Epidemiology

Found at ~1% of appendicectomies on histopathology
Account for 0.4-1% of all GIT malignancies

Presentation

50% present as appendicitis
Variable other presentations are seen, including found on CT

Subtypes:

Appendiceal neuroendocrine neoplasms (ANENs - formerly known as carcinoid tumour)

Epidemiology
- Most common appendiceal neoplasm (65%)
- Seen in 3-5/1000 appendicectomies
- Most commonly diagnosed 10-30yo
Pathophysiology
- Most originate from serotonin-producing enterochromaffin cells
- More benign that other NETs. Prevalent at autopsy. May even undergo spontaneous involution. Overall met rate is 3.8%.
- Can actually cause appendicitis - think about this if tip appendicitis is present
- Typically small, well-circumscribed lesions within the distal appendix
- Variable biological behaviour depending on grade
  - G1 - well-differentiated
  - G2 - intermediately-differentiated
  - G3 - poorly-differentiated neuroendocrine carcinoma
  - Mixed neuroendocrine carcinomas
- Size is the best initial predictor of malignant behaviour and metastatic potential - so base initial management on size and location
Staging

Neuroendocrine tumors of the appendix TNM staging AJCC version 9

Primary tumor (T)*
T category	T criteria
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor ≤2 cm in greatest dimension
T2	Tumor >2 cm but ≤4 cm in greatest dimension
T3	Tumor >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 adjacent subserosa of adjacent bowel), eg, abdominal wall and skeletal muscle
NOTE: Multiple tumors should be designated as such (the largest tumor should be used to assign T category): Use T(#); eg, pT3(4) N0 M0, or Use the m suffix, T(m); eg, pT3(m) N0 M0 Primary tumor suffix (m) Multiple synchronous primary tumors
Regional lymph nodes (N)*
N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No tumor involvement of regional lymph node(s)
N1	Tumor involvement of regional lymph node(s)
Regional lymph nodes suffix (f) FNA or core needle biopsy
Distant metastasis (M)*
M category	M criteria
cM0	No distant metastasis
cM1	Distant metastasis
cM1a	Metastasis confined to liver
cM1b	Metastases in at least one extrahepatic site (eg, lung, ovary, nonregional lymph node, peritoneum, bone)
cM1c	Both hepatic and extrahepatic metastases
pM1	Microscopic confirmation of distant metastasis
pM1a	Microscopic confirmation of metastasis confined to liver
pM1b	Microscopic confirmation of metastases in at least one extrahepatic site (eg, lung, ovary, nonregional lymph node, peritoneum, bone)
pM1c	Microscopic confirmation of both hepatic and extrahepatic metastases
AJCC prognostic stage group is assigned based on the stage classification and categories chosen.*
Prognostic stage groups
When T is...	And N is...	And M is...	Then the stage group is...
T1	NX, N0	M0	I
T2	NX, N0	M0	II
T3	N0	M0	II
T4	N0	M0	III
Any T	N1	M0	III
Any T	Any N	M1	IV

Management
- Treatment based on size:
  - <1cm - mostly benign - treated by appendicectomy and excision of mesoappendix
  - 1-2cm - base decision for right hemicolectomy on histologic factors (Ki-67 index >3%, G2 or higher, lymphovascular or perineural invasion)
  - >2cm - treated more aggressively with right hemicolectomy and regional lymphadenectomy
- Indications for right hemicolectomy if found incidentally on histology:
  - >2cm in diameter
  - Positive or unclear margins
  - Deep meso-appendiceal invasion (>3mm)
  - High proliferation rate (WHO grade 2)
  - Angio-invasion
Surveillance
- Chromogranin-A is a good tumour marker
Prognosis
- Local: 95-100% at 5 year survival
- Regional: 85-100% survival at 5 years
- Metastatic: 34% five year survival

Non-mucinous adenocarcinoma of the appendix

Rare
Typically seen as a focal mass without mucocoele formation
Defining feature compared to mucinous adenocarcinoma is invasion
Treat identically to caecal adenocarcinoma - right hemicolectomy with regional lymphadenectomy, aiming for >12 lymph nodes for accurate staging
Treatment of the incidentally found, completely resected appendiceal adenocarcinoma is somewhat controversial, but most guidelines suggest completion right hemicolectomy
Chemotherapy
- Adjuvant - FOLFOX if indicated
- Neoadjuvant - can be used prior to cytoreductive surgery

Mucinous neoplasms of the appendix

Rare and heterogenous disease - challenging to manage
Pathophysiology
- Likely represents a spectrum of disease, with higher-grade disease developing from lower-grade disease in a sequence
- All subtypes may result in pseudomyxoma peritonei (PMP - a term used to describe the existence of mucinous ascites, and not a specific histopathological category), which occurs secondary to tumour rupture and intra-peritoneal spread
- Histological subtypes
  - Serrated and hyperplastic polyps of the appendix
    - The term adenoma is not quite correct since these are not definitively benign
    - Often KRAS mutated but not BRAF mutated
  - Mucinous appendiceal neoplasms - dysplastic mucinous tumours
    - Low-grade appendiceal mucinous neoplasm
      - Formerly referred to as 'benign mucocoele' - no longer used
      - True neoplasm with dysplastic epithelium that produces abundant mucin, but confined within muscularis propria
      - Often appears grossly fibrotic and hyalinised, and extensive calcification making a 'porcelain appendix'
      - Don't invade the wall, but can 'push' it until the appendix ruptures, causing PMP
      - Often diagnosed incidentally at appendicectomy
    - High-grade appendiceal mucinous neoplasm
      - Differentiate from low-grade neoplasms by the degree of epithelial dysplasia present
      - Still lack infiltrative behaviour
      - Limited data on prognostics because this is a fairly new pathological category
      - Clinical management closer to LAMN than adenocarcinoma
      - Probably more likely to cause PMP than metastases
  - Invasive mucinous adenocarcinoma of the appendix
    - Demonstrate infiltrative invasion
    - Classification
      - Well-differentiated
      - Moderately-differentiated
      - Poorly-differentiated - includes all signet ring cell carcinoma
    - Differentiate from non-mucinous adenocarcinoma of appendix by presence of >50% mucin in microscopic field
    - Generally presents as acute appendicitis (can also present as palpable mass, obstruction, GI bleeding, or symptoms related to mets)

Presentation
- Asymptomatic
- Chronic RIF pain
- Mass
- Pain resembling appendicitis
- Found at colonoscopy - bulging appendiceal orifice
Complications
- Pseudomyxoma peritonei (PMP) - consequence of a perforated mucinous tumour, gradually seeded throughout the cavity. Commonly diagnosed by gynaecologists who see patients with large ovaries.

Staging

Use the following table for both appendiceal mucinous neoplasms and adenocarcinomas
LAMNs confined to appendiceal wall are staged as Tis
HAMNs are staged as invasive adenocarcinomas (T1 to T4)

Primary tumor (T)
T category	T criteria
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ (intramucosal carcinoma; invasion of the lamina propria or extension into but not through the muscularis mucosae)
Tis(LAMN)	Low-grade appendiceal mucinous neoplasm confined by the muscularis propria. Acellular mucin or mucinous epithelium may invade into the muscularis propria. T1 and T2 are 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 (through the muscularis mucosa but not into the muscularis propria)
T2	Tumor invades the muscularis propria
T3	Tumor invades through the muscularis propria into the subserosa or the mesoappendix
T4	Tumor invades the visceral peritoneum, including the acellular mucin or mucinous epithelium involving the serosa of the appendix or mesoappendix, and/or directly invades adjacent organs or structures
T4a	Tumor invades through the visceral peritoneum, including the acellular mucin or mucinous epithelium involving the serosa of the appendix or serosa of the mesoappendix
T4b	Tumor directly invades or adheres to adjacent organs or structures
Regional lymph nodes (N)
N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	One to three regional lymph nodes are positive (tumor in lymph node measuring ≥0.2 mm) or any number of tumor deposits is present, and all identifiable lymph nodes are negative
N1a	One regional lymph node is positive
N1b	Two or three regional lymph nodes are positive
N1c	No regional lymph nodes are positive, but there are tumor deposits in the subserosa or mesentery
N2	Four or more regional lymph nodes are positive
Distant metastasis (M)
M category	M criteria
M0	No distant metastasis
M1	Distant metastasis
M1a	Intraperitoneal acellular mucin, without identifiable tumor cells in the disseminated peritoneal mucinous deposits
M1b	Intraperitoneal metastasis only, including peritoneal mucinous deposits containing tumor cells
M1c	Metastasis to sites other than peritoneum
NOTE: For specimens containing acellular mucin without identifiable tumor cells, efforts should be made to obtain additional tissue for thorough histologic examination to evaluate for cellularity.
Histologic grade (G)
G	G definition
GX	Grade cannot be assessed
G1	Well differentiated
G2	Moderately differentiated
G3	Poorly differentiated
Prognostic stage groups
When T is...	And N is...	And M is...	And grade is...	Then the stage group is...
Tis	N0	M0	–	0
Tis(LAMN)	N0	M0	–	0
T1	N0	M0	–	I
T2	N0	M0	–	I
T3	N0	M0	–	IIA
T4a	N0	M0	–	IIB
T4b	N0	M0	–	IIC
T1	N1	M0	–	IIIA
T2	N1	M0	–	IIIA
T3	N1	M0	–	IIIB
T4	N1	M0	–	IIIB
Any T	N2	M0	–	IIIC
Any T	Any N	M1a	–	IVA
Any T	Any N	M1b	G1	IVA
Any T	Any N	M1b	G2, G3, or GX	IVB
Any T	Any N	M1c	Any G	IVC

Management of mucinous neoplasms

Initial management of radiographically or operatively diagnosed lesions:
- Localised appendiceal mucinous lesions - surgical resection with excision of mesoappendix
- Complicated radiographic mucocoele (involvement of TI or caecum or lymphadenopathy) - may require a more extensive surgical resection including right hemicolectomy and lymphadenectomy
- Ruptured appendiceal mucinous neoplasm - remove the appendix +/- right hemicolectomy, but leave formal cytoreductive surgery to high-volume surgeons. Thoroughly irrigate the abdomen.
- Disseminated intra-peritoneal disease - no need to do appendicectomy. Get a biopsy specimen, possibly percutaneously.
Post-histology management:
- Completely resected LAMN or HAMN: no right hemicolectomy, provided the tumour was confined to the appendix and has not ruptured
- Microscopically positive margin for a LAMN: controversial. Safest thing to do is an ileocaecectomy. Observation is also justified. Right hemicolectomy is not required.
- T4a LAMN or HAMN: no consensus. Right hemicolectomy does not offer any benefit. Patients should probably be followed with regular imaging and tumour markers for PMP. CRS and HIPEC will be required once PMP is identified.
- Completely resected mucinous adenocarcinoma: controversial. UTD says offer completion right hemicolectomy and lymphadenectomy to those with only grade 2 or 3 adenocarcinoma.
- Incompletely resected mucinous adenocarcinoma: completion right hemicolectomy.
Metastatic mucinous adenocarcinoma - CRS + HIPEC (see separate topic)
Metastatic mucinous neoplasm - should be referred to a specialised centre for possible cytoreductive surgery and HIPEC (see separate topic)