Response of Pseudomyxoma Peritonei to Gemcitabine

The term Pseudomyxoma Peritonei (PMP) describes a rare pathological condition where mucinous ascites is associated with tumor implants disseminated over the serous membranes of the abdominal cavity. Recent studies have revealed that the origin of PMP is usually an appendiceal neoplasm [1]. With regard to prognosis and optimal treatment modalities, three histologically defined categories can be distinguished: disseminated peritoneal adenomucinosis (DPAM); peritoneal mucinous carcinomatosis (PMCA); and an intermediate histology composed of both features of DPAM and PMCA, with DPAM having the best prognosis [2]. A feasible and effective approach to patients with DPAM is extensive tumor debulking with chemotherapy administered as intraoperative intraperitoneal hyperthermic perfusion of the abdominal cavity, leading to a 10-year survival of 68% [2]. On the other hand, patients with PMCA often show invasive peritoneal implants and organ involvement, making it impossible to surgically remove all tumors. Accordingly, the prognosis is fatal, with only 3% surviving 10 years [2]. These patients might benefit from postoperative systemic chemotherapy. We report a case, where intravenously administered gemcitabine induced a marked tumor reduction after prior incomplete cytoreductive surgery.

A 74 year-old male patient presented at our hospital with pain in the lower abdomen. Ultrasonography and computed tomography (CT) suggested massive ascites, but a paracentesis was frustrane. A laparotomy revealed a 20×20 cm gelatinous appearing capsulated tumor mass located in the pelvis. The appendix could not be found intraoperatively. Because there was no history of appendectomy, a ruptured appendix was considered to be the source or PMP. Cytoreductive surgery was carried out, leaving gross residual tumor. Histological examination of the peritoneal lesions showed mucinous masses with associated fibrosis. Where present, the epithelium formed gland-like structures and showed signs of atypia. Laboratory data showed an elevated chromogranin A (CgA, 288 µg/l; normal,<110). All other tested tumor markers were within the normal range (CEA, CA 19–9, CA 12–5, AFP, β-HCG, NSE). Immunohistochemistry of the peritoneal lesions was positive for cytokeratin 20 and negative for cytokeratin 7 and neuroendocrine markers (CgA, synaptophysin, NSE, CD56). After surgery, an intravenous chemotherapy was started with cisplatin and 5-fluorouracil (5-FU) in a 3-week schedule. Three cycles were administered, but two months after the first surgery the patient presented with a distended abdominal wall. A CT scan showed a progredient pelvic tumor and prompted another tumor debulking including a right hemicolectomy and the resection of 30 cm of terminal ileum, again leaving residual tumor (Figure 2). Postoperatively, one cycle of intraperitoneal mitomycin-C (MMC, 20 mg, absolute) and gemcitabine (750 mg, absolute) was administered. Due to the obstruction of the implanted intraabdominal port system, intravenous gemcitabine (1000 mg/m²) was initiated, repeated every 2 weeks, and well tolerated. Further CT scans showed a marked tumor reduction (Figure 3). After 11 cycles, chemotherapy was discontinued for two months and then initiated again. The patient is still on treatment, is tolerating well the chemotherapy without toxicity, and remains in a good physical condition.

Figure 1.  CgA levels and tumor site during treatment

Figure 2.  CT scan at week 14

Figure 3.  CT scan at week 37

Using the proposed histological categories of peritoneal lesions in PMP [2], our patient has to be diagnosed PMCA. Although we did not observe lymph node involvement or distant metastasis other than peritoneal lesions, he showed initially an unfavourable clinical course typical of PMCA. Interestingly, CgA levels did reflect the disease dynamics to some extent (Figure 1). This suggested a neuroendocrine differentiation. Although sections from peritoneal lesions stained negative for neuroendocrine markers, this does not exclude the possibility of a mixed differentiation of carcinoid and adenocarcinoma of the primary tumor, as is found in goblet cell carinoid (GCC) of the appendix [3]. Indeed, there are reports of metastasized GCC with different microscopic and immunohistochemical appearance of metastasis depending on their site [4], [5] and furthermore, as in other neuroendocrine tumors, plasma CgA levels are elevated in GCC and correspond to the tumor burden [3]. PMP might therefore be a clinical manifestation of an underlying GCC in our patient. However, because the primary tumor could not be identified, we cannot validate this hypothesis.

PMP is usually an incidential finding on laparotomy, occuring in about 2 of 10 000 laparotomies [6]. The clinical course is characterized by local recurrences and fibrosis, leading to bowel obstruction that eventually causes death [6]. Systemic chemotherapy is recommended for patients with gross tumor residues after surgery [6]. However, in small retrospective series of patients with PMP there was no benefit of chemotherapy compared to best supportive care [7]. 5-FU is among the most often used drugs when chemotherapy is administered. A recent case report describes the response of a patient with PMP and underlying intermediate histological type to capecitabine, an orally administered prodrug of 5-FU [8]. Our patient did not respond to intravenous 5-FU. Intraperitoneally administered MMC is active in PMP [2] and the single cycle of MMC might have initially improved the response. However, intravenous gemcitabine led to a further reduction in tumor volume and a durable partial remission was achieved. Gemcitabine is a nucleoside analogue which has proven to be effective in a number of solid tumors. Another case report describes a stable remission with intravenously administered gemcitabine in a patient with PMP originating from an intraductal papillary mucinous neoplasm of the pancreas [9]. A complete resection of all tumor implants was also impossible in this case. In conclusion, this suggests that gemcitabine might be an alternative treatment option in some patients with PMP where optimal cytoreduction can not be achieved.