Mucinous appendiceal neoplasms: Report of a case and brief literature review

Abstract

Introduction

Appendiceal tumors are rare neoplasms detected in about 2 % of appendicectomies. The clinical presentation is often unspecific, varying from unspecific abdominal pain or presenting as an acute appendicitis or being asymptomatic.

Case presentation

We present a case of a patient presenting as an acute appendicitis with a mucocele, and then classified as HAMN. The patient was treated with initial laparoscopic approach and then conversion in laparotomy with appendectomy. Histology demonstrated a high grade appendiceal mucinous neoplasm limited to submucosa (pT3), with concomitant acute phlegmonous appendicitis. The patient was subsequently sent to a referral center where a right hemicolectomy with HIPEC was performed.

Discussion

HAMN is a rare entity, only recently classified as a new kind of appendiceal mucinous neoplasm. Due to the supposed higher aggressivity, HAMN must be treated as an appendiceal adenocarcinoma. The treatment of this rare entity is not yet well standardized, because of the rarity of this disease.

Conclusion

HAMN is a very rare tumor. In the emergency setting, it is mandatory to avoid rupture of the appendix, to minimize the risk of developing pseudomyxoma peritonei. Pathology is essential for further decisions in these patients and plays a very important role in treatment and prognosis.

Highlights

• •HAMN is an intermediate group between LAMNS and adenocarcinoma.
• •HAMN has a more aggressive clinical course.
• •In cases of nonperforated HAMN the approach is controversial.
• •Avoidance of rupture of the appendix during the first intervention is mandatory.

1. Introduction

Appendiceal tumors are rare neoplasms detected in approximately 2 % of appendicectomies [1]. Primary appendiceal neoplasms include epithelial, mesenchymal, and lymphoma. Mucinous appendiceal neoplasms constitute a heterogeneous group of neoplasms ranging from adenoma to mucinous adenocarcinoma [2]. The clinical presentation is often nonspecific, varying from nonspecific abdominal pain, presenting as acute appendicitis, or being asymptomatic. We present the case of a patient presenting with acute appendicitis with a mucocele, which was then classified as HAMN. A brief review of the literature is also presented. This case was reported in accordance with SCARE criteria [3].

2. Presentation of the case

A 34-year-old male with no significant medical history presented to the emergency department with right iliac fossa pain, suggestive of acute appendicitis. The abdominal pain, which was unspecific and soft on the Mesogastric Abdominal Region, and 12 h after the beginning was then localized on the Abdominal Right Lower Quadrant (RLQ) and started 4 days before admission to the emergency room. It was also associated with nausea, hyporexia, and constipation. No diarrhea or fever was associated, and no analgesics were administered. There was no relevant surgical, family, drug, allergic, medical, or psychosocial history. Blood tests revealed an increased D-dimer level (647 ng/ml), no leukocytosis, and no neutrophilia. Physical examination revealed moderate muscular resistance in the right lower quadrant with positive McBurney and Blumberg signs. Abdominal sonography showed a hypoechoic disomogenic mass terminating in the cecum with a maximum diameter of 85 mm, with fluid collection around the colon (distended ileocecal appendix, with hypoechoic lumen, parietal thickening, and diffuse hyperreflectivity of the surrounding fat) (Fig. 1). Subsequently, an abdominal CT scan was performed, which showed an appendiceal mass with an aspect of mucocele (Fig. 2) and severe fluid distension of the appendix with a diameter of 13 × 7 cm. Laparoscopic exploration was subsequently performed (Fig. 3) in the presence of a tumoral mass in the appendix. Due to adhesions and to avoid possible rupture of the mass, laparotomy was performed. Finally, the appendix was successfully removed with no intraoperative rupture, the postoperative recovery was uneventful, and the patient was discharged after two days. Histology (Fig. 4) revealed a high-grade appendiceal mucinous neoplasm limited to the submucosa (pT3), with concomitant acute phlegmonous appendicitis. The patient was sent to a specialist peritonectomy unit and underwent right ileocecal resection with preventive HIPEC, two months later. The decision to perform a preventive HIPEC was made for the young age of the patient with relatively low operative risk, and the presence of lake of mucus in the subserosa. Histology of the second operation showed no signs of local or disseminated tumors.

Fig. 1.

Abdominal sonography: distended ileocecal appendix, with hypoechoic lumen, parietal thickening, and diffuse hyperreflectivity of the surrounding fat.

Fig. 2.

Abdominal CT scan showed an enlarged appendix with a diameter of 13 × 7 cm.

Fig. 3.

Screen capture of the appendiceal tumor the initial laparoscopic approach.

Fig. 4.

The microscopic findings include high-grade cytology (i.e., enlarged, hyperchromatic, pleomorphic nuclei, and atypical mitotic figures), and presence of lakes of mucus into the appendiceal wall.

In fact, he was followed up with no signs of recurrence and no chemotherapy at two years' follow up.

3. Discussion

Appendiceal tumors are a rare and heterogeneous group of tumors that often pose diagnostic and therapeutic challenges. They are often incidentally discovered. Its incidence has significantly increased over the past few decades [4]. The most frequent finding is in specimens removed for acute appendicitis, with an estimated incidence of 1 % in appendectomy patients [5]. In addition, these neoplasms can be detected incidentally during surgery or imaging studies. Mucinous neoplasms of the appendix may rupture spontaneously or during surgery, giving rise to pseudomyxoma peritonei, a clinical entity characterized by the presence of thick mucus in the peritoneal cavity with progressive filling and distention. In addition, residual tissue during surgery can cause PMP. Pseudomyxoma peritonei can be found incidentally during work-up for abdominal pain and hernia surgery owing to its indolent nature. Appendiceal mucinous neoplasm is a cause of appendiceal mucocele, characterized by dilation of the appendix from mucus accumulation. The mucocele of the appendix is caused by gradual cystic dilation of the vermiform appendix with slow accumulation of mucoid contents. It is an infrequent entity, occurring in 0,2. 0,4 % of appendectomies [5], with an external appearance of a gross appendiceal enlargement with lumen distended by mucin. The causes are heterogeneous and include retention cysts, mucosal hyperplasia, mucinous cystadenomas, and mucinous cystadenocarcinomas.

Appendiceal epithelial tumors are rare. Adenocarcinoma is the most common malignant subtype, present in more than half of the cases. Other malignant subtypes include lymphomas, sarcomas, grade 1 and 2 neuroendocrine tumors (NET), and goblet cell tumors, previously called goblet cell carcinoids. Mucinous appendiceal neoplasms constitute a subgroup of epithelial neoplasms known for their extensive mucus production. Mucinous appendiceal neoplasms are the leading cause of pseudomyxoma peritonei (PMP), a clinical entity characterized by progressive accumulation of mucinous ascites and peritoneal implants, with fatal outcomes [6,7].

The actual classification system was reviewed by Carr et al. [7] in accordance with the 2012 meeting of the Peritoneal Surface Oncology Group International and the 2016 Modified Delphi Consensus Protocol (Delphi). Non-carcinoid epithelial tumors of the appendix were categorized into eight histomorphological architectural groups: adenoma, serrated polyp, LAMN, high-grade appendiceal mucinous neoplasm (HAMN), mucinous adenocarcinoma (well/moderately/poorly differentiated), signet ring cell low-differentiated (mucinous) adenocarcinoma, signet ring cell (mucinous) adenocarcinoma, and adenocarcinoma [9] (Table 1).

Table 1.

Carr classification [8].

Lesion	Terminology
Adenoma (traditional colorectal type)	Tubular, tubulovillous, villous adenoma
Tumor with serrated features	Serrated polyp
Low-grade cytologic atypia and loss of the muscularis mucosa layer, pushing invasion, acellular mucin in the wall, mucin outside the appendix, submucosal fibrosis	Low grade appendiceal mucinous neoplasm (LAMN)
High-grade cytologic atypia without infiltrative invasion	High-grade appendiceal mucinous neoplasm (HAMN)
Infiltrative invasion (single cells), desmoplasia	Mucinous adenocarcinoma
Signet ring cells (≤50 %)	Mucinous adenocarcinoma with signet cells
Signet ring cells (≥50 %)	Signet cell carcinoma
Adenocarcinoma (non-mucinous)	Adenocarcinoma

The term “mucinous adenocarcinoma” is generally reserved for mucinous lesions with features of infiltration into the appendiceal wall, whereas LAMN and HAMN refer to noninvasive lesions with varying degrees of cytologic atypia.

LAMN was first reported in 2003 and is characterized by the replacement of the normal appendiceal mucosa with a villiform, undulating, or flat mucinous epithelial proliferation [9]. The most important feature of LAMN is low-grade cytologic atypia without signs of invasive infiltration in the appendiceal wall. LAMNs are the principal cause of pseudomyxoma peritoneum. This type of lesion generally does not cause nodal or distant metastases [7]. Potential peritoneal spread is associated with appendiceal rupture (including microperforation), presence of extra-appendiceal mucin, or extensive dissection of mucin pools into the appendiceal wall [10]. There is a slight female predominance for LAMN (about 60 %), with a median age of 53 years and a 100 % 5-year overall survival rate [10].

HAMN is a relatively new term, more recently described in 2016 [8], which designs a clinical entity that shows similar changes in appendiceal walls, such as LAMNm, as pushing border invasion into the wall with no infiltration. The cytologic atypia observed in HAMN is of higher grade, and LAMN and HAMN are thought to have a common genesis, likely HAMN arising from LAMN. HAMN can constitute an intermediate group between LAMNS and mucinous adenocarcinoma, and its clinical course can be more aggressive [11]. High-grade dysplasia is characterized by changes, such as cribriform growth, loss of polarity with full-thickness nuclear stratification, enlarged nuclei, marked hyperchromatic or vesicular nuclei, prominent nucleoli, and numerous or atypical mitotic figures. These tumors are rare and poor understood [12]. Tumors with serosal perforation, particularly those with cellular serosal mucin deposits, carry the risk of progressing to PMP. When they spread to the peritoneum, they often produce grade 2 PMP, which may result in a more aggressive course than the classic grade 1 PMP.

Adenocarcinoma of the appendix is classified into two types of lesions: mucinous and non-mucinous (intestinal or colonic). If 50 % or more of the tumor mass was composed of extracellular mucin, the tumor was classified as mucinous. The grading is well, moderately, or poorly differentiated; however, the presence of signet ring cells automatically makes the tumor a poorly differentiated category. The median age is generally lower, and many patients present with synchronous metastatic disease, especially signet ring cell adenocarcinomas [13].

Pseudomyxoma peritonei is the intraperitoneal accumulation of mucus due to mucinous neoplasia, characterized by redistribution. It can include mucinous ascites, peritoneal implants, omental cakes, and ovarian involvement. Most commonly, it arises from appendiceal mucinous neoplasms. The difference from usual peritoneal metastases is represented by the presence of the presence of excessive amounts of mucin in the peritoneal cavity. PMP should only be used for the macroscopic appearance of mucinous ascites as it is not a histological diagnosis [8]. The histologic grade of PMP influences the prognosis of primary appendiceal lesion [14]. PMP can be divided in several categories based on histologic features of the peritoneal disease with its clinical consequences and prognostic value, including acellular PMP, low-grade PMP, high-grade PMP and high-grade PMP with signet ring cells [15]. PMP was graded separately from the primary tumor. Although the grade of the primary neoplasm and its peritoneal metastases are often concordant, they may occur in several patients with high-grade peritoneal lesions despite having low-grade appendiceal neoplasms [16].

Appendiceal mucinous neoplasms are generally discovered during radiological or endoscopic evaluation of unrelated complaints or in appendectomy specimens [16]. Patients can be asymptomatic or present with specific symptoms, such as acute or chronic right lower quadrant abdominal pain mimicking acute appendicitis. Approximately 30–50 % of appendiceal neoplasms initially manifest as acute appendicitis [16]. Rarely, an abdominal mass can be palpated or intussusception of the mucocele can cause gastrointestinal bleeding. Occasionally, obstruction of the right ureter or intestinal obstruction due to a mass effect may occur. AMN can be discovered accidentally during surgery for other reasons, such as hernia surgery, in which mucin can be noted in the hernia sac, cholecystectomies, or diverticulitis, in which mucinous ascites is identified in the peritoneal cavity. Measurement of tumor markers (CEA, Ca 19-9, and CA 125) can be useful in patients with advanced mucinous neoplasms, such as those that correlate with clinical and treatment outcomes, and in monitoring the progression of the disease [17].

An appendiceal mucocele can be diagnosed using abdominal computed tomography (CT) and ultrasonography. Differentiating between neoplastic and non-neoplastic lesions is not simple. The typical CT finding in a patient with an appendiceal mucocele is a low-attenuation, encapsulated, round, or tubular cystic mass in the right lower quadrant adjacent to the cecum. Other significant and suggestive findings are a diameter > 2 cm, absence of periappendiceal stranding, presence of mural curvilinear calcifications, and eggshell [18].

In female patients, the differential diagnosis includes a cystic ovarian neoplasm, tubo-ovarian abscess, or hydrosalpinx, which can have a similar appearance. Identification of a normal right ovary can help to exclude these ovarian pathologies. Other differential diagnoses include enteric duplication and mesenteric cysts. The identification of a mucocoele is of vital importance, as the surgical approach needs to be altered to avoid rupture and, consequently, PMP. Cystic dilatation of the appendix, mural calcification, luminal diameter >1.3 cm, or an outer diameter >1.5 cm are suggestive for mucocele [19].

Abdominal ultrasonography is the first-line diagnostic method for acute abdominal pain. It can be used to differentiate mucoceles from acute appendicitis [20]. An appendix outer diameter threshold of 6 mm and >15 mm indicates the presence of a mucocele; a cystic, encapsulated lesion of the right lower quadrant, firmly attached to the cecum, oblong or piriform with a large vertical axis, with sharp contours can be detected. In some patients, multiple echogenic layers along the dilated appendix produce the appearance of ‘onion skin-like’ circles and are pathognomonic for mucocele. A punctate calcification or soft tissue mass can be detected on abdominal radiography. Positron emission tomography is not recommended because of the high probability of false-negative results. Colonoscopy for the screening or evaluation of symptoms can detect an appendiceal mucinous lesion, with the appearance of a glossy, rounded, protruding mass arising from the appendiceal orifice moving in and out of the latter with respiration. Endoscopically, this lesion appeared as a submucosal mound with a normal mucosa in the cecum. The Volcano sign shows the appendiceal orifice in the center of a mound-like elevation of the cecal wall [21]. When probed with biopsy forceps, the lesion may be firm in consistency or soft, collapsing with central indentation (cushion sign). EUS performed with an ultrasonic probe can show compression of the cecal wall by a cystic mass [22]. EUS can detect the cystic nature of a mucocele, which can be anechoic or hypoechoic.

All mucoceles must be removed surgically because of the absence of reliable criteria to exclude malignant lesions on preoperative imaging [23]. Surgical removal prevents potential future rupture with subsequent PMP. Standard appendectomy was sufficient in most cases. The surgical approach can be either laparoscopic or open depending on the surgeon's experience. In the initial experience with laparoscopy, some authors suggested a conversion to laparotomy [6], providing less traumatic dissection and less contact of tumor-infiltrated serosa with the peritoneal surfaces. In our case, we decided to perform conversion laparotomy to avoid possible spillage of the mucus from the dilated appendix. Conversion to open appendectomy in such cases may demonstrate the most prudent surgical judgment.

Patients with LAMN, as these lesions usually do not cause nodal metastases, can be treated by appendectomy and follow-up [24]. When the tumor extends to the base of the appendix, cecal wedge resection should be performed, or ileocecectomy or right colectomy can be performed at the surgeon's discretion. However, extensive lymphadenectomy is not required for this type of lesion because of the rarity of node involvement. The peritoneal surface should be accurately inspected by biopsies of any suspected lesion. Special care must be taken to avoid accidental rupture or spillage of the appendix. Pathology is extremely important for subsequent decisions. Ideally, the specimen should be evaluated by a referral center with an expert pathologist. If the diagnosis of LAMN is confirmed without tumor perforation of free mucus, no further therapy is required, and the patient can be sent for follow-up. Normal levels of CEA, CA125 and Ca 19.9 are related to longer disease-free survival and can justify a watch and wait approach [24]. In the presence of microscopic or macroscopic tumor perforation and/or extraluminal mucin but without evidence of peritoneal disease, the therapeutic strategy is not linear. At non-specialized centers, the initial approach for ruptured lesions (localized) should be limited to appendectomy/ileocecectomy/right hemicolectomy, careful inspection of the peritoneal cavity, biopsy of any suspicious lesions, and peritoneal washing with fluid cytology [25]. Pathological examination is essential for further treatment in referral centers. In patients diagnosed with LAMN, perforated or extraluminal mucin cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) are considered therapeutic options [26].

In the case of HAMN, treatment is debated. Tumors have a strong tendency for peritoneal diffusion [27] and nodal involvement in 20 % of cases. Due to the rarity of HAMN, this tumor is not well characterized and is probably an intermediate lesion between LAMN and mucinous adenocarcinoma. A more aggressive approach to this tumor seems justified, even if the treatment in cases of nonperforated HAMN is controversial, and the quality of evidence is very low. In our case, in the referral center, an approach of cytoreduction and HIPEC was adopted after careful evaluation of the pathological specimen. HAMN must be considered as a mucinous adenocarcinoma in cases of invasion of the appendicular serosa or extracellular mucin cytoreduction with HIPEC.

4. Conclusions

HAMN is a rare and not yet well-known disease of the appendix and has only recently been categorized as a nosological entity. An aggressive approach with right hemicolectomy and hyperthermic intraperitoneal chemotherapy following initial appendectomy seems justified, with the necessity to refer the patient to a specialized center for peritoneal disease after initial treatment for an acute abdomen. Avoidance of rupture of the appendix during the first intervention is mandatory, with the possibility of converting and performing a laparotomy, especially if there is a larger lesion or more adhesions that could increase the risk of tumor rupture and injury. Due to its supposed higher aggressivity, HAMN must be treated as an appendiceal adenocarcinoma. Further efforts are necessary to gather data on this disease and to identify a standardized treatment plan, even in an emergency setting.

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal upon request.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ethical approval

Ethical approval was waived because this case report is a review of literature with a retrospective case report on one patient.

Funding

This report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contribution

Writing – original draft: Gabriele D'Amata.

Gabriele D'Amata, Luca Musmeci, Gaetano Florio, Daniela Caporilli and Isabella Palmieri participated in the clinical treatment and data collection.

Andrea Giannetti performed the pathological studies.

All authors read and approved the final version of the manuscript.

Guarantor

Gabriele D'Amata is the guarantor for this case report who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

Research registration number

This case report is not a “First in Man” study.

Conflict of interest statement

The Authors Gabriele D'Amata, Andrea Giannetti, Luca Musmeci, Gaetano Florio, Daniela Caporilli, Isabella Palmieri declare no conflict of interest.