Appendiceal tumors encompass a rare and diverse group of neoplasms. With an age-adjusted incidence of about 0.12 cases per 1 million individuals per year, appendiceal tumors represent only 1% of all CRCs diagnosed each year in the United States (56,57). Historically, appendiceal tumors have been grouped together with CRCs. However, appendiceal tumors, in which outcomes are strongly determined by histologic subtype, tend to have a biology very different from that of CRC. Appendiceal tumors comprise two types: appendiceal carcinoid tumors and appendiceal epithelial tumors. Appendiceal carcinoid tumors account for approximately 50% of all appendiceal neoplasms, and appendiceal epithelial tumors represent the remaining 50% (58). This chapter on appendiceal tumors discusses the management of these two tumor types (carcinoid and epithelial) and, in particular, the unusual clinical syndrome of pseudomyxoma peritonei (PMP).
Data derived from the SEER database of the National Cancer Institute between 1973 and 1998 revealed that the most common histologic subtypes of malignant tumors of the appendix were adenocarcinomas (67%) and carcinoids (33%) (56). However, this analysis captured neither adenomatous tumors nor benign carcinoids. The subtypes of adenocarcinoma were mucinous type (56%), nonmucinous intestinal type (38%), and signet ring cell type (6%). Alternatively, in a separate study of 7,970 appendectomy specimens, tumors were identified in 1% of specimens, with carcinoids representing 57% of all tumors identified (58). Adenomas and adenocarcinomas represented 18% and 11% of the identified tumors, respectively.
Presentation and Prognosis
The majority of appendiceal tumors are identified incidentally at the time of pathological review of appendectomy specimens. Symptoms of appendicitis are most often the presenting symptom, especially with tumors located at the base of the appendix, where obstruction is more likely to occur. Other symptoms seen with more advanced appendiceal disease can reflect the nonspecific abdominal symptoms associated with peritoneal involvement: abdominal pain and distention, altered bowel motility, and early satiety. Metastatic carcinoid tumors may also present with symptoms related to the carcinoid syndrome, with episodic flushing, wheezing, and diarrhea. Patient age at presentation differs depending on histologic subtype of the tumor, with the mean age of 38 years for patients with carcinoid tumors and the mean age of 60 years for those with adenocarcinomas (56).
Prognosis for appendiceal cancer is strongly dependent on the histopathologic subtype of the tumor, with patients who have carcinoids having a significantly better survival than do patients with adenocarcinomas (Fig. 23-3) (56). In addition, patients with early-stage tumors identified incidentally at the time of appendectomy have a better prognosis than patients who are diagnosed once symptoms develop.
Overall survival of malignant appendiceal cancers according to the Surveillance, Epidemiology and End Results registry (SEER), stratified by histological subtype. (Reproduced with permission from McCusker ME, Coté TR, Clegg LX, et al. Primary malignant neoplasms of the appendix. Cancer. 2002;94:3307-3312.)
Prognosis for patients with epithelial tumors is also strongly dependent on histopathology of the tumor. Staging for appendiceal carcinomas is based on the TNM) seventh edition staging system and incorporates histological grade in the differentiation between stage IVA and IVB (Table 23-5) (33).
Table 23-5TNM Staging for Appendiceal Carcinomas ||Download (.pdf) Table 23-5 TNM Staging for Appendiceal Carcinomas
|Primary Tumor (T) |
|TX ||Primary tumor cannot be assessed |
|T0 ||No evidence of primary tumor |
|Tis ||Carcinoma in situ |
|T1 ||Tumor invades submucosa |
|T2 ||Tumor invades muscularis propria |
|T3 ||Tumor invades through muscularis propria into subserosa or into mesoappendix |
|T4 ||Tumor penetrates visceral peritoneum, including mucinous peritoneal tumor within the right lower quadrant and/or directly invades other organs or structures |
|T4a ||Tumor penetrates visceral peritoneum, including mucinous peritoneal tumor within the right lower quadrant |
|T4b ||Tumor directly invades other organs or structures |
|Regional Lymph Nodes (N) |
|NX ||Regional lymph nodes cannot be assessed |
|N0 ||No regional lymph node metastasis |
|N1 ||Metastasis in 1-3 regional lymph nodes |
|N2 ||Metastasis in 4 or more regional lymph nodes |
|Distant Metastasis (M) |
|M0 ||No distant metastasis |
|M1 ||Distant metastasis |
|M1a ||Intraperitoneal metastasis beyond the right lower quadrant, including pseudomyxoma peritonei |
|M1b ||Nonperitoneal metastasis |
|Histologic Grade (G) |
|GX ||Grade cannot be assessed |
|G1 ||Well differentiated ||Mucinous low grade |
|G2 ||Moderately differentiated ||Mucinous high grade |
|G3 ||Poorly differentiated ||Mucinous high grade |
|G4 ||Undifferentiated |
|Stage Grouping |
|Stage 0 ||Tis ||N0 ||M0 || |
|Stage I ||T1 ||N0 ||M0 || |
| ||T2 ||N0 ||M0 || |
|Stage IIA ||T3 ||N0 ||M0 || |
|Stage IIB ||T4a ||N0 ||M0 || |
|Stage IIC ||T4b ||N0 ||M0 || |
|Stage IIIA ||T1 ||N1 ||M0 || |
| ||T2 ||N1 ||M0 || |
|Stage IIIB ||T3 ||N1 ||M0 || |
| ||T4 ||N1 ||M0 || |
|Stage IIIC ||Any T ||N2 ||M0 || |
|Stage IVA ||Any T ||N0 ||M1a ||G1 |
|Stage IVB ||Any T ||N0 ||M1a ||G2, 3 |
| ||Any T ||N1 ||M1a ||Any G |
| ||Any T ||N2 ||M1a ||Any G |
|Stage IVC ||Any T ||Any N ||M1b ||Any G |
For metastatic epithelial tumors of the appendix, prognosis is excellent for those with low-grade mucinous tumors, termed disseminated peritoneal adenomucinosis (DPAM), whereas appendiceal adenocarcinomas with high-grade histological features such as poor differentiation or signet ring cell morphology have a much poorer survival. Presence of lymph node metastases is a predictor of recurrence in early-stage tumors (59). Stage IV mucinous appendiceal adenocarcinomas are categorized as either mucinous low grade (well differentiated) or mucinous high grade (moderate and poor differentiation) by the American Joint Committee on Cancer (AJCC) seventh edition. However, recent population-based efforts utilizing the SEER database have demonstrated that mucinous moderate-differentiated adenocarcinomas appear to have a prognosis more akin to mucinous well-differentiated carcinomas as opposed to mucinous poorly differentiated carcinomas (59).
Appendiceal Carcinoid Tumors
Similar to other intestinal carcinoid tumors, appendiceal carcinoid tumors arise from neuroendocrine cells within the lamina propria and submucosa. Appendiceal carcinoid tumors can secrete serotonin and vasoactive substances responsible for the carcinoid syndrome, although this is rarely seen in patients in the absence of extensive liver metastases. Appendiceal carcinoid tumors are usually seen in young patients and are seen slightly more often in women (60,61).
A rare histological variant of carcinoid tumors, termed goblet cell carcinoids or adenocarcinoids, is characterized by malignant cells that demonstrate both exocrine and neuroendocrine characteristics. This histological subtype has outcomes in between that of a carcinoid and that of an adenocarcinoma (see Fig. 23-3).
Management of Appendiceal Carcinoids
As most appendiceal carcinoid tumors are discovered incidentally from an appendectomy specimen, a critical and somewhat-controversial oncologic question relates to the need for performing a more complete surgical staging procedure. For appendiceal cancers, a complete surgical staging procedure would entail a right hemicolectomy with complete removal of the base of the appendix, mesoappendix, and draining lymph nodes.
The most useful criteria for determining the need for a complete right hemicolectomy are tumor size (≥2 cm in diameter) or mesoappendix involvement (62). In a retrospective study of appendiceal carcinoids, Moertel et al reported no metastases in 127 patients with tumors <2 cm, whereas metastatic disease was seen in 3 of the 14 patients with tumors 2 to 3 cm and 4 of the 9 patients with tumors ≥3 cm (63). Patients with an adenocarcinoid histological variant are generally treated as having an appendiceal adenocarcinoma.
For patients with metastatic disease, the use of somatostatin analogues can alleviate the symptoms of the carcinoid syndrome but rarely causes objective tumor regression. Given the slow-growing nature of appendiceal carcinoid tumors, local modality therapies such as hepatic embolization or surgical resection may also be beneficial in selected patients with metastatic disease. For additional information on management of this type of tumor, please refer to Chapter 23.
Appendiceal Epithelial Tumors
Little is known about the risk factors or etiology of epithelial tumors of the appendix. Although generally viewed as a subset of CRC, most epithelial tumors of the appendix have a markedly different biology and natural history than do adenocarcinomas of the colorectum. In particular, a subset of appendiceal epithelial tumors that have disseminated peritoneal mucinous deposits derived from a ruptured appendiceal mucinous adenoma can demonstrate excellent long-term survival with aggressive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) (64,65).
Most appendiceal epithelial tumors begin as a mucinous adenoma with appendiceal distention caused by excessive mucin production. On gross inspection or radiographic evaluation, this dilated mucin-filled appendix is frequently referred to as a mucocele. With progressive growth, the appendiceal lumen can become obstructed and result in increased intraluminal pressure within the appendix, which can cause the appendix to rupture. Appendiceal rupture represents the critical step in the dissemination of the mucinous appendiceal tumor to the peritoneal cavity. For this reason, it is critical that care is taken when surgically removing an appendiceal mucocele to prevent rupture and peritoneal seeding during a routine appendectomy (66). When resecting an appendiceal mucocele, the peritoneum should be inspected closely to evaluate any evidence of dissemination to the peritoneal cavity. During pathological examination of the appendix, any fluid or mucus in the peritoneal spaces surrounding the appendix should undergo cytologic examination (62). In patients with localized disease, the presence of carcinoma requires a completion right hemicolectomy for oncologic staging.
The molecular characterization of appendiceal adenocarcinomas is limited. Mutations are frequently seen in these tumors and include KRAS, GNAS, AKT, MET, PIK3CA, and TP53 genes (67,68,69,70). In a cohort of 149 patients with appendiceal adenocarcinomas at MD Anderson Cancer Center, KRAS, PIK3CA, and BRAF mutations were seen in 55%, 17%, and 4% of patients, respectively (71). The study also demonstrated that well- and moderately differentiated appendiceal adenocarcinomas were molecularly distinct from poorly differentiated appendiceal adenocarcinomas (71).
Pseudomyxoma peritonei, or false mucinous tumor, is a term originally described by Werth in 1884, who described the pathological findings in a patient with a ruptured ovarian cystadenoma who had copious gelatinous intraperitoneal ascites (Fig. 23-4) (72). This term has been applied broadly to include any mucinous tumor type involving the peritoneal cavity with any histologic grade of differentiation. However, this imprecise definition has resulted in the grouping of patients with dramatically different outcomes and has generated considerable confusion for patients and even among clinicians. A better understanding of disease biology has shown that this clinical term is most appropriately applied to the pathological subtype of appendiceal tumors called disseminated peritoneal adenomucinosis (73).
Peritoneal mucin in a patient undergoing surgical cytoreduction for peritoneal mucinous carcinomatosis (PMCA). (Reproduced with permission from Ronnett BM, Zahn CM, Kurman RJ, et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei.” Am J Surg Pathol. 1995;19:1390-408.)
However, the term PMP is frequently utilized to refer to the clinical syndrome of mucinous peritoneal deposits resulting from any mucinous appendiceal tumor. When used in this fashion, this term encompasses both DPAM and the appendiceal epithelial tumor subtype termed peritoneal mucinous carcinomatosis (PMCA). However, the inclusion of these two histological subtypes combines two appendiceal epithelial tumor types with markedly different OSs (Table 23-6) (73,74).
Table 23-6Overall Survival for Appendiceal Epithelial Tumors Stratified by Histology Subtype of Disseminated Peritoneal Adenomucinosis (DPAM) or Peritoneal Mucinous Carcinomatosis (PMCA) ||Download (.pdf) Table 23-6 Overall Survival for Appendiceal Epithelial Tumors Stratified by Histology Subtype of Disseminated Peritoneal Adenomucinosis (DPAM) or Peritoneal Mucinous Carcinomatosis (PMCA)
|Author ||Year ||Study ||DPAM ||PMCA |
|No. of Pts. ||5-Year OS ||10-Year OS ||No. of Pts. ||5-Year OS ||10-Year OS |
|Miner ||2005 ||Retrospective, MSKCC ||42 ||85% ||70% ||46 ||40% ||12% |
|Sugarbaker ||1999 ||Retrospective, Washington Cancer Institute ||224 ||80% || ||161 ||28% || |
|Stewart ||2006 ||Retrospective, Wake Forest University ||55 ||68% || ||29 ||35% || |
|Ronnett ||2001 ||Retrospective, Washington Cancer Institute ||65 ||75% ||68% ||43 ||26% ||9% |
|Smeenka ||2007 ||Retrospective, Netherlands Cancer Institute ||66 ||73%a || ||7 ||0%a || |
Histopathologic Subtypes of Epithelial Appendiceal Tumors
Disseminated Peritoneal Adenomucinosis
Disseminated peritoneal adenomucinosis is characterized by peritoneal lesions composed of abundant extracellular, mucin-containing, scant, simple to focally proliferative mucinous epithelium with little cytologic atypia or mitotic activity, with or without an associated appendiceal mucinous adenoma (73). In essence, the underlying epithelium in DPAM may have low-grade adenomatous changes but may not have any evidence of invasion or carcinoma. This subgroup of tumors (DPAMs) demonstrates the classic PMP clinical syndrome of massive amounts of benign-appearing mucinous ascites that over time slowly fill the entire peritoneal cavity (Fig. 23-5). Although spread to the peritoneal cavity is present, these tumors do not metastasize to regional lymph nodes or via hematogenous spread to the liver or other distant sites.
Histology from a patient with disseminated peritoneal adenomucinosis (DPAM) and the clinical syndrome of pseudomyxoma peritonei (PMP): (A) adenoma-like epithelium with acellular mucin pools dissecting through the fibrous stroma with chronic inflammation, ×40; (B) adenoma-like epithelium with abundant acellular mucin, ×400.
Patients with DPAM typically present with gradually increasing abdominal girth. For women, DPAM may present as a new ovarian mass, and for men it may present as a new-onset hernia. In women, secondary involvement of the ovaries is common, and because histopathological features of DPAM from a primary ovarian tumor are extremely rare, a thorough pathological examination of the appendix should be conducted (75). When molecular and immunohistochemical evaluations have been performed on cases with both appendix and ovarian involvement, these evaluations have uniformly demonstrated the primary site of disease as the appendix (76,77,78).
Peritoneal Mucinous Carcinomatosis
If evidence of invasion and carcinoma is present, then the pathological diagnosis of PMCA should be used (73). Peritoneal mucinous carcinomatosis is characterized by peritoneal lesions composed of more abundant mucinous epithelium with the architectural and cytologic features of carcinoma, with or without an associated primary mucinous adenocarcinoma. A subset of PMCA tumors that demonstrate features of both DPAM and PMCA have been termed PMCA with intermediate or discordant features (PMCA-I/D) (73). In an analysis of 109 patients with clinical features of PMP, 60% were classified as DPAM, 27% were classified as PMCA, and 13% were classified as PMCA-I/D (73,79). In this study, the 5- and 10-year survival rates for patients with DPAM were 75% and 68%, respectively. This was significantly higher than patients with PMCA, who demonstrated 5- and 10-year survival rates of 14% and 3%. Those patients with PMCA-I/D had survival more closely associated with that of PMCA patients (Fig. 23-6).
Overall survival for 109 cases with the clinical syndrome of pseudomyxoma peritonei (PMP) according to histological subtype.
Although appendiceal PMCAs are invasive tumors with distant metastatic potential, the majority of these tumors will remain localized to the peritoneal cavity. Even in the subset of patients with very aggressive-appearing histologies, the rate of distant hematogenous metastases remains low. In one retrospective study of 90 appendiceal adenocarcinomas with either poor differentiation or signet ring cell morphology, the rate of extraperitoneal metastases was only 17% (80).
Occurring less frequently, nonmucinous or colonic-type adenocarcinomas of the appendix demonstrate a different tumor biology than mucinous appendiceal tumors. These cancers are more aggressive and appear to behave more like colonic adenocarcinomas. In a study by Kabbani et al, 43% of patients with nonmucinous apendiceal adenocarcinoma had evidence of extraperitoneal metastases (81). The patients with nonmucinous carcinomas in this study had a significantly worse OS and disease-free survival than those with mucinous carcinomas.
Because of the relative rarity of this disease, prospective randomized clinical trials studying the treatment of appendiceal epithelial tumors are lacking. The majority of data evaluating the various treatment modalities in this disease have been derived from retrospective, single-institution studies. Surgical cytoreduction has been the primary mode of therapy for these tumors based on the following factors:
Lack of extraperitoneal disease spread
Primarily mucinous nature of peritoneal deposits
Indolent growth rate
Limited activity of systemic chemotherapy
Lack of an effective systemic mucolytic agent
The goal of surgical cytoreduction is complete tumor removal from the peritoneal cavity. Because of the large surface area of the peritoneum, surgical cytoreduction to remove all visible sites of disease can be challenging. Optimal CRS may involve removal of the appendix, right colon, intraperitoneal tumor debulking, resection of multiple abdominal and pelvic organs with peritoneal tumor studding, and stripping of all involved parietal peritoneum (82). Following successful surgical cytoreduction, patients with the DPAM or PMCA tumors can experience reaccumulation of mucinous peritoneal implants, which may be complicated by fibrosis from prior surgery, requiring repeated surgical cytoreductive procedures.
In a 97-patient series from Memorial Sloan Kettering Cancer Center, in which surgical resection alone represented the primary treatment modality in over two-thirds of the patients, the 5-year OS rate was 90% for patients with DPAM and 50% for patients with PMCA (64). In the 55% of patients who underwent a complete cytoreduction of all visible tumors, 91% had recurrent disease. The average number of surgical cytoreductions that patients underwent in this study was 2.2, with a range of 1 to 6 (64). In patients who develop recurrence after CRS, repeat CRS should be attempted because survival in these patients is prolonged with repeat CRS (83).
Hyperthermic Intraperitoneal Chemotherapy
In an attempt to diminish the rate of disease recurrence following CRS, the administration of intraperitoneal chemotherapy following a surgical cytoreduction has been used to try to treat any residual microscopic disease in the peritoneal cavity. Historically, a number of methods of delivering intraperitoneal chemotherapy have been utilized, although the most commonly utilized method is HIPEC administered at the time of cytoreduction.
At MD Anderson, following complete CRS, administration of heated mitomycin C at a dose of 25 mg/m2 for patients who are chemonaïve or 20 mg/m2 for patients who have received previous chemotherapy in a volume of 5 to 6.5 L of electrolyte solution at a flow rate of 3 to 3.5 L/min. Intraoperative hemodynamic monitoring and thermal monitoring are essential for optimal outcomes in these patients. The HIPEC is continued for 90 minutes with vigorous shaking of the closed abdomen. On completion of HIPEC, necessary bowel anastomoses are performed, and gastrostomy and jejunostomy tubes are placed for postoperative management of nutritional deficiencies and prolonged gastric ileus.
Intraperitoneal administration of chemotherapy offers an advantage of providing high concentrations of drug directly to the target, while hyperthermia provides a synergistic antitumor effect when combined with chemotherapy (84). However, as a locally applied modality, the maximum penetration into tumor tissue is usually limited to 2 to 5 mm from the surface (85). At present, no randomized study has compared the benefit of adding HIPEC to surgical cytoreduction, although single-institution series have indirectly suggested a benefit when disease-free survival rates of patients treated with surgical cytoreduction and HIPEC (37%-57%) (74,76) are compared with the historical rates of surgical cytoreduction alone (9%-12%) (64,77).
Cytoreductive surgery with HIPEC represents an aggressive treatment requiring significant surgical expertise and should only be conducted at centers experienced in performing peritoneal cytoreduction. Operation time is approximately 8 to 12 h, with an average hospital stay of 20 to 25 days. The 30-day postoperative mortality and morbidity range from 0% to 12% and 12% to 56%, respectively (76,78).
In one of the largest retrospective multi-institutional registry-based study of 2,298 patients with PMP originating from an appendiceal mucinous neoplasm undergoing CRS, the reported median OS was 16.3 years, with a 10-year survival rate of 63% (86). The treatment-related mortality was 2%, and major operative complications occurred in 24% of cases (86). A high PCI, lack of complete cytoreduction, and lack of HIPEC were associated with poorer PFS and OS (86).
Prognosis for patients undergoing CRS with HIPEC is primarily dependent on two critical factors: histologic classification and completeness of surgical resection. A quantitative score, the completeness of cytoreduction score proposed by Sugarbaker and colleagues, categorizes the completeness of cytoreduction (CC) based on the size of nodules remaining at the end of surgery: CC-0 (no visible disease), CC-1 (nodules <0.25 cm), CC-2 (nodules 0.25 to <2.5 cm), and CC-3 (nodules ≥2.5 cm) (65). In an analysis of 224 patients with DPAM histology, Sugarbaker et al found that patients with complete cytoreduction (CC-0 or CC-1) had a 5-year OS rate of 86%, whereas patients with incomplete cytoreduction (CC-2 or CC-3) had a 5-year OS rate of 20% (P < .0001) (Fig. 23-7) (65). The importance of completeness of cytoreduction has been confirmed by other authors, although various methods of categorizing a complete cytoreduction have been used (74,76).
Overall survival for 385 cases with the mucinous epithelial tumors of the appendix (disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis) according to completeness of surgical cytoreduction. Complete cytoreduction defined as a completeness of cytoreduction score (CC) of CC-0 or CC-1, and an incomplete cytoreduction defined as a score of CC-2 or CC-3. [Reproduced with permission from Sugarbaker PH. Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Ann Surg Oncol. 1999;6(8).]
Additional prognostic measures include the peritoneal cancer index (PCI), a quantitative measure of the size and distribution of nodules on the peritoneal surface; the previous surgical score (PSS), a measure of the extent of prior cytoreduction; and the extent of disease on the small bowel and small bowel mesentery (64,65,87,88). The prognostic value of these different factors relates primarily to their ability to predict the likelihood of obtaining a complete cytoreduction.
For patients who cannot undergo complete CRS, the benefit obtained from an incomplete cytoreduction remains unknown. If complete CRS cannot be performed, a surgical cytoreduction is generally considered only if there are particular symptoms that can be palliated by tumor debulking. Given that HIPEC has limited tumor penetration, use of HIPEC should be limited to patients with a complete or near-complete CRS.
The role of systemic chemotherapy has not been well delineated in appendiceal epithelial tumors and has generally been utilized in patients who are not candidates for surgical cytoreduction (82). The challenges of using systemic chemotherapy to treat appendiceal tumors relate to the slow-growing nature of the disease, the primarily mucinous component of the tumors, and the challenges in radiographically measuring disease response.
Traditionally, PMP has been considered resistant to systemic chemotherapy, although a recently completed phase II study evaluating the use of concurrent mitomycin C and capecitabine in patients with advanced, unresectable DPAM or PMCA has suggested a role for systemic chemotherapy (89). In this study of 39 patients, a clinical benefit rate of 38% was determined based on the definition of either semiquantitative reductions in mucinous deposition or stabilization of previously progressive disease (89). In this study, the 2-year cancer-related mortality rate was 39%. Elevations in tumor markers (CEA, CA 19-9, or CA-125) occurred in all patients, and a 50% reduction in one of these markers occurred in 51% of patients (89). Although limited by the small sample size, tumor marker response did not appear to correlate with radiographically assessed clinical benefit rate (89).
Commentary: Surgical Perspectives in Appendiceal Carcinoma
Once the diagnosis of appendiceal carcinoma has been established, a thorough evaluation must be performed, including CT imaging, colonoscopy, laboratory studies, and a complete medical history to determine the potential resectability of the tumor and the appropriateness and fitness of the patient for aggressive treatment.
In our experience, patients over the age of 70 must be approached with caution because the potential risks of CRS and HIPEC may be greater than the potential benefits. A number of studies have also identified an Eastern Cooperative Oncology Group (ECOG) status of <2 as essential for patients to tolerate CRS/HIPEC. Similarly, because of the sensitivity of the liver to hyperthermia, patients with evidence of cirrhosis are not offered HIPEC. Likewise, patients with renal insufficiency may prove difficult to manage postoperatively because of significant fluid shifts associated with surgery and HIPEC. Previous surgical procedures and obesity offer the same challenges as in other complex operations but are not contraindications to surgery.
To determine the extent of the tumor and potential for complete cytoreduction, CT scans of the chest, abdomen, and pelvis appear to be the most useful. We do not use MRI or positron emission tomographic scanning routinely as these offer little advantage over CT alone. Imaging findings suggestive of an inability to completely cytoreduce the tumor include a large volume of disease involving the porta hepatis and the retrohepatic vena cava, large volume of tumor involving the small bowel mesentery with a gathering together of this mesentery termed cauliflowering, obstruction of more than one segment of small bowel, and evidence for retroperitoneal organ involvement. In these patients, consideration for systemic chemotherapy should be given with surgery limited to palliation of symptoms.
At MD Anderson, we often see patients who have been evaluated and treated at outside institutions. Many patients have undergone an incomplete cytoreduction or combinations of therapy that we would not consider standard. The approach to these patients begins with an evaluation of the pathology, review of all operative notes to assess the amount of disease present at the time of surgery, and extent of disease left behind at the completion of surgery. Repeat imaging is obtained as necessary. On completion of the workup, an individualized plan is developed. If the patient had what was described as a complete cytoreduction, and CT imaging demonstrates no evidence of disease, repeat imaging is performed at 6-month intervals and consideration is given to diagnostic laparoscopy at the 1-year anniversary of the original surgery. If there is disease identified during these steps, CRS/HIPEC is offered if the patient meets the selection criteria previously outlined.
In patients who have clearly had an incomplete cytoreduction or have evidence of disease on baseline imaging, if the pathology is low- or moderate-grade appendiceal adenocarcinoma, we offer CRS/HIPEC. In the setting of high-grade/signet ring cell appendiceal adenocarcinoma, we typically have the patient evaluated for systemic chemotherapy. If after completing systemic chemotherapy there is stability of disease and the disease is potentially resectable based on imaging studies, we may offer CRS/HIPEC in selected cases.
Keith F. Fournier
In an additional study supporting the role of systemic chemotherapy in patients with PMCA, Shapiro et al retrospectively reviewed data collected from 54 patients who were suboptimal surgical cytoreductive candidates (82). Systemic chemotherapy in this report consisted of a fluoropyrimidine with or without a platinum agent in 69% of patients. Radiographic stabilization or response to therapy was noted in 55% of patients, median PFS was 7.6 months, and median OS was 56 months (82). In this study, poorly differentiated histology and signet ring histology were both negative prognostic indicators for OS. Systemic chemotherapy may play a role in the management of poorly differentiated and signet ring cell adenocarcinomas of the appendix. In a retrospective review of 142 patients with these tumors, systemic chemotherapy resulted in a response rate of 44%, a median PFS of 6.9 months, and a median OS of 1.7 years (90). Patients with response to chemotherapy and complete CRS were associated with improved PFS and OS (90). Although data regarding role of targeted therapy is limited in appendix cancers, retrospective data suggest that combining bevacizumab with chemotherapy may improve survival outcomes in surgically unresectable appendiceal epithelial neoplasms (71,91).
The studies discussed in this section suggest a role for chemotherapy in patients who are suboptimal candidates for CRS, but further prospective randomized clinical trials will be needed before any definitive statement regarding the exact benefit and timing of chemotherapy use can be made.
The MD Anderson Approach to Epithelial Appendiceal Tumors
Unlike CRC, appendiceal epithelial malignancies have a more indolent natural history that is determined by their underlying histopathology. At MD Anderson, patients with DPAM and well-to-moderately differentiated PMCA tumors are evaluated initially for CRS. Patients with a complete cytoreduction (CC-0 or CC-1) are treated with HIPEC utilizing intraperitoneal mitomycin at 42°C. If a complete CRS is not obtained, if radiographic imaging indicates that obtaining a complete cytoreduction is highly unlikely, or if medical comorbidities preclude a surgical procedure, then patients are considered for systemic chemotherapy. Also, HIPEC is utilized at MD Anderson for the control of refractory ascites. We have found that the use of HIPEC in patients who have undergone an incomplete CRS can provide long-term control of ascites and should be considered in patients with refractory ascites.
Given the indolent nature of well-to-moderately differentiated PMCA tumors, systemic chemotherapy is generally reserved for patients who either have clear evidence of disease progression on radiographic imaging or have significant tumor-related symptoms. Frontline chemotherapy is fluoropyrimidine based, and additional agents may be added based on the perceived tolerance of more aggressive combinations. Given the general good prognosis of these patients, it is critical that treatment is closely aligned with quality of life and that cumulative toxicities are kept to a minimum.
The use of multiagent systemic chemotherapy, as administered in CRC, is the treatment of choice for patients who have signet ring cells, poorly differentiated tumors, or nonmucinous tumors. Because patients with poorly differentiated or signet ring cell appendiceal adenocarcinomas have consistently shown worse outcomes following aggressive CRS, our approach has been only to consider surgical cytoreduction in these patients following initial treatment with systemic chemotherapy. In a recent retrospective study from MD Anderson, Lieu et al showed that patients with stage IV poorly differentiated or signet ring cell morphology appendiceal adenocarcinomas had a median OS of 24 months, which appears similar to the known OS for metastatic CRC (80).
Although trials evaluating the benefit of VEGF inhibitors or EGFR inhibitors in appendiceal epithelial tumors are lacking, their effectiveness in CRC suggests a possible role for these agents in appendiceal epithelial tumors. Expression of VEGF has been demonstrated in appendiceal adenocarcinomas, and high levels of expression have been correlated with poor outcome (92). Although not well studied, it appears that mutations in the K-ras oncogene are common, with 22 of 31 tested samples demonstrating an activating mutation in K-ras (93).
Due to the rarity of appendiceal tumors, our understanding of these tumors is limited, and further research into the molecular characteristics of these tumors is needed. The role of CRS is well established for appendiceal epithelial tumors. The use of systemic chemotherapy in appendiceal epithelial tumors needs further study; in particular, the role of newer targeted therapies needs to be determined.