- Email: [email protected]
Pseudomyxoma peritonei: cytomorphologic findings and clinicopathologic correlates
Journal of the American Society of Cytopathology (2016) 5, 43e49
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jascyto.org/
ORIGINAL ARTICLE
Pseudomyxoma peritonei: cytomorphologic findings and clinicopathologic correlates Irem Onur, MDa, Momin T. Siddiqui, MD, FIACb, Paul E. Wakely Jr., MDc, Syed Z. Ali, MD, FRCPath, FIACa,* a
Division of Cytopathology, Department of Pathology, The Johns Hopkins Medical Institutions, Rm PATH 406, 600 N. Wolfe Street, Baltimore, Maryland 21287 b Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, Georgia c Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio Received 3 February 2015; received in revised form 14 September 2015; accepted 16 September 2015
KEYWORDS Pseudomyxoma peritonei; Abdominal fluid; Gelatinous ascites; Appendiceal mucinous neoplasm; Cytopathology
Introduction To analyze the cytomorphology and clinical correlates of pseudomyxoma peritonei (PP), a frequently fatal pathological entity defined by gelatinous ascites caused by slow but relentless accumulation of mucin produced by neoplastic glandular epithelium. Materials and methods A retrospective search of the electronic pathology data systems of three large tertiary care medical institutions revealed 41 cases from 32 patients with PP and corresponding abdominal fluid cytologic specimens. Cytologic material was available for review in 15 cases. Results The primary tumor site was appendix in 25 (78.1%) of the 32 patients, other regions of the gastrointestinal tract in 2 (6.3%) patients, and in 5 (15.6%) patients, the primary could not be entirely identified. Of the 41 cases, only 15 had available cytologic slides to review. Extracellular mucin was a constant feature in all 15 (100%) cases, being abundant in 13 cases and focal in 2 cases. Predominance of mucin-secreting neoplastic epithelial cells were observed in 10 (66.7%) and muciphages in 11 (73.4%) cases. Cytopathologic interpretations were consistent with the subsequent histopathologic diagnosis in 30 of 32 cases (93.8%). There were two false negative cases, both of which showed scant mucinous material on second review. Conclusions PP is uncommonly encountered in routine cytopathology practice. The common denominator is the presence of an often-abundant extracellular mucin. Epithelial (glandular) component is usually scant. An accurate diagnosis in a fluid specimen requires proper identification of free/extracellular mucin as well as distinguishing the often “benign-appearing” epithelial cells from reactive mesothelial cells and histiocytes. Ó 2016 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.
*Corresponding author: Dr. Syed Z. Ali, MD, FRCPath, FIAC; Professor of Pathology and Radiology, The Johns Hopkins Hospital, Path 406, 600 N. Wolfe St. Baltimore, MD 21287; Tel.: 1-410-955-1180; Fax: 1-410-614-9556. E-mail address: [email protected] (S.Z. Ali). 2213-2945/$36 Ó 2016 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jasc.2015.09.214
44
I. Onur et al.
Introduction
Materials and methods
Pseudomyxoma peritonei (PP) is a rare and frequently fatal disease presenting with gelatinous ascites caused by slow but progressive accumulation of mucin produced by growth of neoplastic mucin-secreting cells.1,2 In most cases, the primary site is the appendix. The majority of the PP cases that were thought to be of ovarian derivative are now considered to be appendiceal in origin with secondary involvement of the ovary.3-7 In rare cases with no evidence of non-ovarian source of mucinous tumor, the ovary is suggested to be a rare primary site when intestinal type mucinous adenocarcinoma arises in mature cystic teratoma.1 Occasionally, PP may also arise from colorectum, urachus, small intestine, stomach, pancreas, gall bladder and bile duct, gastric teratoma, fallopian tube, lung, and breast.1,8,9 There is an ongoing debate on the nature, nomenclature, and classification of PP as well as classification of appendiceal mucinous neoplasms. The controversy focuses on whether the growing epithelium is adenomatous or carcinomatous in PP. Panarelli et al10 do not accept PP as a neoplastic process and conclude that non-neoplastic etiologies such as diverticula of appendix and colon can cause PP. Ronnett et al11 categorize PP into three distinct subcategories: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and peritoneal mucinous carcinomatosis-intermediate/discordant (PMCA-I/D). DPAM consists of peritoneal lesions with mucinous epithelium with little cytologic atypia, mitosis, and abundant extracellular mucin. PMCA constitutes more abundant mucinous epithelium forming glands and/or signet ring cells and shows cytologic atypia and architectural features of mucinous carcinoma. PMCA-I/D cases demonstrate cytologic and architectural features of welldifferentiated mucinous carcinoma in combination with more bland areas. DPAM is associated with ruptured appendiceal mucinous adenomas, whereas most PMCA cases are associated with mucinous adenocarcinoma of appendix or colon. According to both TNM classification and the study of Bradley et al,12 PP is a carcinoma and is classified as low grade and high grade. They avoid DPAM terminology based on their view that low grade and high grade lesions represent a continuous spectrum and the concept of ruptured adenoma does not sufficiently reflect the frequently fatal course of this disease.1,12 Additionally, a new three-tiered classification system has also been proposed for peritoneal metastases arising from a mucinous appendiceal neoplasm consisting of PP1, PP2, and PP3 based on histological grade.2 Although there are numerous studies on histopathologic characteristics of PP, there are limited data on the cytopathology of PP. Therefore, we aimed to elaborate in this study on cytomorphologic features of PP by analyzing 41 cases of PP collected from three large tertiary care institutions.
Case selection and information The institutional review board provided permission to search electronic medical records. All patients with histologically confirmed PP who had abdominal fluid cytology were searched retrospectively. The search included all available records from the electronic pathology data systems of The Johns Hopkins Hospital (JHH) from May 5, 1980 to January 9, 2014; Emory University Hospital (EUH) from January 1, 2006 to February 3, 2014; and The Ohio State University Wexner Medical Center (OSUWMC) from January 1, 1999 to December 31, 2011. Consultation cases were excluded. Over these periods, a total of 41 cases from 32 patients with corresponding surgical pathology diagnosis of PP (33 cases at JHH, 4 cases at EUH, and 4 cases at OSUWMC) were found. Of the 41 cases, 15 (7 cases at JHH, 4 cases at EUH, and 4 cases at OSUWMC) had available cytologic slides to review. Clinicopathologic information including patient age, sex, treatment, and followup information was obtained for each case. If available, the results of immunohistochemical stains were recorded.
Cytopathology Abdominal fluids were obtained either by paracentesis or washing during surgery. Specimens were prepared with cytospin (Thermo Shandon Inc., Pittsburgh, Penn) and Millipore filters (Millipore Corporation, Billerica, Mass) at JHH, with ThinPrep (Cytyc Corp., Boxborough, Mass) at EUH, and with cytospin at OSUWMC. All slides were stained with Papanicolaou stain. At each institution, a cytopathologist re-reviewed the retrieved cytology material. Cytomorphologic findings including presence of epithelial cells, muciphages, and extracellular mucin were analyzed and scored semiquantitatively as 0 (absent), 1þ (rare), 2þ (occasionally), or 3þ (frequent). The presence of high grade cytologic features, significant amount of mesothelial cells, benign-appearing columnar cells, and results of mucicarmine stain, if performed, were noted as well.
Results Patient demographics, clinical data, and follow-up There were 28 women and 4 men, with age ranging from 31 to 76 years (mean 58.4 years). The site of the primary tumor was appendix in 25 (75.7%) patients (21 women, 4 men) (according to histopathological examination in 24 patients and according to intraoperative observation in 1 patient), and other parts of the gastrointestinal system in 2 women according to intraoperative observation. In 5 (21.2%) of 32 patients, primary tumor site could not be exactly identified.
Pseudomyxoma peritonei
45
In terms of treatment, all 32 patients had surgery (1 palliative), chemotherapy was added in 11 patients, and both chemotherapy and radiotherapy in 1 patient. Of the 32 patients, 10 were alive (2-156 months), 15 deceased (2-187 months, mean 62.4) and 7 were lost to follow-up. The relevant clinical data is summarized in Table 1.
Cytomorphologic findings, ancillary tests, and histopathologic correlation Of the 41 cases with the given clinical data in Table 1, 15 cases (36.6%) had cytology slides available for review. Extracellular mucinous material was a constant feature in all 15 (100.0%) PP cases and was abundant in 86.7% of the cases. In all cases reviewed, mucin was observed as a thick,
Table 1 Case No.
amorphous, and clean proteinaceous material diffusely coating the glass surface (better observed in cytospin preparations). Mucin was either extracellular in the slide background or was intracytoplasmic within the muciphages and/or epithelial cells. Neoplastic epithelial cells and muciphages were not seen in every case. The cytomorphologic characteristics included neoplastic glandular cells singly or in small groups in 11 (86.7%) cases (Fig. 1), mostly muciphages in 11 (73.4%) cases (Fig. 2), mostly mesothelial cells in 9 (60.0%) cases, few spindle cells in 2 (13.3%) cases, and benign-appearing columnar cells in 3 (20.0%) cases. In the high grade PP case, malignant cytologic features were readily appreciated (Fig. 3). Table 2 provides the details of cytomorphologic findings and results of mucin stain (cell block) of PP cases.
Demographics, clinical data, and follow-up of 32 patients with pseudomyxoma peritonei. Diagnosis
Age (years)
Sex
The Emory University Hospital 1 PMCA 58 M 2 DPAM 65 M 3 DPAM 56 F 4 DPAM 52 F The Ohio State University Wexner Medical Center 5 PMCA 75 F 6 PMCA 70 F 7 PMCA 50 F 8 PMCA 68 F The Johns Hopkins Hospital 9 DPAM 76 F 10 DPAM 31 F 11 PMCA-I/D 65 F 12 DPAM 58 F 13 DPAM 65 F 14 DPAM 38 F 15 DPAM 68 F 16 PMCA 35 M 17 PMCA 68 M 18 DPAM 49 F 19 DPAM 35 F 20 DPAM 52 F 21 DPAM 51 F 22 PMCA 54 F 23 PMCA 73 F 24 DPAM 52 F 25 DPAM 67 F 26 PMCA 68 F 27 DPAM 65 F 28 DPAM 46 F 29 DPAM 64 F 30 DPAM 76 F 31 DPAM 45 F 32 DPAM 75 F
Primary location
Treatment
Follow-up (months)
Appendix (intraoperative observation) Appendix Appendix Appendix
S (Palliative) S SþCT S
DOD (3) Alive (26) Alive (22) Alive (19)
Appendix Appendix Appendix Appendix
S SþCT SþCT S
DOD (2) AWD (48) AWD (156) LFU
Appendix Appendix Appendix Appendix Appendix Appendix Appendix Appendix Appendix Unknown Appendix Appendix Appendix Unknown Unknown Appendix Gastrointestinal (according to IHC) Unknown Unknown Appendix Appendix Gastrointestinal (according to IHC) Appendix Appendix
S SþCT SþCT S S S S Sþunknown Sþunknown S SþCT S S S SþCT S SþCT SþCTþRT S S S SþCT SþCT S
DOD (89) ANED (60) AWD (12) AWD (4) AWD (2) ANED (113) DOD (140) DOD (187) LFU DOD (130) LFU LFU LFU DOD (57) DOD (45) LFU LFU DOD (32) DOD (78) DOD (37) DOD (45) DOD (17) DOD (54) DOD (20)
Abbreviations: DPAM, disseminated peritoneal adenomucinosis; PMCA, peritoneal mucinous carcinomatosis; PMCA-I/D, peritoneal mucinous carcinomatosis-intermediate/discordant; IHC, immunohistochemistry; S, surgery; CT, chemotherapy; ANED, alive with no evidence of disease; AWD, alive with disease; DOD, died of disease; LFU, lost to follow-up.
46
Figure 1 Pseudomyxoma peritonei: neoplastic glandular epithelium seen as mostly single cells with intracytoplasmic vacuoles. A tissue fragment in mucinous material is also present (Papanicolaou stain, 200).
Based on histopathologic examination, 65.6% (n Z 21) of the patients were low-grade PP (DPAM), 31.3% (n Z 10) high-grade PP (PMCA) and 3.1% (n Z 1) intermediate grade PP (PMCA-I/D). Ovarian involvement was seen in 20 (71.4%) of 28 female patients. Original cytopathologic
I. Onur et al.
Figure 3 Peritoneal mucinous carcinomatosis: fragments of malignant glandular epithelium in a background of mucin. High grade cytologic features are readily seen (H&E stain, 100, cell block).
Table 2 Review of cytomorphologic findings and results of mucin staining: 15 cases of pseudomyxoma peritonei with available cytologic slides. Case No./ Epithelial Muci Extra High Meso Mucin Specimen cells phages cellular grade thelial stain collection mucin features cells method 1/IPW 2/P 3/P 4/P 5/P 6/IPW 7/IPW 8/IPW 9/P 10/P 11/IPW 12/IPW 13/IPW 14/IPW 15/IPW
Figure 2 Pseudomyxoma peritonei: muciphages and mucin (Papanicolaou stain, 200).
2þ 3þ 1þ 0 0 2þ 2þ 0 0 0 3þ 2þ 2þ 3þ 2þ
2þ 3þ 1þ 1þ 0 1þ 1þ 1þ 0 0 1þ 2þ 0 1þ 3þ
3þ 3þ 3þ 3þ 3þ 3þ 2þ 3þ 3þ 1þ 3þ 3þ 3þ 3þ 3þ
þ N/A N/A N/A N/A N/A
þ þ þ þ þ þ þ þ þ
ND þ ND ND ND ND ND þ þ ND ND ND ND ND ND
Abbreviations: IPW, intraoperative peritoneal washing; P, paracentesis; N/A, not applicable; ND, not done.
Pseudomyxoma peritonei Table 3
47
Cyto-histopathologic correlation and immunohistochemical findings.
Patient Original Surgical pathology diagnosis No. cytopathologic Peritoneum Appendix diagnosis The Emory University Hospital 1 PP PMCA
Involved (intraoperative observation) 2 PP DPAM LAMN 3 PP DPAM LAMN 4 PP DPAM LAMN The Ohio State University Wexner Medical Center 5 PP PMCA Mucinous adenocarcinoma 6 PP PMCA Mucinous adenocarcinoma 7 PP PMCA Mucinous adenocarcinoma 8
PP
PMCA
The Johns Hopkins Hospital 9 PP DPAM 10 Nondiagnostic DPAM 11 Nondiagnostic PMCA-I/D
Mucinous adenocarcinoma Carcinoid tumor
12 13 14 15 16 17
PP PP PP PP PP PP
DPAM DPAM DPAM DPAM PMCA PMCA
18
PP
DPAM
LAMN LAMN Mucinous adenocarcinoma arising from LAMN Ruptured LAMN LAMN Mucinous adenoma Mucinous adenoma Cystadenocarcinoma Mucinous adenocarcinoma arising in cystadenocarcinoma Mucocele
19 20 21 22
PP PP PP Atypical
DPAM DPAM DPAM PMCA
Cystadenoma Cystadenoma Cystadenoma NE
23
PP
PMCA
NE
24 25 26 27 28 29 30 31 32
PP Atypical PP PP PP PP PP PP PP
DPAM DPAM PMCA DPAM DPAM DPAM DPAM DPAM DPAM
Ruptured LAMN NE NE NE (history of appendectomy) Ruptured mucinous adenoma Ruptured mucinous adenoma NE Mucinous adenoma Mucinous adenoma
Ovary
IHC (surgical specimen)
N/A
ND
N/A Metastatic LAMN, bilateral -
ND ND ND
Mucinous adenocarcinoma, right CDX2þ/CK20þ/CK7 ND Mucinous adenocarcinoma, ND LG, bilateral Mucinous adenocarcinoma, panCKþ/CEAþ/CK20þ/CK7 LG, bilateral DPAM, bilateral DPAM, bilateral DPAM, bilateral DPAM, bilateral DPAM, bilateral NE N/A N/A
Mucinous cystadenoma with foci of tumor of low malignant potential, left normal ovary, right PP, bilateral Mucinous cystadenoma, bilateral Mucinous tumor with foci of invasion and associated PP, bilateral Mucinous cystadenocarcinoma, side unknown DPAM, bilateral DPAM, bilateral NE NE DPAM, bilateral DPAM, bilateral NE DPAM, bilateral DPAM, bilateral
CK20þ/CK7 CK20þ/CK7 focalþ CK20þ/CK7 diffuse þ/CDX2þ/CK19þ/TTF-1 CK20þ/CK7þ/CDX2þ CK20þ/CDX2þ/CK7 CK20þ/CK7 focalþ ND ND
ND
ND ND ND ND
ND ND CK20þ/CK7 CK20þ/CK7þ CK20þ/CK7 CK20þ/CK7 CK20þ/CK7 CK20þ/CK7 focalþ
Abbreviations: IHC, immunohistochemistry; LAMN, low grade appendiceal mucinous neoplasm; DPAM, disseminated peritoneal adenomucinosis; PMCA, peritoneal mucinous carcinomatosis; PMCA-I/D, peritoneal mucinous carcinomatosis-intermediate/discordant; LG, low grade; HG, high grade; ND, not done; NE, not examined.
diagnoses were consistent with histopathologic diagnoses in 30 (93.8%) of 32 patients. Two false negative cases were identified (1 low grade PP, 1 intermediate grade PP). Rescreening of the slides showed mucinous material in both
of the false negative cases without the presence of epithelial cells or muciphages in the low-grade PP. In the intermediate-grade PP case, bland-looking epithelial cells and muciphages were misinterpreted as mesothelial cells.
48 In Table 3, cytohistopathologic correlation and immunohistochemical staining results of 32 PP cases are given.
Discussion There are limited number of studies describing the cytomorphologic features of PP in abdominal fluid cytology in the literature.13-19 The cytomorphologic findings in abdominal fluid cytology of PP patients that are reported in the literature include abundant extracellular mucin, neoplastic epithelial cells, columnar cells, mesothelial cells, histiocytes, and fibroblast-like/spindle cells in varying proportions.14-20 In the literature, the reported incidence of neoplastic epithelial cells in abdominal fluid cytology ranges from 0.0% to 94.0% in patients with PP.13-16,19,20 This large variation in the range of the prevalence rate of neoplastic epithelial cells is possibly related to the abdominal fluid collection and cytologic preparation method. The reported rate is 91.7% to 94.0% in the studies where the specimens were collected intraoperatively and cytocentrifuged.14,20 In contrast, no epithelial cells were seen when the abdominal fluid was obtained by paracentesis and prepared by direct smear/filter preparation.1,13 Whereas the rate of presence of neoplastic epithelial cells was 88.9% in the intraoperative peritoneal washings of our cases, it was only 33.3% in the paracentesis fluids. It has been proposed that the presence of epithelial cells may be associated with worse prognosis and recurrence in cases of PP.16 In a larger series, however, Jackson et al20 suggested that classification of epithelial cells as either DPAM or PMCA is prognostically significant instead of the presence of epithelial cells alone and that PMCA patients have a worse prognosis than DPMA patients. We did not find a significant correlation between the presence of epithelial cells in abdominal fluid and the prognosis of PP patients. In our series, 34.4% of PP patients had a diagnosis of PMCA. The average time of death from disease was 53.8 months, which was shorter in PMCA patients than that in DPAM patients (71.8 months, on average). Well-differentiated columnar cells with small nuclei and clear cytoplasm floating in the mucus are said to be characteristic of DPAM.1 It has also been suggested that these cells may show the recurrence of PP.21 In our study, 20.0% of cases (n Z 3) had columnar epithelial cells on cytology. In the remaining 12 cases, epithelial cells were cuboidal in shape. Immunohistochemical and molecular data became important evidence in showing the real origin of PP.7,10,22-25 Ronnett et al6 found that the majority of the ovarian mucinous tumors with PP demonstrated an immunohistochemical positivity of CK7, CK18, CK20, CEA, and HAM56dsimilar to associated appendiceal neoplasm and discrepant from primary ovarian mucinous tumors of low malignant potential. Ferreira et al26 showed that ovarian
I. Onur et al. mucinous tumors associated with PP had significantly higher staining with MUC2 and CK20 than intestinal-type mucinous ovarian tumors without PP. In both studies, the interpretation that PP is a secondary disease arising from the appendix instead of the ovary was made. In the immunohistochemical study of Chu et al,27 mucinous carcinomas of appendiceal origin were detected to be positive for CK20, MUC-2, CDX-2 (heterogenous), and CK7, and negative for MUC-1, MUC-6, b-catenin (nuclear); mucinous carcinomas of ovarian origin were positive for PAX-8, CK7, CDX-2 (heterogenous), and ER (stromal), and negative for MUC6, WT-1, b-catenin (nuclear). Vang et al28 found immunohistochemical positivity of CK20 in 100.0% and 56.0%, and CK7 in 13.0%, and 100.0%, of appendiceal mucinous neoplasms and of primary ovarian mucinous carcinomas, respectively. In our study, immunohistochemistry was performed on surgical specimens of 14 patients (43.8%). CK20 positivity was detected in all 14 (100.0%) patients and CK7 positivity was seen in 6 patients (42.9%). The appendix represented the primary tumor site in most (75.7%) of our PP patients, consistent with the literature. Concomitant ovarian involvement was observed in 71.4% (n Z 20) female patients and was bilateral in 85.0% (n Z 17). To conclude, abdominal fluid cytology is highly effective in the diagnosis of PP. The most frequently encountered cytomorphologic feature of PP is abundant extracellular mucin. Neoplastic epithelial cells are usually scant and may be entirely absent. They are less frequently encountered in abdominal fluids obtained by paracentesis than in intraoperative peritoneal washings. Diagnosis of PP on cytology depends on an accurate recognition of extracellular mucin and muciphages. An accurate diagnosis of PP in a fluid specimen requires proper identification of free/extracellular mucin as well as distinguishing the often “benign-appearing” epithelial cells from reactive mesothelial cells and histiocytes.
Funding sources No specific funding was disclosed.
Conflict of interest disclosures The authors have no conflicts of interest to disclose regarding this study.
References 1. Bosman FT, World Health Organization, International Agency for Research on Cancer. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: International Agency for Research on Cancer; 2010. 2. Shetty S, Natarajan B, Thomas P, Govindarajan V, Sharma P, Loggie B. Proposed classification of pseudomyxoma peritonei: influence of signet ring cells on survival. Am Surg. 2013;79:1171e1176.
Pseudomyxoma peritonei 3. Leen SL, Singh N. Pathology of primary and metastatic mucinous ovarian neoplasms. J Clin Pathol. 2012;65:591e595. 4. 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;15:415e429. 5. 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: 591e603. 6. 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;16:1e9. 7. Misdraji J. Appendiceal mucinous neoplasms: controversial issues. Arch Pathol Lab Med. 2010;134:864e870. 8. Carr NJ, Finch J, Ilesley IC, et al. Pathology and prognosis in pseudomyxoma peritonei: a review of 274 cases. J Clin Pathol. 2012;65: 919e923. 9. Rosenberger LH, Stein LH, Witkiewicz AK, Kennedy EP, Yeo CJ. Intraductal papillary mucinous neoplasm (IPMN) with extrapancreatic mucin: a case series and review of the literature. J Gastrointest Surg. 2012;16:762e770. 10. Panarelli NC, Yantiss RK. Mucinous neoplasms of the appendix and peritoneum. Arch Pathol Lab Med. 2011;135:1261e1268. 11. 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;92:85e91. 12. Bradley RF, Stewart JHT, 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;30:551e559. 13. Gupta RK, Naran S. Cytodiagnosis of pseudomyxoma peritonei in cases suspected of ovarian tumours. Diagn Cytopathol. 1993;9: 682e684. 14. Shin HJ, Sneige N. Epithelial cells and other cytologic features of pseudomyxoma peritonei in patients with ovarian and/or appendiceal mucinous neoplasms: a study of 12 patients including 5 men. Cancer. 2000;90:17e23.
49 15. Pisharodi LR, Bedrossian CW. Cytologic diagnosis of pseudomyxoma peritonei: common and uncommon causes. Diagn Cytopathol. 1996; 14:10e13. 16. Mulvany N, Ooi K. Pseudomyxoma peritonei: a cytohistopathologic study of nine cases. Diagn Cytopathol. 1996;15:144e150. 17. Pfitzer P, Richartz G. Cytology of pseudomyxoma peritonei. Cytopathology. 1995;6:304e315. 18. Gupta RK. Pseudomyxoma peritonei and the cytologist. Cytopathology. 1996;7:289. 19. Leiman G, Goldberg R. Pseudomyxoma peritonei associated with ovarian mucinous tumors. Cytologic appearance in five cases. Acta Cytologica. 1992;36:299e304. 20. Jackson SL, Fleming RA, Loggie BW, Geisinger KR. Gelatinous ascites: a cytohistologic study of pseudomyxoma peritonei in 67 patients. Mod Pathol. 2001;14:664e671. 21. Gu M, Zuna RE. Columnar cells in smears from pseudomyxoma peritonei. Diagn Cytopathol. 1997;16:182e183. 22. Young RH. Pseudomyxoma peritonei and selected other aspects of the spread of appendiceal neoplasms. Semin Diagn Pathol. 2004;21: 134e150. 23. Pai RK, Longacre TA. Appendiceal mucinous tumors and pseudomyxoma peritonei: histologic features, diagnostic problems, and proposed classification. Adv Anat Pathol. 2005;12:291e311. 24. Cuatrecasas M, Matias-Guiu X, Prat J. Synchronous mucinous tumors of the appendix and the ovary associated with pseudomyxoma peritonei. A clinicopathologic study of six cases with comparative analysis of c-Ki-ras mutations. Am J Surg Pathol. 1996;20:739e746. 25. Chuaqui RF, Zhuang Z, Emmert-Buck MR, et al. Genetic analysis of synchronous mucinous tumors of the ovary and appendix. Hum Pathol. 1996;27:165e171. 26. Ferreira CR, Carvalho JP, Soares FA, Siqueira SA, Carvalho FM. Mucinous ovarian tumors associated with pseudomyxoma peritonei of adenomucinosis type: immunohistochemical evidence that they are secondary tumors. Int J Gynecol Cancer. 2008;18:59e65. 27. Chu PG, Chung L, Weiss LM, Lau SK. Determining the site of origin of mucinous adenocarcinoma: an immunohistochemical study of 175 cases. Am J Surg Pathol. 2011;35:1830e1836. 28. Vang R, Gown AM, Barry TS, et al. Cytokeratins 7 and 20 in primary and secondary mucinous tumors of the ovary: analysis of coordinate immunohistochemical expression profiles and staining distribution in 179 cases. Am J Surg Pathol. 2006;30:1130e1139.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jascyto.org/
ORIGINAL ARTICLE
Pseudomyxoma peritonei: cytomorphologic findings and clinicopathologic correlates Irem Onur, MDa, Momin T. Siddiqui, MD, FIACb, Paul E. Wakely Jr., MDc, Syed Z. Ali, MD, FRCPath, FIACa,* a
Division of Cytopathology, Department of Pathology, The Johns Hopkins Medical Institutions, Rm PATH 406, 600 N. Wolfe Street, Baltimore, Maryland 21287 b Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, Georgia c Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio Received 3 February 2015; received in revised form 14 September 2015; accepted 16 September 2015
KEYWORDS Pseudomyxoma peritonei; Abdominal fluid; Gelatinous ascites; Appendiceal mucinous neoplasm; Cytopathology
Introduction To analyze the cytomorphology and clinical correlates of pseudomyxoma peritonei (PP), a frequently fatal pathological entity defined by gelatinous ascites caused by slow but relentless accumulation of mucin produced by neoplastic glandular epithelium. Materials and methods A retrospective search of the electronic pathology data systems of three large tertiary care medical institutions revealed 41 cases from 32 patients with PP and corresponding abdominal fluid cytologic specimens. Cytologic material was available for review in 15 cases. Results The primary tumor site was appendix in 25 (78.1%) of the 32 patients, other regions of the gastrointestinal tract in 2 (6.3%) patients, and in 5 (15.6%) patients, the primary could not be entirely identified. Of the 41 cases, only 15 had available cytologic slides to review. Extracellular mucin was a constant feature in all 15 (100%) cases, being abundant in 13 cases and focal in 2 cases. Predominance of mucin-secreting neoplastic epithelial cells were observed in 10 (66.7%) and muciphages in 11 (73.4%) cases. Cytopathologic interpretations were consistent with the subsequent histopathologic diagnosis in 30 of 32 cases (93.8%). There were two false negative cases, both of which showed scant mucinous material on second review. Conclusions PP is uncommonly encountered in routine cytopathology practice. The common denominator is the presence of an often-abundant extracellular mucin. Epithelial (glandular) component is usually scant. An accurate diagnosis in a fluid specimen requires proper identification of free/extracellular mucin as well as distinguishing the often “benign-appearing” epithelial cells from reactive mesothelial cells and histiocytes. Ó 2016 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.
*Corresponding author: Dr. Syed Z. Ali, MD, FRCPath, FIAC; Professor of Pathology and Radiology, The Johns Hopkins Hospital, Path 406, 600 N. Wolfe St. Baltimore, MD 21287; Tel.: 1-410-955-1180; Fax: 1-410-614-9556. E-mail address: [email protected] (S.Z. Ali). 2213-2945/$36 Ó 2016 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jasc.2015.09.214
44
I. Onur et al.
Introduction
Materials and methods
Pseudomyxoma peritonei (PP) is a rare and frequently fatal disease presenting with gelatinous ascites caused by slow but progressive accumulation of mucin produced by growth of neoplastic mucin-secreting cells.1,2 In most cases, the primary site is the appendix. The majority of the PP cases that were thought to be of ovarian derivative are now considered to be appendiceal in origin with secondary involvement of the ovary.3-7 In rare cases with no evidence of non-ovarian source of mucinous tumor, the ovary is suggested to be a rare primary site when intestinal type mucinous adenocarcinoma arises in mature cystic teratoma.1 Occasionally, PP may also arise from colorectum, urachus, small intestine, stomach, pancreas, gall bladder and bile duct, gastric teratoma, fallopian tube, lung, and breast.1,8,9 There is an ongoing debate on the nature, nomenclature, and classification of PP as well as classification of appendiceal mucinous neoplasms. The controversy focuses on whether the growing epithelium is adenomatous or carcinomatous in PP. Panarelli et al10 do not accept PP as a neoplastic process and conclude that non-neoplastic etiologies such as diverticula of appendix and colon can cause PP. Ronnett et al11 categorize PP into three distinct subcategories: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and peritoneal mucinous carcinomatosis-intermediate/discordant (PMCA-I/D). DPAM consists of peritoneal lesions with mucinous epithelium with little cytologic atypia, mitosis, and abundant extracellular mucin. PMCA constitutes more abundant mucinous epithelium forming glands and/or signet ring cells and shows cytologic atypia and architectural features of mucinous carcinoma. PMCA-I/D cases demonstrate cytologic and architectural features of welldifferentiated mucinous carcinoma in combination with more bland areas. DPAM is associated with ruptured appendiceal mucinous adenomas, whereas most PMCA cases are associated with mucinous adenocarcinoma of appendix or colon. According to both TNM classification and the study of Bradley et al,12 PP is a carcinoma and is classified as low grade and high grade. They avoid DPAM terminology based on their view that low grade and high grade lesions represent a continuous spectrum and the concept of ruptured adenoma does not sufficiently reflect the frequently fatal course of this disease.1,12 Additionally, a new three-tiered classification system has also been proposed for peritoneal metastases arising from a mucinous appendiceal neoplasm consisting of PP1, PP2, and PP3 based on histological grade.2 Although there are numerous studies on histopathologic characteristics of PP, there are limited data on the cytopathology of PP. Therefore, we aimed to elaborate in this study on cytomorphologic features of PP by analyzing 41 cases of PP collected from three large tertiary care institutions.
Case selection and information The institutional review board provided permission to search electronic medical records. All patients with histologically confirmed PP who had abdominal fluid cytology were searched retrospectively. The search included all available records from the electronic pathology data systems of The Johns Hopkins Hospital (JHH) from May 5, 1980 to January 9, 2014; Emory University Hospital (EUH) from January 1, 2006 to February 3, 2014; and The Ohio State University Wexner Medical Center (OSUWMC) from January 1, 1999 to December 31, 2011. Consultation cases were excluded. Over these periods, a total of 41 cases from 32 patients with corresponding surgical pathology diagnosis of PP (33 cases at JHH, 4 cases at EUH, and 4 cases at OSUWMC) were found. Of the 41 cases, 15 (7 cases at JHH, 4 cases at EUH, and 4 cases at OSUWMC) had available cytologic slides to review. Clinicopathologic information including patient age, sex, treatment, and followup information was obtained for each case. If available, the results of immunohistochemical stains were recorded.
Cytopathology Abdominal fluids were obtained either by paracentesis or washing during surgery. Specimens were prepared with cytospin (Thermo Shandon Inc., Pittsburgh, Penn) and Millipore filters (Millipore Corporation, Billerica, Mass) at JHH, with ThinPrep (Cytyc Corp., Boxborough, Mass) at EUH, and with cytospin at OSUWMC. All slides were stained with Papanicolaou stain. At each institution, a cytopathologist re-reviewed the retrieved cytology material. Cytomorphologic findings including presence of epithelial cells, muciphages, and extracellular mucin were analyzed and scored semiquantitatively as 0 (absent), 1þ (rare), 2þ (occasionally), or 3þ (frequent). The presence of high grade cytologic features, significant amount of mesothelial cells, benign-appearing columnar cells, and results of mucicarmine stain, if performed, were noted as well.
Results Patient demographics, clinical data, and follow-up There were 28 women and 4 men, with age ranging from 31 to 76 years (mean 58.4 years). The site of the primary tumor was appendix in 25 (75.7%) patients (21 women, 4 men) (according to histopathological examination in 24 patients and according to intraoperative observation in 1 patient), and other parts of the gastrointestinal system in 2 women according to intraoperative observation. In 5 (21.2%) of 32 patients, primary tumor site could not be exactly identified.
Pseudomyxoma peritonei
45
In terms of treatment, all 32 patients had surgery (1 palliative), chemotherapy was added in 11 patients, and both chemotherapy and radiotherapy in 1 patient. Of the 32 patients, 10 were alive (2-156 months), 15 deceased (2-187 months, mean 62.4) and 7 were lost to follow-up. The relevant clinical data is summarized in Table 1.
Cytomorphologic findings, ancillary tests, and histopathologic correlation Of the 41 cases with the given clinical data in Table 1, 15 cases (36.6%) had cytology slides available for review. Extracellular mucinous material was a constant feature in all 15 (100.0%) PP cases and was abundant in 86.7% of the cases. In all cases reviewed, mucin was observed as a thick,
Table 1 Case No.
amorphous, and clean proteinaceous material diffusely coating the glass surface (better observed in cytospin preparations). Mucin was either extracellular in the slide background or was intracytoplasmic within the muciphages and/or epithelial cells. Neoplastic epithelial cells and muciphages were not seen in every case. The cytomorphologic characteristics included neoplastic glandular cells singly or in small groups in 11 (86.7%) cases (Fig. 1), mostly muciphages in 11 (73.4%) cases (Fig. 2), mostly mesothelial cells in 9 (60.0%) cases, few spindle cells in 2 (13.3%) cases, and benign-appearing columnar cells in 3 (20.0%) cases. In the high grade PP case, malignant cytologic features were readily appreciated (Fig. 3). Table 2 provides the details of cytomorphologic findings and results of mucin stain (cell block) of PP cases.
Demographics, clinical data, and follow-up of 32 patients with pseudomyxoma peritonei. Diagnosis
Age (years)
Sex
The Emory University Hospital 1 PMCA 58 M 2 DPAM 65 M 3 DPAM 56 F 4 DPAM 52 F The Ohio State University Wexner Medical Center 5 PMCA 75 F 6 PMCA 70 F 7 PMCA 50 F 8 PMCA 68 F The Johns Hopkins Hospital 9 DPAM 76 F 10 DPAM 31 F 11 PMCA-I/D 65 F 12 DPAM 58 F 13 DPAM 65 F 14 DPAM 38 F 15 DPAM 68 F 16 PMCA 35 M 17 PMCA 68 M 18 DPAM 49 F 19 DPAM 35 F 20 DPAM 52 F 21 DPAM 51 F 22 PMCA 54 F 23 PMCA 73 F 24 DPAM 52 F 25 DPAM 67 F 26 PMCA 68 F 27 DPAM 65 F 28 DPAM 46 F 29 DPAM 64 F 30 DPAM 76 F 31 DPAM 45 F 32 DPAM 75 F
Primary location
Treatment
Follow-up (months)
Appendix (intraoperative observation) Appendix Appendix Appendix
S (Palliative) S SþCT S
DOD (3) Alive (26) Alive (22) Alive (19)
Appendix Appendix Appendix Appendix
S SþCT SþCT S
DOD (2) AWD (48) AWD (156) LFU
Appendix Appendix Appendix Appendix Appendix Appendix Appendix Appendix Appendix Unknown Appendix Appendix Appendix Unknown Unknown Appendix Gastrointestinal (according to IHC) Unknown Unknown Appendix Appendix Gastrointestinal (according to IHC) Appendix Appendix
S SþCT SþCT S S S S Sþunknown Sþunknown S SþCT S S S SþCT S SþCT SþCTþRT S S S SþCT SþCT S
DOD (89) ANED (60) AWD (12) AWD (4) AWD (2) ANED (113) DOD (140) DOD (187) LFU DOD (130) LFU LFU LFU DOD (57) DOD (45) LFU LFU DOD (32) DOD (78) DOD (37) DOD (45) DOD (17) DOD (54) DOD (20)
Abbreviations: DPAM, disseminated peritoneal adenomucinosis; PMCA, peritoneal mucinous carcinomatosis; PMCA-I/D, peritoneal mucinous carcinomatosis-intermediate/discordant; IHC, immunohistochemistry; S, surgery; CT, chemotherapy; ANED, alive with no evidence of disease; AWD, alive with disease; DOD, died of disease; LFU, lost to follow-up.
46
Figure 1 Pseudomyxoma peritonei: neoplastic glandular epithelium seen as mostly single cells with intracytoplasmic vacuoles. A tissue fragment in mucinous material is also present (Papanicolaou stain, 200).
Based on histopathologic examination, 65.6% (n Z 21) of the patients were low-grade PP (DPAM), 31.3% (n Z 10) high-grade PP (PMCA) and 3.1% (n Z 1) intermediate grade PP (PMCA-I/D). Ovarian involvement was seen in 20 (71.4%) of 28 female patients. Original cytopathologic
I. Onur et al.
Figure 3 Peritoneal mucinous carcinomatosis: fragments of malignant glandular epithelium in a background of mucin. High grade cytologic features are readily seen (H&E stain, 100, cell block).
Table 2 Review of cytomorphologic findings and results of mucin staining: 15 cases of pseudomyxoma peritonei with available cytologic slides. Case No./ Epithelial Muci Extra High Meso Mucin Specimen cells phages cellular grade thelial stain collection mucin features cells method 1/IPW 2/P 3/P 4/P 5/P 6/IPW 7/IPW 8/IPW 9/P 10/P 11/IPW 12/IPW 13/IPW 14/IPW 15/IPW
Figure 2 Pseudomyxoma peritonei: muciphages and mucin (Papanicolaou stain, 200).
2þ 3þ 1þ 0 0 2þ 2þ 0 0 0 3þ 2þ 2þ 3þ 2þ
2þ 3þ 1þ 1þ 0 1þ 1þ 1þ 0 0 1þ 2þ 0 1þ 3þ
3þ 3þ 3þ 3þ 3þ 3þ 2þ 3þ 3þ 1þ 3þ 3þ 3þ 3þ 3þ
þ N/A N/A N/A N/A N/A
þ þ þ þ þ þ þ þ þ
ND þ ND ND ND ND ND þ þ ND ND ND ND ND ND
Abbreviations: IPW, intraoperative peritoneal washing; P, paracentesis; N/A, not applicable; ND, not done.
Pseudomyxoma peritonei Table 3
47
Cyto-histopathologic correlation and immunohistochemical findings.
Patient Original Surgical pathology diagnosis No. cytopathologic Peritoneum Appendix diagnosis The Emory University Hospital 1 PP PMCA
Involved (intraoperative observation) 2 PP DPAM LAMN 3 PP DPAM LAMN 4 PP DPAM LAMN The Ohio State University Wexner Medical Center 5 PP PMCA Mucinous adenocarcinoma 6 PP PMCA Mucinous adenocarcinoma 7 PP PMCA Mucinous adenocarcinoma 8
PP
PMCA
The Johns Hopkins Hospital 9 PP DPAM 10 Nondiagnostic DPAM 11 Nondiagnostic PMCA-I/D
Mucinous adenocarcinoma Carcinoid tumor
12 13 14 15 16 17
PP PP PP PP PP PP
DPAM DPAM DPAM DPAM PMCA PMCA
18
PP
DPAM
LAMN LAMN Mucinous adenocarcinoma arising from LAMN Ruptured LAMN LAMN Mucinous adenoma Mucinous adenoma Cystadenocarcinoma Mucinous adenocarcinoma arising in cystadenocarcinoma Mucocele
19 20 21 22
PP PP PP Atypical
DPAM DPAM DPAM PMCA
Cystadenoma Cystadenoma Cystadenoma NE
23
PP
PMCA
NE
24 25 26 27 28 29 30 31 32
PP Atypical PP PP PP PP PP PP PP
DPAM DPAM PMCA DPAM DPAM DPAM DPAM DPAM DPAM
Ruptured LAMN NE NE NE (history of appendectomy) Ruptured mucinous adenoma Ruptured mucinous adenoma NE Mucinous adenoma Mucinous adenoma
Ovary
IHC (surgical specimen)
N/A
ND
N/A Metastatic LAMN, bilateral -
ND ND ND
Mucinous adenocarcinoma, right CDX2þ/CK20þ/CK7 ND Mucinous adenocarcinoma, ND LG, bilateral Mucinous adenocarcinoma, panCKþ/CEAþ/CK20þ/CK7 LG, bilateral DPAM, bilateral DPAM, bilateral DPAM, bilateral DPAM, bilateral DPAM, bilateral NE N/A N/A
Mucinous cystadenoma with foci of tumor of low malignant potential, left normal ovary, right PP, bilateral Mucinous cystadenoma, bilateral Mucinous tumor with foci of invasion and associated PP, bilateral Mucinous cystadenocarcinoma, side unknown DPAM, bilateral DPAM, bilateral NE NE DPAM, bilateral DPAM, bilateral NE DPAM, bilateral DPAM, bilateral
CK20þ/CK7 CK20þ/CK7 focalþ CK20þ/CK7 diffuse þ/CDX2þ/CK19þ/TTF-1 CK20þ/CK7þ/CDX2þ CK20þ/CDX2þ/CK7 CK20þ/CK7 focalþ ND ND
ND
ND ND ND ND
ND ND CK20þ/CK7 CK20þ/CK7þ CK20þ/CK7 CK20þ/CK7 CK20þ/CK7 CK20þ/CK7 focalþ
Abbreviations: IHC, immunohistochemistry; LAMN, low grade appendiceal mucinous neoplasm; DPAM, disseminated peritoneal adenomucinosis; PMCA, peritoneal mucinous carcinomatosis; PMCA-I/D, peritoneal mucinous carcinomatosis-intermediate/discordant; LG, low grade; HG, high grade; ND, not done; NE, not examined.
diagnoses were consistent with histopathologic diagnoses in 30 (93.8%) of 32 patients. Two false negative cases were identified (1 low grade PP, 1 intermediate grade PP). Rescreening of the slides showed mucinous material in both
of the false negative cases without the presence of epithelial cells or muciphages in the low-grade PP. In the intermediate-grade PP case, bland-looking epithelial cells and muciphages were misinterpreted as mesothelial cells.
48 In Table 3, cytohistopathologic correlation and immunohistochemical staining results of 32 PP cases are given.
Discussion There are limited number of studies describing the cytomorphologic features of PP in abdominal fluid cytology in the literature.13-19 The cytomorphologic findings in abdominal fluid cytology of PP patients that are reported in the literature include abundant extracellular mucin, neoplastic epithelial cells, columnar cells, mesothelial cells, histiocytes, and fibroblast-like/spindle cells in varying proportions.14-20 In the literature, the reported incidence of neoplastic epithelial cells in abdominal fluid cytology ranges from 0.0% to 94.0% in patients with PP.13-16,19,20 This large variation in the range of the prevalence rate of neoplastic epithelial cells is possibly related to the abdominal fluid collection and cytologic preparation method. The reported rate is 91.7% to 94.0% in the studies where the specimens were collected intraoperatively and cytocentrifuged.14,20 In contrast, no epithelial cells were seen when the abdominal fluid was obtained by paracentesis and prepared by direct smear/filter preparation.1,13 Whereas the rate of presence of neoplastic epithelial cells was 88.9% in the intraoperative peritoneal washings of our cases, it was only 33.3% in the paracentesis fluids. It has been proposed that the presence of epithelial cells may be associated with worse prognosis and recurrence in cases of PP.16 In a larger series, however, Jackson et al20 suggested that classification of epithelial cells as either DPAM or PMCA is prognostically significant instead of the presence of epithelial cells alone and that PMCA patients have a worse prognosis than DPMA patients. We did not find a significant correlation between the presence of epithelial cells in abdominal fluid and the prognosis of PP patients. In our series, 34.4% of PP patients had a diagnosis of PMCA. The average time of death from disease was 53.8 months, which was shorter in PMCA patients than that in DPAM patients (71.8 months, on average). Well-differentiated columnar cells with small nuclei and clear cytoplasm floating in the mucus are said to be characteristic of DPAM.1 It has also been suggested that these cells may show the recurrence of PP.21 In our study, 20.0% of cases (n Z 3) had columnar epithelial cells on cytology. In the remaining 12 cases, epithelial cells were cuboidal in shape. Immunohistochemical and molecular data became important evidence in showing the real origin of PP.7,10,22-25 Ronnett et al6 found that the majority of the ovarian mucinous tumors with PP demonstrated an immunohistochemical positivity of CK7, CK18, CK20, CEA, and HAM56dsimilar to associated appendiceal neoplasm and discrepant from primary ovarian mucinous tumors of low malignant potential. Ferreira et al26 showed that ovarian
I. Onur et al. mucinous tumors associated with PP had significantly higher staining with MUC2 and CK20 than intestinal-type mucinous ovarian tumors without PP. In both studies, the interpretation that PP is a secondary disease arising from the appendix instead of the ovary was made. In the immunohistochemical study of Chu et al,27 mucinous carcinomas of appendiceal origin were detected to be positive for CK20, MUC-2, CDX-2 (heterogenous), and CK7, and negative for MUC-1, MUC-6, b-catenin (nuclear); mucinous carcinomas of ovarian origin were positive for PAX-8, CK7, CDX-2 (heterogenous), and ER (stromal), and negative for MUC6, WT-1, b-catenin (nuclear). Vang et al28 found immunohistochemical positivity of CK20 in 100.0% and 56.0%, and CK7 in 13.0%, and 100.0%, of appendiceal mucinous neoplasms and of primary ovarian mucinous carcinomas, respectively. In our study, immunohistochemistry was performed on surgical specimens of 14 patients (43.8%). CK20 positivity was detected in all 14 (100.0%) patients and CK7 positivity was seen in 6 patients (42.9%). The appendix represented the primary tumor site in most (75.7%) of our PP patients, consistent with the literature. Concomitant ovarian involvement was observed in 71.4% (n Z 20) female patients and was bilateral in 85.0% (n Z 17). To conclude, abdominal fluid cytology is highly effective in the diagnosis of PP. The most frequently encountered cytomorphologic feature of PP is abundant extracellular mucin. Neoplastic epithelial cells are usually scant and may be entirely absent. They are less frequently encountered in abdominal fluids obtained by paracentesis than in intraoperative peritoneal washings. Diagnosis of PP on cytology depends on an accurate recognition of extracellular mucin and muciphages. An accurate diagnosis of PP in a fluid specimen requires proper identification of free/extracellular mucin as well as distinguishing the often “benign-appearing” epithelial cells from reactive mesothelial cells and histiocytes.
Funding sources No specific funding was disclosed.
Conflict of interest disclosures The authors have no conflicts of interest to disclose regarding this study.
References 1. Bosman FT, World Health Organization, International Agency for Research on Cancer. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: International Agency for Research on Cancer; 2010. 2. Shetty S, Natarajan B, Thomas P, Govindarajan V, Sharma P, Loggie B. Proposed classification of pseudomyxoma peritonei: influence of signet ring cells on survival. Am Surg. 2013;79:1171e1176.
Pseudomyxoma peritonei 3. Leen SL, Singh N. Pathology of primary and metastatic mucinous ovarian neoplasms. J Clin Pathol. 2012;65:591e595. 4. 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;15:415e429. 5. 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: 591e603. 6. 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;16:1e9. 7. Misdraji J. Appendiceal mucinous neoplasms: controversial issues. Arch Pathol Lab Med. 2010;134:864e870. 8. Carr NJ, Finch J, Ilesley IC, et al. Pathology and prognosis in pseudomyxoma peritonei: a review of 274 cases. J Clin Pathol. 2012;65: 919e923. 9. Rosenberger LH, Stein LH, Witkiewicz AK, Kennedy EP, Yeo CJ. Intraductal papillary mucinous neoplasm (IPMN) with extrapancreatic mucin: a case series and review of the literature. J Gastrointest Surg. 2012;16:762e770. 10. Panarelli NC, Yantiss RK. Mucinous neoplasms of the appendix and peritoneum. Arch Pathol Lab Med. 2011;135:1261e1268. 11. 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;92:85e91. 12. Bradley RF, Stewart JHT, 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;30:551e559. 13. Gupta RK, Naran S. Cytodiagnosis of pseudomyxoma peritonei in cases suspected of ovarian tumours. Diagn Cytopathol. 1993;9: 682e684. 14. Shin HJ, Sneige N. Epithelial cells and other cytologic features of pseudomyxoma peritonei in patients with ovarian and/or appendiceal mucinous neoplasms: a study of 12 patients including 5 men. Cancer. 2000;90:17e23.
49 15. Pisharodi LR, Bedrossian CW. Cytologic diagnosis of pseudomyxoma peritonei: common and uncommon causes. Diagn Cytopathol. 1996; 14:10e13. 16. Mulvany N, Ooi K. Pseudomyxoma peritonei: a cytohistopathologic study of nine cases. Diagn Cytopathol. 1996;15:144e150. 17. Pfitzer P, Richartz G. Cytology of pseudomyxoma peritonei. Cytopathology. 1995;6:304e315. 18. Gupta RK. Pseudomyxoma peritonei and the cytologist. Cytopathology. 1996;7:289. 19. Leiman G, Goldberg R. Pseudomyxoma peritonei associated with ovarian mucinous tumors. Cytologic appearance in five cases. Acta Cytologica. 1992;36:299e304. 20. Jackson SL, Fleming RA, Loggie BW, Geisinger KR. Gelatinous ascites: a cytohistologic study of pseudomyxoma peritonei in 67 patients. Mod Pathol. 2001;14:664e671. 21. Gu M, Zuna RE. Columnar cells in smears from pseudomyxoma peritonei. Diagn Cytopathol. 1997;16:182e183. 22. Young RH. Pseudomyxoma peritonei and selected other aspects of the spread of appendiceal neoplasms. Semin Diagn Pathol. 2004;21: 134e150. 23. Pai RK, Longacre TA. Appendiceal mucinous tumors and pseudomyxoma peritonei: histologic features, diagnostic problems, and proposed classification. Adv Anat Pathol. 2005;12:291e311. 24. Cuatrecasas M, Matias-Guiu X, Prat J. Synchronous mucinous tumors of the appendix and the ovary associated with pseudomyxoma peritonei. A clinicopathologic study of six cases with comparative analysis of c-Ki-ras mutations. Am J Surg Pathol. 1996;20:739e746. 25. Chuaqui RF, Zhuang Z, Emmert-Buck MR, et al. Genetic analysis of synchronous mucinous tumors of the ovary and appendix. Hum Pathol. 1996;27:165e171. 26. Ferreira CR, Carvalho JP, Soares FA, Siqueira SA, Carvalho FM. Mucinous ovarian tumors associated with pseudomyxoma peritonei of adenomucinosis type: immunohistochemical evidence that they are secondary tumors. Int J Gynecol Cancer. 2008;18:59e65. 27. Chu PG, Chung L, Weiss LM, Lau SK. Determining the site of origin of mucinous adenocarcinoma: an immunohistochemical study of 175 cases. Am J Surg Pathol. 2011;35:1830e1836. 28. Vang R, Gown AM, Barry TS, et al. Cytokeratins 7 and 20 in primary and secondary mucinous tumors of the ovary: analysis of coordinate immunohistochemical expression profiles and staining distribution in 179 cases. Am J Surg Pathol. 2006;30:1130e1139.