PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
The appendix is a finger-like outpouching from the cecum containing numerous lymphatic nodules similar to Peyer's patches in its wall.
PERSPECTIVE AND PATTERNS OF SPREAD
The appendix has come of age in the seventh edition of the American Joint Committee on Cancer AJCC Cancer Staging Manual, in which it has its own distinct staging system. The introduction of carcinoids has also been emphasized at this site, although it can occur throughout the digestive system. It may be equivalent to the bursa of Fabricius in mammals, where potential B lymphocytes acquire their immunocompetence. It is prone to infection as a blind-ended pouch.
• Appendiceal adenocarcinomas are grouped with mucinous adenocarcinomas, which constitute 50% versus 10% of colon carcinomas and have better survival outcomes. Appendix carcinoids will be considered and contrasted with adenocarcinomas at this site.
• Appendiceal adenocarcinomas tend to ulcerate and perforate, presenting as appendicitis with right lower quadrant pain. Their dissemination is into the peritoneal cavity.
• Appendiceal carcinoids produce a carcinoid syndrome. Carcinoid tumors have the capacity to produce serotonin, histamine, and bradykinin. These compounds cause a clinical syndrome manifested by attacks of watery diarrhea, cutaneous flushing, and asthmatic-type respiratory distress. Lesions of tricuspid and pulmonic valves also occur. This syndrome does not occur in all instances of carcinoid tumor. The syndrome is most frequently associated with carcinoids of the ileum or extensive hepatic metastases. Carcinoids most commonly occur on the appendix but rarely produce carcinoid syndrome from this site. Their dissemination is to the liver, and their hepatic multinodular spread and growth triggers the endocrine syndrome.
PATHOLOGY
Carcinoids that arise from cells of the neuroendocrine system are more in the gastrointestinal tract. The small intestine, especially the ileum, accounts for 30% of all carcinoids, but because small intestine neoplasia is uncommon, it accounts for one third of small bowel cancers. In a similar fashion, Surveillance, Epidemiology and End Results data show that appendiceal carcinoids account for less than 3% of all carcinoids, but as a percentage of appendiceal cancers, their incidence is high and similar to that in the small intestine. Therefore, carcinoid neuroendocrine tumors are covered in this chapter, recognizing the clinical manifestations are similar, independent of origin site (Tables 31.1A and B; Fig. 31.1).
Figure 31.1 | A. Adenocarcinoma. Microscopically, this adenocarcinoma consists of moderately differentiated glands with a prominent cribriform pattern and frequent central necrosis. B. Carcinoid tumors are neuroendocrine tumors (NETs). The appendix and ileum are often cited as the most frequent sites, although they can and do occur throughout the digestive system. Microscopically, NETs appear as nests or rosettes of uniform round cells. Mitosis is rare, and nuclei are often regular. Goblet cells imply more aggressive behavior.
The patterns of spread are limited and illustrated for cancers (Fig. 31.2B) and carcinoids (Fig. 31.2A). Both are summarized in Table 31.2.
The average age of presentation is in the 60s, and all tumors express serotonin. Small bowel carcinoids present with vague abdominal pain, related to intermittent obstruction; bleeding is rare. Appendiceal carcinoids often lead to appendicitis, with early detection and more favorable outcome, with an overall survival of 71%. Appendiceal carcinoids tend to be small, >2 cm, and appendectomy is often adequate. With lymph node invasion or penetration of serosa, or mesoappendix, a wider ileocolectomy is performed.
Figure 31.2 | Carcinoids tend to obstruct the appendix, leading to appendicitis. Cancers tend to invade the wall and their patterns of spread is to adjacent viscera, i.e., secum, ileum, and depending on location, small intestine, and abdominal wall (Fig. 31.2; Table 31.2). The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern i.e., SIMLAP Table 31.2.
TNM STAGING CRITERIA
APPENDICEAL CARCINOMAS
Figure 31.3A | TNM staging criteria for appendiceal carcinomas. These are separately classified in the seventh edition of the AJCC Cancer Staging Manual. The appendiceal adenocarcinoma staging follows the colorectal categories, in that the primary cancer invades the wall, each layer advances T stage, then N stage progresses. Mucus that has spread beyond the right lower quadrant carries a poor prognosis, as does presence of epithelial cells in the peritoneal cavity. Pseudomyxoma peritonea carries M1a designation.
TNM Staging Criteria
The appendiceal carcinomas are separately classified in the seventh edition. The appendiceal adenocarcinoma staging follow the colorectal categories in that the primary cancers invade the wall, each layer advances T stage, Then N stage progresses. Mucous that has spread beyond the RLQ as is presence of epithelial cells in peritoneal cavity carry a poor prognosis. Pseudomyxoma peritonea carries M1a designation (Fig. 31.3A).
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• In the seventh edition, appendiceal carcinomas are separately classified. In the sixth edition, appendiceal carcinomas were classified according to the definitions for colorectal tumors.
• Appendiceal carcinomas are now separated into mucinous and nonmucinous types. Histologic grading is considered of particular importance for mucinous tumors. This is reflected in the staging considerations for metastatic tumors. The change is based on published data and analysis of NCDB data.
• In the seventh edition, the T4 category is divided into T4a and T4b as in the colon and is reflected in the subdivision of Stage II.
• M1 is divided into M1a and M1b where pseudomyxoma peritonei, M1a, is separated from nonperitoneal metastasis, M1b.
• In the seventh edition, Stage IV is subdivided on the basis of N, M, and G status, unlike colorectal carcinomas.
APPENDIX CARCINOID
Figure 31.3B | TNM staging criteria for appendiceal carcinoids. These are new in the seventh edition of the AJCC Cancer Staging Manual. Staging of the appendiceal carcinoid is largely based on size. T1a, ≤1 cm, and T1b, 1 to 2 cm, tend to be localized. T2, T3, and T4 increment size and metastatic potential.
TNM STAGING CRITERIA
• The Appendiceal carcinoids are new in the seventh edition. The appendiceal carcinoid is largely based on size. T1a ≤ 1 cm and T1b 1 − 2 cm tend to be localized. T2, T3, T4 increment size and metastatic potential (Fig. 31.1B).
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• A new classification is added for carcinoid tumors that were not classified previously by TNM. This is a new classification. There are substantial differences between the classification schemes of appendiceal carcinomas and carcinoids and between appendiceal carcinoids and other well-differentiated gastrointestinal neuroendocrine tumors (carcinoids) (see chapters of the digestive system for staging of other gastrointestinal carcinoids).
• Serum chromogranin A is identified as a significant prognostic factor.
T-ONCOANATOMY
ORIENTATION OF TNM ONCOANATOMY
T-oncoanatomy
The appendix is a tubular structure that is 3 to 13 cm in length and is located 2 to 3 cm inferior to the ileocecal valve. It adjoins the cecum medially and is attached to a mesoappendix that contains its blood supply, that is, the appendicular artery. Its position can vary, and although typically it hangs inferiorly, less commonly it can be retrocecal (Figure 31.5A,B).
N-oncoanatomy
The appendiceal lymph nodes drain into ileocecal lymph nodes. Then the superior mesenteric artery lymph node drains into the para-aortic lymph nodes (Fig. 31.6A).
M-oncoanatomy
The drainage of the appendiceal vein is into the ileocolic vein, then midcolic into the superior mesenteric vein, which drains into the portal circulation. Hence, liver metastasis leads to the carcinoid syndrome. Goblet cell carcinoid tends to metastasize to the ovaries. Seeding and spreading directly into peritoneal surfaces can lead to a mucinous ascites.
Figure 31.4 | Typical biochemical carcinoid pathways.
The metastatic capability of carcinoid tumors is a function of size. Once tumors exceed 1.0 cm their risk for metastasizing dramatically increases (Table 31.3; Fig. 31.6B).
The typical pattern of carcinoid syndrome (CS) is triggered by liver metastases by release of tryptophan, which is converted to 5-hydroxytryptophane and then rapidly to serotonin. The serotonin then forms 5-hydroxyindoleacetic acid (5HIAA), which is excreted in the urine. The diagnosis of CS is through elevated plasma serotonin and 5HIAA in the urine (Fig. 31.4).
Typically, there is diarrhea, and flushing occurs. The appearance of red-to-purple discoloration of the face may spread to the entire torso—an erythematous rash that is pruritic with central clearing. Diarrhea also occurs with multiple loose stools. Additional symptoms include abdominal pain, cardiac symptoms, and bronchospasm. Tricuspid valvular lesions and pulmonary valve are most at risk. Carcinoid crisis can be precipitated by anesthetic and surgical intervention to establish the diagnosis. Fortunately, somatostatin analogs can counteract the CS.
Ileal diverticulum is a congenital anomaly that occurs in 1% to 2% of persons. It is a pouchlike remnant (3 to 6 cm long) of the proximal part of the yolk stalk, typically within 50 cm of the ileocecal junction. It sometimes becomes inflamed and produces pain that may mimic that produced by appendicitis.
Figure 31.5 | T-oncoanatomy. A. Blood supply. The appendicular artery is located in the free edge of the mesoappendix. The inferior ileocecal fold is bloodless, whereas the superior ileocecal fold is called the vascular fold of the cecum. B. The approximate incidence at various locations of the appendix.
Figure 31.6 | A. N-oncoanatomy. The sentinel node can be in the mesoappendix or at the ileocecal level, and regional nodes are ileocolic. B. M-oncoanatomy. Appendiceal vein into the ileocolic vein into the superior mesenteric vein, then the portal vein; therefore liver is the target organ for metastases.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
Clinical Staging and Imaging
CT is essential to identify extrabowel invasion, ascites and liver metastases (Fig. 31.7, Table 31.4).
ONCOIMAGING ANNOTATIONS
Adenocarcinoma
• Search for extensions and metastatic disease once the diagnosis is made.
• Staging is based on surgical pathologic criteria, and lymph-adenectomy should take account of 12 or more nodes.
• Presence of peritoneal implants and ascites is considered M1a.
• Satellite peritumoral nodule or tumor deposit in periappendiceal adipose tissue without histologic evidence of residual lymph node may be discontinuous spread (T3), venous invasion with extravascular spread (T3 V1/2), or replaced lymph node (N1/2).
Carcinoids
• 5HIAA elevation or carcinoid syndrome triggers staging workup.
• Computed tomography (CT) scans are abnormal 78% when HIAA is elevated.
• Magnetic resonance imaging (MRI) scans are similar to CTs and detect metastases.
• Positron emission tomography scans may not be useful since carcinoids are slow growing.
• Single photon emission computed tomography using111 In-labeled pentetreotide is positive 80% to 90% and more accurate than CT or MRI in identifying primary, tumor deposits, and metastases.
• Radiolabeled somatostatin is effective in localizing occult tumors >1 cm in size, clarifying equivocal CT/MR findings, and predicting response to treatment.
• Gastrointestinal contrast enteroclysis can detect intraluminal primaries.
• CT can detect primary tumor and mesenteric lymph nodes with a desmoplastic “spokewheel” pattern (Fig. 31.7).
PROGNOSIS AND CANCER SURVIVAL
PROGNOSTIC FACTORS
The limited number of prognostic factors are listed in Table 31.5. Clinically significant prognostic factors are identified for collection in cancer registries including pretreatment CEA and CA 19.9, the number of tumor deposits in the mesentery, and where available, the presence of microsatellite instability and 18q loss of heterozygosity size of primary is important for carcinoids.
Figure 31.7 | Portal venous phase. 1. Sigmoid colon. 2. Cecum. 3. Vermiform appendix. 4. Gluteus medius. 5. Gluteus maximus. 6. Internal iliac art and vein.
Prognostic Factors TABLE 31.5
Figure 31.8 | Five-year survival for carcinoma of the appendix. (Data from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th ed. New York, Springer, 2010, p. 135).