GMKA
Support

Management of Appendiceal Adenocarcinoma

Oncology
Surgery

Authors

Expert image
Karri Hester, MD, MS
Author
Expert image
Garrett M. Nash, MD, MPH, FACS
Author
Read in Ukrainian

Introduction

Primary appendiceal malignancy is a rare diagnosis. It makes up approximately 0.8-1.4% of appendectomy specimens, and its incidence continues to hover around 0.12/1,000,000 person-years [1]. Despite their rarity, the burden of appendiceal tumors lies in their aggressive nature, with at least 74% of appendiceal cancer cases having spread at their initial diagnosis, 39% having developed regional metastases and 35% having developed distant metastases [1].
Although treatment in the early stages of the disease may be definitive, there continues to be significant difficulty in the management and treatment once metastatic disease has occurred.

Anatomic Pathology, Histology and Staging

The classification of primary appendiceal malignancy continues to be debated and to be the source of significant confusion. In 2016, the Peritoneal Surface Oncology Group presented recommendations for nomenclature and terminology for non-carcinoid epithelial appendiceal tumors [2].
The recommendations described eight categories: adenoma, serrated polyp, low-grade appendiceal mucinous neoplasm (LAMN), high-grade appendiceal mucinous neoplasm, mucinous adenocarcinoma (well/moderately/poorly differentiated), poorly differentiated (mucinous) adenocarcinoma with signet ring cells, (mucinous) signet ring cell carcinoma, and adenocarcinoma (well/moderately/poorly differentiated) (Table 1)[2].
Table 1. Staging of adenocarcinomaa  
StageTNMGrade
0Tis, Tis (LAMN)00Any
     
IT1
T2		0
0		0
0		Any
     
IIAT300Any
IIBT4a00Any
IICT4b00Any
IIIAT1
T2		N1
N1		0
0		Any
     
IIIBT3
T4		N1
N1		0
0		Any
     
IIICAny TN20Any
     
IVAAny T
Any T		Any N
Any N		M1a
M1b		Any
G1
     
IVBAny TAny NM1bG2, G3, or GX
     
IVCAny TAny NM1cAny G
aAdapted from AJCC Cancer Staging Manual, 9th ed. [5].
In 2017, the American Joint Committee on Cancer classified appendiceal carcinoma using 14 categories: [3]
  1. adenocarcinoma,
  2. mucinous adenocarcinoma,
  3. LAMN,
  4. high-grade appendiceal mucinous neoplasm,
  5. signet ring cell carcinoma,
  6. goblet cell carcinoma,
  7. mixed goblet cell adenocarcinoma,
  8. large cell neuroendocrine carcinoma,
  9. small cell neuroendocrine carcinoma,
  10. neuroendocrine carcinoma (poorly differentiated),
  11. mixed adenoneuroendocrine carcinoma,
  12. medullary carcinoma,
  13. adenosquamous carcinoma,
  14. undifferentiated carcinoma.
In this system, a new category, Tis, was added to TNM staging of LAMN [4]. Despite the evolving classification for primary tumors of the appendix, a simplified classification can be utilized to distinguish clinically relevant subtypes: epithelial, non-epithelial and mixed [1].
Epithelial type can then further be subdivided into mucinous, non-mucinous and signet cell. Non-epithelial tumors include the various neuroendocrine carcinomas previously mentioned but also lymphoma, leiomyoma and leiomyosarcoma [1]. The mixed type is referred to as goblet cell adenocarcinoma, formerly known as goblet cell carcinoid; however, it is not clinically distinguishable from poorly differentiated adenocarcinoma.
LAMNs are epithelial type lesions that typically comprise 0.2-0.3% of appendectomy specimens. They were initially classified as a benign disease process [6].
A distinction has been made between LAMN and other benign cyst pathologies so that LAMNs are now categorized as low-grade carcinoma [3]. It is generally believed that many LAMNs develop into mucinous appendiceal adenocarcinoma [6], typically of the well-differentiated phenotype, but moderately and poorly differentiated subtypes have been noted to co-exist with precursor LAMN. However, this appears to happen at a very low rate: approximately 5% of T3/4 LAMNs will ultimately recur as adenocarcinoma in the peritoneum (Fig. 1) [7].
Fig. 1. Low-grade mucinous adenocarcinoma of the appendix with peritoneal metastasis.
Mucinous adenocarcinoma can also arise from sessile serrated or tubulovillous adenoma (similar to colorectal or “intestinal type” adenocarcinoma), but this appears to be less common [6]. Additionally, the protocol of the American Joint Committee on Cancer for mucinous adenocarcinoma uses a grading scale of well-differentiated, moderately differentiated and poorly differentiated, which is characterized by atypia and may include signet ring cells.
Low-grade mucinous adenocarcinoma, however, is not to be confused with the signet cell carcinoma type, which does not have abundant extracellular mucin [6]. This is the primary subtype of non-mucinous appendiceal carcinoma; its grading is separated into G1, G2, and G3, which corresponds to well-differentiated, moderately differentiated and poorly differentiated and is determined by the presence of gland formation, with less gland formation consistent with G3 and poorly differentiated disease [3].
Pseudomyxoma peritonei is a term that is broadly used to describe the clinical syndrome of large-volume mucinous spread of appendiceal carcinoma. This term has fallen out of favor in formal nomenclature, as it is not narrowly defined. Nevertheless, many centers continue to use this term in a variety of ways and in connection with the following histopathologic subcategories: peritoneal mucinous carcinomatosis with intermediate or discordant features , disseminated peritoneal adenomucinosis, mucinous carcinomatosis peritonei low-grade, and mucinous carcinomatosis peritonei high-grade/peritoneal mucinous carcinomatosis [8,9].
Goblet cell adenocarcinoma of the appendix was first described as goblet cell carcinoid in 1974 and was noted to be histologically distinct from both appendiceal carcinoma and classic carcinoid, which is now more accurately referred to as neuroendocrine tumor [10]; hence its designation as mixed. Its characteristic Paneth and argentaffin cells along with its acidic mucin distinguish it from the aforementioned lesions, and it was therefore placed in its own category [10]. It has been found to demonstrate both low-grade and high-grade histological features (Table 2).
Table 2. Grading schema for goblet cell adenocarcinoma [11]
One of the notable features of the low-grade type is diffuse infiltration of the appendiceal wall without considerable invasion [11]. High-grade histological features include frequent mitoses, nuclear atypia, invasion into the muscularis propria and lymphovascular invasion [11]. Unlike with mucinous and non-mucinous adenocarcinoma, the grading is based on the proportion of low-grade histological features compared to high-grade histological features [11].
Although grade has been associated with prognosis, management and clinical outcome appear to closely track stage, regardless of grade [11,12].

Clinical Presentation

Appendiceal carcinoma often presents as an incidental finding, at the time of imaging or surgery for another condition. It may occasionally be associated with symptoms of acute or subacute appendicitis, such as right-lower-quadrant pain, fever, chills, nausea, vomiting, and decreased appetite [1]. However, in its later stages, it may present with more generalized symptoms such as generalized abdominal pain and abdominal distension [1].

Diagnostic Workup

Imaging workup for appendiceal adenocarcinoma may include CT or MRI and selective use of PET/SPECT (single photon emission CT). Tumors of at least 15 mm may demonstrate soft-tissue enhancement or cystic dilation [1]. Partial or complete bowel, urinary, or biliary obstruction may be seen in symptomatic patients and typically signifies high-grade serosal and or mesenteric disease. Diffuse mucinous ascites may be observed with liver scalloping (Fig. 2), a hallmark of mass effect from the mucin, and women may have very large adnexal cystic masses [1]. In addition to identifying specific features, the peritoneal carcinomatosis index (PCI) is an important tool in determining both treatment strategy and prognosis [1].
There is a maximum score of 39 points from 9 different abdominal squares and 4 bowel segments; each area is scored on a scale from 0 to a maximum of 3 when the implants are >5 cm[1]. The PCI value can be utilized as an adjunct to evaluate the possibility of complete cytoreductive surgery (CRS) and durable peritoneal control [13]. PCI has also been noted to be associated with overall survival: a PCI of 1–20 is associated with significantly longer survival compared to a PCI of 21–39 [14].
Patients with mucinous appendiceal neoplasms with no invasive component (LAMN with disseminated peritoneal adenomucinosis) and a PCI of 1–20 have been found to have 94% overall survival at 20 years compared to 64% for patients with a PCI of 21-39 [14]. A similar trend of worsening prognosis with increasing PCI was also seen for appendiceal neoplasms with an invasive component (mucinous carcinoma) [14]. PET and SPECT may also be useful in evaluating rare patients with solid organ metastases to the liver or lung, but they are not effective in the assessment of the extent of peritoneal disease [1].
Fig. 2. Scalloping of the liver (left) and implants in Morrison’s pouch (right).
Elevated tumor markers such as carcinoembryonic antigen, CA 19-9, CA 125, and C-reactive protein are observed in appendiceal adenocarcinoma; however, they are nonspecific and not useful as a screening or negative predictive test [1]. The markers are prognostic for overall survival and progression-free survival, specifically in the setting of CRS and intraperitoneal chemotherapy [15]. However, their greatest value is in the setting of indeterminate findings on cross-section imaging during surveillance and as an indicator of response to therapy, when informative [16].
It is important to note that appendiceal carcinomas are not typically detected by colonoscopy but may occasionally be suspected in the setting of external compression resulting in partial obstruction [1]. Nevertheless, once an appendiceal carcinoma is identified, a colonoscopy is still helpful prior to definitive surgical intervention to exclude the possibility of a synchronous lesion [1].

Management

The treatment of early stage appendiceal carcinoma is surgical. An incidental finding of an abnormal appendix, suspicious for neoplasm, may be managed with simple appendectomy. The laparoscopic approach is appropriate for many patients, as it will allow for the assessment of occult peritoneal metastases, which are most commonly seen on the diaphragm, omentum, right-lower-quadrant peritoneum (including the ileal mesentery), and the pelvis (including the ovaries). Frozen section is unreliable, given the heterogeneity of these neoplasms; however, extensive sampling of the peritoneum is helpful.
Once the neoplasm is categorized, definitive surgery can be planned based on the primary and stage. In the absence of invasive cancer, LAMN can be managed by appendectomy alone. In the absence of metastatic disease, staging right colectomy for T3/4 will allow for identification of nodal metastasis, which is the most powerful predictor of relapse; perforation, T-stage, and other histopathology have not be shown to be prognostic [6]. Adjuvant FOLFOX (fluorouracil, leucovorin, oxaliplatin) is routinely used for stage III and selected stage II cancers, based on data extrapolated from colon cancer clinical trials.
The management of metastatic appendiceal carcinoma primarily consists of selective use of systemic chemotherapy and of CRS, often paired with intraperitoneal chemotherapy, which can further be subdivided into the most common methods of delivery: hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy.
CRS consists of performing a laparotomy from xiphoid to pubis, as needed, with the goal of removing all evidence of macroscopic tumor and achieving a complete gross resection (R1) [17]. If unable to achieve an R1 resection, an R2a resection would be attempted, which leaves limited residual tumor deposits <2.5 mm in thickness. An R2b resection would occur if there is any residual tumor >2.5 mm in thickness [17].
R2b has not been associated with better survival and should only be performed if it could palliate symptoms such as bowel obstruction. CRS is performed by a series of visceral resections and peritonectomy procedures as described by Sugarbaker [14]. Then, prior to scar tissue and adhesion formation, high-dose cytotoxicity chemotherapy is administered into the peritoneal space to hypothetically allow for the greatest “tumor cell contact” without significantly increasing systemic chemotoxicity [18].
HIPEC is performed through a laparotomy incision with a central opening through the laparotomy drapes and a perfusion circuit consisting of an inflow catheter, outflow catheter, temperature probes, a roller pump, and a heat exchanger [17]. Dialysate fluid is infused into the peritoneum, and once the temperature is above 41°C, the chemotherapeutic agent as determined by the oncologist is added to the solution. Numerous chemotherapeutic agents have been used for appendiceal cancer, including doxorubicin, mitomycin C, oxaliplatin, and fluorouracil [14].
Typically, a loading dose is given, followed by scheduled redosing. Careful attention is required to ensure that the core temperature does not exceed 39°C. Typically after about 90–120 minutes, the fluid is drained [17].
Early postoperative intraperitoneal chemotherapy is performed through a peritoneal catheter that is left in place at the time of CRS [9]. Treatment is typically started as soon as the same day or the day following surgery and consists of 3-day cycles with daily dosing. Patients may undergo up to 6 cycles, but a single cycle may be sufficient [9]. Regimens consisting of floxuridine (1000 mg/m2) and leucovorin (240 mg/m2) are the most common [9].
Systemic chemotherapy regimens have typically consisted of leucovorin, fluorouracil, oxaliplatin, irinotecan, and bevacizumab, in patients not undergoing surgery [9,17]. As is true for right-colon cancer, epidermal growth factor inhibitors have not been found to have efficacy for appendiceal adenocarcinoma, regardless of KRAS mutation status [19].
Over the past 40 years, the treatment of appendiceal adenocarcinoma has been characterized by widespread use of regional therapy, although no clinical trials with the primary goal of proving efficacy of this approach have been completed. In 1998­­–2001, Verwaal et al. performed a randomized clinical trial comparing best systemic therapy with or without palliative surgery versus CRS with HIPEC and best systemic therapy in patients with peritoneal carcinomatosis of colorectal cancer. Though this was a small trial with high morbidity, the experimental arm (CRS-HIPEC) was superior to the fluorouracil-leucovorin arm [17].
In the Swedish Trial, which was discontinued early for low enrollment, CRS and multiple cycles of catheter-based postoperative intraperitoneal chemotherapy with fluorouracil was associated with longer overall survival compared to FOLFOX alone [20], which further supported the regional approach for gastrointestinal malignancy. More recently, PRODIGE 7, a randomized controlled trial, examined whether the addition of HIPEC to CRS and best systemic therapy improved survival. Overall survival was indistinguishable between the two study arms, indicating no benefit with the addition of HIPEC to CRS; the data also showed that the addition of HIPEC was associated with higher morbidity [21].
However, retrospective data from Paul Sugarbaker demonstrated 10-year overall survival of 55% in appendiceal cancer patients, with median survival of 156 months, and CRS with intraperitoneal chemotherapy became the most popular treatment [18,22].
Additional retrospective studies, using historical controls, have supported this approach, without offering definitive evidence of benefit. A prospective phase II study reported that HIPEC with oxaliplatin was associated with higher toxicity compared to HIPEC with mitomycin, without showing a difference in survival in the secondary analyses [23].
In 2024, the ICARuS trial (Intraperitoneal Chemotherapy After Cytoreductive Surgery) is expected to report the results of the comparative efficacy of HIPEC and early postoperative intraperitoneal chemotherapy for appendix cancer (NCT01815359).
After CRS and intraperitoneal chemotherapy, patients are monitored for tumor marker levels in addition to CT of the chest, abdomen, and pelvis every 3–6 months initially and then every 6–12 months after a period free from recurrence [14]. Additionally, the use of MRI in follow-up continues to be evaluated [16].

Summary

Treatment for LAMN and appendiceal adenocarcinoma has slowly evolved over the past 50 years. Knowledge regarding the effectiveness of this treatment is limited by the rarity of the disease and the small sample sizes of retrospective studies and prospective clinical trials.
Nevertheless, with improved staging and understanding of the clinical behavior of the various subtypes, there is promise for more rational selection of patients for treatment, which may improve survival and decrease morbidity.

References

  1. Steele SR, Hull TL, Read TE, Saclarides TJ, Senagore AJ, Whitlow CB. ASCRS Textbook of Colon and Rectal Surgery Springer; 2016.
  2. Carr NJ, Cecil TD, Mohamed F, Sobin LH, Sugarbaker PH, González-Moreno S, et al. A Consensus for Classification and Pathologic Reporting of Pseudomyxoma Peritonei and Associated Appendiceal Neoplasia: The Results of the Peritoneal Surface Oncology Group International (PSOGI) Modified Delphi Process. Am J Surg Pathol. 2016;40(1):14-26.
  3. Overman MJ, Asare EA, Compton CC. Appendix carcinoma. AJCC Cancer Staging Manual. 8 ed: Springer; 2017. p. 237-50.
  4. Sueda T, Murata K, Takeda T, Kagawa Y, Hasegawa J, Komori T, et al. Survival outcomes of appendiceal mucinous neoplasms by histological type and stage: Analysis of 266 cases in a multicenter collaborative retrospective clinical study. Annals of Gastroenterological Surgery. 2019;3(3):291-300.
  5. American Joint Committee on Cancer. AJCC Version 9 Cancer Staging System. [Available from: https://www.facs.org/quality-programs/cancer-programs/american-joint-committee-on-cancer/version-9/.
  6. Shaib WL, Assi R, Shamseddine A, Alese OB, Staley C, 3rd, Memis B, et al. Appendiceal Mucinous Neoplasms: Diagnosis and Management. Oncologist. 2017;22(9):1107-16.
  7. Yantiss RK, Shia J, Klimstra DS, Hahn HP, Odze RD, Misdraji J. Prognostic significance of localized extra-appendiceal mucin deposition in appendiceal mucinous neoplasms. Am J Surg Pathol. 2009;33(2):248-55.
  8. Ronnett BM, Yan H, Kurman RJ, Shmookler BM, Wu L, Sugarbaker PH. Patients with pseudomyxoma peritonei associated with disseminated peritoneal adenomucinosis have a significantly more favorable prognosis than patients with peritoneal mucinous carcinomatosis. Cancer. 2001;92(1):85-91.
  9. Wagner PL, Jones D, Aronova A, Shia J, Weiser MR, Temple LK, et al. Early postoperative intraperitoneal chemotherapy following cytoreductive surgery for appendiceal mucinous neoplasms with isolated peritoneal metastasis. Dis Colon Rectum. 2012;55(4):407-15.
  10. Subbuswamy SG, Gibbs NM, Ross CF, Morson BC. Goblet cell carcinoid of the appendix. Cancer. 1974;34(2):338-44.
  11. Wang HL. Goblet Cell Adenocarcinoma of the Appendix: Diagnosis, Prognosis and Nomenclature. J Clin Transl Pathol. 2022;2(3):69-74.
  12. Bell PD, Pai RK. Goblet cell adenocarcinoma of the appendix: an update and practical approach to diagnosis and grading. Hum Pathol. 2023;132:183-96.
  13. Dohan A, Hoeffel C, Soyer P, Jannot AS, Valette PJ, Thivolet A, et al. Evaluation of the peritoneal carcinomatosis index with CT and MRI. Br J Surg. 2017;104(9):1244-9.
  14. Sugarbaker PH. Epithelial appendiceal neoplasms. Cancer J. 2009;15(3):225-35.
  15. Chua TC, Chong CH, Liauw W, Zhao J, Morris DL. Inflammatory markers in blood and serum tumor markers predict survival in patients with epithelial appendiceal neoplasms undergoing surgical cytoreduction and intraperitoneal chemotherapy. Ann Surg. 2012;256(2):342-9.
  16. Low RN, Barone RM, Lee MJ. Surveillance MR imaging is superior to serum tumor markers for detecting early tumor recurrence in patients with appendiceal cancer treated with surgical cytoreduction and HIPEC. Ann Surg Oncol. 2013;20(4):1074-81.
  17. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21(20):3737-43.
  18. Yan TD, Black D, Savady R, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei. Ann Surg Oncol. 2007;14(2):484-92.
  19. Raghav KP, Shetty AV, Kazmi SM, Zhang N, Morris J, Taggart M, et al. Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas. Oncologist. 2013;18(12):1270-7.
  20. Cashin PH, Mahteme H, Spång N, Syk I, Frödin JE, Torkzad M, et al. Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial. European Journal of Cancer. 2016;53:155-62.
  21. Quénet F, Elias D, Roca L, Goéré D, Ghouti L, Pocard M, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. The Lancet Oncology. 2021;22(2):256-66.
  22. Sugarbaker PH. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? Lancet Oncol. 2006;7(1):69-76.
  23. Levine EA, Votanopoulos KI, Shen P, Russell G, Fenstermaker J, Mansfield P, et al. A Multicenter Randomized Trial to Evaluate Hematologic Toxicities after Hyperthermic Intraperitoneal Chemotherapy with Oxaliplatin or Mitomycin in Patients with Appendiceal Tumors. J Am Coll Surg. 2018;226(4):434-43.