single isolated tumor cells (SICs) and cohesive cellular strips within mucin pools isolated from DPAM (n = 31) and PMCA (n = 21) patients. In both PMCA and DPAM cases, SICs showed a complete loss of E-cadherin expression, whereas cells in cohesive cellular clusters retained E-cadherin expression. The frequency of high numbers of SICs (>8) in PMCA cases was significantly greater than that in DPAM cases (86% and 26%, respectively) and was correlated with poor progression-free survival (P = 0.019) in a univariate analysis. In both PMP subtypes, strong vimentin expression was identified in most of the SICs but not the cohesive cellular strips. The relatively slow progression of DPAM may be attributable to the smaller number of SICs that lack E-cadherin expression and have increased vimentin expression, whereas the rapid progression of PMCA may be due to larger numbers of these SICs., (© 2014 The Authors. Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Gastrointestinal stromal tumors of the vermiform appendix are rare. To date, only 11 cases have been reported in the English literature. Here, we present a new case of appendiceal gastrointestinal stromal tumor associated with complete situs inversus. A 48-year-old man was operated on due to appendicitis-like symptoms. Laparotomy revealed a ruptured conglomerate tumor in the lower abdomen associated with extensive peritoneal adhesions. Histology showed a spindle cell gastrointestinal stromal tumor with prominent sclerosis and calcification without low mitotic activity. The tumor cells expressed strongly CD117 and CD34. The mutation analysis revealed a heterozygous deletion/insertion involving exon 11 of KIT (pK558&#95;V559delNNins). Because the tumor was ruptured intraoperatively, a high risk was assigned according to the revised National Institute of Health criteria and adjuvant therapy with imatinib mesylate was recommended. The patient is currently alive without evidence of progression 27 months after surgery., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Goblet cell carcinoid (GCC) is a rare neuroendocrine tumor of the vermiform appendix with uncertain clinical behavior. It was first described by Gagné and Subbuswamy in 1969 and 1974, respectively. The tumor occurs almost exclusively in the vermiform appendix. We present a case of a 60-year-old female, who was referred to the Bielanski Hospital with signs and symptoms of acute appendicitis. Microscopic examination of the appendix showed features of acute appendicitis, however scattered groups of cells with clear cytoplasm as well as strands of single cells with no evidence of atypia were seen. The patient underwent a right hemicolectomy due to the diagnosis of GCC.

Objective: To explore the clinicopathological characteristics and prognostic factors of primary appendiceal adenocarcinoma., Methods: The clinicopathological data of 42 patients with primary appendiceal adenocarcinoma treated in the Cancer Hospital of Chinese Academy of Medical Sciences between March 1994 and October 2009 were retrospectively analyzed. The survival analysis was conducted using Kaplan-Meier method. The factors influencing survival were analyzed using univariate (Log-rank) and multivariate (Cox) models., Results: A total of 42 patients (29 female and 13 males, median age 56 years) with appendiceal adenocarcinoma were included in this study. Of them, 26 (61.9%) were mucinous adenocarcinoma, 12 (28.6%) were intestinal-type adenocarcinoma and 4 (9.5%) were signet cell carcinoma. 18 patients underwent curative resection, 20 patients received cytoreductive surgery, and 4 patients underwent biopsy only. Thirty patients received systemic chemotherapy (5-Fu-based regimens). One patient who died of postoperative pulmonary embolism on day 8 was excluded from the survival analysis. The overall 1-, 3-, and 5-year survival rate was 80.3%, 46.0% and 38.3%, respectively. Univariate analysis revealed that presence of symptoms of acute appendicitis, curative resection, histological grade, histological subtype, preoperative CEA level, systematic chemotherapy, and stage were all significant factors affecting the survival. Multivariate analysis showed that the preoperative CEA level (P = 0.01), histological grade (P = 0.001), and stage (P = 0.001) were independent prognostic factors., Conclusions: High level of CEA, G2/3 grade, and advanced stage are associated with poor prognosis in patients with primary appendiceal adenocarcinoma.

Aims: Tubular carcinoid is a rare variant of appendiceal well-differentiated neuroendocrine tumour. Although considered benign lesions, the small infiltrating tubules that characterise the tumour may raise concern for metastatic adenocarcinoma. To our knowledge, the cytokeratin 7 (CK7)/cytokeratin 20 (CK20) expression profile of these neoplasms remains unexplored., Methods: The authors characterised the CK7/CK20 immunophenotype and Ki-67 expression of the eight available tubular carcinoids seen at their institution from 1991 to 2011., Results: CK7 and CK20 staining was variable, ranging from none to focal staining for either or both CK7 and CK20, to diffuse expression of CK7 or CK20., Conclusions: The CK7/CK20 expression profile is of limited value when the differential diagnosis includes primary tubular carcinoid and well-differentiated metastatic adenocarcinoma. In such cases, careful attention to the location of the neoplasm, mitotic count and presence or absence of an associated classic carcinoid component are more useful for arriving at the correct diagnosis.

Purpose: The aim of this study was to evaluate the feasibility of phase 0 trials in the setting of a routine surgical procedure. Logistic considerations, tissue sampling and tissue handling, and variability of a biomarker during surgery, in here PARP, were evaluated., Experimental Design: Patients with highly suspicious or proven diagnosis of advanced ovarian cancer, planned for debulking surgery were asked to allow sequential tumor biopsies during surgery. Biopsies were frozen immediately and PARP activity was measured subsequently., Results: Baseline biopsies were obtained from eight patients after a median time of 88 minutes (minimum of 50 to maximum of 123 minutes). Second and third biopsies were obtained after a median of 60 (32-96) and 101 (79-130) minutes, respectively. Mean tumor load was 44% (5%-100%), with a cellular viability of 98% (85%-100%). Median baseline PARP activity was 1035 pg/mL (range, 429-2663 pg/mL). The observed interpatient variability at baseline was large: SD was 0.59 after natural logarithm transformation., Conclusions: Conducting phase 0 trials during surgery seems to be feasible in terms of logistic considerations. In preparation of a phase 0 trial during surgery, a feasibility study like this should be conducted to rule out major interactions of the surgical intervention with respect to the targeted biomarker., (©2012 AACR.)

Background: Intraperitoneal accumulation of mucinous ascites in pseudomyxoma peritonei (PMP) promotes an inflammatory/fibrotic reaction that progresses to bowel obstruction and eventual patient demise. Cytokines and inflammation-associated transcription factor binding sites, such as glucocorticoid response elements and COX-2, regulate secretory mucin, specifically MUC2, production. We hypothesized that anti-inflammatory drugs targeting inflammation-associated pathways may reduce mucin production and subsequent disease morbidity in PMP., Methods: The effects of dexamethasone and Celebrex were assessed in mucin-secreting human colon cancer LS174T cells in vitro and murine xenograft models of LS174T and human appendiceal PMP in vivo by serial parametric measurements, MUC2 transcripts via real-time RT-PCR, and MUC2 protein expression via immunofluorescence assays., Results: Dexamethasone significantly inhibited basal MUC2 mRNA levels in LS174T cells, inhibited mucinous tumor accumulation in an intraperitoneal PMP xenograft model, and prolonged survival in a subcutaneous LS174T xenograft model. Celebrex significantly inhibited sodium butyrate-stimulated MUC2 mRNA levels in LS174T cells and demonstrated a statistically nonsignificant trend toward reduced mucinous tumor growth and prolonged survival in the xenograft models. MUC2 protein analysis by immunofluorescence demonstrated a dual effect of dexamethasone on mucin production and tumor cell count., Conclusions: Inflammatory mediators are known to regulate mucin production and may promote overexpression of MUC2 by neoplastic cells with goblet cell phenotype in PMP. Anti-inflammatory drugs, dexamethasone and Celebrex, could inhibit extracellular mucin production in PMP by targeting inflammatory cascades and, therefore, may decrease compressive symptoms, increase the disease-free interval, and reduce the extent or frequency of morbid cytoreductive surgeries.

Inflammatory myofibroblastic tumor (IMT) has been described as a pseudosarcomatous proliferation of spindled myofibroblasts admixed with lymphoplasmacytic cells. The various terminologies like inflammatory pseudotumor, plasma cell granuloma, and inflammatory myofibrohistiocytic proliferation, used to describe this entity, highlight the controversial etiopathogenesis of this relatively indolent neoplasm. IMT has now been described in different anatomic locations. However, cases occurring in the gastrointestinal tract are rare with very few cases described in the appendix. We present a case of inflammatory myofibroblastic tumor appendix with mucosal dysplasia in a 41-year-old male, presenting with abdominal pain and lump in the right iliac fossa. Aspiration cytology yielded few atypical epithelial cells and spindle cells in a mucinous background, suggesting the possibility of pseudomyxoma peritonei. Awareness of IMT appendix with rare presence of mucosal dysplasia may help in preventing overzealous resection, especially in situations that on preoperative evaluation may suggest malignancy.

Objective: Leptin contributes to mucin production in colonic epithelium and regulates carcinogenesis via various signalling pathways. We evaluated the proteins involved in mucin-producing carcinogenesis and putative targets for molecular therapy in appendiceal mucinous neoplasms., Methods: Immunohistochemistry and fluorescence in situ hybridization were performed in 22 cases of appendiceal mucinous adenoma, 20 mucinous neoplasms of uncertain malignant potential and 14 mucinous adenocarcinomas., Results: Leptin, MUC2, MUC5AC, mTOR and ERK were more frequently immunopositive in mucinous adenocarcinomas compared with mucinous adenomas or mucinous neoplasms of uncertain malignant potential (p < 0.05). STAT3 revealed immunopositivity in 82% of tumours, regardless of tumour category. MUC2 immunopositivity was associated with pseudomyxoma peritonei (p < 0.05). None of the tumours exhibited c-kitimmunoexpression, amplification of Her2 or EGFR, or translocation of ALK. The mTOR-immunopositive group of patients had a lower rate of disease-free survival compared with the mTOR-immunonegative group (p < 0.05)., Conclusions: Leptin may collaborate with MUC2 and MUC5AC in mucin-producing carcinogenesis in an mTOR-, STAT3- and ERK-dependent manner. STAT3 may be activated early during tumorigenesis. MUC2 and mTOR (but not c-kit, Her2, EGFR and ALK) may represent targets for molecular therapy in pseudomyxoma peritonei and appendiceal mucinous adenocarcinoma, respectively., (Copyright © 2012 S. Karger AG, Basel.)

Ectopic ACTH production causes 10% of Cushing's syndromes. The diagnostic workup is difficult, can last more than 6 months (> 50% of cases), and the underlying tumour is still frequently not located (12%). Carcinoid tumours of the appendix are frequent and are revealed in 0.3% of patients undergoing routine appendectomy. However, neuroendocrine tumours of the appendix with ACTH production are an extremely rare entity. Here we report the case of a female patient with clinically overt Cushing's syndrome due to ectopic ACTH-production from a carcinoid tumour of the appendix. During the diagnostic workup, repeated endocrine tests, multiple different imaging modalities and frequent and lengthy hospitalisations were necessary. Wrongly, even a neurosurgical pituitary exploration was performed. After 12 months from the initial admission, the tumour was finally detected by an ¹⁸F-fluoro-L-dihydroxyphenylalanine (¹⁸FDOPA PET) and an appendectomy followed by right hemicolectomy were performed. The patient recovered rapidly and the symptoms from the hypercortisolism were no more present.In this case, we discuss the multitude of problems, which may delay the diagnosis and the pitfalls, that should be avoided in order to locate the tumour and to initiate adequate therapy as early as possible. Furthermore, our case demonstrates the complexity of diagnostic procedures, which demand most of the times a multidisciplinary approach. In this setting, regular follow-ups in short time intervals and the use of novel imaging techniques can finally cut the diagnostic "Gordian knot"., (© J. A. Barth Verlag in George Thieme Verlag KG Stuttgart · New York.)

Aim: To investigate the histological origin of pseudomyxoma peritonei (PMP) in Chinese women., Methods: The clinical and pathological data were reviewed for 35 women with PMP, and specimens of the peritoneal, appendiceal and ovarian lesions of each patient were examined using the PV-6000 immunohistochemistry method. Antibodies included cytokeratin (CK)7, CK20, mucin (MUC)-1, MUC-2, carbohydrate antigen (CA)-125, estrogen receptor (ER), and progesterone receptor (PR)., Results: Abundant colloidal mucinous tumors were observed in the peritoneum in all 35 cases. Thirty-one patients had a history of appendectomy, 28 of whom had mucinous lesions. There was one patient with appendicitis, one whose appendix showed no apparent pathological changes, and one with unknown surgical pathology. Ovarian mucinous tumors were found in 24 patients. The tumors were bilateral in 13 patients, on the right-side in nine, and on the left side in two. Twenty patients had combined appendiceal and ovarian lesions; 16 of whom had undergone initial surgery for appendiceal lesions. Four patients had undergone initial surgery for ovarian lesions, and relapse occurred in these patients at 1, 11, 32 and 85 mo after initial surgery. Appendiceal mucinous tumors were found in each of these four patients. Thirty-three of the 35 patients showed peritoneal lesions that were positive for CK20 and MUC-2, but negative for CK7, MUC-1, CA125, ER and PR. The expression patterns in the appendix and the ovary were similar to those of the peritoneal lesions. In one of the remaining two cases, CK20, CK7 and MUC-2 were positive, and MUC-1, CA125, ER and PR were negative. The ovaries were not resected. The appendix of one patient was removed at another hospital, and no specimen was evaluated. In the other case, the appendix appeared to be normal during surgery, and was not resected. Peritoneal and ovarian lesions were negative for CK20, MUC-2, CK7, MUC-1, CA125, ER and PR., Conclusion: Most PMP originated from the appendix. Among women with PMP, the ovarian tumors were implanted rather than primary. For patients with PMP, appendectomy should be performed routinely. The ovaries, especially the right ovaries should be explored.

Goblet cell carcinoid (GCC) of the appendix is currently classified as a neuroendocrine tumor, together with typical carcinoid (TC) of the appendix. However, whether GCC is a variant of TC or a mucin-producing adenocarcinoma is still controversial. To get a better understanding, we investigated the clinicopathological features of 55 Chinese patients (26 GCCs and 29 TCs), and explored the histochemical properties and expression profiles of CK7, CK20, P63, CEA, CgA, NSE, CD56, and Ki67 in 37 out of these 55 patients (18 GCCs and 19 TCs). Our results showed GCC had a male predominance, older age involvement, significantly larger tumor size, and significantly more frequency of mesoappendix infiltration than TC. Alcian blue/PAS stains were positive in all the GCC cases, while negative in all the TC cases. CK7 and CK20 expressions were significantly more frequent in GCC (P = 0.03 and 0.00001, respectively). However, P63 expression was detected in none of the GCC cases but in 6 TC cases (P = 0.02). Although the expression of CgA was similar, strong expression (3+) was significantly more frequent in TC (P = 5.7 × 10(-11)). Also, NSE and CD56 expressions were significantly more frequent in TC (P = 0.02 and 1.26 × 10(-4), respectively). CEA expression was significantly more frequent in GCC (P = 2.4 × 10(-6)). Finally, Ki67 index was low in GCC (4.7%), but significantly higher than TC (0.9%) (P = 5.4 × 10(-6)). Taken together, these distinct features support that GCC differs from TC, a classical neuroendocrine tumor, and harbors an immunophenotype of adenocarcinoma. Therefore, the term "low grade adenocarcinoma with neuroendocrine differentiation" might be more appropriate for GCC.

The designation of clear cell/lipid-rich refers to an unusual variant of neuroendocrine tumor ("carcinoid") described in several organs, but only recently observed in the appendix. In this study, we report the morphologic, immunohistochemical, and ultrastructural features of an incidentally discovered appendiceal clear cell/lipid-rich carcinoid in a 32-year-old man without any evidence of von Hippel-Lindau disease. Differential diagnosis with mimicking neoplastic and non-tumor lesions, epidemiology, and clinical behavior of this exceedingly rare variant of carcinoid of the appendix are also discussed.

Goblet cell carcinoid (GCC) of the appendix is characterized by a dual differentiation of both endocrine and gland. This study, therefore, explores its clinicopathological and immunohistochemical features. The authors reviewed clinicopathological and immunohistochemical features of 26 GCC cases in Southwest China between 1991 and 2009. The incidence is 0.0453%, with a gender ratio of 2.71:1 (19 males and 7 females). Three cases were combined with schistosomiasis, suggesting schistosomiasis may be associated with GCC. Eighteen cases available for immunohistochemistry showed a few scattered positive cells for CD56, NSE, CgA, and Syn; diffuse positive for CEA; and preserved positive for E-cadherin and β-catenin. Follow-up data showed that 1 patient died from peritoneal metastasis and that the other 17 cases survived free of the tumor. The authors characterize GCC as a special low-grade malignant carcinoma with a primary epithelial differentiation and little neuroendocrine differentiation. A combination of both histological features and immunoreactivity is needed to diagnose GCC.

We describe the clinical, pathologic and molecular characteristics of a xenograft model of metastatic mucinous appendiceal adenocarcinoma. Tumours from patients with mucinous appendiceal neoplasms were implanted in nude mice and observed for evidence of intraperitoneal tumour growth. Morphologic and immunohistochemical features, temporal growth characteristics relative to controls, and loss of heterozygosity (LOH) at multiple chromosomal alleles were assessed in a successfully engrafted tumour. Two of seventeen implanted tumours successfully engrafted and only one mucinous adenocarcinoma propagated throughout the course of the study. The successful xenograft is morphologically similar to the original tumour, produces abundant extracellular mucin and exhibits non-invasive growth on peritoneal surfaces. The temporal growth characteristics of the xenograft tumour relative to controls reveal that tumour burden can be followed indirectly by measuring the weight or abdominal girth of engrafted animals. The cytokeratin, mucin core protein, CDX2, Ki-67 and p53 expression patterns are identical in the xenograft and resected tumour and are consistent with the expected pattern of protein expression for mucinous adenocarcinoma of the appendix. LOH was found in 1 of 10 informative chromosomal loci (chromosome 10p23) in xenograft tumour cells. Although we were unable to engraft a low-grade appendiceal mucinous neoplasm, the engrafted adenocarcinoma will be useful for future evaluation of novel therapeutic strategies directed at mucinous appendiceal adenocarcinoma and evaluation of strategies for treating widespread, bulky, mucinous peritoneal surface neoplasms. Xenograft tumour enrichment can facilitate molecular studies of appendiceal epithelial neoplasia.

We performed a histologic and immunohistochemical assessment of 53 noninvasive appendiceal epithelial proliferations, appropriating terminology and using markers shown useful in differentiating serrated colorectal polyps. These were classified as hyperplastic polyp (HP), sessile serrated adenoma (SSA), mixed serrated and adenomatous lesion (MSAL), mucinous cystadenoma (MCA), or conventional adenoma (CAD). Immunohistochemical analysis for cytokeratin (CK) 20, Ki-67, MUC6, and beta-catenin was performed. Diagnoses were as follows: HP, 6; SSA, 12; HP vs SSA, 3; MSAL, 16; MCA, 14; and CAD, 2. All HPs showed expanded (beyond surface) CK20 and expanded or normal (base) Ki-67; 1 was MUC6+. Most SSAs and MSALs were CK20-expanded or expanded with random expression in deep crypts (Ex/I) and Ki-67-expanded, Ex/I (expanded with asymmetry), or normal. All SSAs and 8 of 16 MSALs were MUC6+. CADs were CK20-Ex/I, Ki-67-Ex, and MUC6-; 1 showed nuclear beta-catenin expression. Serrated appendiceal lesions can be categorized using colorectal terminology. MUC6 is associated with SSA morphologic features. Similar immunohistochemical patterns in SSA and MSAL suggest a link between these lesions.

Appendiceal mucinous neoplasms confined to the mucosa are benign, whereas those with disseminated peritoneal mucin deposits often follow an indolent, but malignant, course. Not infrequently, appendiceal mucinous neoplasms are associated with localized periappendiceal mucin deposits, but lack diffuse peritoneal involvement. Mucin deposits in these cases may be acellular or contain neoplastic epithelium (cellular mucin). Although some investigators consider both acellular and cellular periappendiceal mucin to pose no, or minimal, risk for recurrent disease, the biologic importance of localized extra-appendiceal mucin has never been evaluated. We identified 65 patients with appendiceal mucinous neoplasms, all of whom had localized periappendiceal mucin deposits without diffuse peritoneal involvement, and assessed them for the presence of extra-appendiceal epithelium and clinical outcome. Forty-nine (75%) appendices were submitted in total for histologic evaluation. Most (77%) cases showed acellular periappendiceal mucin, but 15 (23%) had scant extra-appendiceal epithelium (range: 1 to 12 cell clusters). Upon follow-up (mean: 48 mo), 2 (4%) patients with acellular periappendiceal mucin developed diffuse peritoneal disease, but neither of these appendices was submitted in total for histologic evaluation. In contrast, 5 of 15 (33%) patients with cellular periappendiceal mucin developed mucinous ascites, including 1 who eventually died of disease (P=0.03). Thus, patients with appendiceal mucinous neoplasms and acellular periappendiceal mucin are unlikely to develop recurrent disease. However, microscopic examination of the entire appendix is necessary, as lesions with extra-appendiceal tumor cells are more likely to progress to disseminated disease and result in death of the patient, even if the mucin is paucicellular and confined to the periappendiceal region.

The paper describes a case of appendicular metastatic involvement in breast cancer. The 60-year-old female patient developed the signs of acute appendicitis 18 years after detection of primary tumor; after appendectomy the intraoperative appendular specimens exhibited trains of tumor cells that infiltrated the mid- and lower muscle layer third. Immunohistochemical study revealed a moderate expression of Er and Pgr receptors (150 H scores), a positive reaction with EMA, K7, K6, and lactoalbumin The authors review the data available in the literature on the specific features of metastatic spread into the appendix and on management tactics in these patients.

We report the rare occurrence of an inflammatory fibroid polyp of the appendix. The lesion was diagnosed in a 33-year-old woman presenting with abdominal pain, fever and localized tenderness in right iliac fossa on abdominal palpation. CT-scan showed an 8 cm appendiceal mass and a laparoscopic appendectomy was consequently performed. On microscopic examination, the tumor consisted of spindle cells dispersed in a loose fibromyxoid stroma containing numerous blood cells and inflammatory cells with abundant eosinophils. On immunohistochemistry, the spindle tumor cells were positive for vimentin, fascin and focally for CD34 and CD35. They were negative for smooth muscle actin, desmin, CD21, CD23, CD117 and S100 protein. Inflammatory fibroid polyp is a rare benign mesenchymal tumor of the gastrointestinal tract rarely reported in the appendix. This tumor shares some common pathologic features with the myofibroblatic inflammatory tumor but they are two different entities. The pathogenesis of this tumor remains unclear but fascin and CD35 immunoreactivity of the tumor cells suggests a probable dendritic cell origin.

Aims: Goblet cell carcinoid is a poorly understood tumour of the appendix. The aim of this study was to determine whether it should be regarded as a separate entity or as a variant of classical carcinoid., Methods and Results: The immunohistochemical expression pattern of 21 markers and the mutation status of KRas codon 12 were determined in 16 goblet cell carcinoids and compared with 14 classical carcinoids, 19 colonic adenocarcinomas and 10 appendiceal mucinous cystadeno (carcino)mas. The results were subjected to a stepwise linear discriminant analysis. Goblet cell carcinoids were significantly different from the control groups. The most important markers for discriminating between the groups were CEA (classical carcinoid versus all others), KRas mutation (present in all mucinous cystadeno (carcino)mas), beta-catenin (goblet cell carcinoid versus left sided colonic adenocarcinoma) and chromogranin (goblet cell carcinoid versus right sided colonic adenocarcinoma). Expression of Math1 and HD5 was similar in goblet cell carcinoid and colonic adenocarcinoma but absent in classical carcinoid., Conclusion: The results suggest that goblet cell carcinoids should be regarded as a separate entity. The formerly used term 'crypt cell carcinoma' may be more appropriate because it reflects the more aggressive clinical behaviour of these tumours as well as their greater similarity to adenocarcinomas rather than to carcinoids.

Synchronous and metachronous ovarian and appendiceal mucinous tumors are often the subject of diagnostic consultations in gynecologic pathology practices to address whether the tumors are independent neoplasms or related as primary and metastasis. Those with goblet cell carcinoidlike patterns have not been extensively evaluated in a large series. Clinicopathologic features of 30 cases were examined. All patients presented with signs or symptoms related to a pelvic/adnexal or abdominal mass. The ovarian tumors were bilateral in 25 of 28 cases with data on both ovaries and were typically large (mean/median: 14 cm, range: 4.5 to 24.0 cm). The appendices were often firm or thickened but usually did not have a discrete measurable tumor and were not notably enlarged; microscopically, transmural invasion was present in all of them. The ovarian and appendiceal tumors exhibited a variety of patterns of differentiation, including signet ring cell and glandular, with all displaying some goblet cell carcinoidlike patterns (nests, islands, cords, or cryptlike tubules with goblet cells); teratomatous elements were not identified in any ovarian tumors. Chromogranin was expressed in 7 of 19 ovarian tumors (mean/median: 6.3%/0%; range: 0% to 20%) and synaptophysin was expressed in 4 of 18 of these (mean/median: 7.8%/0%; range: 0% to 90%). Chromogranin was expressed in 6 of 16 appendiceal tumors (mean/median: 11.9%/0%; range: 0% to 70%) and synaptophysin was expressed in 6 of 15 of these (mean/median: 16.7%/0%; range: 0% to 90%). Follow-up was available for 25 patients: 17 died of disease at intervals ranging from 4 to 47 months (mean/median: 18/16) and 8 were alive with disease at 1 to 25 months (mean/median: 11/10); median survival was 19 months and the 1-year and 2-year survival rates were 63% and 34%, respectively. The clinicopathologic features of these ovarian tumors indicate they should be labeled as metastatic appendiceal adenocarcinomas rather than as goblet cell carcinoid tumors both to reflect their behavior and help distinguish them from the rare true primary ovarian goblet cell carcinoid tumors. As the ovarian tumors have appreciable components of signet ring cells they qualify as Krukenberg tumors. In cases in which the primary tumor is not already evident, their "goblet cell carcinoidlike" patterns should direct attention to the appendix as a possible source.

A 58-year-old man with a 1 year history of progressive abdominal distension underwent a laparotomy for pseudomyxoma peritonei. The mucin was identified and characterized in the present study. Approximately 6 L of crude mucus in the sol (highly viscous) and gel (semisolid) phases was obtained from the patient's peritoneal cavity. The sol material was briefly homogenized followed by slow stirring at dilutions of up to 1:10 with 6 mol/L guanidinium chloride and proteolytic inhibitors for periods of up to 48 h. Preparative and analytical gel filtration on Sepharose 2B showed some PAS-positive material eluting in the void volume accompanied by equal or larger amounts of protein in the void and included volumes of the columns. Sodium dodecylsulfate-polyacrylamide gel electrophoresis of purified mucin on a 4-20% gradient gel showed PAS-positive material on the top of the running gel and a distinct smaller-sized species of mucin of higher electrophoretic mobility with background material in between the large and small mucin. Western blot (confirmed by immunohistochemical analysis) after agarose gel electrophoresis showed the presence of MUC2, MUC5AC and MUC5B in the mucus. There was no MUC1, MUC1core or MUC6 in the tissue. Histopathological examination confirmed a mucinous appendicular adenocarcinoma. Histology showed the mucin to be predominantly of the sulfated and non-sulfated acidic type. Serine, threonine and proline comprised 21.6% of the total amino acid composition of the sample. The viscous nature of the material is due to the presence of three gel-forming mucins and possibly to its high content of protein.

The immunoexpression of CK19 recently has been identified as a marker of poor prognosis in pancreatic endocrine tumors and hepatocellular carcinoma. Conversely, the loss of expression of CD99 has been suggested to play a role in the tumorigenesis and dedifferentiation and is associated with poor outcome in some malignancies. The purpose of this study was to explore CK19 and CD99 immunostaining in mucin-producing neuroendocrine (goblet cell) and classical carcinoids of the appendix. Eighteen goblet cell carcinoids (GCCs) and 20 classic carcinoids were stained with CK19, CD99, and Ki-67, and these results were correlated with known pathological features of aggression: extent of invasion, mitoses, necrosis, and histological pattern. All 18 GCCs were CK19 strongly positive, whereas 16/20 classic carcinoids were also CK19 positive. Fourteen of 18 GCCs and 14/20 classic carcinoids were CD99 positive. CK19/CD99 immunoexpression did not correlate with extent of tumor invasion and mesoappendiceal extension, mitotic activity, Ki-67 labeling index, presence of extracellular mucinous pools dissecting muscle, and angiolymphatic and perineural/neural invasion. There is no difference in the immunostaining for CK19 and CD99 between GCCs and classic carcinoids, and both types of neuroendocrine tumor show the same extent of expression of both markers.