Appendix - acute appendicitis, appendiceal tumours and pseudomyxoma peritonei

Welcome to First Incision, the podcast about preparing for the General Surgery Fellowship exam. I'm your host, Amanda Nikolic. Let's get started with our team timeout. Our patient today is the emergency module from the general surgical curriculum. And the topics we're going to be covering today is everything to do with the appendix. So we're going to be talking about acute appendicitis. and appendiceal tumors, with a little bit at the end about pseudomyxoma peritonei.

So let's start off with a little bit about appendiceal anatomy and embryology. So the appendix is a mid-gut organ and it appears in the eighth week of life as an outpouching from the cecum. It's a worm-shaped blind-ending tube and is considered a lymphoid organ. On average, it's six to nine centimeters in length, but it can be anywhere from two to 25 centimeters. And the base, as we would all know from appendisectomies, is identified at the convergence of the three tenia coli of the cecum.

The tip of the appendix can be located variably in the retrocecal position, which is most common about 64% of the time. In the pelvic position, which is the next most common about 30% of the time. in the pre- and post-ileal positions, which is about 1% of the time, and also behind the cecum in the sub-cecal position. The surface marking is McBurney's point. which is located a third of the distance from the anterior superior iliac spine towards the umbilicus.

The blood supply of the appendix is that it's from the posterior cecal artery and it runs in the free edge of the meso appendix. The lymphatics drain into the ileacolic lymph nodes and then up to the para-aortic lymph nodes. And the nerve supply is carried via the sympathetic. And so you get visceral pain. which is located in the mid-abdomen because it's a mid-gut organ. And then as the inflammation spreads into the parietal peritoneum, you get parietal pain localized over the right aliac fossa.

And briefly to review the histopathology of the appendix, because this is going to be relevant later when we're talking about tumors of the appendix. The appendix has a mucosal layer. Outside that is the submucosa. then the muscularis propria, the subserosa, and then the serosa. And in the submucosa are located reactive lymphoid follicles or lymphoid tissue. And then also the appendix has goblet cells, which creates mucus.

So I'm going to spend a little bit of time talking about acute appendicitis. I don't want to bore all of the general surgical trainees out there because we've all probably seen this a thousand times, but I'm just going to briefly run through the background pathophysiology. the Alvarado score and a quick discussion about antibiotics versus surgery. So in terms of introduction, there's a 7% to 8% lifetime risk of appendicitis.

with a slightly higher incidence in men compared to females. The main types are suppurative, gangrenous, and perforated appendicitis. There's a few different theories for the pathophysiology of why appendicitis actually happens. The classical theory is that there's obstruction of the lumen of the appendix, either by a faecolith or inflamed lymphatic tissue.

And this leads to bacterial overgrowth in the appendix and ongoing secretions within the appendix, which causes an increase in the intraluminal pressure, distension of the appendix. pressure on the wall and subsequent impaired venous and lymphatic drainage. This causes further vascular congestion and higher wall pressures, which eventually overcome the arterial inflow pressures, causing ischemia, necrosis and perforation. Some other pathophysiology theories include the infective hypothesis.

which is that pathogens directly invade the lamina propria and initiate an edematous obstruction of the lumen of the appendix. And there's also a hygiene hypothesis. which has to do with the fact that we have better housing and sanitation, which causes compromised gastrointestinal immune system responses and an abnormal response to gut pathogens.

In terms of bacteria that cause appendicitis, the most common include anaerobic bacterias like Bacteroides and Peptostreptococcus and aerobic bacteria such as E. coli. Streptococcus and Pseudomonas aeruginosa. We all know about the signs and symptoms of appendicitis and the typical textbook presentation of generalized... sort of peri-umbelical abdominal pain and discomfort with some nausea, progressing to localized right lower quadrant pain.

Anorexia and nausea are common signs. And in terms of clinical signs, patients can have cross tenderness, which is known as a Rovsing sign. Rebound tenderness in the right lower quadrant. A psoas sign, which is pain on a straight leg raise and also an obturator sign, which is pain on flexion and internal rotation of the hip, which is more common in a pelvic appendix.

The Alvarado score is a score for acute appendicitis that predicts the likelihood of appendicitis being the diagnosis. This score looks at a number of clinical... and laboratory values that you plug into a calculator to give you a score that correlates with the likelihood of this being appendicitis.

I don't use this routinely, but I do find that it basically is the list of signs, symptoms, and lab values that increase your likelihood that this is actually appendicitis. You can kind of run through this list in your head when you're seeing a patient. So the signs are right lower quadrant tenderness, which gets two points, an elevated temperature, which is one point, and rebound tenderness, which is one point.

The symptoms you might find that all get one point are migration of pain to the right lower quadrant, anorexia, and nausea or vomiting. And the lab values are leukocytosis, more than 10,000, which gets two points, and a leukocyte shift to the left, so more than 75% neutrophils on the blood tests, which gets one point. And if you have a score of between three and four or less, then this has a sensitivity of 96% of ruling out appendicitis.

If the score is more than six or seven, then there's a 58 to 88% likelihood that this is appendicitis. which doesn't sound particularly high, but if you put it in the clinical context that there's up to only a 12% chance that this is not appendicitis, then it's a pretty useful scoring system. And you can use this if you have a family or a patient who's not sure. whether to proceed directly to surgery can be helpful with your discussion with the patient.

So diagnosis of appendicitis can either be made clinically with your examination, history and blood tests. or can be done radiologically with a CT scan, which has a really high sensitivity and specificity for the diagnosis of appendicitis. CT scan is used more commonly in older patients, where the likelihood that another pathology could be the cause of their symptoms is higher than in young, healthy patients, and the risk of the radiation dose associated with the CT is less concerning.

CT scan may also demonstrate consequences of appendicitis such as perforation or may identify an appendifecolith which could influence your management.

So moving on to talk about management of appendicitis, really there are two options, medical and surgical. Medical management involves... broad-spectrum intravenous antibiotics. And in my institution, we would typically give one gram daily of Keftriaxone and 500 milligrams BD of metronidazole, both intravenously. In terms of antibiotic therapy as the only treatment, so not performing an appendectomy, there's been increasing amounts of evidence to support this approach over the last few years.

The first main trial that came out about this was in 2015, which is the APAC randomized clinical trial, which was antibiotic therapy versus appendisectomy for treatment of uncomplicated acute appendicitis. This study... was a little bit difficult to apply to my clinical practice because all of the patients got a CT scan. And if there was a faecolith, those patients went directly to surgery. So they weren't randomized to receive antibiotics or not.

And also in order to apply the results of this to the wider world, the trial was designed to have open appendectomy as the operation that was performed, which is pretty rare to occur at my institution. More recently, though, the CODA trial results have been published. And the one-year results of this have recently been published in the New England Journal of Medicine. And the CODA trial is antibiotics versus appendicectomy for acute appendicitis.

longer-term outcomes being one year, published this year in 2021. This study had a wider inclusion criteria, including patients who had a fecal lift diagnosed on CT scan.

and patients with perforated appendicitis. And they used both the outcomes of whether patients failed medical management and needed an appendicectomy, but more importantly, they looked at the patient's general health status at 30 days and looked at the patient reported outcomes to try to determine whether antibiotics were inferior to surgery. In the antibiotic group, the percentage of patients who underwent a subsequent appendisectomy was 40% at one year and 46% at two years.

They had limited follow-up for three and four years, but they found that it was up to 50% who needed an appendectomy at three and four years. And they found that the risk of requiring an appendisectomy was higher in patients who had an appendicolith compared to those who didn't have an appendicolith. They did find, though, that there was no difference in general health status.

as reported by the patients, at 30 days, whether they underwent an operation or antibiotic treatment. And they found that some patients preferred antibiotics, even if they would subsequently require an appendisectomy. based on their personal and life characteristics. So it might have been a bad time for them to have an operation, for example. So the outcome of this trial is basically that antibiotics are not inferior to surgery and therefore...

We should be having an open conversation with our patients and having shared decision-making to make sure that we're offering them both options and letting them choose the option that's best for them. Surgery is the other management option and surgery in my institution would typically be a laparoscopic appendicectomy.

Let's move on to talking about appendiceal tumours. Most appendiceal tumours are diagnosed post-appendisectomy on histopathology specimens, but they may be suspected intraoperatively or diagnosed preoperatively on imaging. They are very rare. and can be classified in multiple ways, but the way that I like to split them up are into epithelial and non-epithelial tumours. In epithelial tumors, I split these up further into mucinous and non-mucinous tumors.

So mucinous tumors are classified by their grade. So there's low grade appendiceal mucinous neoplasms and high grade. appendiceal mucinous neoplasms. And this includes the rare variant of mucinous adenocarcinoma. Still under the heading of epithelial neoplasms are the non-mucinous tumors. And this essentially includes colonic type adenocarcinoma. So the next group is the non-epithelial tumors of the appendix. And this includes neuroendocrine tumors.

lymphomas, and very rarely sarcomas. There is one tumor type that sits between the epithelial and non-epithelial groups. And this is the goblet cell carcinoma, which is also known as a mucinous adenoneuroendocrine carcinoma. So let's talk a little bit about each of these tumors in turn. I'm going to start with the epithelial neoplasms, and let's start by talking about the mucinous epithelial neoplasms.

So these are split up into low-grade and high-grade mucinous neoplasms. And they are a group of tumors that are both biologically and histologically distinct from colonic-type adenocarcinoma of the appendix. and there's no known risk factors for the development of mucinous tumors of the appendix. Patients may present with an incidental finding on CT of a fluid-filled dilated appendix, or maybe... identified with acute appendicitis, or after rupture of the primary tumor.

which results in spread of mucin and tumor cells throughout the peritoneal cavity and leads to pseudomexoma peritonei, which we'll talk about at the end of this episode. Low-grade appendiceal mucinous neoplasms is a generic descriptor term for appendiceal adenomas, cyst adenomas, borderline tumors, and mucinous tumors of uncertain malignant potential. They are characterized as slow-growing, well-differentiated lesions, which lead to cystic dilatation of the appendix.

And microscopy shows replacement of the normal mucosa by an adenomatous proliferation of villus, papillary, serrated, or flat mucinous cells. And the epithelial lining will be a mucin-laden columnar cells, which can herniate into the muscularis propria and therefore perforate through the wall of the appendix. And that's how they can lead to spread of mucin into the peritoneal cavity.

High-grade tumors of the appendix can be further sub-categorized into high-grade appendiceal mucinous neoplasms, into mucinous adenocarcinoma, and mucinous adenocarcinoma with signet ring cells. And if we talk about high-grade appendiceal neoplasms, these are less invasive and aggressive than mucinous adenocarcinoma, which in turn is less aggressive and invasive than mucinous adenocarcinoma with signet ring cells, which has a really...

poor prognosis. High-grade appendicillomusinous neoplasms are tumors that have high-grade cytology features. but don't have any evidence of infiltration or destructive invasion of the appendix. Tumors that do demonstrate infiltration or invasion of the appendiceal wall are called mucinous appendiceal adenocarcinomas. And these tumors have a risk of invasion and spread to lymph nodes.

Mucinous adenocarcinomas can either be moderately differentiated, so grade 2, or poorly differentiated, which are grade 3. And of this poorly differentiated subgroup, there is a type called signet ring. adenocarcinoma and these can either be where there's less than 50% of signet ring cells present which are mucinous adenocarcinomas with signet rings or

where there's more than 50% signet ring cells present, and these are mucinous signet ring cell carcinomas. And the WHO classification of these tumours are that low-grade appendiceal mucinous neoplasms are grade one, High-grade appendiceal mucinous neoplasms and mucinous adenocarcinomas are grade 2. And mucinous adenocarcinomas with signet ring cells are grade 3 tumors.

The AJCC staging guidelines do have a TNM staging for appendiceal mucinous tumors. So tumor in situ is carcinoma in situ. And tumor in situ bracket LAMN or low-grade appendiceal mucinous neoplasm is a low-grade appendiceal mucinous neoplasm confined to the muscularis propria. with acellular mucin or mucinous epithelium that can invade into the muscularis propria. T1 are tumors that invade the submucosa.

So through the muscularis mucosa, but not into the muscularis propria. T2 invade the muscularis propria. T3 invade through the muscularis propria into the sub serosa or the meso appendix. and T4 invade the visceral peritoneum, including acellular mucin or mucinous epithelium involving the serosa of the appendix or the mesoappendix. or directly invading adjacent organs or structures. And for nodal disease, N1 is one to three regional lymph nodes. N2 is four or more regional lymph nodes.

And the M staging, metastasis staging, is interesting. So M1 is distant metastases, and this is broken up into M1A to C. So M1A is intraperitoneal acellular mucin without any identifiable tumor cells in the disseminated peritoneal mucinous deposits. M1b is intraperitoneal metastases only, including peritoneal mucinous deposits containing tumor cells. And M1c is metastases to sites other than the peritoneum.

That was probably a bit of an overload of information. Let's go on to something a little bit more clinically relevant. So let's talk about low-grade appendiceal mucinous neoplasms and their management. So if you have a low-grade appendiceal mucinous neoplasm and it's not ruptured, then surgery to remove the appendix and the mucosal. with a seekectomy if required to get clear margins without spilling any mucin is the treatment of choice. And if it's a very small...

mucosal, then you could do a laparoscopic approach. But if it's larger, then you would say, especially in the exam, that you would do an open approach to avoid rupture and spillage of mucin. And this is enough for a low-grade appendiceal mucinous neoplasm. In general, they don't need a right hemicolectomy and the risk of spread to lymph nodes is nearly zero.

However, it may be considered if there's high-risk features or if the base of the appendix is involved with the tumor. If you have a low-grade appendiceal mucinous neoplasm and it has ruptured, then the first step is to stage the disease. And the way you do that for mucinous tumors is with the peritoneal carcinomatosis index.

And this is essentially a way of assessing and documenting the extent of disease within the peritoneal cavity. And it's a little sort of scoring system you can have a look at. One of them, if you Google it online, and it talks about different regions in the abdomen and there's 12 regions and what the size of the tumor or mucin is. So there's either no tumor, tumor up to 0.5 centimeters.

up to five centimeters or more than five centimeters in size, which gives you a grade of zero to three in each of those 12 areas. And then you get a overall. peritoneal carcinomatosis index number that comes out of that. And then that's how you can communicate with a peritoneal carcinomatosis center about the extent of disease. And you want to take a lot of pictures as well.

In the first instance, with a ruptured low-grade appendicillomucinous neoplasm, you will still need to remove the appendix with either an appendisectomy or a c-kectomy if required. I'm going to explore the abdomen and complete the peritoneal carcinomatosis index, as we've discussed, as well as biopsy any peritoneal deposits of tumor. and send any mucin that you find for cellular examination because you can get spread of acellular mucin, which doesn't have any cells in it, or cellular mucin.

And the risk of developing pseudomyxoma peritonei is higher if there's cellular mesin that's spelled out. You then would discuss the case with a peritoneal carcinomatosis center, and they can do regional therapies, including cytoreductive surgery with removal of all of the gross disease. and intraperitoneal chemotherapy, which is usually mitomycin C, which is heated to 40 degrees and left in the peritoneal cavity for 60 minutes.

If you find on the pathology that there's rupture of the tumor or infiltration of the mucinous cells through the wall of the appendix that wasn't appreciated at the time of surgery, you also need to assess disease.

burden with a laparoscopy. See if there's any gross tumor or mucin in the peritoneal cavity and complete the peritoneal carcinomatosis index. If the pathology was that it's a low-grade mucinous lesion, Then surveillance with clinical examination and CT scan is the recommended follow-up and they would do intraperitoneal chemotherapy only if patients developed recurrent gross disease.

So let's move on to talk about high-grade appendiceal mucinous neoplasms. High-grade appendiceal mucinous neoplasms and... mucinous adenocarcinomas are considered grade 2 tumors and they have positive lymph nodes in up to 17% of cases. So for these tumours, a right hemicolectomy is the operation of choice with oncological removal of the draining lymph nodes.

If you find the diagnosis of a high-grade appendiceal mucinous neoplasm or a mucinous appendiceal adenocarcinoma on the post-operative specimen, then it's worth talking to a specialty peritoneal center. before you go and do the right hemicolectomy because if there's a really high-grade tumor...

If it's T4 or perforated or has positive margins, they may consider doing prophylactic HIPEC at the time of the right hemicolectomy because these are such high risk of metastasizing to the peritoneum. So you could at least... say, I think the safe thing to say in the exam is that you would at least discuss it with a specialty peritoneal carcinomatosis center.

If the tumor is perforated, then again, you would talk to a specialty center and they would consider doing debulking surgery and HIPEC or intraperitoneal chemotherapy. For patients who have high-grade disease, nodal positivity, or a mucinous adenocarcinoma, these patients should be staged with a CT chest abdo pelvis. And if they have metastatic disease, then systemic chemotherapy is offered to these patients. And it's the same chemotherapy as they would offer for colonic adenocarcinoma.

And the recurrence of these tumors is very high. So we've talked about the epithelial mucinous tumors of the appendix. So let's now talk about the epithelial non-mucinous appendiceal tumors, which is essentially colonic type adenocarcinoma. And these tumors arise from pre-existing adenomas and are basically the same pathology and treatment pathway as colorectal adenocarcinoma. And they don't have their own...

independent staging system in the AJCC guidelines. They're just considered with adenocarcinoma of the colon. The management of appendiceal colonic type adenocarcinomas depends on whether it's identified preoperatively or postoperatively. If you're identifying it pre-operatively, you may see it on some imaging and you want to complete the staging with a CT chest abdo pelvis and sending a CEA level.

And also want to do a colonoscopy. And you may be able to see the tumor through the appendiceal orifice. And there's about a 20% likelihood of a concurrent tumor or a synchronous tumor. So they need a full colonoscopy. And if you identify it post-operatively, then you still want to stage the patient and do a colonoscopy, but the management's really going to depend on the T stage of the tumor. So if a tumor in situ...

These tumors are completely resected with an appendicectomy as long as there's clear margins. For T1 tumors, I like to think of these as like a malignant polyp. So... If you have a low-grade tumor, so grade one, with no lymphovascular invasion and a negative resection margin, then you could consider that the tumor has been completely removed.

But if you have a T1 tumor with unfavorable characteristics, such as a high-grade tumor, lymphovascular invasion, or positive margins, then they need a formal resection, which for an appendiceal tumor is a right hemicolectomy. And for T2 plus tumors, you're going to stage them with a CT scan and do a colonoscopy. If there's no metastases, then the patient needs a right hemicolectomy.

If the patient has their right hemicolectomy and they're node positive, then they're stage three and they get adjuvant chemotherapy. Or if they're stage two, so node negative, but they have high risk features, they may also qualify for chemotherapy, just like colon cancer and other locations would be. And the chemotherapy is similar to what you would give to colon. so something like 5-FU leucovorin and capcitabine and exaliplatin. For patients with metastatic disease to...

the peritoneum, you could consider cytoreductive surgery and intraperitoneal chemotherapy, although this is a little controversial and would need to go through an MDT. If the patient has systemic disease, to liver or lungs or elsewhere, then systemic chemotherapy is first line. In the same way that for colonic cancer, we would consider metastatectomy in certain situations, you would consider it for adenocarcinoma of the appendix as well.

So moving on now to the non-epithelial appendiceal tumors. And the first one of these are neuroendocrine neoplasms. Neuroendocrine neoplasms are a tumor that arises from the enterochromaffin-like cells and often produces substances such as serotonin. They used to be called carcinoid tumors, but now they're called neuroendocrine tumors if they're grade one and two and neuroendocrine carcinomas if they're grade three.

They often are found incidentally following appendisectomy, or they may present with symptoms such as abdominal pain, distension, diarrhea, or appendicitis. And in metastatic disease, they can create carcinoid syndrome in liver metastases where they get a lot of serotonin release that isn't metabolized in the liver and leads to episodic flushing and diarrhea. The staging of neuroendocrine neoplasms is defined by the WHO as grade one, grade two, and grade three.

So I mentioned grade one is a neuroendocrine tumor and it's a low grade neuroendocrine tumor. So it has to have less than two mitoses per high powered field and a KI67 index of less than. or equal to 2%. A grade 2 tumor is an intermediate grade neuroendocrine tumor. And this has 2 to 20 mitoses per high-powered field and a KI-67 index of 3 to 20%.

And a grade three is a high-grade, poorly differentiated neuroendocrine carcinoma. And this has more than 20 mitoses per high-powered field and a KI-67 index of more than 20%. And the management of neuroendocrine tumors of the appendix depends on its size, its grade.

what stage it is, so these patients need staging with the CT chest, abdo, pelvis, and the presence of any high-risk features microscopically. So basically... A grade one neuroendocrine tumor that is less than one centimeter in size and is not located at the base of the appendix is completely removed with an appendicectomy and no further surgery is required.

If you have a neuroendocrine tumor that's less than one centimeter in size but has high risk features, so it's a grade two or grade three tumor, is located at the base of the appendix, has a positive margin.

then you would consider a right hemicolectomy for that patient. If you have a one to two centimeter tumor, this is considered the gray zone. So less than one centimeter, pretty clear that it... appendix removal is enough but if there's really high risk features you may consider surgery if they're one to two centimeters it's not quite as clear whether an appendisectomy would be enough there is lymph node

involvement rates that aren't insignificant so if there's any high risk features you would consider a right hemicolectomy so if it's grade two or three if there's a positive surgical margin It's located at the base of the appendix. There's any invasion into the meso appendix, especially if it's more than three millimeters in size. And if there's any lymphovascular invasion, you'd be thinking about a right hemicolectomy for that patient.

And then if it's more than two centimeters, we're out of that gray zone, the lymph node metastasis rate is quite high, somewhere between 25 and 40%. So these patients get a right hemicolectomy. I mentioned that you would stage all of these patients. Metastatic disease is relatively rare, but the management is really as per neuroendocrine tumors elsewhere. So if the tumours or metastases are unresectable, then you can give patients somatostatin analogues and even chemotherapy.

And if it's resectable, then you can consider debulking surgery and metastatectomy. And because it's a neuroendocrine tumor, you can use the tumor marker chromogranin A. at the time of diagnosis and then as a tumor marker to monitor and surveil patients after their surgery and treatment.

So to finish off today's episode, I'm going to talk about pseudomyxoma peritonei. Pseudomyxoma peritonei is a rare malignant tumor growth characterized by progressive accumulation of mucinous. tumor cells within the peritoneal cavity. And most commonly, these come from an appendiceal mucinous neoplasm. The cause of this is typically mucinous tumors perforating through the appendiceal mucosa and then translocation of cells throughout the abdomen.

Non-appendiceal mucinous tumors, if they do this, are more aggressive and they can come from the ovary, colon, stomach, or gallbladder. The nomenclature is... that it's not metastatic, but it's locally invasive within the peritoneal cavity with the malignant appearing cells.

The staging assessment or workup of the disease, as I've mentioned, is with the peritoneal carcinomatosis index, and this should be done for every patient. I'd highly suggest you have a look at some pictures of what... pseudomyxoma peritoneia looks like, especially on CT scan. because it has this characteristic appearance of scalloping of abdominal organs. And the typical picture I've seen is of the liver. And I think this is something they could definitely show us a picture of in the exam.

Treatment of pseudomyxoma peritonei has two main elements, which I've briefly mentioned. So the first one is cytoreductive surgery, and the second is intraperitoneal chemotherapy. Cytoreductive surgery involves removal of all macroscopic tumor deposits and often this involves quite an extensive resection of omentum, all of the peritoneum on the diaphragm, pelvis.

and all visible tumor cells. And then intraperitoneal chemotherapy is also called HIPEC, which stands for hyperthermic intraperitoneal chemotherapy. And this is usually done with mitomycin C and it's put into the peritoneal cavity at about 40 degrees for 60 minutes. And the combination of the cytoreductive surgery and the warm mitomycin allows it to perfuse across the peritoneal plasma barrier and have the best effect. And that completes this episode on the appendix.

Thanks so much for listening. Please rate, review and subscribe to the podcast. It makes it easier for others to find. And I really love reading your reviews. It's time to close up. Thanks for listening to First Incision. If you have any comments or feedback, send us a message at firstincisionpodcast at gmail.com or follow us on Instagram at firstincision. Happy studying!