Appendiceal mucinous neoplasms: Optimizing treatment strategies based on clinical, histological, and molecular features

Abstract

Appendiceal mucinous neoplasms (AMNs) are rare tumors originating from mucin-producing epithelial cells of the appendix. They can exhibit both benign and malignant behavior. They are often incidentally discovered during appendectomy. Clinical presentation ranges from asymptomatic to mimicking acute appendicitis. Histologically, noninvasive AMNs are classified as low-grade AMNs (LAMNs) or high-grade AMNs (HAMNs), whereas invasive tumors are categorized as mucinous adenocarcinomas. Although LAMNs and HAMNs are generally nonmalignant, rupture can lead to pseudomyxoma peritonei (PMP). Surgical resection is the primary diagnostic and therapeutic approach, with intraoperative assessment to prevent rupture. Treatment strategies vary based on findings and include appendectomy, right hemicolectomy, and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Histological diagnosis relies on mucin detection, and immunohistochemical markers such as cytokeratin 20 (diffusely positive), cytokeratin 7 (often negative), mucin 5AC, and special AT-rich sequence-binding protein 2 assist in characterization. Molecular profiling frequently identifies KRAS, GNAS, and TP53 mutations. KRAS mutations are generally associated with a favorable prognosis, whereas GNAS and TP53 mutations correlate with poorer survival outcomes. These findings highlight the potential role of molecular profiling in guiding treatment strategies for AMN and PMP.

Key Words: Low-grade appendiceal neoplasms; High-grade appendiceal neoplasms; Mucinous adenocarcinomas; Pseudomyxoma peritonei; Immunohistochemistry; Molecular markers; Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy

Core Tip: Appendiceal mucinous neoplasms (AMNs) are rare tumors originating in mucin-producing epithelial cells of the appendix. They can be benign or malignant. AMN is often discovered during appendectomy, presenting asymptomatically or mimicking acute appendicitis. Noninvasive AMNs include low-grade and high-grade lesions, whereas invasive types are mucinous adenocarcinomas. Rupture may lead to pseudomyxoma peritonei (PMP). Surgery is the primary treatment, with options including appendectomy, hemicolectomy, or cytoreductive surgery with chemotherapy. Histological diagnosis involves mucin detection and immunohistochemistry markers. Molecular profiling has revealed mutations in KRAS (favorable prognosis) and GNAS and TP53 (poor prognosis), guiding treatment strategies for AMN and PMP.

INTRODUCTION

The appendix is a small organ located at the tip of the cecum. It is thought to play an important role in immune function and the regulation of intestinal microbiota. Although rare, various diseases can arise in the appendix, including appendiceal mucinous neoplasms (AMNs). In the United States, 1000-2000 cases of AMNs are diagnosed annually[1-3]. However, the number of diagnosed cases has been increasing. Turaga et al[3] reported an age-adjusted incidence of four cases per million population, increasing from two cases per million in 1973 to five to six cases per million in 2007. This trend was attributed to an increase in disease incidence and improvements in diagnostic methods such as computed tomography (CT) and colonoscopy and the widespread use of laparoscopy, which has allowed for comprehensive visualization of the peritoneal cavity.

The prognosis of AMNs varies widely. It largely depends on the degree of atypia and disease progression, which ranges from benign to malignant. Histologically, noninvasive AMNs are classified as low-grade AMN (LAMN) or high-grade AMN (HAMN). LAMNs exhibit minimal cytological atypia and relatively slow tumor progression, and are typically associated with favorable clinical outcomes. In contrast HAMNs demonstrate greater cytological atypia, faster progression, and an increased risk of metastasis and peritoneal dissemination. Invasive tumors are classified as mucinous adenocarcinomas.

Complete resection of LAMNs or HAMNs without residual tumor margins significantly reduces the risk of recurrence. Rupture of the appendix can lead to the spread of extracellular mucin and tumor cells into the peritoneal cavity, potentially resulting in pseudomyxoma peritonei (PMP). PMP is a rare condition characterized by mucinous ascites and peritoneal implants. It has slow but persistent intraperitoneal growth and no distant metastasis[4]. Although PMP presents significant treatment challenges, cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy is the standard of care[5].

Recent advances have improved our understanding of the pathogenesis, diagnosis, and treatment of AMNs. This review summarizes the epidemiology, pathophysiology, diagnostic modalities, histological features, immunohistochemistry, molecular characteristics, diagnostic strategies, treatment options, and surveillance protocols for AMNs. Furthermore, we discuss the clinical significance of these tumors, highlighting limitations in current knowledge and exploring future directions for research and therapeutic strategies.

EPIDEMIOLOGY

AMNs are rare, accounting for approximately 0.5% of all gastrointestinal tract neoplasms[6]. Among these, LAMNs represent one of the most common histological subtypes, comprising approximately half of all AMNs[7]. An estimated 1000-2000 cases are diagnosed annually[1-3]. AMNs are observed more frequently in the fifth and sixth decades of life and show a slight female predominance[2,6].

LAMNs are identified in approximately 0.13%-0.30% of appendectomy specimens[6,7]. HAMNs are presumed to be even rarer than LAMNs, representing an uncommon subset of AMNs. Although precise incidence rates of LAMN and HAMN are not clearly documented, reports indicate a higher prevalence of LAMNs compared with HAMNs, with estimated ratios ranging from 8:1 to 20:1[8,9].

AMNs are frequently diagnosed incidentally because they are often asymptomatic. When symptoms are present, they typically manifest as acute or chronic right lower quadrant abdominal pain, mimicking appendicitis. Núñez-Rocha et al[10] reported an AMN incidence rate of 2.1% among patients undergoing emergency appendectomy for acute appendicitis. A randomized clinical trial further suggested that the incidence of AMNs may be higher in specimens obtained from interval appendectomy specimens compared with emergency appendectomies[11]. Moreover, the incidence of neoplasms increases to 10%-29% in cases of appendicitis associated with an appendiceal inflammatory mass[12].

PATHOPHYSIOLOGY

The precise mechanisms underlying the development of AMNs remain unclear. A proposed explanation is the high concentration of mucus-secreting epithelial cells in the appendix compared with other parts of the gastrointestinal tract. The appendix is prone to mucus retention due to its blind-ended structure. Mucus retention may promote mucocele formation and secondary neoplastic transformation[13]. Consequently, AMNs are typically characterized by cystic lesions resulting from mucus accumulation. This structural characteristic complicates differentiation from primary ovarian mucinous tumors (POMCs) because both entities present with similar clinical and radiological findings. The concept of PMP was first introduced by Werth[14], who described mucinous ascites arising from a mucinous ovarian tumor. Immunohistochemical staining has become essential for the definitive diagnosis of AMNs and for distinguishing them from POMCs through exclusion.

DIAGNOSTIC MODALITIES

Imaging plays a vital role in the evaluation of AMNs. Abdominal CT and magnetic resonance imaging (MRI) are key modalities for assessing the extent of peritoneal disease[15,16]. The sensitivity and specificity rates of CT for diagnosing AMNs are 83% and 92%, respectively[8]. A representative CT image is shown in Figure 1. Although MRI offers superior soft tissue contrast compared with CT, its diagnostic sensitivity and specificity for AMNs have been less extensively reported. Therefore, CT is the primary imaging modality. Positron emission tomography-CT has limited efficacy in detecting AMNs and evaluating low-volume peritoneal diseases[17].

Figure 1 Abdominal contrast-enhanced computed tomography scan (axial view). A 38-mm cystic mass was observed within the appendix. It features a non-enhanced hypodense area and surrounding curvilinear calcifications (yellow arrowheads).

Colonoscopy should also be considered during evaluation, particularly when inspecting the appendiceal orifice. If mucus discharge is observed, a specimen should be obtained. A bulge or protrusion at the appendiceal orifice, known as “the volcano sign”, is a characteristic colonoscopic finding of an appendiceal mucocele[18]. Additionally, colonoscopy allows the examination of the entire colon. This is an advantage because synchronous colonic lesions are identified in 13%-42% of patients with AMNs[17]. A German multicenter study reported synchronous colorectal neoplasia in 8.9% of patients with AMNs[19].

No specific laboratory tests exist to diagnose AMNs. However, while monitoring treatment response, Carmignani et al[20] reported that patients with peritoneal dissemination from appendiceal epithelial neoplasms often exhibit elevated levels of carcinoembryonic antigen and carbohydrate antigen 19-9.

Recent studies suggest that the analysis of circulating tumor DNA and microRNAs (miRNAs) is useful for detecting colorectal cancer, including appendiceal tumors, at an early stage and for screening metastatic diseases[21,22]. Belmont et al[23] reported that the detection of circulating tumor DNA was associated with shorter recurrence-free survival in appendiceal cancer cases. The hazard ratio was 14.1 (95% confidence interval: 1.7-113.8; P = 0.01) and demonstrated high accuracy in detecting recurrence (sensitivity: 93.8%, specificity: 85.0%). Additionally, it showed higher sensitivity compared with conventional biomarkers (carcinoembryonic antigen: 62.5%, carbohydrate antigen 19-9: 25.0%, carbohydrate antigen 125: 18.8%). Similarly, Kothary et al[24] found that circulating tumor DNA was detected in 51% of appendiceal cancer cases. It may serve as an earlier indicator of recurrence compared with CT or other imaging techniques.

Macha et al[25] reported that miRNAs serve as valuable diagnostic and prognostic markers in gastrointestinal cancers due to their stability and tissue-specific expression profiles. Additionally, Wu et al[26] identified seven differentially expressed miRNAs that can distinguish mucinous cystadenocarcinoma from cystadenoma of the appendix. However, studies specifically addressing AMNs and further research are needed.

HISTOLOGICAL FEATURES

Histologically, AMNs are classified based on the World Health Organization[27] and the Peritoneal Surface Oncology Group International[28] criteria into LAMNs, HAMNs, and mucinous adenocarcinomas, with or without signet ring cells (Table 1).

Table 1 Comparison of pathological features of low-grade appendiceal mucinous neoplasms, high-grade appendiceal mucinous neoplasms, and invasive mucinous adenocarcinomas.

Criteria	LAMN	HAMN	Invasive mucinous adenocarcinoma
WHO criteria	Mucinous epithelial tumor with low atypia; mild cellular atypia without invasive growth; loss or thinning of the lamina muscularis; submucosal fibrosis; flattening or pushing growth of the tumor epithelium	Severe cellular atypia; loss of nuclear polarity, multilayered nuclei throughout all layers, enlarged and hyperchromatic nuclei, and an active mitotic profile are observed; patterns of non-invasive growth; the tumor demonstrates a ‘pushing-type’ growth pattern and lacks a clear invasive profile; similar to LAMN, the mucosa-specific layer and mucosal muscle plate disappear, accompanied by fibrosis of the submucosal layer; resembles LAMN, except for distinct foci of high-grade dysplasia	More than 50% of the tumor tissue consists of mucus, with glandular duct structures and epithelial cells suspended within it; mucinous adenocarcinoma exhibiting moderate to severe atypia
PSOGI criteria	Mucinous neoplasm exhibiting low-grade cytologic atypia; loss of the muscularis mucosae; submucosal fibrosis; pushing invasion (characterized by expansile or diverticulum-like growth); dissection of acellular mucin within the wall; undulating or flattened growth of the epithelium; appendiceal rupture; mucin and/or cells beyond the appendix	Mucinous neoplasm exhibiting the architectural features of LAMN, lacking infiltrative invasion, but demonstrating high-grade cytologic atypia	Mucinous neoplasm with infiltrative growth; features of infiltrative invasion include tumor budding (discohesive single cells or small clusters of up to five cells) and/or small, irregular glands typically embedded in a desmoplastic stroma with a proteoglycan-rich extracellular matrix and activated fibroblasts/myofibroblasts exhibiting vesicular nuclei

HAMN: High-grade appendiceal mucinous neoplasm; LAMN: Low-grade appendiceal mucinous neoplasm; PSOGI: Peritoneal Surface Oncology Group International; WHO: World Health Organization.

LAMN is defined as a low-grade mucinous neoplasm characterized by mucinous epithelium. It demonstrates minimal cytological atypia and a distinct “pushing” invasion front into the appendiceal wall, resulting in expansile or diverticulum-like growth. This “pushing” growth pattern is considered a hallmark feature of LAMN. Histologically, LAMNs exhibit low mitotic activity, absence of signet ring cells, and no evidence of angiolymphatic or perineural invasion. Other characteristic features include villous or flat proliferation of mucinous epithelial cells, lamina propria atrophy, crypt loss, and effacement of the muscularis mucosa. Dissection of mucin and epithelial cells into or beyond the appendiceal wall is common. Consequently, LAMNs are typically described as well-differentiated tumors.

HAMN is defined as a mucinous neoplasm exhibiting architectural features similar to LAMN but with high-grade cytological atypia and without infiltrative invasion[4]. While LAMNs display abundant apical mucin and elongated nuclei with low-grade atypia, HAMNs are characterized by compressed nuclei and more complex architectural patterns, such as micropapillary or cribriform structures[29]. Representative macroscopic and microscopic images are provided in Figure 2.

Figure 2 Macroscopic and microscopic findings. A: Macroscopic view of a low-grade appendiceal mucinous neoplasm (LAMN), showing cystic dilation of the appendix filled with mucinous content; B: Microscopic view of a LAMN with hematoxylin & eosin staining (× 40 magnification), showing a mucosal surface lined by a single layer of mucin-producing columnar epithelium without high-grade cytologic atypia; C: Additional microscopic view of a LAMN with hematoxylin & eosin staining (× 40 magnification), highlighting features similar to panel B.

IMMUNOHISTOCHEMISTRY AND MOLECULAR FEATURES

Immunohistochemistry

Immunohistochemical analysis plays an essential role in the definitive and differential diagnosis of AMNs, particularly in excluding metastatic mucinous tumors from other organs, particularly the ovaries. Several studies have reported that AMNs typically show positive immunoreactivity for cytokeratin 20 (CK20), caudal type homeobox 2, mucin 5AC, and deleted in pancreatic cancer 4, whereas paired box gene 8 is usually negative[13,17,30-32]. In contrast POMCs frequently demonstrate positivity for CK7 and paired box gene 8, with variable CK20 expression[13,31-33]. Representative immunohistochemical staining images of AMNs are shown in Figure 3.

Figure 3 Immunohistochemical findings. A: Immunohistochemical staining for cytokeratin 20, showing diffuse positivity on the mucosal surface layer (× 40 magnification); B: Immunohistochemical staining of cytokeratin 7, showing partial positivity on the mucosal surface layer (× 40 magnification); C: Immunohistochemical staining for mucin 5AC, showing partial positivity on the mucosal surface layer (× 40 magnification).

Differentiating AMNs from metastatic ovarian mucinous tumors can be challenging. Strickland and Parra-Herran[31] highlighted the utility of special AT-rich sequence-binding protein 2, reporting positivity in 93.8% of appendiceal tumors while being only rarely positive in ovarian tumors. They demonstrated a specificity of 97.5% for identifying an appendiceal origin.

Molecular features

Genetic analysis has become increasingly important in AMNs, aiding both prognostication and the development of targeted therapies. Molecular profiling has revealed a high prevalence of KRAS, GNAS, and TP53 mutations in AMNs[13,29,32,34]. Multiple reports indicated that KRAS mutations activated the mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/protein kinase B signaling cascades, which promote cell proliferation, mucin production, and angiogenesis[35-37]. Additionally, KRAS mutations often coexist with other genetic alterations. Nishikawa et al[38] reported that the coexistence of KRAS and GNAS mutations is frequently observed in low-grade tumors. Other genetic variants, such as TP53 and SMAD4, which may modify the effects of KRAS mutations, have been reported by Constantin et al[37].

Matson et al[39] described a case in which the same KRAS mutation was identified in both ovarian and appendiceal tumors, suggesting a potential role of KRAS mutations in metastasis. Furthermore, Constantin et al[37] stated that KRAS mutations may stimulate angiogenesis, a crucial process in both tumor growth and metastasis. Dilly et al[40] reported that KRAS mutations are involved in the regulation of mucin production, with increased mucin potentially altering the physical properties of the tumor and surrounding tissues, thereby facilitating local invasion and metastasis.

GNAS mutations are also frequently detected in AMNs. Nishikawa et al[38] found that GNAS mutations activated the cyclic adenosine monophosphate/protein kinase A signaling cascade. This led to increased mucin production and tumor progression, which may elevate the likelihood of peritoneal dissemination and metastasis. Additionally, GNAS mutations frequently coexist with KRAS mutations. Singhi et al[41] reported that tumors harboring GNAS mutations had a higher frequency of concurrent KRAS mutations compared with tumors with wild-type GNAS (65% vs 29%, P = 0.018).

TP53 mutations are considered more common in high-grade tumors. Tang et al[42] reported that mutant p53 protein loses its tumor suppressor function and acquires oncogenic characteristics that enhance cancer cell motility, invasion, and metastasis. It plays a significant role in promoting tumorigenesis and metastasis in AMNs. Zhu et al[43] further associated TP53 mutations with shorter progression-free survival. Moreover, Constantin et al[37] reported that TP53 mutations frequently coexist with KRAS, GNAS, and BRAF mutations, suggesting a synergistic effect in promoting tumor progression by enhancing cell proliferation, angiogenesis, and resistance to apoptosis.

In a study involving 52 patients with LAMNs, PMP, or recurrent PMP, mutations were detected in 12 of 50 analyzed genes. KRAS mutations were identified the most frequently in 98.1% of cases, followed by GNAS mutations in 55.8% of cases[44]. Importantly, KRAS and/or GNAS mutations were the only alterations observed in LAMNs confined to the mucosal surface. Additionally, GNAS mutations are thought to drive excessive mucin production, while TP53 mutations are associated with progression toward invasive mucinous adenocarcinomas. These findings suggest that GNAS and TP53 mutations may be linked to poorer survival outcomes.

TREATMENTS

Surgery and outcomes

Most AMN cases require surgical intervention, which serves both diagnostic and therapeutic purposes. Surgery is considered the optimal approach even in cases of suspected benign appendiceal diseases as it can prevent appendix rupture and dissemination of mucinous material into the peritoneal cavity[8].

For localized disease a standard appendectomy is sufficient if clear surgical margins are achieved. However, when the appendiceal root is involved, more extensive procedures, such as a cecectomy, ileocecal resection, right colectomy, or right hemicolectomy, may be necessary. Ibrahim et al[45] retrospectively analyzed 98 patients with uncomplicated LAMNs involving neoplastic epithelium or dissecting mucin at the resection margin. Eight patients (8.2%) exhibited margin involvement. Among these patients, 5 underwent additional surgery with no residual neoplasm identified, while the remaining 3 patients were managed conservatively without recurrence during a follow-up of 18-69 months.

A literature review identified 52 cases of LAMNs with positive margins. Among these patients, 4 underwent additional resection, and 3 had acellular mucin while 1 had residual LAMN. However, none of the 52 patients experienced disease recurrence. This lack of recurrence may be explained by two factors: (1) Appendectomy margins often involve stapler lines rather than true anatomical margin[45,46]; and (2) Mucin at the resection margin may result from mechanical extrusion rather than true tumor extension[45,47].

Management of positive resection margins

The management of LAMNs with microscopically positive resection margins remains controversial. Traditionally, complete surgeries such as cecectomy, ileocecal resection, or right hemicolectomy were recommended. Recently, the published Chicago Consensus guidelines[16] recommended resection of the appendiceal root or partial cecectomy in such cases and discouraged routine right hemicolectomy. Similarly, the American Society of Colon and Rectal Surgeons guidelines[48] recommend against complete right colectomy and favor more conservative approaches. These recommendations are based on growing evidence. Turaga et al[49] compared appendectomy and right hemicolectomy for mucinous adenocarcinoma of the appendix and found no significant difference in adjusted survival rates. Arnason et al[46] similarly reported that LAMN involvement of the surgical margin does not predict recurrence, thus questioning the need for radical right colectomy. In summary conservative surgical approaches or observation are now considered reasonable alternatives for patients with uncomplicated LAMNs and positive margins (Figure 4).

Figure 4 Decision tree for positive surgical resection margins. CRS: Cytoreductive surgery; HIPEC: Hyperthermic intraperitoneal chemotherapy; PMP: Pseudomyxoma peritonei.

Chemotherapy

Ayala-de Miguel et al[17] reviewed the role of systemic chemotherapy in AMN management. They determined that 5-fluorouracil (5-FU)-based chemotherapy is particularly beneficial in advanced or metastatic disease. For palliative chemotherapy, LAMNs tend to respond poorly to 5-FU-based regimens, whereas colorectal cancer protocols are recommended for HAMNs[16,17]. The Peritoneal Surface Oncology Group International consensus also recommended combining chemotherapy with a neoangiogenesis inhibitor, such as bevacizumab, for patients with PMP[50].

Currently, there are no definitive recommendations regarding adjuvant chemotherapy for AMNs. Kolla et al[51] demonstrated improved overall survival in patients with moderate-to-poor mucinous tumors who received adjuvant chemotherapy compared with those who did not (9.03 years vs 2.88 years). Common regimens include capecitabine alone, capecitabine plus oxaliplatin, and the combination of 5-FU and oxaliplatin.

CRS combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is the standard treatment for LAMNs with peritoneal spread[16]. However, strong evidence supporting the use of neoadjuvant chemotherapy before CRS and HIPEC is lacking[17].

Immune checkpoint inhibitors have demonstrated success in other malignancies and are under investigation for AMNs. KRAS mutation-specific therapies such as sotorasib[52], adagrasib[53], and MRTX1133[54] offer promising targets for various tumors. Mausey and Halford[55] reported that sotorasib and adagrasib are promising in the treatment of carcinomas harboring KRAS mutations, particularly G12C mutations. Zheng et al[56] specifically demonstrated efficacy in non-small cell lung cancer. However, Ji et al[57] suggested that these drugs provided limited benefits in colorectal cancer cases, likely due to rapid resistance driven by upregulation of the epidermal growth factor receptor signaling cascade. To counter this combination therapy with epidermal growth factor receptor inhibitors has been proposed. However, the application of these KRAS inhibitors to AMNs remains poorly documented. No specific inhibitors are currently available for GNAS mutations, although peptide vaccine-based therapies have been proposed for PMP[58].

Specific considerations for PMP

Rupture of AMNs can lead to peritoneal dissemination resulting in PMP, which is a rare condition characterized by mucinous ascites and peritoneal implants[4,59,60]. The presence of intraperitoneal acellular mucin or intraperitoneal metastases from LAMN or HAMN is classified as PMP and requires specialized management. Baumgartner et al[61] conducted a multi-institutional study and found that 7 out of 46 patients with histological perforation developed peritoneal recurrence, whereas 0 of the 76 patients without perforation experienced peritoneal dissemination. The presence of acellular mucin and neoplastic cells outside the appendix is associated with an increased risk of PMP development.

Although PMP typically exhibits indolent behavior, aggressive treatment is often warranted to improve prognosis. The current standard of care includes CRS combined with HIPEC, including mitomycin, doxorubicin, and oxaliplatin[50,62]. The representative dosing regimens include the Dutch protocol[63] with mitomycin C (mitomycin C was added to 1.5% peritoneal dialysis solution at an initial dose of 17.5 mg/m², followed by 8.8 mg/m² after 30 minutes and 8.8 mg/m² after 60 minutes), the American Society of Peritoneal Surface Malignancy low-dose mitomycin C regimen[64] (add mitomycin C to 1.5% peritoneal dialysis solution with an initial dose of 30 mg/3 L and then add 10 mg after 60 minutes), the Sugarbaker regimen[65] using mitomycin C and doxorubicin (add 15 mg/m² of mitomycin C and doxorubicin to 2 L 1.5% dextrose peritoneal dialysis solution and maintain intraperitoneal chemotherapy for 90 minutes), the Glehen medium-dose oxaliplatin regimen (add 360 mg oxaliplatin to 2 L/m² 5% dextrose solution and maintain intraperitoneal chemotherapy for 30 minutes)[66], and the Elias high-dose oxaliplatin regimen (add 460 mg oxaliplatin to 2 L/m² 5% dextrose solution and maintain intraperitoneal chemotherapy for 30 minutes)[66].

SURVEILLANCE

Currently, there are no standardized surveillance guidelines for postoperative management of AMNs. However, the American Society of Colon and Rectal Surgeons guidelines[48] suggest that patients with low-grade, localized tumors who undergo appendectomy alone have a low risk of developing PMP. Therefore, they do not require frequent postoperative imaging over extended intervals. Nevertheless, some degree of follow-up is recommended[48].

For patients with localized and completely resected LAMN, MRI and tumor marker assessment every 6 months for the first 2-3 years is advised because most recurrences occur within this timeframe[67]. For patients with HAMNs, locally advanced LAMNs, or perforated tumors, surveillance with CT or MRI every 4-6 months for the first 2 years, followed by annual imaging for at least 5 years, is recommended.

For patients with PMP who have undergone CRS and HIPEC, CT or MRI imaging of the abdomen and pelvis should be performed 2 months postoperatively and then annually for a minimum of 5 years. Although peritoneal recurrence has been reported more than a decade after surgery, current evidence does not support prolonged surveillance beyond 5 years. Therefore, extended follow-up should be adopted cautiously.

CONCLUSION

The prognosis of AMNs varies depending on the degree of atypia and disease progression. Advances in diagnostic modalities and therapeutic strategies have led to improved patient outcomes. However, significant challenges remain in both early detection and management of AMNs. Early diagnosis is a major hurdle. Once an AMN ruptures and peritoneal dissemination occurs, treatment becomes substantially more complex. Therefore, further research aimed at developing early diagnostic techniques and identifying reliable predictors of tumor behavior is urgently needed. Emerging genetic analysis technologies are anticipated to play a transformative role by enabling the molecular characterization of AMNs and facilitating the development of personalized treatment strategies. Novel therapies, including immune checkpoint inhibitors and innovative chemotherapy regimens, also offer promising prospects. A phase III clinical trial is currently underway in Japan for previously untreated metastatic colorectal cancer patients with KRAS G12C mutations. The trial is comparing the combination of sotorasib, panitumumab, and FOLFIRI with FOLFIRI alone or in combination with FOLFIRI and bevacizumab (Trial ID: JRCT2071240009). To date no clinical trials have specifically evaluated these therapies in AMNs. Based on current evidence we have proposed an algorithm for the treatment of AMNs (Figure 5). Continued research, technological innovation, and collaborative efforts are expected to refine treatment approaches, address existing limitations, and ultimately improve patient outcomes.

Figure 5  Proposed algorithm for the treatment strategy of appendiceal mucinous neoplasms.