Experience with adjuvant chemotherapy for pseudomyxoma peritonei secondary to mucinous adenocarcinoma of the appendix with oxaliplatin/fluorouracil/leucovorin (FOLFOX4)
© Chen et al; licensee BioMed Central Ltd. 2008
Received: 03 July 2008
Accepted: 11 November 2008
Published: 11 November 2008
Pseudomyxoma peritonei (PMP) is a rare condition characterized by mucinous tumors, disseminated intra-peritoneal implants, and mucinous ascites. So far its diagnosis remains challenging to most clinicians.
A 55-year-old male patient had suffered from acute onset of abdominal pain and abdominal distension for one day prior to his admission. Physical examination revealed tenderness over the right lower quadrant of the abdomen without diffuse muscle guarding. A large amount of ascites was identified by abdominal computed tomography (CT) scan. Paracentesis showed the appearance of sticky mucinous ascites. He underwent laparotomy under the impression of pseudomyxoma peritonei. There was a lot of mucinous ascites, one appendiceal tumor and multiple peritoneal implants disseminated from the subphrenic space to the recto-vesicle pouch. Pseudomyxoma Peritonei caused by mucinous adenocarcinoma of appendiceal origin, was confirmed by histopathology. We performed an excision of the appendiceal tumor combined with copious irrigation and debridement. After the operation, he received 10 cycles of systemic chemotherapy with FOLFOX4 regimen, without specific morbidity. Follow-up of abdominal CT and colonoscopy at post-operative 17 months showed excellent response without evidence of local recurrence or distal metastasis. He made an uneventful recovery (up to the present) for 21 months after the operation.
This case report emphasizes the possible new role of systemic chemotherapy in the treatment of patients with this rare clinical syndrome.
Pseudomyxoma peritonei (PMP) is a rare condition characterized by mucinous tumors, disseminated intra-peritoneal implants, and mucinous ascites. It may represent a pathologic diagnostic term to both benign and malignant mucinous neoplasms that produce abundant extracellular mucin. Therefore, poorly predictable clinical course and variable prognosis could be expected. A definitive diagnosis of PMP requires the presence of mucinous neoplastic epithelium and mucinous ascites, and may also include the diffuse mucinous implants . In spite of more detailed understanding of PMP based on the clinical case series, there is still some debate about its clinical behavior, pathogenesis, and treatment strategy. We report our clinical experience concerning systemic chemotherapy (FOLFOX4 regimen) for one case of pseudomyxoma peritonei secondary to appendiceal mucinous adenocarcinoma and review the literature.
Pseudomyxoma peritonei (PMP) is a rare clinical syndrome with an estimated incidence of approximately one per million per year and preferentially affects women (2–3 times more common than men) [3, 4]. Since Werth  first described PMP produced by an ovarian neoplasm and Frankel  first reported on the association of PMP with an appendiceal mucocele, there have been many reports focusing on the pathogenesis, diagnosis, treatment and prognosis of PMP.
The primary origin of the mucinous peritoneal implants in PMP has remained controversial for a long time. Some reports indicated that ovarian tumor is more likely to be the primary neoplasm of PMP [3, 7], however, others favor the appendiceal tumor as the answer [4, 8, 9]. Because immunohistochemical stains and molecular genetic studies both show the evidence of these tumors being secondary to appendiceal neoplasms [10–12], most people agree that the primary tumor of PMP is predominately a mucinous epithelial neoplasm of the appendix. Other possible primary sites being reported include: colorectum, gallbladder, pancreas, urachus, urinary bladder, breast and lung, but these are uncommon [13, 14]. PMP is characterized by an abundant amount of mucinous ascites produced by adenomucinous tumor cells in implants on peritoneal surfaces. These implants are the final stage of a distribution process following the rupture of the mucinous neoplasm. The key associated finding is the presence of epithelium outside the appendix in association with the mucin and the peritoneal implants .
Ronnett et al  first described a widely accepted and useful definition of PMP. They classified PMP into three pathological subtypes with different pathological characteristics and different prognosis: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and an intermediate subtype (PMCA-I). Histopathologically, DPAM is characterized by an abundance of mucus with focally adenomucinous epithelium without atypia or mitotic activity. In contrast to this, PMCA is characterized by peritoneal tumor composed of more abundant mucinous tumor cells with the architecture and cytological features of carcinoma. Finally, the intermediate subtype PMCA-I is characterized by an abundance of DPAM lesions, but with focal areas with PMCA lesions [15, 16].
Besides the histopathological difference, their clinical behaviors are also quite different. DPAM remains potentially non-invasive and stays localized to the abdomen without metastatic behavior. In contrast to this, PMCA behaves with invasive and metastatic potential, as is characteristic of mucinous adenocarcinoma. Patients with PCMA are associated with the possibilities of liver, lung and lymph node metastatic disease .
As symptoms remain non-specific, PMP presents a great diagnostic challenge to clinicians. A precise diagnosis is difficult due to the lack of specific symptoms in the early stages of the disease. The most important symptom is a gradually increasing abdominal girth. Patients may present a typical "jelly belly" appearance . Sometimes patients present symptoms mimicking appendicitis with intra-operative identification of a perforated appendiceal mucocele. In other cases, they present an inguinal herniated sac or an ovarian mass . For 30% of female patients, the first symptom is an ovarian mass .
Routine laboratory studies are seldom helpful in making this diagnosis. Ultrasound is useful for initial establishment of the diagnosis. Echo-guided paracentesis may reveal mucinous ascites. Abdominal computed tomography (CT) scan may demonstrate the characteristics of mucinous ascites by analyzing the density properties (Hounsfield Units [H.U.]), as it is significantly higher (5–20 H.U.) than normal ascites (0 H.U.) . CT may also show the characteristic of "scalloping effect" on the surface of the visceral organs resulting from compression by the viscous mucinous secretions . In the majority of cases, however, PMP is often an unexpected finding of laparoscopy or exploratory laparotomy .
When mucinous tumors on the peritoneal surface or mucinous ascites are visualized on CT or during abdominal surgery, treatment of PMP should be performed since untreated PMP patients will eventually suffer from intestinal obstruction and mortality . In spite of the controversial standard treatment strategies for PMP, the current mainstay of the treatment remains surgical resection of the lesions. Alternative non-surgical treatment, such as: peritoneal washing with 5% dextrose and systemic chemotherapy, have been reported; however, their roles in PMP are still uncertain because of the limited case number and short follow-up time [21, 22].
Repeated cytoreductive surgical de-bulking procedures as treatment for PMP have been described in earlier literatures. Since the 1990s, a new combined treatment approach was introduced by Sugarbaker et al . They defined it as peritonectomy procedures in combination with intra-operative hyperthermic intra-peritoneal chemotherapy (HIPEC). Now this new combination treatment is increasingly performed as treatment for PMP patients, with promising results [24, 25]. The available evidence suggests that cytoreductive surgery with perioperative intraperitoneal chemotherapy should replace serial de-bulking as the standard of care for patients with peritoneal spread of appendiceal epithelial neoplasms . PMCA behaves like peritoneal carcinomatosis from the original colorectal adenocarcinoma; however, its poor prognosis in comparison with DPAM after the similar management by cytoreductive surgery and HIPEC was still demonstrated in the two studies conducted by Sugarbaker et al . and Smeenk et al . Moreover, Verwaal et al, also showed a similar result in their randomized study, that patients with peritoneal carcinomatosis of colorectal cancer (CRC) origin combined with cancer implant involvement of six or more regions of the abdominal cavity, got little survival benefit after the cytoreductive surgical procedures and intra-operative HIPEC .
Herein, further clinical trials with investigations of different treatment strategies for patients with PMCA, are still needed. This contributes to the application of systemic chemotherapy for the patient in our case report since the new therapeutic agent Oxaliplatin and its combination with 5-fluorouracil/leucovorin (FOLFOX4 regimen) has been used widely as first-line treatment in patients with advanced CRC, and the promising results in these patients have been demonstrated in several randomized studies [29, 30].
The effect of systemic chemotherapy in PMP seems questionable. Jones et al  reported their experience in the treatment of pseudomyxoma peritonei of ovarian origin with cisplatinum, doxorubicin, and cyclophosphamide, with excellent responses. On the other hand, Smeenk et al  reported the poor response of six patients (3 patients with DPAM, another 3 patients with PMCA-I, and all 6 patients with lesions diffusely spread throughout the abdomen) after 5-FU based systemic chemotherapy, and subsequent poor prognosis was noted in the study. Regarding the benefit of new therapeutic agents (including Capecitabine, Oxaliplatin, Irinotecan and Bevacizumab) and modern schedules for patients with metastatic CRC, clinical experience with the use of these agents for PMP are still absent, and it is questionable whether they will do any better in this situation, especially for patients with PMCA. Due to the limited experience and indeterminate effects of systemic chemotherapy in PMP, some studies still suggest that systemic therapy should be reserved for a palliative setting in patients with recurrent or progressive disease [20, 32].
Because of the high grade mucinous adenocarcinoma of the appendix with disseminated peritoneal lesions both confirmed by histopathology, instead of the treatment strategies (including aggressive peritonectomy procedures), we used oxaliplatin/5-FU/leucovorin combination systemic chemotherapy (FOLFOX4 regimen) in our patient after less invasive surgery, as the treatment for the metastatic colorectal cancer. After 10 cycles of FOLFOX4 chemotherapy, excellent response was achieved. Colonoscopy and abdominal CT scan 17 months after the operation both showed no evidence of development of local recurrent or metastatic lesions. The patient had an uneventful recovery up to now without any disease-related morbidity. We believe that our experience is one of the few reports about effective treatment of PMP with systemic chemotherapy. More clinical experience and further studies are still needed for determination of the benefit of systemic chemotherapy for these patients.
We report our clinical experience regarding the use of systemic chemotherapy (FOLFOX4 regimen) for one case of pseudomyxoma peritonei secondary to mucinous adenocarcinoma of the appendix. This case report emphasizes the possible new role of systemic chemotherapy in the treatment of patients with this rare clinical syndrome.
Written informed consent was taken from the patient for publication of this case report.
- Li C, Kanthan R, Kanthan SC: Pseudomyxoma peritonei – a revisit: report of 2 cases and literature review. World J Surg Oncol. 2006, 4: 60-10.1186/1477-7819-4-60.PubMed CentralView ArticlePubMedGoogle Scholar
- de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000, 18: 2938-2947.PubMedGoogle Scholar
- Galani E, Marx GMF, Steer CB, Culora G, Harper PG: Pseudomyxoma peritonei: the 'controversial' disease. Int J Gynecol Cancer. 2003, 13: 413-418. 10.1046/j.1525-1438.2003.13318.x.View ArticlePubMedGoogle Scholar
- Mukherjee A, Parvaiz A, Cecil TD, Moran BJ: Pseudomyxoma peritonei usually originates from the appendix: a review of the evidence. Eur J Gynaecol Oncol. 2004, 25: 411-414.PubMedGoogle Scholar
- Werth R: Klinische und anatomische untersuchungen zur lehre von den bauchgeschwuelsten und der laparotomie. Arch Gynaecol Obstet. 1884, 24: 100-118.Google Scholar
- Frankel E: Uber das sogenannte pseudomyxoma peritonei. Med Wochenschr. 1901, 48: 965-970.Google Scholar
- Ronnett BM, Kurman RJ, Zahn CM, Shmookler BM, Jablonski KA, Kass ME, Sugarbaker PH: Pseudomyxoma peritonei in women: a clinicopathologic analysis of 30 cases with emphasis on site of origin, prognosis, and relationship to ovarian mucinous tumors of low malignant potential. Hum Pathol. 1995, 26: 509-524. 10.1016/0046-8177(95)90247-3.View ArticlePubMedGoogle Scholar
- van Ruth S, Acherman YIZ, Vijver van de MJ, Hart AAM, Verwaal VJ, Zoetmulder FAN: Pseudomyxoma peritonei: a review of 62 cases. Eur J Surg Oncol. 2003, 29: 682-688. 10.1016/S0748-7983(03)00149-5.View ArticlePubMedGoogle Scholar
- Young RH, Gilks CB, Scully RE: Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei. A clinicopathological analysis of 22 cases supporting an origin in the appendix. Am J Surg Pathol. 1991, 15: 415-429.View ArticlePubMedGoogle Scholar
- Prayson RA, Hart WR, Petras RE: Pseudomyxoma peritonei. A clinicopathologic study of 19 cases with emphasis on site of origin and nature of associated ovarian tumors. Am J Surg Pathol. 1994, 18: 591-603.PubMedGoogle Scholar
- Szych C, Staebler A, Connolly DC, Wu R, Cho KR, Ronnett BM: Molecular genetic evidence supporting the clonality and appendiceal origin of pseudomyxoma peritonei in women. Am J Pathol. 1999, 154: 1849-1855.PubMed CentralView ArticlePubMedGoogle Scholar
- Ronnett BM, Shmookler BM, Diener-West M, Sugarbaker PH, Kurman RJ: Immunohistochemical evidence supporting the appendiceal origin of pseudomyxoma peritonei in women. Int J Gynecol Pathol. 1997, 16 (1): 1-9.View ArticlePubMedGoogle Scholar
- de Bree E, Witkamp A, Vijver Van De M, Zoetmulde F: Unusual origins of Pseudomyxoma peritonei. J Surg Oncol. 2000, 75: 270-274. 10.1002/1096-9098(200012)75:4<270::AID-JSO9>3.0.CO;2-V.View ArticlePubMedGoogle Scholar
- Sherer DM, Abulafia O, Fliakim R: Pseudomyxoma peritonei. A review of current literature. Gynecol Obstet Invest. 2001, 51: 73-80. 10.1159/000052897.View ArticlePubMedGoogle Scholar
- Ronnett BM, Zahn CM, Kurman RJ, Kass ME, Sugarbaker PH, Shmookler BM: 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: 1390-1408.View ArticlePubMedGoogle Scholar
- Smeenk RM, Verwaal VJ, Zoetmulder FAN: Tumor Review-pseudomyxoma peritonei. Cancer Treatment Reviews. 2007, 33: 138-145. 10.1016/j.ctrv.2006.11.001.View ArticlePubMedGoogle Scholar
- Bradley RF, Stewart JH, Russell GB, Levine EA, Geisinger KR: Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 patients uniformly treated at a single institution, with literature review. Am J Surg Pathol. 2006, 30: 551-559. 10.1097/01.pas.0000202039.74837.7d.View ArticlePubMedGoogle Scholar
- Esquivel J, Sugarbaker PH: Clinical presentation of the pseudomyxoma peritonei syndrome. Br J Surg. 2000, 87: 1414-1418. 10.1046/j.1365-2168.2000.01553.x.View ArticlePubMedGoogle Scholar
- Sugarbaker PH: New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome?. Lancet Oncol. 2006, 7: 69-76. 10.1016/S1470-2045(05)70539-8.View ArticlePubMedGoogle Scholar
- Sugarbaker PH: Pseudomyxoma peritonei. Cancer Treat Res. 1996, 81: 105-119.View ArticlePubMedGoogle Scholar
- Green N, Gancedo H, Smith R, Bernett G: Pseudomyxoma peritonei – nonoperative management and biochemical findings. A case report. Cancer. 1975, 36: 1834-1837. 10.1002/1097-0142(197511)36:5<1834::AID-CNCR2820360539>3.0.CO;2-6.View ArticlePubMedGoogle Scholar
- Jones CM, Homesley HD: Successful treatment of pseudomyxoma peritonei of ovarian origin with cisplatinum, doxorubicin, and cyclophosphamide. Gynecol Oncol. 1985, 22: 257-259. 10.1016/0090-8258(85)90035-6.View ArticlePubMedGoogle Scholar
- Sugarbaker PH, Ronnett BM, Archer A, Averbach AM, Bland R, Chang D, Dalton RR, Ettinghausen SE, Jacquet P, Jelinek J, Koslowe P, Kurman RJ, Shmookler B, Stephens AD, Steves MA, Stuart OA, White S, Zahn CM, Zoetmulder FA: Pseudomyxoma peritonei syndrome. Adv Surg. 1996, 30: 233-280.PubMedGoogle Scholar
- Sugarbaker PH: Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol. 2001, 27: 239-243. 10.1053/ejso.2000.1038.View ArticlePubMedGoogle Scholar
- Loungnarath R, Causeret S, Bossard N, Faheez M, Sayag-Beaujard AC, Brigand C, Gilly F, Glehen O: Cytoreductive surgery with intraperitoneal chemohyperthermia for the treatment of pseudomyxoma peritonei: a prospective study. Dis Colon Rectum. 2005, 48: 1372-1379. 10.1007/s10350-005-0045-5.View ArticlePubMedGoogle Scholar
- Sugarbaker PH, Chang D: Results of treatment of 385 patients with peritoneal surface spread of appendiceal malignancy. Ann Surg Oncol. 1999, 6: 727-731. 10.1007/s10434-999-0727-7.View ArticlePubMedGoogle Scholar
- Smeenk RM, Verwaal VJ, Antonini N, Zoetmulder FAN: Survival analysis of pseudomyxoma peritonei patients treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Annals of Surgery. 2007, 25 (1): 104-109. 10.1097/01.sla.0000231705.40081.1a.View ArticleGoogle Scholar
- Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA: 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: 3737-3743. 10.1200/JCO.2003.04.187.View ArticlePubMedGoogle Scholar
- Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts S: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004, 22: 23-30. 10.1200/JCO.2004.09.046.View ArticlePubMedGoogle Scholar
- Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, van Cutsem E, Scheithauer W, Gruenberger T: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008, 371: 1007-1016. 10.1016/S0140-6736(08)60455-9.PubMed CentralView ArticlePubMedGoogle Scholar
- Smeenk RM, Verwaal VJ, Antonini N, Zoetmulder FA: Progression of pseudomyxoma peritonei after combined modality treatment: Management and outcome. Annals of Surgical Oncology. 2006, 14 (2): 493-499. 10.1245/s10434-006-9174-x.View ArticlePubMedGoogle Scholar
- Smith JW, Kemeny N, Caldwell C, Banner P, Sigurdson E, Huvos A: Pseudomyxoma peritonei of appendiceal origin. The Memorial Sloan-Kettering Cancer Center experience. Cancer. 1992, 70: 396-401. 10.1002/1097-0142(19920715)70:2<396::AID-CNCR2820700205>3.0.CO;2-A.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.