Low-grade Appendiceal Mucinous Neoplasm: A Series of Four Cases

1. Assistant Professor, Department of Pathology, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair, Andaman and Nicobar, India. 2. Associate Professor, Department of Pathology, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair, Andaman and Nicobar, India. 3. Associate Professor, Department of Pathology, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair, Andaman and Nicobar, India. 4. Assistant Professor, Department of Pathology, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair, Andaman and Nicobar, India. 5. Professor and Head, Department of Pathology, Andaman and Nicobar Islands Institute of Medical Sciences, Port Blair, Andaman and Nicobar, India.

Abstract

Low-grade Appendiceal Mucinous Neoplasm (LAMN) is a rare malignant neoplasm seen in less than 0.3% of appendectomy specimens. Patients with LAMN can present with abdominal pain, mimicking appendicitis clinically. In later stages, it can rupture, leading to Pseudomyxoma peritonei (PMP). Therefore, a high clinical suspicion is needed for correct diagnosis and management. The prognosis of LAMN depends on the presence or absence of mucin/neoplastic epithelium outside the appendix. For LAMN confined to the appendix, appendectomy alone is sufficient for management, with conservative follow-up. For LAMN with extruded acellular mucin localised to the appendiceal serosa, management involves appendectomy and PMP surveillance. For all mucinous lesions of the appendix, it is essential to submit the entire appendix for histopathologic examination, thoroughly evaluating the presence of mucin/neoplastic epithelium involving the serosa/extra appendiceal tissue for accurate staging and to predict the risk of recurrence and determine further management. Here four cases of LAMN due to their rarity and clinical importance is presented. This study of four cases emphasises that the clinical diagnosis of this rare malignancy is difficult, and radiological investigations were not available as these patients presented with clinical features mimicking appendicitis. Emergency appendectomy was performed in all cases. LAMN should be considered as a differential diagnosis because if not diagnosed and treated in the early stages, it can lead to dreaded complications like PMP. The histopathological examination of all four cases of LAMN showed dissecting acellular mucin in various stages of progression in the appendicular wall, but none involving the serosa. This highlights the importance of timely surgical intervention and histopathological examination for an exact diagnosis and staging of LAMN for further follow-up or treatment.

Appendicectomy, Mucin, Pseudomyxoma peritonei

LAMN is a rare malignant neoplasm, accounting for 1% of gastrointestinal neoplasms and is found in <0.3% of appendectomy specimens (1). This rare malignancy is most commonly discovered incidentally during operative exploration and is often diagnosed late. It can also present with symptoms such as abdominal pain, vomiting, abdominal distention, mass lesion, or intestinal obstruction. In rare cases, urological findings such as haematuria, ureteral obstruction, hydronephrosis, and urinary tract infection may occur (1),(2),(3). LAMN often presents similarly to acute appendicitis due to appendix distension, and a definitive diagnosis can only be made through histopathological examination of the appendix (4). Ultrasound of the abdomen is considered the primary diagnostic modality for appendiceal lesions, which can potentially differentiate between benign and malignant lesions (5). LAMNs typically appear as cystic, thin-walled, fluid-filled structures with or without calcifications in the appendix wall (6). Tumour marker tests, including Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 19-9 (CA-19.9), should be included in the lab work-up (7). Research has shown that these tumour markers are more useful as predictive indicators of recurrence rather than diagnostic biomarkers (8). This appendix tumour presents serious complications, including the risk of appendix rupture and the spread of mucin and neoplastic cells into the peritoneum, leading to PMP (2),(3). Peritoneal seeding typically occurs in the advanced stages of the disease.

In present case series, patients presented with vague appendicitis symptoms, and appendectomies were performed with a clinical diagnosis of acute appendicitis. Histopathological examination of all four cases revealed LAMN with varying degrees of dissecting acellular mucin progression through the appendiceal wall but without involvement of the serosa. Histopathological diagnosis is crucial for staging the neoplasm and guiding further follow-up and treatment. Therefore, timely intervention is necessary to prevent LAMN dissemination and further progression to PMP.

Case Report

The study was conducted at the Department of Pathology of a tertiary care hospital. Out of 166 appendectomy specimens received in the Department of Pathology, Andaman & Nicobar Islands Institute of Medical Sciences, Portblair, Andaman & Nicobar, India from January 2021 to December 2022, four cases were diagnosed as LAMN, based on the World Health Organisation (WHO) diagnostic criteria (9).

Case 1

A 51-year-old female presented with a sudden onset of colicky pain in the right iliac fossa lasting for one day, accompanied by nausea, vomiting, and fever. She had a history of constant dull aching pain for one month, initially around the umbilicus and later shifting to the right iliac fossa. There was no history of dysphagia, constipation, or urinary symptoms. Physical examination revealed tenderness at the right lower quadrant and McBurney’s point. Complete blood count was within normal limits. Radiological investigations were not performed as emergency laparoscopic appendectomy was carried out.

Gross examination revealed an appendix measuring 4.5 cm in length with a grey-brown and congested external surface. On cut-section, a dilated lumen at the tip measuring 2.2 cm in diameter was observed, filled with mucinous material, and mild wall thickening measuring 0.4 to 0.6 cm. Gross examination did not reveal any evidence of perforation or extrusion of mucin (Table/Fig 1)a.

Histomorphology showed a mildly dilated lumen with extensive denudation of the lining epithelium, which was replaced by acellular pools of mucin with pushing invasive margins. This mucin was confined to the lamina propria. The subepithelium exhibited loss of lymphoid follicles and areas of congestion. There was no evidence of invasion into the muscularis propria (Table/Fig 1)b. No definite evidence of dysplasia in glandular epithelium or invasive malignancy was observed. The resected margin was free of mucin or tumour. The final diagnosis of LAMN (pTis-pathological tumor stage carcinoma in situ) was made, and the postoperative period was uneventful. The patient was discharged, and during regular follow-up after three months, the patient remained asymptomatic. Abdominal ultrasound showed no significant findings, and no further intervention was required.

Case 2

A 35-year-old female presented with right lower abdominal pain persisting for three weeks. Upon examination, a mass was palpated in the right lower quadrant. Laboratory investigations revealed elevated CEA levels. During the surgery, a large dilated appendix containing inspissated mucoid material was observed, leading to an open appendectomy.

Gross examination showed an 8 cm long appendix with a diameter of 2.5 cm. The external surface appeared congested. Upon sectioning, the entire lumen was found to be dilated and filled with mucoid material (Table/Fig 2)a. The wall thickness measured between 0.2 to 0.5 cm. No gross evidence of mucin perforation or extrusion was observed.

Histomorphology revealed that the appendix was partially lined by a villiform layer of pseudostratified columnar cells with elongated pencil-shaped nuclei displaying mild atypia (Table/Fig 2)b. Extensive denudation of the surface epithelium was observed, with acellular pools of mucin dissecting through the lamina propria into the fibrotic submucosal layer. The subepithelial tissue showed marked congestion, oedema, and chronic inflammatory infiltrate with loss of lymphoid follicles. Foci of dystrophic calcification were also present (Table/Fig 2)c. There was no evidence of high-grade nuclear features, intramural glandular epithelium, dissection of mucin into the muscularis propria, periappendiceal tissue, or serosa. The resected margin was free of mucin or tumour. The final diagnosis of LAMN (pTis) was made, and the postoperative period was 7uneventful. The patient was discharged, and during regular follow-up after three months, she remained asymptomatic. Abdominal ultrasound showed no significant findings, and no further intervention was required.

Case 3

A 50-year-old female presented with acute and sharp pain in the right lower abdomen. The patient had been experiencing dull constant pain in the periumbilical region for one month. Imaging studies were not performed due to the long waiting period in the busy emergency ultrasound setup of the limited resource facility. The patient underwent emergency laparoscopic appendectomy.

Gross examination revealed an appendix measuring 6.2 cm in length. The tip of the appendix was dilated, measuring 0.6 cm in diameter, and filled with mucoid material (Table/Fig 3)a. Histomorphology showed villous proliferation of mucinous epithelial cells in the tip of the appendix, displaying abundant apical mucin, elongated nuclei, low N:C ratio, and fine chromatin. The underlying subepithelium exhibited inflammatory cells and abundant extracellular mucin reaching the subserosa (Table/Fig 3)b. Multinucleated giant cells and foamy macrophages were also observed in the subserosal adipose tissue (Table/Fig 3)c. The resected margin was free of mucin or tumour. There was no evidence of high-grade nuclear features, glands, or mucinous epithelial cells in the serosa. The final diagnosis of LAMN (pT3) was made, and the postoperative period was uneventful. The patient was discharged, and during regular follow-up after three and six months, the patient remained asymptomatic. Abdominal ultrasound showed no significant findings, and no further intervention was required. The patient is currently on regular follow-up.

Case 4

A 37-year-old male presented with dull right lower abdominal pain persisting for two months, with recent worsening of symptoms and the pain becoming sharp. The patient underwent emergency open appendectomy. Imaging studies were not performed.

Gross examination revealed an appendix measuring 3 cm in length and 1.0 cm in diameter. The appendix appeared thickened and fibrosed (Table/Fig 4)a. Histomorphology showed a mildly dilated lumen with denudation of the lining epithelium. The lining was partially composed of a flat layer of columnar cells and replaced by acellular pools of mucin reaching until the muscularis propria (Table/Fig 4)b. The subepithelium exhibited loss of lymphoid follicles and areas of congestion. There was no definite evidence of dysplasia in the glandular epithelium or invasive malignancy. The resected margin was free of mucin or tumour. The final diagnosis of LAMN (pTis) was made, and the postoperative period was uneventful. The patient was discharged, and during regular follow-up after three months, the patient remained asymptomatic. Abdominal ultrasound showed no significant findings, and no further intervention was required.

A summary comparing the four cases is shown in (Table/Fig 5).

Discussion

LAMNs are rare gastrointestinal tract neoplasms that are often misdiagnosed as acute appendicitis. LAMNs commonly present with pain in the right iliac fossa, resembling acute or recurrent appendicitis. According to the 5th edition of the WHO classification of digestive system tumours (9), the histological criteria for LAMN in the appendix are a mucinous tumour with low-grade cytology and a pushing margin/invasion. High-Grade Appendiceal Mucinous Neoplasm (HAMN) in the appendix refers to a mucinous tumour with high-grade cytology and a pushing margin/invasion. Invasive mucinous adenocarcinoma refers to high-grade appendiceal tumours with features of tissue invasion and irregular gland proliferation, often associated with stromal desmoplasia and signet ring cells.

LAMNs are a relatively homogeneous group of mucinous tumours with low-grade cytologic atypia, similar to low-grade dysplasia in other parts of the gastrointestinal tract (2). In later stages, LAMNs can rupture and disseminate as intraperitoneal mucinous tumours, which is associated with a poor prognosis (3).

Pai RK et al., first used the term “low-grade mucinous neoplasm with low risk of recurrence” if the mucin located outside the appendix was acellular, or “low-grade mucinous neoplasm with high risk of recurrence” if it contained neoplastic epithelium (10).

LAMNs should be differentiated from serrated lesions. LAMNs exhibit pushing infiltration with varying degrees of appendiceal wall fibrosis (11), whereas serrated lesions have intact mucosal muscle and no fibrosis. All patients in present case series exhibited different degrees of appendiceal fibrosis.

Present case series revealed that LAMNs were more likely to occur in adult females, which was consistent with previous reports (2),(11),(12),(13). The symptoms of LAMNs were mainly similar to appendicitis, presenting with lower abdominal pain. In a study by Bell PD et al., it was found that more than half of the patients were symptomatic, with abdominal pain being the most common presentation (13). The tip or the entire appendix was dilated to varying degrees. Calcification, as noted in one of the cases, is a good indication for the preoperative diagnosis of LAMNs by radiologists (10). However, no imaging was available in any of these cases.

The microscopic findings in all cases showed the appendix partially lined by a villiform layer of pseudostratified columnar cells or a flat layer of columnar cells with apical mucin. There were also instances of extensive denudation, covered by acellular pools of mucin, which dissected through the lamina propria into the fibrotic submucosal layer. In one case, extracellular mucin invaded the muscularis propria and reached the subserosa, resulting in pT3 staging. In a series of five cases by Wang AS et al., all cases were limited to the appendix, and one out of five cases (20%) had pT3 staging (14). A similar percentage was also found in the study by Misdraji J et al., (20%) (12). The underlying subepithelial tissue exhibited marked congestion, oedema, scattered chronic inflammatory infiltrate, and the loss of lymphoid follicles in all cases, which was consistent with the study by Misdraji J et al., (12). One case showed foci of dystrophic calcification. Calcification was found in 42% of cases in the study by Misdraji J et al., (12) and 50% of cases in the study by Bell PD et al., (13). Many multinucleated giant cells and foamy macrophages were also noted in one case of the present study. Pai RK and Longcare TA mentioned in a study of appendiceal mucinous tumours that extravasated mucin initiates a chronic inflammatory reaction associated with fibrosis, granulation tissue, and dystrophic calcification (15).

The surgical margins of the appendix were free of tumour in all four cases. In the study by Wang AS et al., all five cases of LAMN had tumour-free surgical margins (14), while Pai RK et al., and Bell PD et al., reported 9% and 6% of the cases, respectively, with positive surgical margins (10),(13). Three cases showed acellular mucin confined to the lamina propria and muscularis propria, resulting in a pathological staging of pTis (LAMN), and one case showed acellular mucin dissecting the muscularis propria and invading the subserosa, staged as pT3 (LAMN). In the present study, the majority (75%) of cases were confined to the muscularis (pTis), which was similar to the studies by Bell PD et al., (66%), Wong M et al., (61%), and Wang AS et al., (80%) (13),(14),(16).

A summary comparing the present case series with other studies is shown in (Table/Fig 6) (10),(12),(13),(14),(16).

In cases of LAMN confined to the appendix, appendectomy alone is the appropriate treatment since these tumours do not spread through lymphatics or haematogenous routes. However, in cases where the appendectomy margins are involved by acellular mucin or neoplastic epithelium, patients are managed through conservative follow-up and surveillance (2),(17). When acellular mucin is found on the surface of the appendix without spreading into the peritoneal cavity, an appendectomy is usually sufficient, along with routine follow-up and imaging to detect PMP (2),(18). Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC) is now recognised as the standard care for cases where appendiceal neoplasms have spread to the peritoneum (19),(20).

All four cases in the present study were limited to the appendix, and appendectomy alone was deemed sufficient as the standard treatment. No further management was required, and all cases had uneventful follow-up.

Conclusion

LAMN is a rare appendiceal mucinous tumor and prognosis is dependent on the presence or absence of extra appendiceal mucin and neoplastic epithelium. Evaluation of the appendix should be performed carefully to determine the prognosis and treatment of these tumours. Low-grade appendiceal mucinous neoplasms can rupture and lead to PMP with high-risk of mortality. For LAMN confined to the appendix, appendectomy alone is sufficient for management, with conservative follow-up and imaging if the margins involved by acellular mucin or neoplastic epithelium. For LAMN with extruded acellular mucin localised to the appendiceal serosa, management is done with appendectomy and PMP surveillance. This case series of LAMN suggests the importance of considering the possibility of appendiceal neoplasm in patients presenting with symptoms of acute appendicitis and timely intervention for management of such patients and preventing development of PMP.

DOI and Others

DOI: 10.7860/JCDR/2023/63453.18232

Date of Submission: Feb 15, 2023
Date of Peer Review: Mar 31, 2023
Date of Acceptance: May 20, 2023
Date of Publishing: Jul 01, 2023

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? No
• For any images presented appropriate consent has been obtained from the subjects. No

PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Feb 22, 2023
• Manual Googling: Apr 13, 2023
• iThenticate Software: May 17, 2023 (19%)

ETYMOLOGY: Author Origin

EMENDATIONS: 6