Practice patterns for reporting digestive system neuroendocrine neoplasms: results from a large, comprehensive international survey.

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.

Differential expression of Chitinase 3-Like 1 protein in appendicitis and appendix carcinomas.

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.

Prevalence of mesothelin expression in peritoneal disease from colorectal and appendiceal cancers.

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.

Neuroendocrine neoplasms of the appendix: Characterization of 335 patients referred to the Copenhagen NET Center of Excellence.

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.

Ectopic ACTH production by thymic and appendiceal neuroendocrine tumors - two case reports.

OBJECTIVES: Ectopic adrenocorticotropic syndrome (EAS) causes approximately 10-18% of cases of Cushing's syndrome (CS) in adults, while in children it occurs much less frequently. CASE PRESENTATION: We report two cases of neuroendocrine tumors (of the thymus and the appendix) in a 12-year-old boy and a 15-year-old girl who presented with the clinical features of CS. Elevated serum cortisol, ACTH, and chromogranin levels were observed in both patients. Diagnoses were made on the basis of a mass in the thymus/appendix region visualized with chest/abdominal CT scan and radiotracer accumulation in scintigraphy in the same areas. Histopathological examinations confirmed the diagnoses of NET. CONCLUSION: EAS is an extremely rare endocrine disorder. However, it should be taken into consideration in the diagnostic process of every case of ACTH-dependent CS.

INSM1 Is a Highly Specific Marker of Neuroendocrine Differentiation in Primary Neoplasms of the Gastrointestinal Tract, Appendix, and Pancreas.

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.

Appendix Tumor Microenvironment.

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.

Immunophenotypic Comparison of Neoplasms of the Appendix, Right Colon, and Left Colon in Search of a Site-Specific Phenotypic Signature.

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 utility of PAX8 and SATB2 immunohistochemical stains in distinguishing ovarian mucinous neoplasms from colonic and appendiceal mucinous neoplasm.

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.

Appendiceal mucinous neoplasm mimics ovarian tumors: Challenges for preoperative and intraoperative diagnosis and clinical implication.

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.

Genomic profile of appendiceal goblet cell carcinoid is distinct compared to appendiceal neuroendocrine tumor and conventional adenocarcinoma.

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.

SATB2 is a supportive marker for the differentiation of a primary mucinous tumor of the ovary and an ovarian metastasis of a low-grade appendiceal mucinous neoplasm (LAMN): A series of seven cases.

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.

Appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid are genetically distinct from primary colorectal-type adenocarcinoma of the appendix.

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.

Elevated brain natriuretic peptide (BNP) is an early marker for patients at risk for complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC).

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.

Differing expression profiles of Notch/enterocyte and Wnt/secretory lineage signallings are associated with morphological diversity of appendiceal tumours.

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.

Synchronous Ovarian and Appendiceal Mucinous Neoplasms in the Absence of Pseudomyxoma Peritonei.

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.

Histologic and Immunohistochemical Alterations Associated with Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy.

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.

"Pseudomyxoma Endometrii": Endometrial Deposition of Acellular Mucin from a Low-Grade Appendiceal Mucinous Neoplasm as a Rare Mimic of Myxoid Uterine Tumors.

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.

Clear cell carcinoid of the appendix: Report of two cases with literature review.

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.