Acute appendicitis, inflammatory appendiceal mass and the risk of a hidden malignant tumor: a systematic review of the literature

Recognizing the differences in the clinical presentation and the prognosis of appendiceal primary tumors is essential. When the tumor presents a signet-ring cell formation, the average survival is 6 months. Meanwhile, when histology shows a low-grade mucinous neoplasm, the median overall survival increases to 8 years [17].

Recently, a study based in the database produced by the Surveillance, Epidemiology and End Results (SEER) of the National Institute of Cancer of Bethesda revealed different survival rates for 5655 patients diagnosed with a primary appendiceal tumor, depending on the histology. The same study also showed an increased number of accidental diagnosis, which can be explained by a boost in the number of patients submitted to computed tomography and by the substantial use of laparoscopy, improving the sight of the abdominal cavity [19] (Fig. 2).

The overall survival rate related to the disease in the five coming years changed in line with the histologic subtype [19] (Fig. 3; Table 3).

The World Health Organization (WHO) classifies appendiceal tumors in two main groups: appendiceal carcinomas and neuroendocrine neoplasia (Table 4).

Oberndorfer first described NET tumors in the ileum and appendix in 1907, with mention to an indolent course, although some of them, with a different phenotype, had a more unfavorable outcome [20]. The two sub-groups of carcinoids based on their histological characteristics are Enterochromaffin cell serotonin producing carcinoid and its tubular variation with L-cell glucagon-like peptide, and PP/PPY producing tumor.

Therefore, carcinoid is a definition mostly used for tumors with more favorable histological characteristics while neuroendocrine is a broader description, which includes more aggressive attributes of the disease.

NETs have approximately 0.15 per 100,000/year incidence, according to the SEER registry. The frequency is similar to other populations, based on European databases [21‐24].

Those NETs are frequent when considering only neuroendocrine gastroenteropancreatic tumors. There is slight prevalence among women, affecting mostly Caucasians, and its incidence could be underestimated, since most of the cases, which are incidentally diagnosed, may not be notified in tertiary centers. The frequency of appendectomies performed without any particular reason is 3–9 per 1000 inhabitants [25, 26].

Appendiceal NET belongs to a sub-group of neoplasia with a significant number of incidental diagnosis, representing about 80% of the neoplasia, including benign and malignant tumors. The average age of the diagnosis varies from 38 to 51 years old [27‐29].

In most cases, the prognosis is excellent, with 100% of overall 5-year survival rate for localized disease and 85–100% for regional disease. Nevertheless, when including staging, the 5-year survival rates vary between 70 and 85%. Advanced disease has unfavorable prognosis with a 5-year survival rate of 12 and 28%. Tumors with more aggressive histology, such as Goblet cell carcinoids and mixed adenoneuroendocrine carcinomas, were not included in this study [27].

For NETs, Location, tumor depth, dimensions and possible invasion of the mesoappendix are important factors to calculate disease recurrence. In 70% of the cases, the tumors are located at the tip of the appendix, leading to a lower recurrence rate (Fig. 4). About its length, tumors with 1 cm (60 to 80% of the cases), invading through the subserosa or into the mesoappendix for 3 mm also have a lower recurrence rate. However, tumors with positive margins, located in the appendicular base, larger than 2 cm, or deeply invading the mesoappendix, have a higher recurrence rate, suggesting the need to perform additional resection [30‐32].

The presentation of the disease is usually associated with acute appendicitis. It rarely evolves into a metastatic disease and hardly ever develops carcinoid syndrome.

Because there is no suspicion of NET before an appendectomy is performed, preoperative exams do not offer additional information. Computed tomography or nuclear magnetic imaging could be used in postoperative exams, to clinically stage the regional (lymph nodes) or metastatic disease. Usually, colonoscopy will not reveal the tumor, since in 70% of the time it occurs in the tip of the appendix, rarely invading the caecum. Metabolic studies, such as Octreo Scan and gallium 68 PET-CT, are unusually performed. Laboratory tests, such as serum chromogranin A and 5-hydroxyndoleaticeticacid, are used selectively in the follow-up, or for suspicion of possible carcinoid syndrome, respectively. A well-differentiated NET, smaller than one centimeter and treated with R0 resection, usually do not evolve into a metastatic or regional disease in follow-up. Postoperative computed tomography and MRI are justified when tumors measure 1 to 2 cm. In cases of larger tumors, deep invasion of the mesoappendix or angiolymphatic invasion, image-led exams and metabolic tests, such as OctreoScan and gallium 68 PET-CT, are often required.

The histopathological test should be revised and must describe location of the tumor, grade, mitotic index, Ki-67 rate, dimension of the tumor, potential multifocal/ multicentric disease, vascular invasion, perineural invasion, presence of non-endocrine component, presence and number of lymph nodes, margin status, and TNM system (Table 5).

Individual immunohistochemical studies could be included to detect neuroendocrine markers, including chromogranin A, synaptophysin, specific peptides and others.

Tumor grade is determined by the mitotic index and Ki-67 (Table 6).

A major factor in the grading risk is the accurate staging of T in the TNM system since the diagnosis is usually incidental. For tumors T1a (UICC/AJCC), a simple appendectomy is appropriate treatment, also in the pediatric population. The overall survival in this group is 100% [33, 34].

Tumors larger than 2 cm (T2) are rare (<10%), but carry a risk of becoming a metastatic disease in 25 to 40% of the cases. Because of such previous data, radical resection is indicated, with follow-up for high-risk disease [35‐39].

Other criteria also considered is the location of the tumor in the cecal appendix. Most of the tumors (60 to 75%) are located in the tip of the appendix, 5 to 20% in the middle third and less than 10% in the appendiceal base. It has been suggested metastasis frequently appear in tumors located at the base, suggesting additional resection when the tumors have 1 to 2 cm length.

The decision to perform additional resection depends on the extent of mesoappendix invasion, if present. Up to 20% of the adults and 40% of the children undergo further resection. It is possible that the invasion of the mesoappendix be greater than initially reported. Despite not being considered in the TNM staging, the invasion of the mesoappendix could be related to a higher appearance of lymphatic invasion. When the malignancy compromises more than 3 mm, there is increased risk of nodal metastasis, and additional resection should be considered [40, 41].

Resection options for NET are appendectomy, ileocolectomy, and right colectomy. For T1a tumors with no invasion of the mesoappendix or not located in the appendiceal base, an appendectomy should suffice. When the tumor has invaded the mesoappendix in more than 3 mm, or the tumor is located in the base, an ileocolectomy and right colectomy should be indicated. However, there is not enough data to support the hypothesis that an additional resection will increase patient survival and its morbidity should also be considered.

When tumors have dimensions greater than 2 cm, the ileocolectomy or right colectomy should be performed. For those between 1 and 2 cm, other criteria are considered before performing additional resection, including age, extension of mesoappendix invasion, and location. However, there is scarce long-term follow-up information of the patients. Angioinvasion or G2 could also be taken into consideration when deciding for additional resection. However, there is even less evidence published about such criteria. Nevertheless, additional resection has been used based on the consensus of the European Neuroendocrine Tumor Society and when certain histologic characteristics are present.

It is a mixed phenotype tumor, with goblet cell morphology and neuroendocrine features more or less pronounced. The incidence of such tumor is extremely rare, representing less than 5% of primary appendiceal tumors. The disease is common among Caucasians, who represent 80% of the studied population [42].

The overall 5-year survival rate is lower than well-differentiated NET and varies between 40% and 75%. The disease can behave as adenocarcinomas with more or less pronounced phenotype of goblet cells or neuroendocrine tumors [43]. In two-thirds of the goblet cell tumor patients, the diagnosis is incidental, resulting from an appendectomy for acute appendicitis, which represents 50 to 60% of the initial presentation. Ten to 20% of them present peritonitis resulting from perforation [44, 45].

In 50% of the cases, the tumor invades the serosa and the mesoappendix. In 15 to 30% of the patients, there is the occurrence of distant metastasis, commonly in the ovaries, or in the lymph nodes. However, when measurement is possible, the progression of the disease is increased when tumors have more than 2 cm in length.

Other parameters foreseeing the aggressive behavior of the illness include high mitotic counts (more than two mitoses per 10 high-power fields); a Ki-67 greater than 3%; invasion into the serosa and into the mesoappendix; angioinvasion; increased number of Paneth cells; enhanced production of mucin; production of pancreatic polypeptide and lymph node involvement [46, 47].

In a retrospective series of 63 patients with carcinoid/goblet cell carcinoid, Tang and collaborators demonstrated the correlation between the pathological analysis and the, aggressiveness of the disease. According to the morphologic characteristics, three subgroups were found [48]:

Merling published the first reference to appendiceal neoplasms in 1838. In 1903, Elting published a series of patients with tumors emerging from preexisting adenomas in the appendix, assuming a growth pattern with cystic dilatation of the appendix (mucinous tumors). He realized that sometimes it could exhibit a growth pattern similar to primary colon tumors (colonic-types), these are either polypoid or ulcerative, emerging from tubular or tubulovillous adenomas [49].

The mucinous-type is inclined to rupture and mucin extravasation, with or without mucin epithelia into the abdominal cavity, resulting into Pseudo myxoma Peritonei [42, 50]. The Colonic-type is similar to colon adenocarcinomas and results in lower overall survival rate than mucinous-type tumors [51].

In an analysis based on the SEER registry between 1973 and 2004, 2791 patients with malignant appendiceal neoplasm were studied. Adenocarcinomas were more frequent, responding for 65.4% of the cases. While neuroendocrine tumors have presented a regular occurrence in the same period, there was a 260% increase in carcinoma rates. The overall 5-year survival rate for those patients was 46.5%. When considering mucinous cystadenocarcinoma, it rose to 59% in all stages, and in signet-ring cell formation tumors, to 20.3% [52].

Although appendiceal mucinous tumors are recognized as benign, as per their histology, those tumors can progress to peritoneal dissemination.

Ronnet and collaborators, in 1995, published a classification based on 109 patients who presented peritoneal dissemination caused by mucinous epithelial tumor in appendix [53].

In 2003, Misdraji and collaborators reclassified mucinous disease to low-grade mucinous neoplasia (LGMN) and mucinous adenocarcinoma (Figs. 5 and 6) [10].

Performance and patient prognosis vary, and the diagnosis can be incidental, in a case of complicated acute appendicitis. However, preoperative diagnosis can be made by abdominal ultrasound with the finding of an appendix mucocele, indicating a dilated appendix filled with mucinous content (Figs. 7 and 8).

Eventually, in a similar clinical scenario, there is a condition in which the disease is located and restricted to the right lower quadrant of the abdomen. In those cases, mucin deposits can be found in the serosa, in the mesoappendix or extending to right iliac fossa. Those mucin lakes do not contain any neoplastic cells when submitted to pathological analysis [54].

Yantiss and collaborators have studied the prognosis of patients with appendiceal mucinous neoplasms and mucin deposits in the right lower quadrant. Of 65 patients, 77% did not present cells in the mucin lakes while 23% had low-grade mucin epithelial cells. In follow-up after 52 months, 96% of the patients without cells in the mucin lakes were free the disease. In that group of patients showing no extra-appendicular mucinous epithelium, two of them developed peritoneal dissemination, but the appendix of those two individuals was not analyzed in the study [55]. Regarding patients presenting extra-appendicular mucinous epithelium, 33% evolved to pseudomyxoma peritonei. The study demonstrated excellent prognosis for patients with mucin dissemination in the right lower quadrant and no extra-appendicular mucinous epithelium [55] (Figs. 9 and 10).

Pseudomyxoma peritonei is considered by the UICC/AJCC and the WHO a malignant disease secondary to a carcinoma [56, 57].

The extension of a disease with extra-appendicular mucinous epithelium significantly affects patient prognosis. In a series of 184 patients, Carr and collaborators observed that mucinous disease restricted to the appendix has an indolent course. When the neoplasia is limited to the muscular mucosa, which is intact, it is called adenoma. When there is invasion of deeper layers or extra-appendicular extension, it is called carcinoma. Tumors that do not invade the muscular mucosa, but develop mucin deposits in the serosa without cells, are referred as uncertain potential for malignity [58].

Tumors characterized by neoplastic mucinous epithelium invading the muscular mucosa should be considered as high risk of peritoneum dissemination and classified and staged according to WHO and AJCC. Mucinous tumors with extra-appendicular dissemination of mucinous epithelium are considered by WHO low or high-grade mucinous adenocarcinoma, depending on the cytoarchitecture atypia.

Miner and collaborators analyzed histologic characteristics of appendiceal mucinous tumors presenting with peritoneal dissemination treated with surgical cytoreduction. In a retrospective series of 97 patients, complete cytoreduction was possible in 53% of the patients. Low-grade cytology was independently associated with longer disease-free survival. Some 90% of patients who lived an additional 10 years were diagnosed with low-grade tumors [59].

Traditional treatment for pseudo myxoma peritonei is composed of surgical cytoreduction associated with hyperthermic intraperitoneal chemotherapy (HIPEC) [60].

A retrospective analysis based on 2289 patients diagnosed with pseudo myxoma peritonei resulting from perforated appendiceal mucinous tumors showed the importance of associating complete macroscopic cytoreduction and HIPEC. The study reported 10 and 15 years survival in 63 and 59% of the cases respectively, with perioperative mortality of 2% [61].

There are few studies on Colonic-type appendiceal adenocarcinoma. In a recent German multi-centric study about primary appendiceal carcinomas, 99 patients, with an average age of 64 years old, were identified. Those tumors had an average length of 3.27 cm, 72% were T3/T4 tumors, and 36.4% of them had lymph node metastasis. More than 60% were moderately differentiated, and more than 20% were poorly differentiated. Stage IV disease represented 23.2% of the cases, and overall survival was 47.5% for all stages. When compared to other more frequent primary appendiceal tumors (carcinoid and mucinous adenocarcinoma), the colonic-type has the higher incidence of lymph nodes metastasis [62, 63].

Such information reinforces the indication of any surgical intervention (appendectomy/ileocolectomy) required to treat and appendiceal inflammatory mass after conservative treatment (Figs. 11 and 12).

Literature is scarce when discussing patients diagnosed with adenocarcinomas with signet-ring cell formation or undifferentiated. The effects of therapeutic interventions (cytoreduction and systemic chemotherapy) in this group are unknown. In a series analyzing 142 patients diagnosed with undifferentiated tumors or with signet-ring cell formation (defined by the WHO as more than 50% of the cells in the tumor in a signet-ring formation), the average age was 52 years old, and 75% presented metastatic disease. In patients with metastatic disease, all of them had peritoneum involvement, and 36% also had it in the ovaries. The median survival rate was 2 years for patients diagnosed with undifferentiated adenocarcinomas and 2.5 years for those with adenocarcinomas with signet-ring cell formation. Patients who were submitted to surgical cytoreduction had a median recurrence-free survival of 1.2 years, and an overall survival of 4.2 years was achieved when patients underwent a complete cytoreduction. This surgical approach is also improves overall survival of patients with A oligometastatic peritoneal disease. Unfortunately, complete cytoreduction was only achieved in 21% of the patients [64].