Prophylactic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for low-grade appendiceal mucinous tumors with early and limited disease after completely removed

doi:10.21203/rs.3.rs-3874943/v1

Background

The necessity of prophylactic cytoreductive surgery (PCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for low-grade appendiceal mucinous neoplasms (LAMN) after complete removal is still controversial. This study aims to determine the role of PCRS + HIPEC and identify optimal strategies for managing these patients.

Methods

One hundred and fifty-nine patients who sought medical advice at Aerospace Center Hospital were retrospectively analyzed from January 2011 to December 2021. All the patients were divided into the PCRS group and the observation group. The data of surgical specimens and pathology was collected, and the effect on recurrence-free survival (RFS) was analyzed.

Results

Of these 159 patients, 88 were in the PCRS group, and 71 were in the observation group. The median follow-up time was 38 months. Seven patients recurred and developed into pseudomyxoma peritonei, one in the PCRS group and six in the observation group. The median RFS in the PCRS group was significantly longer than the observation group (48.0 vs. 36.0, p = 0.002). The analysis of RFS showed that patients who underwent PCRS (p = 0.009 ) and HIPEC (p = 0.007) had better survival. After multivariate analysis, Surgical specimen accompanied by disseminated peritoneal adenocarcinoma was identified as an independent prognostic factor for RFS. In the study of surgical resection content, patients with greater omentum (p = 0.007) and bilateral fallopian tubes and ovaries of women (p = 0.002) resection had a more prolonged RFS with statistical significance.

Conclusion

Without higher-level evidence, PCRS and HIPEC are necessary for LAMN after complete removal in patients with a high risk of recurrence. We recommend removing at least the greater omentum and women's bilateral fallopian tubes and ovaries. For women who are unwilling to remove the bilateral fallopian tubes and ovaries, they should be fully informed of the risks.

prophylactic cytoreductive surgery(PCRS)

hyperthermic intraperitoneal chemotherapy(HIPEC)

low-grade appendiceal mucinous(LAMN)

greater omentum

bilateral fallopian tubes and ovaries

Mucous tumors of the <link rid="Sec4">appendix</link> are a rare malignancy, particularly the low-grade appendiceal mucinous neoplasms (LAMN), which are the main cause of pseudomyxoma peritonei (PMP), a clinical syndrome which causes mucinous ascites and mucinous tumor implantation along the abdominal and pelvic cavity.^1–2 The primary LAMN can be unexpectedly detected in any abdominal surgery, especially acute appendicitis. Patients with PMP can achieve a pretty good prognosis after undergoing complete or near complete cytoreductive surgery(CRS)combined with hyperthermic intraperitoneal chemotherapy (HIPEC),^3–4 a standard treatment for tumors with peritoneal metastases. The possibility of recurrence or progression to PMP may occur after being completely removed for a long time. This may be related to the pathological characteristics of the <link rid="Sec4">appendix</link>, including perforation of the <link rid="Sec4">appendix</link>, positive surgical margin, and distribution of mucus. For these patients, the necessity of prophylactic CRS (PCRS) and HIPEC is confusing.

In this manuscript, we identify a group of patients who had a LAMN histology with complete tumor resection and a long long-term follow‐up. Some patients underwent PCRS, while others did not. The purpose of studying these patients is to determine the role of PCRS + HIPEC and identify optimal strategies for management of these patients.

Ethical Approval

The protocol for this study was approved by the Ethics committee of the Aerospace Center Hospital, Beijing, China (No. 2022-061). All methods were performed in accordance with the relevant guidelines and regulations. The written informed consent was abandoned due to the retrospective.

Patient selection

We conducted a retrospective analysis of the clinical data of patients who had a LAMN histology with complete tumor resection from January 2011 to December 2021. All patients sought consultation within six months after the initial surgery, and all diagnoses were confirmed by 2 experienced pathologists in our center. The patients were divided into two groups, the PCRS+HIPEC group, and the observation group. The indications of PCRS include: mucin or neoplastic epithelium extending into muscularis propria/serosa, mucin on mesoappendix and/or excised specimens were affected, perforation and positive margin, strong surgical willingness in any pathological situation. Patients with tumors confined to the mucosa or who refused surgery were included in the observation group(Fig 1) . All patients had not experienced serious complications and were alive during the follow-up period.

Surgical procedure

All CRS+HIPEC procedures were performed by the same surgical team with expertise in PMP. An abdominal and pelvic contrast-enhanced CT was performed for all patients to evaluate the condition of the abdomen. All patients showed no obvious lesions in preoperative CT evaluation. Laparoscopic exploration was the first choice for patients, and an open CRS was selected when laparoscopic CRS was difficult or directly selected for patients with multiple organ removal. The omentectomy and peritonectomy for implantation were performed in all CRS patients. Bilateral salpingo-ovariectomy was performed in postmenopausal females or premenopausal females with a desire to resection, whether the fallopian tubes and ovaries were normal or not. The uterus was preserved if it appeared normal and did not show adherence to the surrounding tissues. Ileocecal resection or right hemicolectomy was performed for patients with positive margins or implantation. Excision of the lesser omentum and ligamentum teres hepatis was performed for patients with open surgery CRS. After CRS, a HIPEC was performed with a closed procedure. Two inflow and two outflow catheters were placed in the abdomen and connected to a hyperthermia chemotherapy perfusion machine (Jilin Minda Company products, RHL - 2000B) with a 60 min treatment time. Cisplatin 60-80 mg was used with 3500~4000ml physiological saline and warmed to 41~43.5℃.

Follow-up protocol

The frequency of follow-up was twice a year in the first five years and then once a year with abdominal pelvic enhanced CT examination. The follow up time, i.e. RFS, starts from the initial surgery for the appendix, and the last follow-up was conducted in December 2022 via telephone or at an outpatient clinic.

Statistical Analysis

Statistical analysis was performed by using SPSS 25.0 (IBM Corporation, Armonk, NY, USA) and R 4.1.2 (http://www.r-project.org) . The continuous data were expressed as median (interquartile ranges, IQR) and analyzed by the Mann-Whitney U test. The categorical data were presented as frequency and compared with chi-square or Fisher’s exact test. Survival analysis was performed by using Kaplan-Meier method and tested by Log-rank test. A multivariable Cox proportional hazards model was established to obtain independent prognostic factors. The significance level for all statistical tests was set at 0.05.

The patient characteristics

A total of 159 patients were included in this study, 75 were females, and 84 were males. Eighty-eight patients were included in the PCRS group, and 71 patients were included in the observation group. The median age was 51.0 (IQR, 43.0-61.0) years. In the observation, 13 patients did not recommend surgery because the lesion was limited to the appendix mucosa, and 58 patients who were recommended PCRS choose observation. Between the two groups, there was significant difference in whether the laparoscope and HIPEC were performed, mucus and/or neoplastic epithelium distributed in the appendix. All the patient characteristics were as shown in Table 1.

The result of surgery and pathology

As shown in Table 2, the primary surgical procedures in the PCRS group include omentectomy and bilateral salpingo-ovariectomy. The average length of hospital stay was 12 days, and the average surgical time was 6 hours. Eighteen patients found mucus in their excised specimens after PCRS. 14 were acellular mucus, and 4 were LAMN. In the observation group, the treatment was mainly focused on the primary lesion. Only three patients found mucus in specimens. 2 were acellular mucus and 1 was LAMN.

The 7 patients who experienced recurrence all received CRS+HIPEC, 1 patient each for completeness of cytoreduction (CCR) score 0, 2, and 3, with 3 patients reaching CCR1. One was disseminated peritoneal adenomucinosis, and six were peritoneal mucinous carcinomatosis with signet ring cells (PMCA-S).

The analysis of recurrence-free survival

Of the 159 patients, the median follow-up time was 38 months. The median RFS time was not reached. Seven patients relapsed during follow-up and developed PMP through CRS, one in the PCRS group and six in the observation group. The pathological diagnosis showed that five were disseminated peritoneal adenomucinosis (DPAM), one was peritoneal mucinous carcinomatosis (PMCA), and another one was peritoneal mucinous carcinomatosis with signet ring cells (PMCA-S). The patients who underwent PCRS and HIPEC had longer RFS with significant survival differences (Fig2 A-B). The univariate analysis showed that the presence of DPAM was an independent factor affecting the prognosis for RFS (Table 3).In the analysis of surgical content, only the omentectomy and bilateral salpingo-ovariectomy were significantly associated with RFS(Fig 3 A-B, Table 4).

Although CRS+HIPEC has been recognized as a highly effective treatment for PMP,^5-6considering the possibility of developing into PMP, its role in patients of LAMN with early and low tumor burden that has been completely removed is still controversial. As the largest center for the diagnosis and treatment of PMP in China, we treated many LAMN patients with early and low tumor burden that have been completely removed. Some patients underwent PCRS+HIPEC, while others chose observation. By analyzing the 159 patients included, we found that PCRS+HIPEC could significantly prolong the RFS of patients.

It is extremely difficult to identify high-risk recurrence populations from such patients. Some early studies showed that LAMN confined to the mucosa of the appendix that was completely resected without rupture represent no further risk of developing PMP.^7-8Even with perforation and distribution of acellular mucin, the risk of developing PMP also was shallow.⁹ Hegg et al., through observing the macroscopic and microscopic characteristics of LAMN, found that more than 80% of cases with PMP had a microscopic presence of acellular mucin on the surface of the serosa, which is twice as high as in cases without PMP. Meanwhile, none of the cases that later developed into PMP had acellular mucin confined to the mucosal layer, and none of the cases where mucin was confined to the mucosa later developed into PMP.¹⁰ When cellular mucin was found in the specimen, the probability of PMP occurring was higher.¹¹ Among the seven relapsed patients in this study, two were affected by the appendix muscle layer, five were affected by the appendix serosa, one had acellular mucus distribution, and one was accompanied by DPAM. These results indicated that tumors invade the muscular and/or serosal layers of the appendix, and the distribution of acellular and/or cellular mucus are important factors in the occurrence of PMP.

The risk of developing PMP in patients with perforation and surgical margin remains diffificult to predict. Some studies have found that appendix perforation is an important factor in the development of PMP.^12-13 However, perforation of the appendix does not necessarily mean the formation of PMP. Mehta et al. found compared to non perforated patients, appendiceal perforation does not increase the risk of progression to PMP.¹⁴ Among the 7 patients with recurrence in this study, 3 had appendiceal perforation, and the perforation had no significant impact on RFS. A negative surgical margin has always been an ideal state pursued by surgeons, which could significantly reduce the risk of recurrence.¹⁵But Misdraji's study found that 16 patients with positive margins did not develop PMP.¹⁶In the observation group of this study, all patients had negative surgical margins, but 6 patients still developed PMP. These findings indicate that the development of PMP caused by surgical margin positivity is not absolute. In other words, a negative margin cannot completely block the occurrence of PMP.

The factors contributing to the development of PMP from LAMN remain unclear. However, based on the results of the above research, patients with mucin on mesoappendix or neoplastic epithelium extending into muscularis propria /serosa, perforation, and positive margin have a higher risk of developing into PMP. Therefore, we suggested and performed PCRS+HIPEC on these patients. For patients with tumors limited to the mucosa and strong surgical intention, we also performed the same treatment. Enomoto et al. found that HIPEC did not present a significant advantage in preventing recurrence in patients with appendiceal neoplasms after complete resection.¹⁷ In this study, the median RFS of the PCRS+HIPEC group was significantly longer than that of the observation group, and it significantly prolonged the RFS.

There is currently no clear recommendation for the removal content of PCRS. From the characteristics of tumor implantation, PMP usually manifests as tumor deposition throughout the entire peritoneal cavity, which is composed of a redistribution pattern related to peritoneal fluid flow and gravity, which can also easily cause metastasis of the greater omentum and ovaries.¹⁸Meanwhile, the unique physiological characteristics of the ovary provide favorable conditions for tumor implantation.¹⁹Mehta et al. discovered that the ovarian tumor metastasis rate in the appendiceal tumor group was 58.1%. Even if both ovaries appear normal macroscopically, 17% of patients were still affected.²⁰ Hench, omentectomy was performed for all patients who underwent PCRS in our center, and bilateral salpingo-ovariectomy was performed in postmenopausal females or premenopausal females with a desire to resection, whether the fallopian tubes and ovaries are normal or not. Although omentectomy and bilateral salpingo-ovariectomy were not independent factors affecting RFS in this study, they significantly prolonged the patient's RFS. In addition, we also removed other organs or tissues that were suspected or had potential implantation risks. However, they had no impact on RFS. Interestingly, as shown in the table, all excised specimens may had microscopic tumor implantation.

This study was associated with two limitations. First, this is a retrospective cohort study with a low number of patients and limited conclusions. Second, the important indicator of tumor markers was not included in the study due to severe data loss.

To our knowledge, this is the largest study to evaluate PCRS+HIPEC in patients with LAMN after complete removal. Although the recurrence rate is low, based on the results of this study, PCRS and HIPEC are necessary for LAMN after complete removal in patients with a high risk of recurrence. We recommend removing at least the greater omentum and women's bilateral fallopian tubes and ovaries. For women who are unwilling to remove the bilateral fallopian tubes and ovaries, they should be fully informed of the risks. A multicenter, prospective, randomized trial will be required to definitively address the role of PCRS+HIPEC for LAMN after complete removal.

Author contributions

All authors contributed extensively to the article and approved the submitted version.The author contributions were as follows:

C.W. and R.M. designed the work.

L.A., G.S., X.F., and P.Z. collected the data.

C.W. and Y.J. analyzed the data.

C.W. and Y.J. drafted the document.

R.M. made the final confirmation.

Consent for publication

Not applicable.

Funding/Support

This study was supported by Youth Innovation Fund of Aerospace Center Hospital, Beijing, China (No.2022GN03).

Disclosure of conflicts of interest: There are no ethical/legal conflicts involved in the article.

“Data availability” statement

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Whether the paper is based on a previous communication to a society or meeting： No

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Table 1 Clinical variable characteristics of patients

Variable	No.	No.		P value
Variable	All （n=159)	PCRS (n=88)	Non-PCRS (n=71）	P value
Age, median (IQR), y	51.0(43.0~61.0)	53.0(46.0~64.0)	47.0(41.0~59.0)	0.030
Sex
Male	75	42	33
Female	84	46	38	0.875
Term of history, median (IQR), months	1.0(1.0~2.0)	1(1.0~2.0)	1.0(1.0~2.0)	0.880
PSS
0-1	126	71	55
2-3	33	17	16	0.619
Perforation
No	113	56	57
Yes	46	32	14	0.021
Appendicitis
No	64	40	24
Yes	95	48	47	0.136
Mucinous ascites
No	151	84	67
Yes	8	4	4	1.000
laparoscope
No	72	49	23
Yes	87	39	48	0.003
PMP
No	131	69	62
Acellular	18	14	4
DPAM	10	5	5	0.125
HIPEC
No	68	3	65
Yes	92	85	7	< 0.001
Mucin/tumor cell dissection of appendix
Mucosa	19	6	13
Muscularis propria	53	26	27
Serosa	87	56	31	0.018
RFS, median (IQR), months	41.0(28.0~60.0)	48.0(29.0~68.5)	36.0(26.0~46.0)	0.002

Operation

PCRS Tumor implantation

Non-PCRS Tumor implantation

PCRS: prophylactic cytoreductive surgery; PSS: prior surgical score; PMP: peritoneal pseudomyxoma; HIPEC: hyperthermic intraperitoneal chemotherapy; DPAM: disseminated peritoneal adenomucinosis; RFS: recurrence-free survival.

Table 2 Surgical resection content and tumor implantation site in the PCRS+HIPEC and observation groups.

Table 3 Univariate and multivariate analyses for prognostic factors affecting RFS.

Variables	No.	Univariate analysis		Multivariate analysis
Variables	No.	Hazard ratio(95%CI)	P	Hazard ratio(95%CI)	P
Age(years)
≤50	75	1	-	-	-
>50	84	5.058(0.608~42.045)	0.134	-	-
Gender
Female	84	1		-	-
Male	75	0.470(0.091~2.243)	0.367	-	-
Term of history, month
≤1	117	1		-	-
>1	42	0.032(0.001~49.317)	0.358	-	-
PSS
0-1	126	1	-	-	-
2-3	33	1.489(0.288~7.682)	0.635	-	-
Perforation
No	113	1	-	-	-
Yes	46	1.701(0.380~7.626)	0.488	-	-
Appendicitis
No	64	1	-	-	-
Yes	95	1.624(0.314~8.386)	0.563	-	-
Mucinous ascites
No	151	1	-	-	-
Yes	8	3.529(0.423~29.425)	0.244	-	-
laparoscope
No	72	1	-	-	-
Yes	87	0.177(0.021~1.492)	0.111	-	-
PMP			-	-	-
No/Acellular	140	1	-	-	-
DPAM	9	7.477(1.448~38.615)	0.016	5.682(1.066~30.297)	0.042
HIPEC
No	68	1	-	-	-
Yes	91	0.095(0.011~0.797)	0.030	-	-
Mucin/tumor cell dissection of appendix
Mucosa/Muscularis propria	72	1		-	-
Serosa	87	1.924(0.373~9.933)	0.434	-	-
PCRS
No	71	1	-	-	-
Yes	88	0.097(0.011～0.823)	0.032	-	-

PSS: prior surgical score; PMP: peritoneal pseudomyxoma; HIPEC: hyperthermic intraperitoneal chemotherapy; DPAM: disseminated peritoneal adenomucinosis; PCRS: prophylactic cytoreductive surgery.

Table 4 Survival analysis of surgical resection content after log rank test.

Organ or Tissue Resection	No.	P values
Greater omentum
No	75
Yes	84	0.007
Lesser omentum
No	84
Yes	75	0.131
Ligamentum teres hepatis
No	117
Yes	42	0.276
Operation
Appendix	126
Ileocecum/RH	33	0.729
Peritoneum
No	156
Yes	3	0.454
Bilateral fallopian tubes and ovaries
No	40
Yes	44	0.002
Uterus
No	72
Yes	12	0.255

No competing interests reported.

Prophylactic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for low-grade appendiceal mucinous tumors with early and limited disease after completely removed

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Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Materials and methods

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Status:

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