Local Protocol for Management of Low-Grade Appendiceal Mucinous Neoplasm (LAMN)

Abstract

The management and surveillance of low-grade appendiceal mucinous neoplasm (LAMN) is a confusing topic in the colorectal MDM. This study was aiming to provide a local protocol for our trust for such cases. From prospectively maintained database, patients who underwent appendicectomy between 2011 and 2017 were identified. Those with histological confirmation of LAMN were included. Retrospective analysis of operative notes, investigations and follow-up, return to theatres or development of pseudomyxoma peritonei (PMP) was performed. Four thousand six hundred twenty-eight patients had appendicectomy; 36 were diagnosed with LAMN. Age range was 30–88 (20 females). Fifteen had their operation as emergency and 13 elective, either for abnormal-looking appendix on CT scan or as part of elective right hemicolectomy. In 8 patients, LAMNs were diagnosed incidentally during other surgery either intraoperatively or on histology. Two patients had mucus in the peritoneal cavity (not sampled). The remaining 34 had either contained mucocele or inflamed appendix. Regarding follow-up, 28 patients had CT scans only, and 2 had ultrasound scan (USS). Two had both CT and USS. Three had CT and MRI scans. One patient did not have radiological investigations. Eighteen patients had colonoscopies (50%). Three patients had no follow-up, while 33 had 5-year follow-up. Ten patients are still currently under follow-up. None of the 36 patients required further surgeries related to LAMN, and none has developed PMP to date of the study. We have developed a local protocol based on our findings and literature review for management and surveillance of LAMN in line with national centres.

Introduction

Appendiceal tumours are rare, representing less than 1% of all appendicectomy specimens [1]. They can be generally divided into neuroendocrine and epithelial tumours. The term “carcinoid” has generally applied to neuroendocrine tumours (NETs) originating in the digestive tract, lung, or rare primary sites, such as the kidneys or ovaries. As with other intestinal NETs, those arising in the appendix can secrete serotonin and other vasoactive substances that are responsible for the carcinoid syndrome. Histologically, 65% of appendiceal tumours are of neuroendocrine origin [2].

The literature is confusing with regard to the classification of epithelial tumours of the appendix. The 2010 World Health Organization (WHO) classification recognizes three main categories of mucinous neoplasms: mucinous adenoma, low-grade appendiceal mucinous neoplasm (LAMN, also called appendiceal neoplasms of uncertain malignant potential) and appendiceal adenocarcinoma [3].

Low-grade appendiceal mucinous neoplasms (LAMNs) were used to refer to mucinous cystadenomas. In 2016, a new classification of mucinous appendiceal neoplasia was developed, and it was agreed that “mucinous adenocarcinoma” should be reserved for lesions with infiltrative invasion. The term “low-grade appendiceal mucinous neoplasm” was supported, and it was agreed that “cystadenoma” should no longer be recommended. A new term of “high-grade appendiceal mucinous neoplasm” was proposed for lesions without infiltrative invasion but with high-grade cytologic atypia. Serrated polyp with or without dysplasia was preferred for tumours with serrated features confined to the mucosa with an intact muscularis mucosae [4].

The typical feature of LAMN is the pattern of invasion of layers of the appendix which is known as “pushing invasion”. It can have different patterns. There may be attenuated or absent muscularis propria; frequently it may be fibrotic or hyalinised. Neoplastic epithelium growing over hyalinised or fibrotic stroma rather than lamina propria or muscularis mucosae is a feature of pushing invasion [5]. The 4th edition of the World Health Organization (WHO) classification has accepted low-grade appendiceal mucinous neoplasms (LAMN) as the official nomenclature [6].

LAMN could be localized to the appendix only or they can perforate the appendix resulting in intraperitoneal spread of neoplastic cells and the clinical picture of pseudomyxoma peritonei (PMP), thus acting like a low-grade malignancy. Therefore, whenever suspected, as in the presence of mucocele picture characterized by a distended mucus-filled appendix either radiologically or intraoperatively, treatment should always be surgical removal of the appendix with care to prevent the spillage of mucin which can lead to PMP.

The aim of this study was to evaluate all the patients diagnosed with LAMN with regard to their management and outcomes, as well as to provide a local protocol for our trust for such cases.

Methods

All patients who underwent appendicectomy from 2011 to 2017 were identified from a prospectively maintained database. Those with histological confirmation of LAMN were included. We have performed a retrospective analysis of their mode of admissions and presentations. Operative notes were reviewed with regard to the intraoperative findings and the presence of perforation of the appendix or intraperitoneal mucin. Postoperative investigations and follow-up plans were analysed. During follow-up period, data regarding the return to theatres either locally or at a tertiary centres, in addition to any radiological signs of development of pseudomyxoma peritonei (PMP), were collected.

The main objective of this study was to review our practice as well as the current literature to develop a local protocol for our trust. The secondary outcome was to assess the recurrence rate or the development of pseudomyxoma peritonei (PMP) after LAMN diagnosis.

Results

Four thousand six hundred twenty-eight patients had appendicectomy in the period between 2011 and 2017. We have included all the patients with histological diagnosis confirming low-grade appendeceal mucinous neoplasm ,and they were 36 patients. Twenty were females and 16 males. Age ranged between 30 and 88 years (average 66.8).

Fifteen patients (41.7%) presented as emergency, 14 had appendicectomy for suspicious acute appendicitis and one had emergency right hemicolectomy for caecal mass. Elective surgery was done for 13 patients (36.1%) either in a form of elective appendicectomy for abnormal looking appendix on computed tomography (CT) scan which was the case in 8 patients or elective right hemicolectomy for suspicious caecal mass on CT scan in 5 patients, where preoperative diagnosis was not confirmed but oncological resection was required. In the other 8 patients (22.2%), LAMNs were diagnosed incidentally during other surgery either intraoperatively or as an incidental finding on histology (Table 1).

Table 1.

Patients’ presentations and indications for surgery

	Operation	Indication	Number of patients
Emergency	Appendicectomy	clinical suspicious of appendicitis	14
	Right hemicolectomy	Caecal mass	1
Elective	Appendicectomy	Abnormal looking appendix on CT	8
	Right hemicolectomy	Caecal mass	5
Incidental	Right hemicolectomy	Caecal cancer	2
	Panproctocolectomy	Ulcerative colitis (UC)	1
	Laparotomy, small bowel resection and appendicectomy	small bowel obstruction secondary to incisional hernia containing small bowel and appendix	1
	Laparotomy, Hartmann’s procedure and appendicectomy	Incidental finding of abnormal appendix	1
	Laparoscopic cholecystectomy and appendicectomy	Incidental finding of abnormal appendix	1
	Laparoscopy for gynaecological pathology and appendicectomy	Incidental finding of abnormal appendix	2

Two patients (5.5%) had mucus in the peritoneal cavity (not sampled). The remaining 34 had either contained mucocele or inflamed appendix. With regard to follow-up, 28 patients were followed up by yearly CT scans only; 2 had ultrasound scan (USS). Two patients had both CT and USS on alternative basis. Three patients were followed up by CT and MRI scans on alternative occasions. One patient did not have any radiological investigations. Eighteen patients were sent to have a complete colonoscopy (50%).

Three patients had no follow-up, while 33 had 5-year follow-up. Ten patients are still currently under their follow-up surveillance. To the date of the study, none of the 36 patients required further surgeries related to LAMN, and none has developed PMP.

Discussion

Low-grade appendiceal mucinous neoplasms (LAMN) are poorly understood lesions characterized by their potential to spread to the peritoneal cavity as pseudomyxoma peritonei (PMP).

Rokitansky first described appendiceal mucocele in 1842 [7]. It has a low incidence of 0.2–0.3% of all appendicectomy performed and 8–10% of all appendiceal tumours [8]. It can be asymptomatic and in many occasions will be diagnosed incidentally or may present with appendicitis-like symptoms.

Peritoneal Surface Oncology Group International (PSOGI) recognized persistent lack of uniform diagnostic terminology in appendiceal mucinous neoplasia. A group of 71 participants including surgical pathologist, surgical and medical oncologist from 13 countries, led by Dr. Norman Carr of Basingstoke Hospital in the UK worked on appendiceal mucinous neoplasia and adopted a consensus on diagnostic terminology published in the American Journal of Surgical Pathology in 2016 [4].

Mucinous neoplasm with low-grade cytology and any of the following: loss of muscularis mucosae, fibrosis of submucosa, undulating or flattened epithelial growth, “pushing invasion” (expansile or diverticulum like growth), dissection of acellular mucin in the wall, and/or mucin and/or neoplastic cells outside of the appendix can lead to LAMN diagnosis.

Appendiceal neoplasms are considered a distinct group from colorectal carcinoma and tend to have a less aggressive natural history. LAMNs confined to the appendix rarely recur [9]. Nevertheless, patients with just acellular mucin deposits on the visceral peritoneal surface of the appendix have a recurrence rate of 3 to 7%, while for those with cellular mucin outside of the appendix, the risk is higher and ranges from 33 to 78% [10–12]. In our study, none of the patients developed a recurrence or progressed to PMP. However, this is a small sample size, and only 2 patients had mucous inside the peritoneal cavity.

All appendiceal mucinous lesions should be resected for both diagnostic and therapeutic purposes. Surgery is still advised even if the radiological impression suggesting a benign nature as there are no reliable criteria to exclude malignancy. Elective surgery for radiologically diagnosed lesions is indicated to prevent potential future rupture which can lead to PMP if the lesion is neoplastic [13]. Appendicectomy should be performed with care and limited handling to the appendix with extraction of the specimen through an extraction bag to prevent perforation and spillage of mucin which can result into development of PMP [14].

At non-specialised centres, the initial surgery for a ruptured appendiceal mucinous lesion should be limited to an appendicectomy or right hemicolectomy if required, peritoneal washing with fluid cytology, careful inspection of the abdominal cavity with documentation and biopsy of any suspicious peritoneal lesions [15].

Additional treatment will be based on pathology and any intraoperative findings of disseminated peritoneal disease. While some authors perform a completion right hemicolectomy in patients who have a positive surgical margin after appendicectomy for an unruptured LAMN [16], others report that involvement of the appendicectomy margin by neoplastic epithelium or acellular mucin does not predict recurrence of disease even without further surgery [17].

Although the presence of cells outside of the appendix increases the risk for a recurrence, right hemicolectomy appears to offer no additional benefit over appendicectomy alone [11, 18]. At most institutions, such patients are just followed with regular imaging and tumour markers for evidence of PMP, which can then be treated with cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) if PMP has developed. In such cases, management plan should always be discussed in a multidisciplinary setting in specialized centres.

There are no data addressing post-treatment surveillance, and local protocols should be developed in line with the national centres. Until now, there are no recommendation with regard to a close surveillance for patients with completely resected LAMN with no intraoperative findings of peritoneal mucin spilling and with no cells or mucin outside of the appendix on the pathology specimen [19]. However, care should be taken prior to discharging patients from surveillance especially if there is no clear documentation of the intraoperative findings.

For patients with either acellular or cellular mucin outside of the appendix or those with perforated appendix, regularly scheduled imaging and tumour marker follow-up are advised to allow earlier detection and management of recurrence. However, there is no consensus regarding the adequate follow-up schedule, and duration varies from imaging every 6 months [16] to 2 years [12].

There is not enough data to show the significance of tumour markers for the prognosis of LAMN in the follow-up stage. Although few studies and case reports have shown that several tumour markers, including CEA, CA 19–9 and CA 125, have diagnostic and prognostic significance [20–22], other showed that they were not significant in terms of follow-up, treatment, prognosis and recurrence [23].

Local Protocol

1. All appendiceal mucinous lesions should be resected for both diagnostic and therapeutic purposes in both elective and emergency setting (if fit for surgery) [13, 24–26].

2. Appendicectomy should be performed carefully and with limited handling to the appendix. Extraction of the specimen should be through an extraction bag to prevent perforation and spillage of mucin [14, 24, 27].

3. For a ruptured appendiceal mucinous lesion, initial operation should entail [15]:

1. Limited resection in form of appendicectomy or right hemicolectomy if required

2. Peritoneal washing with fluid cytology

3. Careful inspection of the abdominal cavity

4. Biopsy of any suspicious peritoneal lesions

5. Clear documentation of operative details

• 4-Patients with LAMN that is confined to the appendix with negative resection margin have not ruptured and with no cells or mucin outside the appendix on histology do not require a completion right hemicolectomy. They might also not require a close surveillance if there is clear documentation of no intraoperative findings of peritoneal mucin spilling and there is no other clinical suspicion [19].
• 5-In patients with positive resection margin or in ruptured LAMN with cellular or acellular mucin on the serosal surface of the appendix or the mesoappendix, right hemicolectomy appears to offer no additional benefit over appendicectomy alone. A conservative approach can be justified [11, 18, 28, 29].
• 6-Patients who are found to have peritoneal mucin at the time of initial surgery should be referred to a centre specializing in management of peritoneal surface malignancies for possible CRS/HIPEC [29].
• 7-Patients with either acellular or cellular mucin outside of the appendix or those with perforated appendix will require close monitoring for 10 years with follow-up abdominal CT scan yearly for 4 years and then every 2 years. MRI can be used instead in young patients to limit cumulative radiation exposure [30]. Shorter duration of follow-up can be applied in unfit patients where further surgical management is unlikely. Utilization of tumour markers as prognostic tool is probably of a limited value unless further robust evidence suggesting otherwise.
• 8-Colorectal cancer should be excluded by pre- or postoperative colonoscopy due to associated risk of colorectal cancer with appendiceal mucinous lesions [31].

Conclusion

We have developed a local protocol for the trust based on our findings and literature review for the management and surveillance of LAMN in line with national centres. None of our patients developed PMP. Larger studies with longer follow-up would be of paramount help to our understanding to the nature and progression of this pathology.

Authors’ Contributions

MB has performed data analysis, literature search and writing the manuscript. MT shared in the study design, data collection and reviewed the manuscript. AH critiqued and edited the manuscript. NP designed the study, reviewed and edited the manuscript. All authors read and approved the final manuscript.

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.