Histopathologic Analysis in 46 Patients with Pseudomyxoma Peritonei Syndrome: Failure versus Success with a Second-Look Operation Hui Yan, M.D., Sophie R. Pestieau, M.D., Barry M. Shmookler, M.D., Paul H. Sugarbaker, M.D., F.A.C.S., F.R.C.S. From the Washington Cancer Institute (SRP, PHS) and the Department of Pathology (HY), Washington Hospital Center, Washington, DC; and Academic Oncology Resources, LLC, Rockville, Maryland (BMS) inally designated pseudomyxoma peritonei were re- Pseudomyxoma peritonei syndrome is a disease classified as hybrid-type malignancy (four patients) characterized by mucinous ascites and mucinous or mucinous adenocarcinoma (seven patients). tumor disseminated on peritoneal surfaces; the dis- Only two patients were reclassified in the successful Transitions from a .(0005. ؍ ease almost always originates from a perforated ap- second-look group (P pendiceal epithelial tumor. Histopathologic assess- less aggressive to a more invasive histology from ment of aggressive versus noninvasive character of one cytoreduction to the next occurred on 13 occa- the mucinous tumor has been shown to have an sions in patients whose second-look surgery failed impact on survival in patients treated with cytore- and in one patient with a successful second-look ductive surgery and intraperitoneal chemotherapy. surgery (P < .0001). Seven patients retained a his- Out of a database of 312 patients having a complete tologic classification of disseminated peritoneal ad- cytoreduction for pseudomyxoma peritonei syn- enomucinosis but went on to die of an aggressive drome, 46 patients (24 male and 22 female) had at disease process. Clinical assessments suggested that least one second-look surgery. Before this review, failure of second-look surgery for pseudomyxoma all 46 of these patients were clinically uniformly peritonei was associated with a biologically more categorized with a diagnosis of pseudomyxoma aggressive disease. Unsuccessful second-look sur- peritonei. Using the criteria described by Ronnett gery for patients with a clinical diagnosis of and colleagues, all specimens from the multiple sur- pseudomyxoma peritonei tumor was often related gical procedures performed on these patients were to an inaccurate initial histologic classification of reviewed and reclassified as disseminated perito- appendiceal mucinous tumor. Also, a transition neal adenomucinosis (adenomucinosis), adenomu- from less to more aggressive histology was fre- cinosis/mucinous adenocarcinoma (hybrid), or mu- quently seen in patients dying of this disease. As- cinous adenocarcinoma. The review was performed sessment of tumor histology can predict the out- in a blinded fashion by a single pathologist (HY). To come if a uniform surgical treatment is used in facilitate a critical evaluation of these histopatho- patients with peritoneal dissemination of mucinous logic assessments, the patients were separated into epithelial tumors of the appendix. two groups: (1) 19 patients who had a second-look surgery that was unsuccessful in that they went on KEY WORDS: Cytoreductive surgery, Disseminated to die of their disease or in that they currently have peritoneal adenomucinosis, Intraperitoneal chemo- disease progression and a limited survival and (2) 27 patients who had a successful second look and cur- therapy, Mucinous adenocarcinoma, Pseudomyxoma rently continue disease free with a minimum 3-year peritonei syndrome, Second-look surgery. follow-up period. As a result of this review, 11 of 19 Mod Pathol 2001;14(3):164–171 patients with an unsuccessful second look and orig- Pseudomyxoma peritonei syndrome is a rare dis- ease usually characterized by a perforated appen- diceal epithelial tumor that causes mucinous as- Copyright © 2001 by The United States and Canadian Academy of Pathology, Inc. cites and multifocal mucinous tumor implants VOL. 14, NO. 3, P. 164, 2001 Printed in the U.S.A. diffusely involving the peritoneal surfaces. The syn- Date of acceptance: December 4, 2000. Address reprint requests to: Paul H. Sugarbaker, M.D., F.A.C.S., F.R.C.S., drome includes patients with diverse and poorly The Washington Cancer Institute, Washington Hospital Center, 110 Irving Street, CG-185, NW, Washington, DC 20010; e-mail: [email protected]; fax: predictable prognosis. Since Werth first introduced 202–877–8602. the term pseudomyxoma peritonei in 1884 (1), its 164 features, definition, origin, and prognosis have Histopathological Classification been debated for more than a century. Recently, In a blinded re-study, all tissue specimens were morphologic, immunohistochemical, and molecu- reclassified according to Ronnett’s criteria (4, 5); lar genetic studies have analyzed a large number of the average number of slides reviewed for each pseudomyxoma peritonei cases in an effort to doc- patient was 50, with a range of 30 to 90. The tissues ument the appendix as the primary site in both were divided into one of three following histological men and women and to more clearly define the categories of mucinous appendiceal epithelial ma- natural history of the disease (2–12). Also, the de- lignancies. Then, the group identified as mucinous scription of a new histopathologic classification of adenocarcinoma was subdivided as well differenti- appendiceal mucinous tumors suggested that prog- ated, moderately differentiated, or poorly differen- nosis was correlated with morphology if a uniform tiated. Each patient, at a minimum of three differ- treatment strategy was used. In the publication by ent points in time, had the histology of these Ronnett and coworkers (5), the mucinous appen- mucinous tumors identified as one of five different diceal tumors were classified as disseminated peri- subtypes. toneal adenomucinosis, peritoneal mucinous carci- Adenomucinosis was characterized by multifocal nomatosis, or hybrid tumor. This new histologic mucinous tumors adherent to but not invading into classification may be significant for understanding visceral and parietal peritoneal surfaces. Micro- the history of this disease and in helping patholo- scopically, the peritoneal lesions contained scant gists and surgeons to knowledgeably treat it. The histologically benign mucinous epithelium within purpose of this study was to correlate the morphol- abundant extracellular mucin (Fig. 1). An intense hyalinizing fibrotic reaction that separated pools of ogy, as defined by the modern classification, with mucin was another important histologic feature of the results of a uniform treatment plan to test the this lesion. Also, the dissecting quality of the mucin predictive value it offered over an extended time was consistent. Intraoperatively, the mucinous im- period. Forty-six patients who had multiple tissue plants have a characteristic distribution by perito- samples available at a minimum of three different neal fluid and by the forces of gravity. There was surgeries were used to complete this evaluation. noninvasive involvement of the parietal peritoneal surfaces with sparing of the peritoneal surfaces of the bowel and its mesentery. This has been referred MATERIALS AND METHODS to as a redistribution phenomenon (8). The need to distinguish secondary involvement of the ovaries by Clinical Features a perforated mucinous appendiceal tumor from From a database of 312 patients with a clinical mucinous borderline tumors of the ovary has been diagnosis of pseudomyxoma peritonei syndrome, previously established (7). an attempt was made to retrieve and review the Mucinous adenocarcinoma was characterized by clinical data and the pathologic material on all pa- invasive peritoneal lesions composed of abundant tients who had at least one second-look procedure epithelium with glandular or signet-ring cell mor- between 1987 and 1999. The original histologic di- phology with sufficient architectural complexity agnoses in all these patients was low-grade muci- and cytological atypia to warrant a diagnosis of nous appendiceal tumor or malignancy compatible with pseudomyxoma peritonei. These histologic di- agnoses were made before the uniform application of the Ronnett criteria to the evaluation of muci- nous appendiceal tumors. This included the appen- dectomy specimen and the peritoneal surface mu- cinous tumor. All patients underwent an appendectomy for their primary appendiceal tumor at an outside institution (n ϭ 38) or at Washington Hospital Center concomitantly with cytoreductive surgery (n ϭ 8). The 46 patients eligible for this analysis were separated into two categories based on failure versus success with second-look surgery: 19 patients who failed the treatment approach and went on to die of their disease or who currently have progressive disease (failure group) and 27 pa- FIGURE 1. Disseminated peritoneal adenomucinosis: peritoneal lesion showed simple mucinous epithelial strips with abundant tients who currently have disease-free survival (suc- extracellular mucin. Bland epithelium had no cytologic atypia or cess group). mitosis (hematoxylin and eosin, ϫ200). Histopathologic Analysis of Pseudomyxoma (H. Yan et al.) 165 mucinous adenocarcinoma (Fig. 2). Mucinous ade- nocarcinomas were further separated into three grades (13) by evaluating epithelial content of the tumors in order to more completely describe the histological progression (1). Well-differentiated mucinous adenocarcinoma was composed pre- dominantly of single tubular glands. The tumor cells were well polarized similar to epithelium of an adenoma. Atypia of the tumor cells was remarkable, and an invasive component was identified (2).