Low‐grade appendiceal mucinous neoplasm encountered during risk‐reducing salpingo‐oophorectomy: A case of laparoscopic surgery

Low‐grade appendiceal mucinous neoplasm (LAMN) is a rare epithelial malignancy of the appendix. If it perforates the abdominal cavity, it can cause a serious clinical syndrome called pseudomyxoma peritonei. In the present case, we laparoscopically removed a LAMN encountered during risk‐reducing salpingo‐oophorectomy (RRSO). The patient was a 53‐year‐old woman who was diagnosed with hereditary breast and ovarian cancer syndrome. RRSO was planned, and magnetic resonance imaging revealed a large cystic tumor in the right lower abdomen. We expected an ovarian cyst; however, it was a primary tumor of the appendix. Partial cecal resection was performed laparoscopically by a surgical oncologist. The pathological diagnosis was LAMN. Gynecologists may encounter this disease incidentally. Mucinous appendiceal neoplasm (MAN) may be encountered during RRSO. If a right lower abdominal mass is found near a normal ovary preoperatively, gynecologists should consider MAN as well as paraovarian cyst.


INTRODUCTION
In Japan, risk-reducing salpingo-oophorectomy (RRSO) has been covered by insurance for breast cancer patients with hereditary breast and ovarian cancer (HBOC) syndrome since 2020; thus, there have been increased opportunities to perform it.RRSO is recommended to be performed laparoscopically.
Mucinous appendiceal neoplasm (MAN) is a rare epithelial malignancy of the appendix, with approximately 1000-2000 cases diagnosed each year in the United States. 1 In Japan, the frequency of low-grade appendiceal mucinous neoplasm (LAMN) remains to be elucidated.According to the Multi-Institutional Registry of Large Bowel Cancer in Japan of the Japanese Society for Cancer of the Colon and Rectum, of 8893 colorectal cancers, 48 (0.5%) were appendiceal cancers in 2013.The frequency of LAMN is estimated to be less than that of appendiceal cancers.LAMN is included in MAN; however, if LAMN perforates and spreads into the abdominal cavity, it can cause a serious clinical syndrome called pseudomyxoma peritonei (PMP). 2 The site of origin is very close to the right adnexa, and it is often diagnosed preoperatively as a right adnexal tumor.Gynecologists may encounter this disease incidentally during surgery, and it requires appropriate treatment.No reports of LAMN have been found in RRSO for HBOC syndrome.In the present case, we were able to laparoscopically remove LAMN encountered during RRSO in a breast cancer patient with BRCA2 pathogenic variant (PV) without rupture.

CASE PRESENTATION
The patient was a 53-year-old female.Her medical history included endometrial hyperplasia and bilateral breast cancer for which she underwent bilateral mastectomy at age 51.The patient did not use selective estrogen receptor modulators, such as tamoxifen or raloxifene, because both bilateral breast cancers were ductal carcinoma in situ and the patient underwent mastectomy rather than breast-conserving surgery.For concurrent bilateral breast cancer, she met the Gene Testing Criteria of the National Comprehensive Cancer Network guidelines.BRCA genetic testing identified BRCA2 PV (c.4339del).She requested RRSO, and a laparoscopic procedure was planned.Physical examination revealed no abdominal pain.Tumor marker findings were carcinoembryonic antigen 2.6 ng/mL (normal value <5 ng/mL) and cancer antigen 125 13.7 U/mL (<35 U/mL), both within normal range.
Transvaginal ultrasound showed a cyst in the pelvis, and ovarian cyst was predicted.Abdominal magnetic resonance imaging showed uterine fibroids, but no abnormalities in the endometrium.A cystic lesion was seen near the right iliopsoas muscle, showing high intensity on T2-weighted imaging and low intensity on T1-weighted imaging.Although a normal right ovary was observed, a cystic region was seen in close location.There was no solid component and the radiologist diagnosed it as a right ovarian cyst (Figure 1).
As the patient had a history of endometrial hyperplasia, endometrial biopsy was performed but was normal.However, due to hypermenorrhea, she strongly desired hysterectomy.Laparoscopic RRSO and total hysterectomy were planned.Intraperitoneal findings revealed that the right and left ovaries and fallopian tubes were of normal size.Part of the appendix was cystically enlarged, showing a primary tumor of the appendix (Figure 2).After consulting with the surgical oncologist during the surgery, we decided on a two-stage radical surgery in case of malignancy.The appendiceal root was not found to be abnormal in appearance; however, the possibility of invasion could not be ruled out, and a laparoscopic partial cecal resection was performed.An automatic anastomosis machine (GIA-tri-staple 60 mm) was used for suture dissection.The tumor contents were stored in collection bags without leakage.Then, hysterectomy and RRSO were performed, and all the explants were removed transvaginally.
The appendix was dilated, and mucus was found in the lumen.Histologically, columnar epithelial cells with intracytoplasmic mucus were seen.These epithelial cells showed a basement alignment and no apparent infiltration.LAMN was diagnosed (Figure 3).Pathological examination of the removed fallopian tubes was performed by the Sectioning and Extensively Examining the Fimbria protocol (SEE-FIM protocol).The ovaries and fallopian tubes showed no malignant findings.The uterus showed only leiomyoma and no abnormalities in the endometrium.
Postoperative colonoscopy was performed.Low-grade tubular adenoma was found in the descending colon, but no malignant lesion was identified.
This report was submitted and approved by the Institutional Review Board of Kanagawa Cancer Center (Yokohama, Japan; 2021-EKI-90), and informed consent was obtained from the patient.

DISCUSSION
MAN may be encountered during RRSO of HBOC.In the present case, cooperation with the surgical oncologist made it possible to perform the laparoscopic procedure without perforating the tumor.
MAN may be encountered in patients with ovarian tumor.Most cases of MAN are asymptomatic 3 and are discovered incidentally during radiological or endoscopic examination for unrelated complaints or during surgery.According to its anatomic location, MAN is often misidentified as an adnexal mass in diagnostic imaging. 4In the present case, MAN could not be diagnosed preoperatively.The main reason for this was that the patient was female and the radiologist misdiagnosed MAN as an ovarian cyst.Furthermore, the wall calcifies in about half of MAN cases; however, in the present case, there was no calcification, so imaging studies were not able to diagnose MAN.On computed tomography, it is difficult to clearly distinguish between nonneoplastic and neoplastic lesions.Irregular walls and soft-tissue thickening are features most likely to be associated with malignancy. 5n HBOC syndrome, the incidence of female breast and ovarian cancer as well as several other cancers has been reported to be higher than the general frequency.Data from 5341 families examining the association of BRCA1/2 PVs with the risk of 22 cancers reported an increased risk of male breast, pancreatic, stomach, and prostate cancer. 6Another study used data from 63 828 Japanese patients and 37 086 controls to study the risk of 14 cancers, they reported that there was increased risk of biliary tract, gastric, male breast, pancreatic, prostate, and esophagus cancer. 7Both studies showed no increased risk of colorectal cancer.In addition, two meta-analyses that analyzed the association between being a BRCA mutation carrier and colorectal cancer had different conclusions.One meta-analysis using 11 studies reported no increased risk, 8 whereas a second meta-analysis using 14 studies reported an increased risk in BRCA1 mutation carriers. 9The latter study included BRCA family members with unknown mutation status; however, when limited to BRCA carriers, the risk was not significant. 10In addition, there have been no reports of an increased risk of appendiceal neoplasms in HBOC.The association of HBOC with MAN was reported in a study of BRCA1 carriers who developed LAMN after RRSO. 11The evidence for surveillance of the lower gastrointestinal tract for HBOC syndrome is unclear, but to the best of our knowledge, this is the first report of MAN during RRSO.
Cooperation with the surgical oncologist made it possible to perform the laparoscopic procedure without perforating the tumor.An important point is that MAN containing LAMN, unlike benign lesions such as appendiceal serrated lesions and polyps, can perforate and spread intraperitoneally, causing PMP, a clinical syndrome. 2PMP is a clinically malignant condition.As the disease progresses, the peritoneal cavity becomes filled in a characteristic pattern with mucinous neoplasm and mucinous ascites. 12Tumor rupture is a potential cause of PMP and requires careful intraoperative handling of the lesion and adequate resection margins. 3A retrospective study comparing open surgery and laparoscopic surgery reported that operation time, intraoperative rupture, and rate of postoperative complications were similar, and the time to flatus, time to soft food intake, and length of hospital stay were shorter for laparoscopic surgery. 13Today, with the widespread use of laparoscopic surgery in the treatment of colorectal cancer, surgeons may elect to perform laparoscopic surgery.Laparoscopic surgery for LAMN has been increasing in recent years and has proven to be minimally invasive, with minimal postoperative pain and quick recovery. 14f MAN is diagnosed, colonoscopy is recommended.It has been reported that 13% of patients diagnosed with MAN had concurrent colonic lesions. 2 It is also recommended that patients with MAN be followed for at least 5 years to ensure that they do not develop PMP.
In conclusion, MAN may be encountered during RRSO of HBOC.In the present case, cooperation with the surgical oncologist made it possible to perform the laparoscopic procedure without perforating the tumor.If a right lower abdominal mass is found near a normal right ovary preoperatively, MAN should be considered before surgery as well as paraovarian cyst.Radiologists should consider it as a differential diagnosis.In the present case, RRSO helped trigger the discovery of an unruptured MAN, which was successfully removed.However, MAN in the majority of women could be misdiagnosed as a benign ovarian tumor.Furthermore, since MAN is rare, it is not known if it is an HBOCassociated tumor.MAN is often misidentified as an adnexal tumor, so gynecologists may encounter it incidentally; however, they should be aware that MAN containing LAMN may develop PMP.

F
I G U R E 1 Magnetic resonance imaging (MRI) findings.Abdominal MRI shows cystic lesion near the right iliopsoas muscle (arrow), with high intensity on T2-weighted imaging (a) and low intensity on T1-weighted imaging (b).F I G U R E 2 Intraperitoneal findings.Intraperitoneal findings reveal that the right ovarian fallopian tubes are of normal size (white arrow).Part of the appendix is cystically enlarged (black arrow), showing a primary tumor of the appendix.

3
Macroscopic and pathological findings of the appendiceal neoplasm.Macroscopic view of the resected specimen (A).The tumor cells have tall cytoplasmic mucin vacuoles that compress the nucleus.The nuclei of the epithelial cells are oval and slightly darkly stained; however, the degree of atypia is mild.These epithelial cells show a basement alignment and no apparent infiltration (hematoxylin and eosin staining 20Â) (B).