Diverse presentations of low-grade appendiceal mucinous neoplasm

INTRODUCTION

Low-grade appendiceal mucinous neoplasms (LAMN) are rare tumors arising from the mucinous epithelium of the appendix with an incidence of 0.7-1.7%.^[1] Lack of any characteristic clinical symptoms makes pre-operative diagnosis difficult.

LAMNs are diagnosed in <1% of all appendicectomies performed. They often remain asymptomatic or are diagnosed incidentally when patients present with severe abdominal pain or intussusception. The most common mimicker is acute appendicitis, and in women, they often simulate a right ovarian neoplasm.^[2,3] Tumors confined to the appendix without any serosal breach carry a good prognosis; however, rupture leads to seeding of the entire peritoneum with mucin, causing pseudomyxoma peritonei (PMP), associated with high mortality.^[4] Histologically, they are characterized by bland mucinous lining epithelium of the appendiceal mucosa, no destructive invasion of the wall by mucinous cells, and characteristic atrophy of underlying lymphoid follicles and lamina propria/muscularis mucosae, which is replaced by fibrosis. We herein report three interesting cases of LAMN, one of which was incidentally detected, a second presented with diffuse abdominal pain, and imaging showed loculated ascites with peritoneal deposits. The third was an elderly female detected with ascites and a large right adnexal mass.

CASE SERIES

Case 1

A 61-year-old female with known comorbidities (diabetes mellitus and hypertension) presented with bloody diarrhea and significant weight loss (3 kg in 1 month). Colonoscopy revealed a large, irregular, ulcerated growth at 70 cm from the anal verge toward the proximal end of the ascending colon. It was confirmed on biopsy as an adenocarcinoma. Computed tomography done at an outside hospital showed an uneven concentric growth involving the ascending colon; however, there were no comments or mention about the appendix. The patient thereafter underwent right hemicolectomy at our hospital. Gross examination of the specimen showed a large ulceroproliferative growth in the ascending colon. Interestingly, the appendix was enlarged and dilated, measuring 7.5 × 3.5 cm. On cutting open, the entire lumen was filled with thick, gelatinous mucinous material [Figure 1a and b]. Histopathology confirmed adenocarcinoma (AJCC TNM stage T2N0Mx) with LAMN (AJCC TNM stage T4aN0M0), dual synchronous malignancies arising in the same specimen. There was no evidence of PMP intraoperatively, and the post-operative imaging was unremarkable. The patient is on regular follow-up in the gastroenterology outpatient department (OPD) and is presently asymptomatic 2 years post-surgery.

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Figure 1:

(a) Macroscopic pictures showing the ulcerated growth in the ascending colon (encircled) and the dilated, enlarged appendix (marked with red arrow), (b) The cut open lumen of appendix is filled with thick gelatinous mucin.

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Case 2

A 48-year-old female, hypertensive, presented with complaints of diffuse abdominal pain with a history of intermittent fever, anorexia, and vomiting of 3 months duration. On per abdominal examination, the abdomen was soft with tenderness at McBurney’s point. There was no guarding, rigidity, or rebound tenderness. There was no hepatosplenomegaly. Bowel sounds were checked and were audible. Ultrasonography of the abdomen showed a fluid collection in the Pouch of Douglas and minimal ascites. Contrast-enhanced computed tomography (CECT) abdomen and pelvis showed grossly hyperdense, loculated ascites with peritoneal deposits suggestive of carcinoma ovary/peritoneal carcinomatosis. Both ovaries were not clearly visualized in the CECT films. Tumor marker Ca 125 was 12.5 U/mL (normal range 0-35 U/mL), which was within the normal range. Her colonoscopy did not show any colonic growth. A diagnostic Laparotomy with appendectomy was performed. Intraoperatively, there were extensive mucinous deposits over the liver surface, serosal surface of bowel, and a few peritoneal deposits. Additionally, 2 L of mucinous fluid were removed. The appendix was perforated and removed in fragments, showing mucinous serosal deposits. Macroscopic examination revealed a partially fragmented appendix specimen with a proximal margin marked with a suture. Sections taken showed mucosa lined by flattened epithelium, which at places was thrown into epithelial projections. The lining cells were columnar with stratification and showed apical mucin. Focally, there were features of high nuclear grade in the form of nuclear stratification, hyperchromasia, and coarse vesicular chromatin. The peritoneal deposit was positive for malignancy and showed few tumor cells with mild atypia in pools of mucin (G1, low-grade PMP). Immunohistochemistry (IHC) done on the main specimen was positive for CK20, CDX2, and SATB2 [Figure 2a-d]. All microsatellite markers (MSL1, PMS2, MSH2, MSH6) was retained. A final diagnosis of LAMN with focal high-grade nuclear features (progressing to high-grade mucinous appendiceal neoplasm [HAMN]) and PMP was offered (AJCC stage T4a M1b). The patient had an uneventful postoperative recovery, underwent chemotherapy, and is on close follow-up at the oncosurgery OPD for the past old female, postmenopausal, presented with a history of pain right lower abdomen, anorexia, bloating, and gradually increasing girth of the abdomen over a period of 1½ months. There was no history of fever, constipation, or any urinary complaints. The patient underwent an ultrasound sonography of the abdomen and pelvis that revealed ascites with an adnexal mass. She was referred to the gynecologist, who ordered an urgent CECT abdomen and pelvis. Meanwhile, her tumor markers showed an elevated CA-125-350 U/mL (normal range: 0-35U/mL). CECT abdomen and pelvis showed a poorly defined, lobulated, multiseptated, predominantly cystic abdominopelvic mass with an eccentric solid component measuring 10.4 × 8.8 × 13.1 cm (AP × TR × CC) in the midline. Both ovaries could not be delineated separately. Massive ascites was seen. Mucinous ovarian carcinoma was suspected clinically and on imaging. Positron emission tomography scan revealed ascites with a non-fluorodeoxyglucose avid lesion arising from the left ovary [Figure 3]. She was taken up for planned surgery and underwent a hysterectomy with removal of the left adnexal mass, appendix, and omentum. Macroscopic examination revealed the appendix to be enlarged, dilated, and, on cutting open, it was filled with mucin. The left adnexal mass was received, cut open, and was cystic and showed multiloculated cysts with seromucinous fluid. Omentum was thickened and showed mucin deposits. No solid areas were identified. Histopathology confirmed LAMN of the appendix with mucin reaching the serosa. Sections from the ovary showed a cystic lesion lined by mucinous epithelium without atypia. The omentum showed large areas of acellular mucin suggestive of G1 PMP [Figure 4a-d]. IHC attempted to confirm LAMN with PMP and ovarian metastasis (AJCC staging T4a M1b). The patient was advised chemotherapy; however, they refused further treatment, and the patient was lost to follow-up.

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Figure 2:

(a) Hematoxylin and Eosin (H&E, ×400) shows the lining epithelial thrown into villous projections and lined by mucinous pseudostratified epithelium, (b) H&E, ×400 magnification highlights the nuclear psuedostratification, hyperchromasia, and atypia, (c) CK20 diffuse cytoplasmic positive in the lining cells, (d) Nuclear positivity in the lining cells by SATB2.

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Figure 3:

Positron emission Tomography (PET scan) image shows gross ascites (marked with red arrows) with no significant FDG uptake seen in the whole of the abdomen. A non FDG avid large multiloculated solid cystic lesion is seen in the lower abdomen and pelvis arising from left adnexa.

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Figure 4:

(a and b) Hematoxylin ad Eosin (H&E, ×40 and ×200) shows appendiceal subserosa being infiltrated by mucin with strips of epithelium and (b) serosa shows mucin deposits with surrounding peritoneal reaction, (c) (H&E, ×200) The ovarian stroma is infiltrated by mucinous epithelium lined glands with pools of extracellular mucin, (d) Omental biopsy shows large dissecting pools of acellular mucin.

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DISCUSSION

LAMN is a low-to-intermediate grade appendiceal mucinous neoplasm with a preponderance in elderly females.^[5] Most of the patients are asymptomatic, whereas others present with right lower quadrant pain or distention. Occasionally, the patients present with abdominal distension due to rupture and subsequent extrusion of mucin in the peritoneal cavity, causing PMP.^[6] Two of our cases had PMP, which portends a worse outcome and requires clinical close follow-up. LAMN can occur in any part of the appendix and typically involves the entire luminal circumference. Histologically, LAMN is characterized by flattened to villiform intestinal-type epithelium lined by basally located pseudostratified elongated nuclei with apical mucin. Often, the lining is flattened or denuded. The underlying lamina shows fibrosis and atrophy. Unlike conventional mucinous adenocarcinoma, infiltrating malignant glands with surrounding desmoplasia are not a feature of LAMN.^[7] Mucin dissecting through the wall may be seen with periappendiceal serosal mucin deposit. Mucinous neoplasms of the appendix are classified as per the World Health Organization and by the Peritoneal Surface Oncology Group International Consensus as LAMN, HAMN, and mucinous adenocarcinoma.^[8,9] Distinctive features of HAMN include architectural abnormalities such as micropapillary formation, piling up of the cells, and cribriforming. These are associated with nuclear atypia in the form of a high N/C ratio, loss of polarity, full-thickness stratification of nuclei, and frequent atypical mitosis.^[10] Case 2 on extensive sampling showed a focal area of nuclear atypia constituting <10% of the tumor volume, hence was diagnosed as LAMN progressing to HAMN. The Royal College of Pathologists dataset for histopathological reporting of carcinomas and mucinous neoplasms of the appendix mentions that there is genetic evidence that HAMN have evolved from low-grade lesions.^[11,12]

Appendiceal mucinous tumors are the most common cause of PMP unless proven otherwise.^[13,14] Ovarian origin of PMP is rare and may be seen in mucinous adenocarcinoma arising in mature cystic teratoma. In cases of appendiceal mucinous neoplasm with a coexisting mucinous lesion in the ovary, immunostains are useful to differentiate the primary. A panel of CK7, CK20, CDX2, SATB2, and PAX8 is often helpful. LAMN is positive for CK20, CDX2, and SATB2 and negative for CK7 and PAX8, which are ovarian markers. SATB2 is highly specific for appendiceal and colorectal malignancies.^[15,16] Case 3 was proven on IHC to be a primary appendiceal mucinous neoplasm involving the ovary and peritoneum. It is challenging to differentiate LAMN from primary ovarian neoplasm preoperatively on imaging, as they are in proximity, have nonspecific expression of tumor markers, and the fact that mucinous tumors of the appendix are known to metastasize to the ovary, as was seen in our case 3.^[17] Appendectomy is the only treatment option. If associated with PMP, the patient requires cytoreduction surgery with peritoneal lavage and drainage, followed by hyperthermic intraperitoneal chemotherapy.

CONCLUSIONS

LAMN is usually an incidental or intraoperative finding during resection for acute appendicitis or in a suspected ovarian neoplasm. Awareness and a high index of suspicion can help diagnose the appendiceal neoplasm in early stages before it ruptures. At this stage, appendectomy suffices, and early intervention prevents the development of PMP, which is associated with high mortality.