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Clinicopathological spectrum of appendiceal mucinous neoplasms and associated pseudomyxoma peritonei
*Corresponding author: V. Pratheep, Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India. pradooo93@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Pratheep V, Archana B, Gayathri K, Srinivasan N, Sundaram S, Rajendiran S. Clinicopathological spectrum of appendiceal mucinous neoplasms and associated pseudomyxoma peritonei. Sri Ramachandra J Health Sci. 2025;5:25-30. doi: 10.25259/SRJHS_5_2025
Abstract
Objectives:
Appendiceal mucinous neoplasms (AMNs) are uncommon tumors distinguished by dysplastic characteristics and typically manifest with atypical symptoms. These tumors demonstrate varied biological behaviors, and around 40% are initially misdiagnosed as acute appendicitis. Pseudomyxoma peritonei (PMP) is a rare disorder characterized by the buildup of mucinous deposits within the abdominal cavity. It typically begins with mucinous tumors in the appendix that spread gelatinous material to surrounding tissues and organs. The condition may involve cancerous or non-cancerous cells. While PMP has been recognized for many years, there have been recent efforts to create a standardized classification system to guide treatment strategies and clinical management. The aim of this study was to evaluate the clinicopathological spectrum of AMN by analyzing the appendectomy specimens, with specific emphasis on the importance of histopathological examination.
Material and Methods:
Between 2016 and 2019, a retrospective analysis was performed on a cohort of patients with AMN, comparing outcomes for those with and without PMP.
Results:
This study examined 13 cases of AMN. The demographic breakdown showed a male-to-female ratio of approximately 1.07:1, with a median age of 53.8 years, ranging from 42 to 70 years. Most patients initially presented with symptoms consistent with acute appendicitis, such as right lower quadrant pain. Among them, 69% had low-grade AMN, while the remaining cases exhibited high-grade features. Peritoneal biopsies were performed in 53% of cases. Of those, 5 out of 7 (71.42%) revealed low-grade mucinous carcinoma peritonei/disseminated peritoneal adenomucinosis (DPAM), 1 out of 7 (14.28%) showed high-grade mucinous carcinoma peritonei/peritoneal mucinous carcinomatosis (PMCA), and 1 out of 7 (14.28%) contained mucin without epithelial cells.
Conclusion:
Appendiceal neoplasms associated with PMP are infrequent, but the incidence of this condition has been steadily rising. Early detection and intervention are of vital importance due to its unusual appearance and variable biological behavior. A strong collaborative effort between the pathologist, surgeon, and oncologist is essential for a proper and effective histopathologic classification and prediction of tumor behavior. This reimposes the fact that both pathologists and clinicians should update themselves with the latest consensus guidelines as this will enable them to follow uniform terminology and institute a multidisciplinary team approach for appropriate management.
Keywords
Appendicitis
Appendix
Mucin
Pathology
Pseudomyxoma peritonei
INTRODUCTION
Primary appendiceal neoplasms encompass a diverse array of tumor types, including epithelial tumors (such as mucinous and colonic subtypes), mesenchymal tumors, neuroendocrine tumors, lymphomas, goblet cell carcinomas, and sarcomas. Mucinous tumors, which range from adenomas to mucinous adenocarcinomas, account for approximately 58% of appendiceal malignancies, with the remainder primarily consisting of carcinoid tumors.[1-3] Although they are rare, appendiceal mucinous neoplasms (AMNs) can exhibit a range of biological features in addition to distinct clinical traits. These tumors are frequently misdiagnosed as acute appendicitis before surgery and are commonly discovered incidentally during appendectomies for appendicitis, accounting for about 0.9% of appendectomy samples.[1,4] In addition to common symptoms, AMNs can exhibit fewer common presentations, including appendiceal masses, intussusception, bowel obstruction, and secondary genitourinary issues, complications such as perforation, abscess formation, or ovarian damage may also arise, highlighting the complexity and potential severity of these rare tumors.[1,4]
Pseudomyxoma peritonei (PMP)
PMP involves the buildup of mucinous tumor deposits within the peritoneal cavity, usually stemming from AMNs. This condition spreads mucin throughout the abdomen and nearby organs, sometimes containing cancerous cells. Advances in treatments such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have enhanced PMP management.[1,4,5]
This research aims to explore the clinicopathological diversity of AMN, emphasizing the detailed analysis of pathological findings.
MATERIAL AND METHODS
Ethics
This research was carried out following the ethical standards set forth with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards and all procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Research Committee. Ethical approval was secured from the Institutional Ethics Committee of Sri Ramachandra Institute of Higher Education and Research, with approval number CSPMED/21/APR/68/68, before starting the study.
This case series analyzed 13 instances of AMNs, including both those with and without PMP, identified between 2016 and 2019. The study aimed to analyze these rare and complex tumors, which can present with or without PMP, a condition characterized by the spread of mucin within the abdominal cavity. Appendectomy specimens from 13 patients diagnosed with mucinous neoplasms at Sri Ramachandra Institute of Higher Education and Research, Chennai, a tertiary center in India, from January 2016 to September 2019 were identified. The study included both male and female participants aged 18 and above, with a histopathological diagnosis of AMN, either with or without peritoneal biopsies. The diagnostic criteria were based on the modified Delphi consensus (2016) and the American Joint Commission on Cancer (AJCC) manual,[2] whereas cases with lack of representative tissue blocks, insufficient medical records, and other types of appendiceal tumors (non-mucinous epithelial neoplasms, neuroendocrine tumors, mesenchymal tumors and inflammatory tumors) were excluded from the study.
Demographic, clinical, and corresponding surgical information were obtained from the Medical Records department following approval from the Medical Director. Slides stained with hematoxylin and eosin were obtained from the department’s archives and reviewed by two pathologists working independently. The collected data were then organized, compiled, and analyzed.
Statistical analysis
The study analyzed various factors, including sex, age, type of neoplasm, clinical manifestations, diagnostic methods (such as computed tomography [CT] scans, colonoscopy, exploratory laparoscopy, and histopathological evaluation), peritoneal biopsy diagnosis, and the presence of PMP. The data were organized in a computerized database using Microsoft Office Excel 2013 and analyzed with the Statistical Package for the Social Sciences software version 26. To summarize the variables across the cases, descriptive statistics such as frequencies and percentages were calculated.
RESULTS
A review of 13 cases of AMNs is presented in Table 1. The male-to-female ratio was approximately 1.07:1, with a median age of 53.8 years, spanning from 42 to 70 years. The most common clinical symptoms were right lower quadrant (RLQ) pain, observed in 69% of cases (n = 9), and abdominal masses, often accompanied by fever. Four cases were asymptomatic. Imaging studies identified a primary appendiceal tumor in eight cases, including one with a mucocele-like appearance visible on both axial and sagittal abdominal CT scans [Figure 1a and b]. Three cases suggested acute appendicitis, one was identified as a mesenteric cyst, and another showed bilateral adnexal masses along with appendiceal deposits. Histopathological analysis, however, showed that the most common diagnosis was low-grade appendiceal mucinous neoplasm AMN (LAMN), accounting for 69.23% of cases (n = 9). Two cases (15.38%) were classified as high-grade appendiceal mucinous neoplasms (HAMNs), and two (15.38%) as mucinous adenocarcinomas, with one of these having secondary ovarian deposits.
| S. No. | Gender | Age | Imaging diagnosis | Clinical presentation | Pre-operative diagnosis | Biopsy report | HPE diagnosis |
|---|---|---|---|---|---|---|---|
| 1. | F | 44 | Primary appendiceal tumor | RLQ pain | Appendiceal tumor | PMCA | |
| 2. | F | 70 | Appendiceal mucinous lesion | Abdominal mass, fever | PMP | Acellular mucin | LAMN |
| 3. | M | 42 | Acute appendicitis | Abdominal mass, fever | Appendiceal tumor | - | LAMN |
| 4. | F | 42 | Appendiceal mucinous tumor | RLQ pain | Appendiceal tumor | DPAM | LAMN |
| 5. | F | 52 | Acute appendicitis | Abdominal pain | Acute appendicitis | - | LAMN |
| 6. | F | 54 | Mesenteric cyst | RLQ pain | Mucinous tumor | DPAM | LAMN |
| 7. | M | 64 | Appendiceal mucinous tumor | RLQ pain | Acute appendicitis | - | LAMN |
| 8. | M | 56 | Primary appendiceal tumor | Abdominal mass, fever | Acute appendicitis | DPAM | LAMN |
| 9. | F | 54 | Mucocele | Abdominal mass, fever | Acute appendicitis | - | LAMN |
| 10. | M | 60 | Appendiceal mucinous tumor | Abdominal mass | Mucinous adenoma | DPAM | Mucinous adenocarcinoma |
| 11. | M | 60 | Acute appendicitis | RLQ pain | Acute appendicitis | - | LAMN |
| 12. | M | 51 | Primary/metastatic ovarian tumor | Bilateral Adnexal mass with CEA elevation | Ovarian tumor | DPAM | Mucinous adenocarcinoma with 2° deposits in bilateral ovaries |
| 13. | M | 53 | Acute appendicitis | RLQ pain | Acute appendicitis | - | LAMN |
HPE: Histopathological examination, RLQ: Right lower quadrant, CEA: Carcinoembryonic antigen, PMP: pseudomyxoma peritonei, PMCA: Peritoneal mucinous carcinomatosis of appendiceal origin, DPAM: Disseminated peritoneal adenomucinosis, LAMN: Low-grade appendiceal mucinous neoplasms, F: Female, M: Male
- (a and b) Axial and sagittal view of appendiceal mucocele like lesion (black asterisks), (c and d) gross picture of low-grade appendiceal mucinous neoplasms and high-grade appendiceal mucinous neoplasms showing a (c) mucinous lesion (black asterisk), and (d) gelatinous appendiceal lesion (black asterisk).
Peritoneal biopsies were performed in seven out of the 13 cases. Among these, 5 (71.42%) were diagnosed with low-grade mucinous carcinoma peritonei/diffuse peritoneal adenomucinosis (DPAM), the most common biopsy finding associated with both LAMN and mucinous adenocarcinoma. One case (14.28%) exhibited high-grade mucinous carcinoma peritonei/peritoneal mucinous carcinomatosis (PMCA), and another (14.28%) showed mucin without epithelial cells. In addition, one patient presented with concurrent mucinous adenocarcinoma and DPAM, along with secondary deposits in both ovaries [Table 1].
On macroscopic inspection, both LAMN and HAMN were predominantly limited to the appendix, with or without partial colon resection [Figure 1c and d]. The surface of the tumors appeared smooth and distended. In HAMN, the cut surface displayed a distinct gelatinous mass with gray-yellow firm sections, while LAMN had a smoother internal surface. One case of mucinous adenocarcinoma showed a widely spread mucinous lesion in the bilateral ovaries, originating from the appendix.
Microscopically, one case showed acellular mucin pools without epithelial cells [Figure 2a]. LAMN was characterized by neoplastic cells with both intra- and extracellular mucin and mild atypia, confined to the appendix [Figure 2b]. HAMN exhibited similar features to LAMN but with pronounced cytological atypia [Figure 2c]. Mucinous adenocarcinoma, on the other hand, displayed high-grade cytological atypia, having large pools of mucin and signet ring cells [Figure 2d].
- Microscopy of appendiceal mucinous neoplasms (a) Acellular mucin (black asterisk) (×100), (b) low-grade appendiceal mucinous neoplasms, neoplastic cells with minimal atypia (black arrowhead), interspersed with intraluminal (black asterisk), and extraluminal mucin (red asterisk) (×100), (c) high-grade appendiceal mucinous neoplasms, neoplastic cells with high-grade cytological atypia (black asterisk) (×400), and (d) mucinous adenocarcinoma with signet ring cells (black asterisk) (×400). Scale bar: (a -b): 100 micrometer (3000 pixels); (c-d): 50 micrometer (3000 pixels). H and E stain for all images.
DISCUSSION
Patients with appendiceal tumors commonly experience symptoms similar to those of acute appendicitis, with RLQ pain being a frequent early sign. The risk of developing appendicitis or appendix perforation is higher if the tumor blocks the appendix opening. Carr et al. reported that approximately 32% of patients with appendiceal tumors were initially diagnosed with acute appendicitis before surgery, while about 23% were discovered incidentally during other medical procedures.[2,6] Our study found that 69% (n = 9) of patients exhibited symptoms consistent with acute appendicitis, whereas 31% (n = 4) were asymptomatic and identified incidentally during unrelated medical procedures. This disparity suggests a potential rise in the misdiagnosis or underreporting of AMNs. CT, the gold standard for pre-operative imaging, typically shows a fluid-density cyst near the cecum and retrocecal region in most cases, with peritoneal mucus accumulation observed in advanced stages.[1] PMP, a rare disorder frequently caused by a ruptured AMN, is characterized by the buildup of ascites and mucosal or peritoneal implants. The “redistribution” process in PMP involves the spread of mucin and tumor cells through the peritoneal cavity, following the natural flow of peritoneal fluid and utilizing lymphatic pathways. This results in the accumulation of tumor deposits in dependent areas such as the pelvis, paracolic gutters, omentum, and liver capsule.[1,6-8]
AMN classification system
Van De Moortele et al. highlight that various classification systems for AMNs have been used historically.[7] Initially, AMN was classified into three primary subtypes: Disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and PMCA with indeterminate or discordant features (PMCA I/D).[9] This classification system effectively predicted survival outcomes, with DPAM patients typically experiencing a shorter clinical course and no distant (extraperitoneal) metastases.[7,9] Conversely, PMCA was linked to a worse prognosis due to an increased propensity for metastasis to lymph nodes and extraperitoneal organs.[2,10-13]
The AJCC’s eighth edition transitioned to a three-tiered grading system for mucinous appendiceal neoplasms, reflecting a shift from earlier two-tiered systems. Tumors are now categorized as well-differentiated (G1), moderately differentiated (G2), or poorly differentiated (G3), with G1 representing low-grade tumors and G2/G3 categorized as high-grade. This system further divides AMNs into serrated polyps (with or without dysplasia), LAMN, HAMN, mucinous adenocarcinomas (with or without signet ring cells), and mucinous signet ring cell carcinoma (defined by more than 50% signet cells).[2,7]
In addition, the peritoneal surface oncology group international classification system categorizes PMP into four subtypes: Acellular mucin (mucin without neoplastic epithelium), low-grade mucinous carcinoma peritonei (featuring low-grade cytology, minimal mitotic activity, and neoplastic mucinous epithelium constituting <20% of the tumor volume), high-grade mucinous carcinoma peritonei (where neoplastic mucinous epithelium exceeds 20% of the tumor volume, accompanied by high-grade cytology, infiltrative growth, and potential vascular or perichondral invasion), and high-grade mucinous carcinoma peritonei with signet ring cells.[14]
Genetic susceptibility, immunohistochemistry, and molecular alterations
Appendiceal tumors and colorectal cancer display comparable CK expression patterns, with patchy CK7 and diffuse CK20 positivity, indicating a shared underlying pathophysiological mechanism. AMNs often develop from adenomatous polyps and progress through the classic adenoma-carcinoma sequence. This sequence involves: (a) Point mutations in the kirsten rat sarcoma viral oncogene homolog (KRAS) proto-oncogene and mutations or deletions in the TP53 gene on chromosome 17p, (b) truncating mutations or small deletions in the adenomatous polyposis coli gene on chromosome 5q, and (c) mutations in the beta-catenin gene. Another critical carcinogenic pathway is microsatellite instability, driven by mutations in mismatch repair genes such as mutS homolog 2 (MSH2), MutL homolog 1 (MLH1 ), postmeiotic segregation increased 1 (PMS1), postmeiotic segregation increased 2 (PMS2), and mutS homolog 6 (MSH6). In addition, appendiceal tumors are marked by the expression of Cytokeratin 20 (CK20), Carcinoembryonic Antigen (CEA), Caudal-type homeobox transcription factor 2 (CDX2), mucin 2 (MUC2), and mucin 5AC (MUC5AC), as well as increased N-Cadherin and decreased E-Cadherin expression, which promote metastasis through epithelialmesenchymal transition.[5-8,11]
Several studies have shown that ovarian masses found in patients with appendiceal adenocarcinoma are more often secondary rather than primary in nature, as confirmed by molecular genetic analysis and immunohistochemistry.[3,5] This observation is reinforced by the tendency of these tumors to occur more often on the right side or, in some cases, bilaterally.[3,5] In cases of PMP, an appendectomy is typically required because the appendix is the primary source of the condition in approximately 94% of cases. Our study corroborates this data, highlighting a case of AMN with DPAM and secondary ovarian deposits in both ovaries.
Treatment strategies and follow-up
Treatment for both acute appendicitis and LAMN in an intact appendix typically involves appendectomy for tumors smaller than 2 cm. For tumors larger than 2 cm, treatment often includes a right-sided partial colon resection. However, some research suggests that a radical appendectomy alone may be sufficient without leading to complications.[4,11] In cases of LAMN, postponing surgical intervention can have serious implications, as a ruptured appendix may disperse neoplastic cells into the peritoneal cavity, potentially resulting in PMP.[1,2] For patients with LAMN that is entirely removed with clear margins, without signs of mucin leakage or appendix rupture, and with no extrappendiceal mucin or cells identified on pathological examination, the recurrence risk is extremely low. Therefore, these patients typically do not require regular follow-up.[5-8,11]
The grade of the tumor is a crucial factor in guiding treatment decisions. For tumors classified as low-grade, the standard treatment typically includes CRS paired with HIPEC. Meanwhile, high-grade tumors usually require a more aggressive approach, incorporating chemotherapy alongside surgery and HIPEC. If PMP is discovered incidentally during exploratory surgery, peritoneal biopsies should be performed, the appendix removed, and the patient referred to a specialized center for further management.[2,3,5]
For post-treatment follow-up, patients are advised to undergo clinical examinations and CEA level testing every 3 months for the first 2 years, followed by every 6 months for the next 3 years. Imaging surveillance includes CT scans of the chest, abdomen, and pelvis every 2 years for 5 years. In addition, colonoscopy is recommended at 1 and 3 years post-treatment, with subsequent colonoscopies every 5 years based on the findings.[4-6] The follow-up approach for neuroendocrine tumors is customized according to the specific characteristics of the tumor. Tumors smaller than 2 cm without high-risk features are usually considered curative after complete resection, eliminating the need for routine monitoring. Conversely, tumors larger than 2 cm or those with high-risk features require continued surveillance, which includes regular clinical checks, CT scans, and tumor marker testing to detect any potential recurrence early.[6,11]
The 5-year overall survival rate for individuals with a diagnosis with low-grade diffuse mucosal cancer (G1, well-differentiated) varies between 60% and 90%, with the 10-year survival rate hovering around 50%. Regarding individuals with high-grade mucinous adenocarcinoma (G2, moderately differentiated), the 5-year survival rate falls within the range of 30–60%, and the 10-year survival rate is estimated at 20–30%. For those with high-grade mucinous adenocarcinoma (G3, poorly differentiated) or mucinous adenocarcinoma featuring signet ring cells, the 5-year survival rate is between 10% and 40%, while the 10-year survival rate ranges from 10% to 20%.[5-7]
Key limitations of our research are the limited sample size and the unavailability of follow-up data.
CONCLUSION
Recent advancements in imaging technologies have likely contributed to the increased incidence of AMN, enabling earlier and more accurate detection. These neoplasms have very subtle differences in gross and microscopic findings, often being misdiagnosed as appendicitis. The spectrum of AMN and PMP has separate specific histologic criteria regarding their nomenclature. Numerous terminologies in nomenclature adopted by clinicians and pathologists earlier had created confusion. With the latest consensus guidelines adopted for AMN and PMP, pathologists and clinicians are in accord with the same. There is no major role for ancillary testing. Hence, a high index of suspicion with correct histologic diagnosis is imperative and has a distinct implication on treatment. A multidisciplinary approach involving pathologists, surgeons, and oncologists is essential for optimum management.
Acknowledgment:
The authors sincerely acknowledge the dedicated staff of the Department of Pathology at Sri Ramachandra Institute of Higher Education and Research, including laboratory technicians, faculties, and administrative personnel, for their exceptional technical support and valuable insights.
Ethical approval:
The research/study approved by the Institutional Review Board at the Institutional Ethics Committee of Sri Ramachandra Institute of Higher Education and Research, number CSP-MED/21/APR/68/68, dated 7th July, 2021.
Declaration of patient consent:
Patient’s consent was not required as there are no patients in this study.
Conflicts of interest:
Dr. Sandhya Sundaram is on the Editorial Board of the Journal.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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