ASO Visual Abstract: The Impact of Preoperative Colonoscopy for Appendiceal Mucinous Neoplasms.

Preoperative colonoscopy is recommended for colorectal cancers to exclude synchronous tumors.However, data are lacking regarding this recommendation for appendiceal mucinous neoplasms. This study evaluated whether preoperative colonoscopy in patients with appendiceal mucinous lesions would reveal a significant finding, modify the operative plan, or be associated with adverse events. This mixed-methods retrospective cohort study included all mucinous appendiceal neoplasms between 2017 and 2024 at a tertiary care hospital. Overall, 100 patients were included: 15% presented with acute appendicitis, 31% presented with an appendiceal mucinous lesion, and 54% presented with pseudomyxoma peritonei. Preoperative colonoscopy was performed in 83% of patients, 73.4% of which were normal, 19.3% showed benign polyps, 3.6% demonstrated caecal base invasion, 2.4% showed appendicular orifice invasion, and 1.2% had extrinsic caecal compression. No synchronous colorectal tumors were identified. When caecal invasion was demonstrated on colonoscopy, it had already been identified on preoperative computed tomography scan. The operative approach was never modified based on the colonoscopy results. There was no difference in discovery of tumor perforation between patients who underwent colonoscopy and those who did not (85% vs. 75%; p=0.286). Longer time to surgery for those undergoing preoperative colonoscopy (325.9 vs. 116.1 days; p=0.034) reflected the need for thorough work-up, neoadjuvant therapy, specialist consultations, and tertiary-care center referrals for patients with advanced appendiceal mucinous neoplasms. Preoperative colonoscopy demonstrated a low yield, a limited capacity to modify operative management, and was not associated with a higher probability of tumor perforation. Colonoscopy may be safely postponed postoperatively in select patients.

Low-Grade Appendiceal Mucinous Neoplasm Versus High-Grade Appendiceal Mucinous Neoplasm

The classification of appendiceal mucinous tumors is controversial and terminology used for them inconsistent, particularly when they lack overtly malignant features but are associated with extra-appendiceal spread. We reviewed 107 appendiceal mucinous neoplasms and classified them as low-grade appendiceal mucinous neoplasm (LAMN) (n = 88), mucinous adenocarcinomas (MACAs) (n = 16), or discordant (n = 3) based on architectural and cytologic features. LAMNs were characterized by a villous or flat proliferation of mucinous epithelium with low-grade atypia. Thirty-nine tumors were confined to the appendix, but 49 had extra-appendiceal tumor spread, including 39 with peritoneal tumor characterized by mucin pools harboring low-grade mucinous epithelium, usually dissecting in a hyalinized stroma. Eight of the 16 MACAs lacked destructive invasion of the appendiceal wall and eight showed an infiltrative pattern of invasion. Extra-appendiceal tumor spread was present in 12 MACAs (four peritoneum, seven peritoneum and ovaries; one ovaries only). In MACAs with an infiltrative pattern, peritoneal tumor consisted of glands and single cells in a desmoplastic stroma. The peritoneal tumor in the remaining cases consisted of mucin pools that contained mucinous epithelium with high-grade atypia and, in some cases, increased cellularity compared with that seen in peritoneal spread in cases of LAMN. Three cases were classified as discordant because the appendiceal tumors were LAMNs but the peritoneal tumors were high-grade. Follow-up was available for 49 LAMNs, 15 MACAs, and 2 discordant cases. None of the patients with LAMNs confined to the appendix experienced recurrence (median follow-up 6 years). LAMNs with extra-appendiceal spread were associated with 3-, 5-, and 10-year survival rates of 100%, 86%, and 45%, respectively. Patients with MACA had 3- and 5-year survival rates of 90% and 44%, respectively (p = 0.04). The bulk of peritoneal disease correlated with prognosis among patients with MACA (p = 0.04) and, to a lesser degree, among patients with LAMNs (p = 0.07). We conclude that: 1) appendiceal mucinous neoplasms can be classified as either low-grade mucinous neoplasms or mucinous adenocarcinoma based on architectural and cytologic features; 2) tumors that can be confidently placed in the low-grade group (which requires rigorous pathologic evaluation of the appendix) and are confined to the appendix are clinically benign in our experience to date; 3) low-grade tumors confined to the appendix are morphologically identical to those with extra-appendiceal spread (except for the usual identification of breach of the wall in the latter cases) and the same designation is appropriate for the appendiceal neoplasia in each situation; 4) the long-term outlook for patients with low-grade tumors and peritoneal spread is guarded with just over half dying of disease after 10 years; 5) appendiceal mucinous tumors with destructive invasion of the appendiceal wall, complex epithelial proliferations, or high-grade nuclear atypia generally pursue an aggressive clinical course and should be classified as mucinous adenocarcinomas; 6) peritoneal tumor can be classified as involvement by LAMN or MACA, and this distinction is of prognostic significance; 7) bulky peritoneal tumor worsens prognosis; and 8) LAMNs associated with high-grade peritoneal tumor behave as adenocarcinoma.

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.

Appendiceal mucinous neoplasms (AMNs) are rare tumors accounting for less than 1% of all cancers. The clinical presentations of AMN vary significantly and the diagnosis of most patients is during surgery for suspected appendicitis, peritonitis or gynecological cancer. There were many case reports AMN mimicking an ovarian cancer. In this case, we reported a 64-year postmenopause woman with diagnosed peritonum carcinomatosis dd/ ovarian cancer and it actually AMN in RSUP dr. M. Djamil Padang, West Sumatera. The diagnosis is estimated by ultrasonography (USG), computed tomography (CT), magnetic resonance imaging (MRI) and diagnostic laparoscopy followed by histopathologic verification. The evaluation of the prognosis of appendix mucinous adenocarcinoma mainly depends on whether the tumour is in an advanced stage, the degree of malignancy, and whether an AMN is formed

The role of somatic mutation profiling in the management of appendiceal mucinous tumors (AMTs) is evolving. Using a systematic review, we identified somatic alterations (SAs) that comprise histopathologic types of AMTs and those associated with aggressive clinical phenotypes. MEDLINE/PubMed was searched for studies on AMTs including molecular markers or genomic alterations, published between 1990 and 2018. Studies were grouped under low- and high-grade histological type for primary and metastatic tumors. Twenty-one studies involving 1099 tumors (primary/metastatic) were identified. Seven studies involving 101 primary low-grade AMTs identified KRAS (76.5%) as the predominant SA. Four studies noted GNAS in 45.2% of 42 low-grade appendiceal mucinous neoplasms, and KRAS was identified in 74.4% of 14 studies with 238 low-grade pseudomyxoma peritonei (PMP). GNAS was noted in 56% of 101 tumors and TP53 was noted in only 9.7% of 31 tumors. Primary high-grade tumors demonstrated lower SAs in KRAS (50.4% of 369 tumors) and GNAS (27.8% of 97 tumors), and higher SAs in TP53 (26.0% of 123 tumors). In high-grade PMP, SAs were noted in KRAS (55.0% of 200 tumors), GNAS (35.0% of 60 tumors), and TP53 (26.3% of 19 tumors). No clear association was noted between SAs and survival. KRAS and GNAS are frequently altered in low-grade AMTs, while TP53 is frequently altered in high-grade AMTs, with no apparent change in expression between primary and metastatic tumors. Although SAs may provide valuable insights into variability in tumor biology, larger studies utilizing clinically annotated genomic databases from multi-institutional consortiums are needed to improve their identification and clinical applicability.

Review: Pathology and Its Clinical Relevance of Mucinous Appendiceal Neoplasms and Pseudomyxoma Peritonei

Mucinous appendiceal tumors consist of mucinous adenocarcinoma, low-grade appendiceal mucinous neoplasm, and high-grade appendiceal mucinous neoplasm. The incidence of non-mucinous adenocarcinomas is reduced. The most recent edition of the World Health Organization classification and recent consensus guidelines will enable the consistent application of agreed nomenclature. Not only is precise diagnosis essential for effective patient management, but it also facilitates the comparison of results across centers and tumor registries. The most prevalent benign adenoma in the appendix is serrated. It is imperative to differentiate these conditions from low-grade appendiceal mucinous neoplasms, as the latter can also resemble harmless ailments. Adenocarcinomas of the goblet cells are a rare subtype of appendiceal neoplasm. While appendiceal neoplasms are uncommon, they are not entirely so, and even the most seasoned pathologists may find them difficult to diagnose. In addition, appendiceal neoplasia classification and terminology have been subjects of contention for decades. Nonmucinous appendiceal neoplasms are less prevalent than mucinous tumors, and their association with other appendiceal neoplasm subtypes remains uncertain. A literature review of appendiceal mucinous neoplasms identified during laparoscopic appendicectomies is presented here.

Low grade appendiceal mucinous neoplasms can spread to the peritoneum as pseudomyxoma peritonei even though they are not obviously invasive in the appendix. During the past several decades, several problematic issues surrounding this enigmatic tumor have been debated in the literature, including appropriate nomenclature for the appendiceal tumors and their peritoneal metastases. In this article, the most contentious issues in the area of appendiceal mucinous tumors are examined. First, the classification systems that have been proposed for these tumors are compared in the context of whether the appendiceal mucinous tumors are ruptured adenomas or invasive carcinomas. The controversy about the nature of pseudomyxoma peritonei and its classification systems is discussed in the following section. A brief discussion follows that examines the issue of localized pseudomyxoma peritonei and its clinical significance. Next reviewed is the largely resolved controversy about whether ovarian mucinous tumors in this setting are separate primaries or are metastases from the appendiceal tumor. Finally, the controversy about the most effective treatment of patients with pseudomyxoma peritonei is discussed.

Introduction: Appendiceal mucinous neoplasms (AMNs) are an exceedingly rare gastrointestinal malignancy with in incidence of 2.8 cases per million, accounting for less than 1% of all GI cancers, and approximately 1,500 new cases in the US annually. AMNs typically present as acute appendicitis, given the predilection for appendiceal perforation, however as many as 23% are incidentally diagnosed. They are generally thought to be indolent compared to their colorectal counterparts and rarely metastasize outside of the peritoneum. Case description/methods: A 71-year-old female with a 6 pack-year smoking history and long-term methotrexate use for lichen planus presented to her PCP’s office for her annual evaluation. Routine urinalysis at that time showed microscopic RBCs so CT abdomen/pelvis was ordered and showed a 7.9 × 4.8 × 5.1 cm complex right adnexal cyst with adjacent free fluid. Subsequent pelvic ultrasound re-demonstrated the same plus a thickened 6 mm endometrial strip. MRI pelvis was pursued and showed this large adnexal cystic mass to be contiguous with the tip of the appendix, in addition to multiple uterine fibroids. After an unremarkable cystoscopy, suspicions were raised for an exophytic ovarian neoplasm, so the patient proceeded with laparoscopic bilateral salpingo-oophorectomy, appendectomy, collection of pelvic ascites, peritoneal biopsies and liver serosa biopsy, hysteroscopy and endometrial polypectomy. Intraoperatively, the patient had a mucinous fluid covering her pelvic and abdominal cavity with normal appearing uterus, and a ruptured 6 cm complex mass encompassing the appendix. Pathology revealed low grade primary appendiceal mucinous carcinoma with rupture and mucin extravasation, without gynecologic dysplasia. Colonoscopy was then done and only a 3 mm sessile polyp with benign morphology was found in the descending colon. PET CT showed no evidence of metastatic disease. The hospital course was complication by septic shock with polymicrobial bacteremia requiring prolonged mechanical ventilation and tracheostomy. She was discharged to an acute rehab hospital around 8 weeks later, and at 6-month follow-up had no disease recurrence. Discussion: Demonstrated is of the many potential red herrings observed in the evaluation of invasive GI cancers, emphasizing the importance of maintaining broad differentials and an interdisciplinary approach. Also unique was the lack of substantial symptoms despite rupture of said AMN and peritoneal spread - often an acutely clinically significant and painful event.Figure 1.: Figure A: Whirl sign on CT, with a dilated descending colon. Figure B-C: Benign-appearing, intrinsic twisted stenosis in the descending colon. Markedly dilated descending colon after a gentle advance of the colonoscope. The rectal tube was navigated proximal to the volvulus area. Figure D: Abdominal x-ray showing resolution of massive colonic distension after detorsion and rectal tube placement.

Appendiceal mucinous neoplasm (AMN) with peritoneal metastasis is a rare but deadly disease with few prognostic or therapy-predictive biomarkers to guide treatment decisions. Here, we investigated the prognostic and biological attributes of gene expression-based AMN molecular subtypes. AMN specimens (n = 138) derived from a population-based subseries of patients treated at our institution with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) between 05/2000 and 05/2013 were analyzed for gene expression using a custom-designed NanoString 148-gene panel. Signed non-negative matrix factorization (sNMF) was used to define a gene signature capable of delineating robustly-classified AMN molecular subtypes. The sNMF class assignments were evaluated by topology learning, reverse-graph embedding and cross-cohort performance analysis. Three molecular subtypes of AMN were discerned by the expression patterns of 17 genes with roles in cancer progression or anti-tumor immunity. Tumor subtype assignments were confirmed by topology learning. AMN subtypes were termed immune-enriched (IE), oncogene-enriched (OE) and mixed (M) as evidenced by their gene expression patterns, and exhibited significantly different post-treatment survival outcomes. Genes with specialized immune functions, including markers of T-cells, natural killer cells, B-cells, and cytolytic activity showed increased expression in the low-risk IE subtype, while genes implicated in the promotion of cancer growth and progression were more highly expressed in the high-risk OE subtype. In multivariate analysis, the subtypes demonstrated independent prediction power for post-treatment survival. Our findings suggest a greater role for the immune system in AMN than previously recognized. AMN subtypes may have clinical utility for predicting CRS/HIPEC treatment outcomes.

Appendiceal mucinous neoplasm (AMN) can present with a spectrum of disease. Predicting factors in development of pseudomyxoma peritonei (PMP) from AMN could aid in management and treatment. The aim of this study was to determine factors predictive of PMP from AMN. This was a retrospective multicenter study of all patients diagnosed with AMN from 2006-2017. Diagnosis of PMP was compared by (1) patient demographics, (2) tumor characteristics, and (3) surgery. Secondary end points were disease-specific survival (DSS) and overall survival (OS).One-hundred thirty-eight patients with AMN were identified. Thirty-six patients (26.1%) had a ruptured appendix at presentation, and 12 patients (8.7%) were diagnosed with PMP during the study period. Eight patients presented with PMP at the time of surgery. No demographic factors were predictive of PMP. Operative approach and extent of initial resection did not correlate with PMP. Tumor rupture at presentation was the only factor associated with PMP, though only 14% of patients who presented with simple rupture eventually progressed to PMP.OS was not different between those who were diagnosed with PMP and those who were not. DSS was significantly lower for the group diagnosed with PMP (P = .007). Tumor rupture at presentation did not influence OS or DSS. The only factor found to be significantly associated with PMP was tumor rupture at presentation. Diagnosis of PMP did not affect OS but did lead to decreased DSS.In conclusion, though a majority of patients who presented with rupture did not go on to develop PMP, tumor rupture at presentation was the only factor significantly associated with PMP. Diagnosis of PMP did not affect OS at 5years. In patients with AMN who present with a ruptured appendix on final pathology, we recommended continued surveillance, though overall risk of PMP is relatively low.

Low-grade appendiceal mucinous neoplasm (LAMN) is a rare malignancy and is found in less than 0.3% of appendectomy specimens. Patients with LAMN can present with abdominal pain and mimic clinically as appendicitis, intussusception or obstruction, hence high clinical suspicion is needed for correct diagnosis and management. The exact nature and nomenclature of these tumors when they disseminate into the peritoneum is controversial. The prognosis of LAMN is highly dependent on the presence or absence of neoplastic epithelium outside the appendix. Tumors with extra appendiceal acellular mucin in the right lower quadrant only rarely recur but tumors with extra appendiceal mucin and neoplastic epithelium recur more often. LAMNs with diffuse peritoneal seeding of neoplastic epithelium and mucin have a progressive clinical course that frequently results in death of the patient. Hence whenever a case of mucinous neoplasm of the appendix is encountered, it is essential that the entire appendix be submitted for histopathologic examination and should be thoroughly evaluated for presence of extra appendiceal mucin and neoplastic epithelium, and also for the type of invasion in order to obtain the correct diagnosis and to predict the risk of recurrence. We present here three cases of low grade appendiceal tumors with their varied clinical presentation and histopathological findings, for their rarity and clinical importance.

Simple SummaryThe cecal appendix is known to the general population because it is where acute appendicitis develops and it usually needs a surgical intervention for treatment. However, it is also the place of origin of tumors with special behavior. Those tumors are uncommon and generate specific clinical situations, such as the mucocele or the pseudomyxoma peritonei syndrome, which are the subject of much debate regarding definitions and pathologic classification. There is great interest in achieving a common language for these tumors that will allow the sharing of research and treatment results which will improve the existing information and management of our patients.Appendiceal mucinous neoplasms have been classified differently over time causing confusion when comparing results between working groups in this field and establishing a prognosis of the disease. A historical perspective of the different classification systems of these tumors is essential for the understanding of the evolution of concepts and histopathological definitions that have led up to the present moment. We carried out a systematic review of the pathological classifications of appendiceal mucinous tumors and how they have included the new criteria resulting from clinical and pathological research. The latest classifications by PSOGI and AJCC 8th edition Cancer Staging have made a great effort to incorporate the new pathological descriptions and develop prognostic groups. The introduction of these new classification systems has posed the challenge of verifying how they adapt to our casuistry and which one defines best the prognosis of our patients. We reclassified our series of patients treated for mucinous appendiceal tumors with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy following the PSOGI and the AJCC 8th edition criteria and concluded that both classifications correspond well with the OS and DFS of these patients, with some advantage relative to the PSOGI classification due to a better histopathological description of the different groups.

ObjectiveMucinous cystadenocarcinoma of appendix is a rare entity. Differentiating mucinous cystadenocarcinoma from mucinous cystadenoma is very challenging and depends on establishing the presence of malignant cells in the appendix wall. The invasion may be very difficult to assess in some cases, especially in early stages of the disease, which could have devastating prognostic effects on patients. Therefore, it is necessary to develop an ancillary test that can differentiate the mucinous cystadenocarcinoma from mucinous cystadenoma. So far, there is no report available about the role of differentially expressed miRNAs in the diagnosis of appendiceal mucinous cystadenocarcinoma.Materials and MethodsSix confirmed mucinous appendiceal cystadenocarcinoma and twelve mucinous appendiceal cystadenoma cases were selected. The total RNAs were extracted from the formalin-fixed paraffin-embedded specimen of these cases. The comprehensive miRNA microarray expression profiling from pooled aliquots of RNA samples from these two entities were analyzed to detect the differentially expressed miRNAs in mucinous cystadenocarcinoma. The best seven differentially expressed miRNAs were validated in individual cases by quantitative reverse transcriptase PCR (qRT-PCR).ResultsThe microarray miRNA expression profiling analysis revealed 646 miRNAs that were differentially expressed in the mucinous cystadenocarcinoma. Among these differentially expressed miRNAs, the expression of 80 miRNAs showed statistical difference (p<0.01). The quantitative RT-PCR validated that the expression of miR-1, miR-4328 was significantly down regulated in mucinous cystadenocarcinoma compared to the mucinous cystadenoma (p<0.05). On the other hand, the expression of miR-200b, miR-200c, miR-451, miR-223 and miR-21 were significantly upregulated in mucinous cystadenocarcinoma (p<0.05).ConclusionThe expression levels of miRNAs tested were significantly altered in the appendiceal mucinous cystadenocarcinoma samples compared to the mucinous cystadenoma. These data suggest that the miRNA expression in mucinous appendiceal neoplasm may help to supplement the morphological evaluation in distinguishing benign from malignant tumors.