Appendiceal Neoplasms

Appendiceal Neoplasms – 32 Interesting Facts

Appendiceal neoplasms are benign and malignant neoplasms that arise from epithelial or neuroendocrine cells within the appendix
Appendiceal neoplasms are broadly divided into epithelial neoplasms and NENs
Epithelial neoplasms consist of invasive neoplasms (eg, appendiceal adenocarcinoma, goblet cell adenocarcinoma) and noninvasive neoplasms (eg, LAMN, HAMN)
NENs can range from well-differentiated NETs to poorly differentiated NECs
PMP is a clinical finding that describes the diffuse spread of mucin throughout the peritoneum
PMP most often occurs from a ruptured LAMN, resulting in peritoneal spread of acellular mucin
Less commonly, PMP may occur with spread of cellular mucin; cellular PMP can be classified according to the presence of low-grade histologic features, high-grade histologic features, or signet ring cells
Appendiceal neoplasms are rare; the incidence is approximately 0.97 per 100,000 people³⁴
Appendiceal neoplasms are most often diagnosed incidentally in the surgical specimen after an appendectomy
Preoperative suspicion for appendiceal neoplasms most often occurs after cross-sectional imaging performed when evaluating patients for suspected appendicitis
A thorough history and physical examination are key in the evaluation of patients with suspected (or confirmed) appendiceal neoplasm
Patients may present with concomitant appendicitis, because appendiceal neoplasms may cause secondary appendicitis
Cross-sectional imaging, most commonly a CT scan of the abdomen and pelvis, is often performed for the workup of appendicitis
CT scan of the abdomen and pelvis can often suggest an appendiceal neoplasm but cannot definitely distinguish between appendicitis and neoplastic lesions
Definitive diagnosis is by surgical resection and pathologic examination
Differential diagnosis for appendiceal neoplasms includes appendicitis, mesenteric or duplication cysts, Meckel diverticulum, simple mucoceles, and other types of neoplasms
Approach to treatment is dependent on the presence of metastatic disease (either peritoneal or distant) and whether the patient is symptomatic
Management of nonmetastatic disease usually involves surgical resection; extent of resection is dependent on histologic findings
LAMN or HAMN: simple appendectomy is likely sufficient
Appendiceal adenocarcinoma: formal right hemicolectomy is recommended
Appendiceal NENs: dependent on the size and grade of the lesion
Adjuvant chemotherapy should be considered for stage II or III appendiceal adenocarcinoma
Patients with PMP or peritoneal metastasis should be referred to a center specializing in peritoneal malignancies
Patients with distant metastasis should be referred to a medical oncologist for systemic therapy
Surveillance after resection is dependent on histology
LAMN or HAMN likely needs surveillance with cross-sectional imaging (ie, MRI of the abdomen) every 6 to 12 months for 2 years
Appendiceal adenocarcinoma should be monitored similarly to colon cancer
Appendiceal NEN surveillance is dependent on the size and grade of the lesion
Prognosis of appendiceal neoplasms ranges widely
Completely resected LAMNs have excellent prognosis overall
Prognosis of appendiceal adenocarcinomas is dependent on stage and differentiation
Prognosis of appendiceal NENs is dependent on tumor size and presence of metastasis

Alarm Signs and Symptoms

In patients with cross-sectional imaging performed for appendicitis, but with imaging characteristics consistent with mucin, wall calcifications, wall irregularity, and soft tissue thickening without associated wall thickening or fat stranding, an appendiceal neoplasm should be suspected
PMP should be suspected in patients with vague symptoms such as fatigue, weight gain, chronic abdominal pain, and early satiety
Rarely, patients may present with “carcinoid syndrome” (eg, facial flushing, diarrhea, dyspnea); this should raise suspicion for metastatic NEN
Appendiceal neoplasms may be discovered intraoperatively. In this case, perform a limited resection (eg, appendectomy alone) if the appendix appears grossly abnormal

Introduction

Figure 1. Histologic classification of appendiceal neoplasms.Dotted lines indicate that GCAs and MiNENs exhibit both neuroendocrine and epithelial features; the behavior of GCAs is closer to that of epithelial adenocarcinomas, whereas MiNENs are treated like NECs. GCA, goblet cell adenocarcinoma; HAMN, high-grade appendiceal neoplasm; LAMN, low-grade appendiceal mucinous neoplasm; MiNEN, mixed neuroendocrine non-neuroendocrine neoplasm; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor.

Appendiceal neoplasms are benign and malignant neoplasms that arise from epithelial or neuroendocrine cells within the appendix
Appendiceal neoplasms are histologically classified into epithelial neoplasms and NENs (neuroendocrine neoplasms) (Figure 1)
- Epithelial neoplasms can be subdivided into invasive and noninvasive neoplasms
  - Invasive neoplasms include invasive adenocarcinoma and goblet cell adenocarcinomas
    - Goblet cell adenocarcinomas exhibit both neuroendocrine and epithelial features; however, they often exhibit much more aggressive behavior, making them more similar to epithelial adenocarcinoma¹
  - Noninvasive neoplasms include LAMNs (low-grade appendiceal mucinous neoplasms) and HAMNs (high-grade appendiceal neoplasms)
    - Polyps of the appendix are rare noninvasive neoplastic lesions. These resemble the polyps found in the colon
  - Epithelial neoplasms can also be classified based on mucin production (eg, mucinous versus nonmucinous appendiceal adenocarcinoma)
    - Mucinous appendiceal lesions are also clinically classified as appendiceal mucoceles
    - Appendiceal mucoceles can occur without neoplastic changes to the epithelial cells; in this setting, they are also known as retention cysts
- NENs include well-differentiated NETs (neuroendocrine tumors), poorly differentiated NECs (neuroendocrine carcinomas), and MiNENs (mixed neuroendocrine non-neuroendocrine neoplasms)¹²
  - MiNENs are a combination of NECs and adenocarcinomas. They are treated like NECs
Rarer appendiceal neoplasms, including melanoma, leiomyoma, lipoma, fibroma, neuroma, lymphangioma, and metastatic lesions, are not discussed in this Clinical Overview
PMP (pseudomyxoma peritonei) refers to diffuse spread of mucin throughout the peritoneum
- PMP is not a histopathologic diagnosis (as the term is often colloquially used) but rather a clinical syndrome often associated with a mucinous appendiceal lesion
- PMP is often associated with ruptured LAMN or mucinous adenocarcinoma of the appendix

Background Information

Appendiceal neoplasms are rare entities. Therefore, much of the evidence is based on retrospective analyses that span many years
- Analysis may be limited due to changes in the histologic classification of certain pathologies, most notably PMP
Recommendations are often extrapolated from experience with related, more common pathologies, such as colorectal adenocarcinoma

Epidemiology

Most recent estimate for the incidence of appendiceal tumors is approximately 0.97 per 100,000 people³⁴
- Epithelial neoplasms likely account for the most, with an estimated incidence of 0.70 per 100,000 people³
- Incidence of LAMNs or HAMNs is poorly characterized, because previous studies often did not distinguish LAMNs or HAMNs from adenocarcinomas
- Incidence of appendiceal NENs is estimated to be approximately 0.16 per 100,000 people⁵
Most appendiceal neoplasms are discovered incidentally in the surgical specimen after appendectomy
- It is estimated that epithelial tumors and NENs can be found in approximately 1% of all appendectomy specimens⁶⁷⁸⁹
Appendiceal neoplasms appear to have a slight female predominance⁴⁶
Epithelial neoplasms are most often detected in patients in their 50s to 60s,¹⁰ whereas NENs are most often diagnosed in patients in their 40s¹¹

Etiology

Epithelial neoplasms
- Cause of epithelial neoplasms is poorly understood
- It is hypothesized that epithelial neoplasms likely follow an adenoma-carcinoma sequence of carcinogenesis similar to colon cancer
  - This sequence typically begins with variants in APC, followed by variants in KRAS and TP53 (among other genes)¹²
NENs
- NETs and carcinomas arise from neuroendocrine cells, which are differentiated cells that secrete a variety of peptides and hormones based on their organ of origin¹³
- Currently, there is no clear genetic pathway to explain tumorgenesis from differentiated neuroendocrine cells¹

What are the Risk Factors and Associations?

Epithelial neoplasms
- Risk factors likely mirror those of colorectal cancer
- Major risk factors include:¹⁴¹⁵
  - Hereditary colorectal cancer syndromes (including familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, MUTYH-associated polyposis)
  - Personal or family history of colorectal cancer or adenomatous polyps
  - Inflammatory bowel disease
  - Older age
  - Black race or ethnicity
  - Obesity
  - Diabetes
  - Smoking
  - High red or processed meat intake
  - Excessive alcohol intake
NENs¹⁶
- Multiple endocrine neoplasia type 1 and neurofibromatosis type 1 confer the highest risk
- Other risk factors include:
  - Age older than 65 years
  - Female sex
  - White race or ethnicity
  - History of excessive alcohol intake
  - Smoking
  - Obesity
  - Family history of gastrointestinal malignancy
  - Inflammatory bowel disease

How is Appendiceal Neoplasms Diagnosed?

Approach to Diagnosis

Most appendiceal neoplasms are discovered at the time of appendectomy or incidentally in the surgical specimen postoperatively
Most appendiceal neoplasms are asymptomatic, though appendiceal adenocarcinomas are more likely to present with appendicitis¹⁷
- Patients with PMP often present with progressive abdominal girth and may undergo cross-sectional imaging for this reason
Preoperative suspicion for appendiceal neoplasms most often occurs in the setting of cross-sectional imaging performed when evaluating patients for suspected appendicitis
- Imaging findings suspicious for appendiceal neoplasms include wall calcification, wall irregularity, and soft tissue thickening without associated wall thickening or fat stranding
- Alternatively, appendiceal neoplasms may also be discovered incidentally. Most often, this is in the setting of cross-sectional imaging performed for other reasons
A thorough history and physical examination are key in the evaluation of patients with suspected (or confirmed) appendiceal neoplasms
Definitive diagnosis of appendiceal neoplasms is by surgical resection. In almost all circumstances, do not biopsy (percutaneously or surgically) an appendiceal neoplasm¹⁸
If a grossly abnormal appendix is encountered during an unrelated surgical procedure, an appendectomy should be performed.¹⁹ There is no need to perform a prophylactic right hemicolectomy in this scenario
Primary appendiceal NENs typically do not present with “carcinoid” syndrome (eg, flushing, diarrhea, bronchospasm) unless there is extensive metastasis
- If these symptoms are present, then perform a workup for potential metastatic disease, including a CT scan of the abdomen and pelvis, and/or DOTATATE PET-CT²⁰
Appendiceal neoplasms are generally staged pathologically after evaluation of the surgical specimen
- For neoplasms not discovered incidentally, clinical staging is achieved by cross-sectional imaging, as described in the Imaging Studies section below

Diagnostic Criteria

A definitive diagnosis of appendiceal neoplasms is established by pathologic review of the surgical specimen

Staging or Classification

Staging

Appendiceal neoplasms are staged per American Joint Committee on Cancer staging
Epithelial neoplasms²¹
- Tumor
  - Tx: cannot assess primary tumor
  - T0: no evidence of primary tumor
  - Tis: carcinoma in situ (does not invade through the muscularis mucosae)
  - Tis(LAMN): LAMN confined to the muscularis propria (acellular mucin or mucinous epithelium may invade into the muscularis propria). T1 and T2 not applicable to LAMN; acellular mucin or mucinous epithelium that extends into the subserosa or serosa should be classified as T3 or T4a, respectively
  - T1: tumor invades the submucosa but not into the muscularis propria
  - T2: tumor invades the muscularis propria
  - T3: tumor invades through the muscularis propria into the subserosa or mesoappendix
  - T4: tumor invades the visceral peritoneum (acellular mucin or mucinous epithelium may involve the serosa of the appendix or mesoappendix, or adjacent organs or structures)
    - T4a: tumor invades through the visceral peritoneum (acellular mucin or mucinous epithelium involving the serosa of the appendix or mesoappendix)
    - T4b: tumor directly invades or adheres to adjacent organs or structures
- Node
  - Nx: cannot assess regional LNs (lymph nodes)
  - N0: no regional LN metastasis
  - N1: 1 to 3 regional LNs positive (ie, tumor in LN 0.2 mm or greater) or any number of tumor deposits present and all identifiable LNs negative
    - N1a: 1 regional LN positive
    - N1b: 2 or 3 regional LNs positive
    - N1c: no regional LN positive, but tumor deposits present in the subserosa or mesentery
  - N2: 4 or more regional LNs positive
- Metastasis
  - cM0: no distant metastasis
  - cM1: distant metastasis
    - cM1c: metastasis to sites other than the peritoneum
  - pM1: microscopic confirmation of distant metastasis
    - pM1a: intraperitoneal acellular mucin; no identifiable tumor cells in disseminated peritoneal mucinous deposits
    - pM1b: intraperitoneal metastasis only
    - pM1c: microscopic confirmation of metastasis to sites other than the peritoneum
- Grade
  - Gx: grade cannot be assessed
  - G1: well differentiated
  - G2: moderately differentiated
  - G3: poorly differentiated
- Staging
  - Stage 0: Tis or Tis(LAMN), N0, M0, and any grade
  - Stage I: T1 or T2, N0, M0, and any grade
  - Stage IIA: T3, N0, M0, and any grade
  - Stage IIB: T4a, N0, M0, and any grade
  - Stage IIC: T4b, N0, M0, and any grade
  - Stage IIIA: T1 or T2, N1, M0, and any grade
  - Stage IIIB: T3 or T4, N1, M0, and any grade
  - Stage IIIC: any T, N2, M0, and any grade
  - Stage IVA: any T, any N, and M1a with any grade or M1b with G1
  - Stage IVB: any T, any N, and M1b with G2, G3, or Gx
  - Stage IVC: any T, any N, M1c, and any grade
NENs²²
- Tumor
  - Tx: cannot assess primary tumor
  - T0: no evidence of primary tumor
  - T1: tumor 2 cm or less in greatest dimension
  - T2: tumor greater than 2 cm but 4 cm or less in greatest dimension
  - T3: tumor greater than 4 cm in greatest dimension or with subserosal invasion or involvement of the mesoappendix
  - T4: tumor perforates the peritoneum or directly invades other adjacent organs or structures (excluding direct mural extension to the adjacent subserosa)
- Node
  - Nx: cannot assess regional LNs
  - N0: no regional LN metastasis
  - N1: regional LN metastasis
- Metastasis
  - M0: no distant metastasis
  - M1: distant metastasis
    - M1a: metastasis confined to the liver
    - M1b: metastasis in at least 1 extrahepatic site
    - M1c: hepatic and extrahepatic metastases
- Staging
  - Stage I: T1, N0, and M0
  - Stage II: T2 or T3, N0, and M0
  - Stage III: T4 with N0 or any T with N1, M0
  - Stage IV: any T, any N, and M1

Classification

Histologic classification of appendiceal neoplasm subtypes is discussed in the Terminology section and illustrated in Figure 1
PMP is classified histologically per categories developed by Peritoneal Surface Oncology Group International¹⁹²³²⁴²⁵
- Acellular mucin
  - PMP most often occurs from a ruptured LAMN, resulting in peritoneal spread of mucin without epithelial cells
- PMP with low-grade histologic features
  - Abundant extracellular mucin containing scant epithelial cells with little cytologic atypia or mitotic activity
  - Also known as disseminated peritoneal adenomucinosis or low-grade mucinous carcinoma peritonei
- PMP with high-grade histologic features
  - More abundant epithelial cells with cytologic atypia, as seen in carcinoma
  - Also known as peritoneal mucinous carcinomatosis or high-grade mucinous carcinoma peritonei
- PMP with signet ring cells
  - Any lesion with signet ring cell component
  - Also known as high-grade mucinous carcinoma peritonei with signet ring cells
WHO classification and grading are used for NENs (Table 1)
- Used to establish a common nomenclature to describe the clinical behavior of NENs
- Well-differentiated NETs have increasingly aggressive behavior with increasing mitotic rate and Ki-67 index, though they remain less aggressive overall compared with NECs
- MiNENs show a combination of NECs and adenocarcinoma features and behave more closely to NECs²

Table 1. WHO’s 2019 classification and grading for NENs.

Terminology	Differentiation	Grade	Mitotic rate (mitoses/2 mm²)	Ki-67 index
NET, G1	Well differentiated	Low	Less than 2	Less than 3%
NET, G2		Intermediate	2-20	3%-20%
NET, G3		High	More than 20	More than 20%
NEC, small-cell type	Poorly differentiated	High	More than 20	More than 20%
NEC, large-cell type			More than 20	More than 20%
MiNEN	Well or poorly differentiated	Variable	Variable	Variable

Caption: MiNEN, mixed neuroendocrine non-neuroendocrine neoplasm; NEC, neuroendocrine carcinoma; NEN, neuroendocrine neoplasms; NET, neuroendocrine tumor.

From Nagtegaal ID et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182-188, Table 2.

Workup

History

Perform a thorough history, specifically current symptoms and previous surgical and medical history
- Many tumors will be completely asymptomatic and can only be found incidentally on imaging or at surgery
- Because appendicitis may be a concomitant finding, patients may present with symptoms such as abdominal pain, fevers, chills, nausea, and vomiting
- Vague symptoms such as fatigue, weight gain, chronic abdominal pain, and early satiety may indicate PMP
- Advanced tumors may cause mass effects with resultant symptoms of bowel or ureteral obstruction
- Occasionally, patients may also report colicky abdominal pain with gastrointestinal bleeding. This is likely due to intermittent intussusception of the mucinous lesion
- Patients with suspected NENs should be asked regarding symptoms of “carcinoid syndrome,” including facial flushing, diarrhea, and dyspnea; presence of such symptoms suggests metastatic disease
If an appendectomy has already been performed, a review of the previous operative note and pathology report is imperative

Physical Examination

Perform a thorough physical examination, concentrating on the abdominal and pelvic examinations
- Rule out peritonitis, though this is rare even in the setting of acute appendicitis
- Examine for abdominal scars that may indicate a previous surgery
- PMP most often presents with nonspecific increased abdominal girth
  - Rarely, PMP may present as ventral, incisional, or inguinal hernias²⁶²⁷

Laboratory Tests

Tumor markers are checked to establish baseline measures for future surveillance and disease monitoring. This is not done to establish a diagnosis
For patients with epithelial neoplasms, collect a baseline carcinoembryonic antigen level²⁸
- Utility of CA 19-9 (carbohydrate antigen 19-9) and CA 125 (cancer antigen 125) is less clear, but they may be of some benefit in patients with PMP¹⁹²⁹
For patients with appendiceal NENs, collect a baseline serum chromogranin A level. A 24-hour urine collection for 5-HIAA (5-hydroxyindoleacetic acid) is also reasonable.¹⁹ However, the utility of these tests is debated
For patients undergoing surgery, collect a CBC, basic metabolic panel, INR, and type and screen

Imaging Studies

Appendiceal neoplasms are most often detected incidentally when cross-sectional imaging is performed during the workup of appendicitis³⁰
- Most often, a CT scan of the abdomen and pelvis with IV contrast is performed
  - Can often suggest an appendiceal neoplasm but cannot definitively distinguish between appendicitis (or other non-neoplastic lesions) and neoplastic lesions
  - Wall calcifications, wall irregularities, soft tissue thickening without associated wall thickening or fat stranding, presence of mucin, and adjacent lymphadenopathy may suggest a neoplastic lesion¹³³¹
  - Patients may present with both appendicitis and a neoplastic lesion
- An abdominal ultrasonography can also suggest an appendiceal neoplasm
  - Obtain a CT scan of the abdomen and pelvis with IV contrast if ultrasonography suggests an appendiceal neoplasm
Staging scans
- Obtain a CT scan or MRI of the chest, abdomen, and pelvis in all patients with suspected or confirmed appendiceal adenocarcinoma²⁸²⁹
- NETs 2 cm or less do not require staging scans. For NETs greater than 2 cm, positive margins or nodes from initial resection, or incompletely resected, a multiphasic CT or MRI of the abdomen and pelvis should be performed²⁰
  - In patients with NECs, a CT scan of the chest, abdomen, and pelvis should be performed with consideration for PET-CT and brain MRI²⁰
NEN-specific imaging
- It is not necessary to obtain NEN-specific imaging (eg, somatostatin receptor scintigraphy) for all patients with appendiceal NENs²⁰
- In patients with suspected metastatic appendiceal NENs (eg, those with “carcinoid syndrome”), obtain a DOTATATE PET-CT.²⁰ Alternatively, a combination of CT or MRI plus somatostatin receptor scintigraphy is reasonable¹⁹

Diagnostic Procedures

Obtain a colonoscopy in all patients diagnosed with, or suspected to have, an appendiceal neoplasm due to the increased risk of harboring a synchronous colonic lesion¹⁹²⁹
- If the diagnosis is established preoperatively (rare), then perform the colonoscopy before planned surgical resection
- Otherwise, perform the colonoscopy after the patient has recovered from surgery (usually 4-6 weeks postoperatively)
In most cases, do not biopsy a suspected appendiceal neoplasms given the potential risk of peritoneal seeding¹⁸
Appendiceal neoplasms are most commonly discovered at the time of appendectomy or incidentally in the surgical specimen postoperatively
- Most common indication for appendectomy is for the treatment of presumed appendicitis
- Considering the increased utilization of nonoperative management in appendicitis, the decision for interval appendectomy in these cases is complex
  - Older adults, those with indeterminant imaging, and those with periappendiceal abscess seem to be at higher risk for appendiceal cancer.³²³³³⁴³⁵ Unless there are prohibitive perioperative risk factors, these patients should undergo interval appendectomy
  - If there are imaging findings concerning for appendiceal neoplasm, appendicitis should not be managed nonoperatively
Patients without appendicitis but with an incidentally discovered suspected appendiceal neoplasm should be treated with an appendectomy to obtain a pathologic diagnosis¹⁹
Patients diagnosed with PMP should be referred to a center specializing in peritoneal malignancies

Differential Diagnosis of Appendiceal Neoplasms

Table 2. Differential Diagnosis: Appendiceal neoplasms

Condition	Description	Differentiated by
Appendicitis	Inflammation or infection of the appendix	Periappendiceal inflammation or abscess on cross-sectional imaging
Mesenteric or duplication cyst	Rare congenital anomalyEpithelial-lined cyst that arises from the mesentery or gastrointestinal tract	Anatomic evaluation on cross-sectional imagingResection offers definitive diagnosis
Meckel diverticulum	Congenital anomaly resulting in a true diverticulum of the small intestine	Anatomic evaluation on cross-sectional imagingMay need endoscopy, Meckel scan, or surgical exploration for definitive diagnosis
Appendiceal non-neoplastic mucoceles	Non-neoplastic process leading to chronic luminal distention due to continued mucin production by mucosal epithelium	Resection offers definitive pathologic diagnosis and differentiation from neoplastic mucinous lesions
Colonic (cecal) or terminal ileum lesion	Cecal or terminal ileal neoplasms may mimic appendiceal neoplasms due to proximity	High-quality cross-sectional imaging may be helpful, though a colonoscopy with intubation of the terminal ileum will provide greater detail
Retroperitoneal mass	Retroperitoneal masses (eg, lymphoma, sarcoma) in the right lower quadrant may mimic due to proximity	Colonoscopy will differentiate luminal lesion from retroperitoneal lesionHigh-quality cross-sectional imaging also helpful
Adnexal or ovarian lesion	Symptoms may mimic appendicitis in females; cause ranges from benign (eg, ovarian cyst) to malignant (mucinous cystadenoma)	Cross-sectional imaging and ultrasonographic evaluation are necessaryMay require resection for histopathologic diagnosis

How is Appendiceal Neoplasms treated?

Approach to Treatment

Goal of treatment is to prolong survival in patients with appendiceal neoplasms, though this needs to be individualized based on specific tumor pathology, patient characteristics, and overall goals of care with consideration for quality of life
Treatment approach is determined by the presence of metastatic disease and symptoms at the time of diagnosis
Management of appendiceal neoplasms is largely based on expert opinion and extrapolated from experience with other neoplasms, such as colon adenocarcinoma and other gastrointestinal endocrine neoplasms
Nonmetastatic disease¹⁹²⁰²⁸
- For patients with suspected epithelial tumors or NENs, perform upfront surgical resection
- Extent of the surgical resection (appendectomy alone versus right hemicolectomy) is dependent on factors described below (see the Treatment Procedures section)
- Adjuvant chemotherapy should be considered for stage II or III appendiceal adenocarcinoma²⁸
  - Use of adjuvant chemotherapy for NENs and LAMNs or HAMNs is not indicated²⁰
Peritoneal metastasis¹⁹²⁰²⁸
- Preoperatively suspected and asymptomatic patients
  - Refer these patients to a center specializing in peritoneal malignancies to evaluate for possible CRS (cytoreductive surgery) with or without HIPEC (hyperthermic intraperitoneal chemotherapy)¹⁹
- Preoperatively suspected and symptomatic patients
  - Symptoms are most likely due to appendicitis, which can lead to sepsis and/or perforation if left untreated³⁰³⁶
    - If clinically stable, attempt a course of nonoperative management with IV antibiotics (eg, piperacillin-tazobactam)
    - If there is an abscess of size greater than 3 cm and imaging characteristics not consistent with mucin, consult an interventional radiologist to evaluate for percutaneous drainage³⁷
      - Percutaneous drainage should not be attempted if there is concern for mucin, given the theoretical risk of intraperitoneal seeding
    - In the rare scenario of clinical instability where the patient has not responded to nonoperative measures, perform a limited resection (most often appendectomy alone), peritoneal washings with cytology, and biopsy of suspicious peritoneal lesions
  - Refer this patient to a center specializing in peritoneal malignancies
  - In cases of obstruction, either due to peritoneal implants or more rarely, the appendiceal lesion, then attempt a course of nonoperative management barring any emergent surgical indications (eg, closed-loop obstruction)
- Intraoperatively encountered peritoneal metastatic disease
  - In this scenario, perform an appendectomy (if technically possible), peritoneal washings with cytology, and biopsy of suspicious peritoneal lesions
  - Unless there are extraordinary circumstances, do not perform cytoreduction at the index operation
  - Refer this patient to a center specializing in peritoneal malignancies to evaluate for possible CRS or HIPEC
Distant metastasis¹⁹²⁰²⁸
- This is more likely in patients with appendiceal adenocarcinoma or NECs
- Most common sites of distant metastasis are the liver and/or lung³⁸
- In patients with symptomatic appendicitis, attempt a course of nonoperative management with IV antibiotics (eg, piperacillin-tazobactam)³⁶ to minimize perioperative risks and any possible delay in cytotoxic chemotherapy
- In the rare clinical scenario of sepsis or obstruction, perform a limited resection (ideally appendectomy alone) if technically possible³⁶
- Referral to a medical oncologist for systemic therapy
  - Treatment of metastatic appendiceal adenocarcinoma closely follows the pathway for metastatic colon cancer²⁸
  - Treatment of metastatic NENs may include the use of octreotide, everolimus, PRRT (peptide receptor radionuclide therapy), and cytotoxic chemotherapy²⁰
- Decision for metastasectomy is highly nuanced and requires discussion among multiple specialties, ideally in the setting of a multidisciplinary tumor board

Drug Therapy

There are currently no medications approved specifically for the treatment of appendiceal neoplasms
Systemic therapies, including cytotoxic chemotherapy, immunotherapy, and PRRT options, exist for the treatment of appendiceal neoplasms in the adjuvant or metastatic setting
- LAMNs or HAMNs
  - Completely resected LAMNs or HAMNs do not need any adjuvant therapy
- Appendiceal adenocarcinoma²⁸
  - Adjuvant therapy is extrapolated from experience with colon cancer and typically consists of cytotoxic chemotherapy, most commonly FOLFOX (leucovorin-fluorouracil-oxaliplatin) or CAPEOX (capecitabine-oxaliplatin) for 3 to 6 months
  - Patients with stage I cancer do not need any adjuvant therapy
  - Patients with stage III (node-positive) cancer typically receive 3 to 6 months of adjuvant chemotherapy
  - Patients with high-risk stage II cancer should also be considered for adjuvant chemotherapy
    - High-risk features include T4, poor differentiation, bowel or tumor perforation, and lymphovascular or neurovascular invasion
  - Patients with stage IV metastatic disease are treated similarly to those with metastatic colon cancer, which most often consists of cytotoxic chemotherapy regimens (FOLFOX, CAPEOX, FOLFIRI [leucovorin-fluorouracil-irinotecan]) with or without bevacizumab (or other immunotherapy based on molecular targets)
  - Typically, there is no role for adjuvant radiation therapy
    - Use of neoadjuvant therapy (radiation therapy and/or chemotherapy) for locally advanced lesions should be done in the setting of a multidisciplinary tumor board discussion
- Appendiceal NENs²⁰
  - In general, completely resected appendiceal NETs do not need further adjuvant treatment, especially if they are smaller than 2 cm
    - Role of adjuvant therapy in NENs larger than 2 cm is not well established
  - Factors that harbor increased risk for recurrence and/or metastatic disease include size greater than 2 cm and poor differentiation (most often based on Ki-67 index and mitotic rate)
  - Locally advanced, recurrent, or metastatic NETs that are unresectable should be considered for octreotide therapy, with consideration for more advanced therapy (eg, everolimus, PRRT, cytotoxic chemotherapy) with disease progression
    - Cytotoxic chemotherapy options include fluorouracil, capecitabine, dacarbazine, oxaliplatin, and temozolomide
    - Liver-directed therapy and radiation therapy are other options for locoregional disease
  - Patients with poorly differentiated NECs should be considered for a combination of resection (if possible), cytotoxic chemotherapy, and radiation therapy
    - If disease progresses, can consider more advanced therapy options (eg, everolimus, PRRT, immunotherapy)
    - Cytotoxic chemotherapy options include carboplatin-cisplatin + etoposide-irinotecan, FOLFIRI, FOLFOX, and temozolomide ± capecitabine
    - Given the rarity of these lesions, consultation with a specialized center is indicated

Table 3. Drug Therapy: Appendiceal neoplasms.

Medication	Drug class	Common regimens	Life-threatening or dose-limiting adverse reactions	Notable or nonemergent adverse reactions	Special considerations
Carboplatin^D1	Alkylating agent—platinum	Carboplatin + etoposide	AnaphylaxisBone marrow suppressionNausea/vomitingNephrotoxicity	Electrolyte lossOtotoxicityPeripheral neuropathySecondary malignancy	Avoid coadministering nephrotoxic or ototoxic agentsEnsure adequate hydration
Cisplatin^D2	Alkylating agent—platinum	Cisplatin + etoposide	AnaphylaxisBone marrow suppressionNausea/vomitingNephrotoxicityOcular toxicity	Electrolyte lossOtotoxicityPeripheral neuropathySecondary malignancy	Avoid coadministering nephrotoxic or ototoxic agentsEnsure adequate hydrationCisplatin has been associated with optic neuritis, papilledema, vision lossEffective contraception required during and after therapy for 14 months for females of reproductive potential and for 11 months for males with female partners of reproductive potential
Oxaliplatin^D3	Alkylating agent—platinum	Capecitabine + oxaliplatin ± bevacizumabFluorouracil + oxaliplatin + leucovorin ± bevacizumab	AnaphylaxisBleedingBone marrow suppressionNausea/vomitingPeripheral sensory neuropathyPRESPulmonary fibrosisQT prolongation and ventricular arrhythmiasRhabdomyolysis	DiarrheaFatigueIncreased hepatic enzymesStomatitis	Effective contraception required during and after therapy for 9 months for females of reproductive potential and for 6 months for males with female partners of reproductive potential
Dacarbazine^D4	Alkylating agent—triazene	Dacarbazine monotherapy	AnaphylaxisBone marrow suppressionHepatotoxicity	AnorexiaNausea/vomiting
Temozolomide^D5	Alkylating agent—triazene	Temozolomide monotherapyCapecitabine + temozolomide	Bone marrow suppressionHepatotoxicityPneumocystis jirovecii pneumonia	AlopeciaAnorexiaConstipationFatigueHeadacheNausea/vomitingSecondary malignancySeizures	Effective contraception required during and after therapy for at least 6 months for females of reproductive potential and for at least 3 months for males with female partners of reproductive potential
Capecitabine^D6	Antimetabolite—nucleoside metabolic inhibitor	Capecitabine + oxaliplatin ± bevacizumabCapecitabine + temozolomide	Bone marrow suppressionCardiotoxicityDehydrationDermatologic toxicityHyperbilirubinemiaRenal failure	Abdominal painDiarrheaFatigue/weaknessNausea/vomiting	Increased risk of serious or fatal adverse reactions in patients with low or absent dihydropyrimidine dehydrogenase activityEffective contraception required during and after therapy for 6 months for females of reproductive potential and for 3 months for males with female partners of reproductive potential
Fluorouracil^D7	Antimetabolite—nucleoside metabolic inhibitor	Fluorouracil monotherapyFluorouracil + oxaliplatin + leucovorin ± bevacizumabFluorouracil + irinotecan + leucovorin ± bevacizumab	Bone marrow suppressionCardiotoxicityDiarrheaHyperammonemic encephalopathyMucositisNeurotoxicityPalmar-plantar erythrodysesthesia (hand-foot syndrome)		Increased risk of serious or fatal adverse reactions in patients with low or absent dihydropyrimidine dehydrogenase activityEffective contraception required during and after therapy for 3 months for females of reproductive potential and males with female partners of reproductive potential
Everolimus^D8	Kinase inhibitor	Everolimus monotherapy	AnaphylaxisAngioedemaBone marrow suppressionFebrile neutropeniaHypercholesterolemiaHyperglycemiaHyperlipidemiaImpaired wound healingInfectionPneumonitisRadiation sensitization or recallRenal failureStomatitis	Abdominal painAnorexiaAstheniaCoughDiarrheaEdemaFatigueFeverHeadacheNauseaRash	Drug interactions: may need to avoid or adjust dosage of certain drugsAvoid use of live vaccines and close contact with those who have received live vaccines; complete recommended childhood vaccinations before starting treatmentWithhold therapy for at least 1 week before elective surgery and for at least 2 weeks after major surgery and until adequate wound healingTherapeutic drug monitoring may be indicatedEffective contraception required during and after therapy for 8 weeks for females of reproductive potential and for 4 weeks for males with female partners of reproductive potential
Octreotide^D9	Somatostatin analog	Octreotide monotherapy	BradycardiaCardiac arrhythmiaCholelithiasisHyperglycemiaHypoglycemiaThyroid dysfunctionVitamin B12 deficiency	Abdominal painBack painDiarrheaDizzinessFatigueFlatulenceHeadacheNausea	Effective contraception required during therapy for females of reproductive potential
Irinotecan^D10	Topoisomerase I inhibitor	Fluorouracil + irinotecan + leucovorin ± bevacizumab	AnaphylaxisBone marrow suppressionDiarrheaInterstitial lung diseaseRenal failure	Abdominal painAlopeciaAnorexiaAstheniaConstipationFeverNausea/vomitingWeight loss	Increased risk of neutropenia in patients with reduced UGT1A1 activityEffective contraception required during and after therapy for at least 6 months for females of reproductive potential and for 3 months for males with female partners of reproductive potential
Etoposide^D11	Topoisomerase II inhibitor—epipodophyllotoxin	Carboplatin + etoposideCisplatin + etoposide	AnaphylaxisBone marrow suppression	AlopeciaNausea/vomitingSecondary malignancy	Effective contraception required during and after therapy for at least 6 months for females of reproductive potential and for 4 months for males with female partners of reproductive potential
Bevacizumab^D12	Vascular endothelial growth factor inhibitor	Fluorouracil + oxaliplatin + leucovorin ± bevacizumabFluorouracil + irinotecan + leucovorin ± bevacizumab	BleedingGastrointestinal perforation or fistulaHeart failureHypertensionImpaired wound healingInfusion-related reactionsNephrotoxicity and proteinuriaOvarian failurePRESThromboembolic events	Abdominal painAnorexiaConstipationCoughDiarrheaDizzinessDyspneaFatigueHeadacheHypomagnesemiaInsomniaMusculoskeletal painNausea/vomitingNephrotoxicityRashUrinary tract infection	Withhold therapy for at least 28 days before elective surgery and for 28 days after major surgery and until adequate wound healingEffective contraception required during and after therapy for 6 months for females of reproductive potential

Caption: PRES, posterior reversible encephalopathy syndrome.

Treatment Procedures

LAMNs or HAMNs
- LAMNs and HAMNs are defined by histologic findings, most often on pathologic review after appendectomy
- Perform an appendectomy with complete resection of the mesoappendix in patients with suspected LAMNs or HAMNs¹⁹
  - In patients confirmed to have LAMNs or HAMNs on final pathologic evaluation, negative margins, and with no evidence of perforation or peritoneal involvement, do not perform any additional resections²⁹
  - If an invasive adenocarcinoma is found on the final surgical specimen, then perform a formal right hemicolectomy¹⁹
- Patients with PMP or peritoneal deposits should be referred to a center specializing in peritoneal malignancies to consider for CRS or HIPEC¹⁹
  - CRS refers to surgical removal of all macroscopic peritoneal disease, which may include removal of the peritoneal lining of the abdomen and any nonessential organs
  - HIPEC refers to administration of heated chemotherapy solution directly into the peritoneal cavity
Appendiceal adenocarcinoma
- Perform a formal right hemicolectomy in patients with appendiceal adenocarcinoma¹⁹
  - For patients with tumors that are T1, low-grade disease without lymphovascular invasion, and not involving the base of the appendix, appendectomy alone may be acceptable, especially in patients with high perioperative risk factors for colectomy²⁸
- In the setting of peritoneal metastasis, do not routinely perform a right hemicolectomy, because this has not been shown to improve survival¹⁹
  - Refer these patients to a center specializing in peritoneal malignancies
Appendiceal NENs
- Extent of surgical resection is based on size and histology of the lesion¹⁹
  - Unfortunately, histologic features can only be accurately determined postoperatively. Therefore, return to the operating room for right hemicolectomy is not an uncommon scenario in the setting of unfavorable features on a final pathologic evaluation
  - Unfavorable features include mesoappendiceal invasion greater than 3 mm, elevated mitotic index more than 2 mitoses per high-powered field, Ki-67 index more than 3%, and lymphatic or vascular invasion¹⁹
- Lesions less than 1 cm without unfavorable features
  - Perform an appendectomy with complete mesoappendix resection¹¹⁹²⁹
- Lesions 1 to 2 cm
  - Extent of surgical resection is based on a combination of histologic features (if available) and patient comorbidities and preference¹⁹
  - In most cases, an appendectomy alone is sufficient
- Lesions more than 2 cm
  - Perform a formal right hemicolectomy¹¹⁹²⁹³⁹
  - Although most lesions are at the tip of the appendix, lesions at the base of the appendix may require extended resection to achieve a negative margin¹⁹
  - Options include partial cecectomy (with preservation of the ileocecal valve), ileocecectomy, or right hemicolectomy¹

Persistent or Recurrent Disease

LAMNs or HAMNs
- Recurrence of LAMNs or HAMNs most likely presents as recurrent accumulation of intraperitoneal mucin
  - Rate of recurrence of HAMNs, given their increased cellular atypia, is assumed to be higher than that of LAMNs⁴⁰
- Decision for repeat CRS or HIPEC is highly nuanced, and these patients should be evaluated at a specialized center
Appendiceal adenocarcinoma
- Recommendations are extrapolated from colon cancer experience²⁸
- Patients with persistent or recurrent disease who are resectable should undergo a formal right hemicolectomy (if not already performed)
- Patients may also be candidates for cytotoxic chemotherapy (eg, FOLFOX, CAPOX) either before and/or after an attempt at resection
NENs
- Treatment of recurrent or persistent NENs is highly nuanced and optimal management is not well established. Consultation with a multidisciplinary tumor board is advised²⁰
- In general, if complete resection is possible, then this should be considered (most likely a formal right hemicolectomy if one was not already performed)
  - For patients who are unresectable, consider systemic therapy with octreotide
  - If persistent progressive disease, then consider everolimus, PRRT, or cytotoxic chemotherapy
  - For patients with NECs, consideration of radiation therapy in addition to chemotherapy is appropriate for persistent or recurrent disease

Admission Criteria

Concurrent appendicitis³⁶
- Patients with appendiceal neoplasms may have concurrent appendicitis
- As described above, patients may require appendectomy or an attempt at nonoperative management with antibiotics; either of these strategies will typically require an admission to the hospital
- For patients with perforated appendicitis, hospital admission for antibiotics and/or percutaneous drainage is typically required
Postsurgical intervention
- Simple appendectomy
  - Typically, these patients can be discharged the same day or next day after a simple appendectomy unless there were intraoperative or postoperative issues of concern
- Right hemicolectomy
  - Typically, these patients are admitted to the hospital and use standard ERAS (Enhanced Recovery After Surgery) pathways
  - These patients are typically discharged between 2 and 3 days after surgery
- Postoperative complications, including bleeding, wound infection, and enteric or anastomotic leak, and medical complications (eg, thromboembolic disease) require evaluation by practitioners depending on the acuity and may warrant admission

Special Considerations

Ruptured or Perforated Appendiceal Neoplasms

Mucinous appendiceal neoplasms
- Evidence-based guidelines are lacking for this scenario; recommendations are based on expert opinion
- When encountered intraoperatively, limit initial resection to appendectomy alone if possible
- Also perform careful inspection of the abdominal cavity and biopsy of any suspicious lesions. Peritoneal cytology can be considered, though its utility is not well established¹⁹
- If the perforation involves the right colon and/or mesentery, then a right hemicolectomy may be required
- Do not perform CRS at the index operation¹⁹
Perforation of appendiceal NENs does not seem to affect prognosis and can be managed expectantly⁴¹

Follow-Up

Monitoring

In general, there are no consensus guidelines for surveillance in appendiceal neoplasms
LAMN or HAMN
- Surveillance guidelines for LAMNs or HAMNs are highly variable
- For completely resected LAMNs, surveillance protocols range from abdominal MRI every 6 to 12 months for 2 years¹⁹ to routine postoperative care without additional surveillance⁴²
- Patients with cellular or acellular mucin deposits outside the appendix, or those with perforation, should get CT scan of the abdomen and pelvis every 6 months for 2 years, then annual imaging until 5 years, and then CT scan every 2 years until 10 years after resection¹⁹
  - This surveillance protocol should also be performed for all HAMNs given the higher risk of recurrence¹⁹
Appendiceal adenocarcinoma
- Although formal surveillance guidelines specifically for appendiceal adenocarcinoma have not been developed, monitoring regimens similar to those used for resected colon cancer are generally followed²⁸
  - Stage I
    - Colonoscopy 1 year after surgery
      - If advanced adenoma is present, repeat in 1 year
      - Otherwise, can repeat in 3 years and then every 5 years
  - Stages II, III, and IV
    - History and physical examination every 3 to 6 months for 2 years and then every 6 months for at least 5 years
    - Tumor markers every 3 to 6 months for 2 years and then every 6 months for a total of at least 5 years
      - Carcinoembryonic antigen is routinely used for colon cancer surveillance; CA 125 and CA 19-9 have also been used for appendiceal adenocarcinoma¹⁹
    - Cross-sectional imaging of the chest, abdomen, and pelvis every 6 to 12 months for at least 5 years for patients with stage II or III cancer; for patients with stage IV cancer, imaging every 3 to 6 months after surgery for 2 years and then every 6 months for a total of at least 5 years
      - CT is the most used imaging modality, but MRI appears superior in detection of peritoneal disease, and is often used for surveillance after CRS or HIPEC¹⁹
      - PET scan does not appear to change management and is not routinely indicated
    - Colonoscopy 3 to 6 months after surgery, if preoperative colonoscopy could not be completed due to obstructing lesion
    - Colonoscopy 1 year after surgery otherwise
      - If advanced adenoma is present, repeat in 1 year
      - Otherwise, repeat in 3 years and then every 5 years
    - There is limited evidence supporting prolonged surveillance beyond 10 to 15 years¹⁹
Appendiceal NENs¹⁹²⁰
- For tumors 2 cm or less without unfavorable features, there is no need for formal surveillance
- For tumors greater than 2 cm
  - Within 12 months postresection: history and physical examination, CT scan of the abdomen and pelvis, and chromogranin A or 5-HIAA; consider CT scan of the chest as indicated
  - After 12 months: history and physical examination, CT scan of the abdomen and pelvis, and chromogranin A or 5-HIAA every 12 to 24 months for up to 10 years postresection. Consider CT scan of the chest as indicated
- Patients with tumors 2 cm or less with unfavorable features are surveyed similarly to patients with tumors greater than 2 cm
- Chromogranin A or 5-HIAA levels can correlate with response to therapy or recurrence. However, correlation with imaging is required due to the nonspecific nature of these tumor markers
- If recurrence is suspected on CT imaging, then NEN-specific imaging such as DOTATATE PET-CT is reasonable to confirm findings if there is diagnostic uncertainty
  - There is insufficient evidence for the use of NEN-specific imaging during routine surveillance

Complications

Appendiceal neoplasms may lead to appendicitis and, rarely, peritonitis
Mucinous appendiceal neoplasms may progress to PMP
Complications after appendectomy or right hemicolectomy include surgical site infection, anastomotic leak, bleeding, ileus, postoperative bowel obstruction, fistula formation, ureter injury, and risks of anesthesia (including cardiopulmonary complications)

Prognosis

LAMN or HAMN
- Prognosis is dependent on histology and presence or extent of peritoneal spread
- Non-neoplastic lesions, such as mucoceles or retention cysts and serrated polyps, have excellent overall survival in the range of 91% to 100% after appendectomy¹⁰⁴³⁴⁴
- LAMNs confined to the appendix, typically classified as Tis(LAMN), have very rare recurrence
  - LAMNs with peritoneal spread also have good 5-year survival, ranging from 79% to 86%⁴⁵
- Survival rates for HAMNs appear to be similar to those for LAMNs
  - However, HAMNs, by definition, exhibit more cellular atypia compared with LAMNs. Therefore, risk of recurrence of HAMNs may be higher, though data are limited⁴⁰
Appendiceal adenocarcinoma
- Prognosis is dependent on LN metastasis, distant metastasis, and tumor differentiation¹³⁴⁶
- Tumor perforation does not seem to adversely affect prognosis⁴⁷
- Tumor histology also plays a role, with signet ring cell being the worst, mucinous and intestinal intermediate, and goblet cell the most favorable⁴⁸
- An analysis of Surveillance, Epidemiology, and End Results Program registry data from 1973 to 2005 encompassing 931 cases reported overall 5-year survival rates of 81.1% for patients with stage I cancer, 52.6% for patients with stage II cancer, 32.9% for patients with stage III cancer, and 22.7% for patients with stage IV cancer⁴⁹
Appendiceal NENs
- Prognosis is dependent on tumor size and presence of metastasis⁵⁰
- Tumors 2 cm or less have excellent prognosis and rarely metastasize
- However, up to one-third of patients with lesions greater than 2 cm have metastatic disease at diagnosis, most commonly to the liver⁵¹⁵²⁵³
- Perforation does not appear to negatively affect prognosis and therefore, should not affect treatment or surveillance⁴¹
- A retrospective review of 114 patients who presented to a tertiary referral center from 1998 to 2019 reported 5- and 10-year survival stratified by stage group as shown in Table 4

Table 4. 5- and 10-year overall survival for patients with appendiceal NETs stratified by stage group.

Stage group	5-year overall survival (%)	10-year overall survival (%)
I	100	100
II	100	100
III	78	63
IV	32	17
Overall	90	85

Caption: NET, neuroendocrine tumor.

From Landry JP et al. Management of appendiceal neuroendocrine tumors: metastatic potential of small tumors. Ann Surg Oncol. 2021;28(2):751-757.

Referral

LAMN or HAMN
- In patients with a completely resected LAMN without peritoneal spread, there is no need for additional surveillance other than yearly medical checkup by the patient’s primary care practitioner
  - There is limited utility in referring to a specialized center
- In patients with cellular or acellular mucin deposits outside the appendix, or a history of perforation without obvious peritoneal disease, it is reasonable to refer to a center that specializes in peritoneal malignancies
- All patients with a final histology of HAMN should be referred to a specialized center
Appendiceal adenocarcinoma
- Depending on the stage, referral to a medical oncologist may be necessary
- In cases of peritoneal disease, referral to a center specializing in peritoneal malignancies is necessary
Appendiceal NENs
- For patients with NECs or positive LNs, referral to a medical oncologist is recommended
  - Patients with tumors greater than 2 cm can also be referred to a medical oncologist, though the utility for adjuvant therapy is unclear
  - Referral to a center with experience in appendiceal NENs is reasonable, especially if metastatic disease is present

References

1.Boudreaux JP et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: Well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas. 2010;39(6):753-766.