Obstetrics & Gynecology Track the topics, authors and articles important to you
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Obstetrics & Gynecology 2002;100:1290-1295
© 2002 by The American College of Obstetricians and Gynecologists
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Holcomb, K.
Right arrow Articles by Chambers, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Holcomb, K.
Right arrow Articles by Chambers, J.

ORIGINAL RESEARCH

E-Cadherin Expression in Endometrioid, Papillary Serous, and Clear Cell Carcinoma of the Endometrium

Kevin Holcomb, MD, Roberto Delatorre, MD, Bader Pedemonte, MD, Carla McLeod, MD, Lisa Anderson, MD and Joseph Chambers, MD, PhD

From the Departments of Obstetrics and Gynecology and Surgical Pathology, St. Luke’s–Roosevelt Hospital and Beth Israel Medical Center; and Bioreference GEMPATH Laboratories, Columbia University College of Physicians and Surgeons, New York, New York.

Address reprint requests to: Kevin Holcomb, MD, Beth Israel Medical Center, Department of Obstetrics and Gynecology, 350 East 17th Street, 8BH27, New York, NY 10003; E-mail: kholcomb{at}chpnet.org.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To compare the frequency and pattern of E-cadherin expression in endometrioid, papillary serous, and clear cell carcinomas of the endometrium.

METHODS: E-cadherin expression was examined in 76 endometrial carcinomas by immunohistochemistry using a monoclonal antibody to E-cadherin and was correlated with poor prognostic indicators such as depth of myometrial invasion, lymph node status, and intraperitoneal spread. The frequency of expression was compared between endometrioid, papillary serous, and clear cell carcinomas by the Fisher exact test. Logistic regression was used to examine the simultaneous effect of histological type and tumor grade on E-cadherin expression.

RESULTS: Sixty-three endometrioid, nine papillary serous, two clear cell, and two carcinomas of mixed histology were examined. E-cadherin negative tumors were more likely to be poorly differentiated (P < .01), have cervical extension (P = .02), have positive peritoneal cytology (P < .01), and have adnexal spread (P = .01) when compared with E-cadherin positive tumors. Papillary serous and clear cell carcinomas were significantly less likely to express E-cadherin than endometrioid carcinoma (38% versus 95%, P < .001). Tumor grade and histological type were identified as significant predictors of E-cadherin expression in univariable analysis; however, only histological type remained significant in multivariable analysis (P = .01). When grade was controlled, endometrioid carcinoma remained 23 times more likely to express E-cadherin than papillary serous and clear cell carcinomas.

CONCLUSION: Papillary serous and clear cell carcinomas are significantly less likely to express E-cadherin than endometrioid tumors. This difference may account for the more aggressive behavior of papillary serous and clear cell carcinomas.

Uterine papillary serous carcinoma—a rare variant established as a distinct entity by Lauchlan1 and Hendrickson et al2—accounts for 3–10% of endometrial cancers. Clear cell carcinoma, another rare variant, may coexist with papillary serous carcinoma and accounts for 0.8–5.5% of all endometrial cancers. Numerous studies suggest an aggressive behavior and poor survival for papillary serous3–5 and clear cell6–8 carcinomas due to their propensity for extrauterine metastasis at the time of diagnosis. In contrast, the majority of endometrioid carcinomas are confined to the uterus at the time of diagnosis, and survival rates of 75% or more can be expected.9

It is possible that the more aggressive behavior of papillary serous and clear cell carcinoma is due to a decrease in tumor cell cohesiveness in these cancers relative to endometrioid carcinoma. In epithelial cells, the loss of cell-cell contact is associated with downregulation in the expression of E-cadherin. Cadherins are cell surface glycoproteins that mediate cell-cell adhesion through a Ca2+-dependent mechanism. Previous studies suggest that decreased expression of cadherin is associated with metastases in ovarian,10 breast,11 and endometrial12 cancers and that expression is significantly less likely in poorly differentiated tumors. No difference in E-cadherin expression was found between the various histological subtypes of breast and ovarian cancer, and no previous comparison was performed between the histological subtypes of endometrial cancer.

Our study examines the relative probability of E-cadherin expression between papillary serous, clear cell, and endometrioid carcinomas as well as the degree to which E-cadherin expression is independently associated with extrauterine metastasis.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Ninety-two women were diagnosed with endometrial cancer between 1997 and 2001. Of these, 76 who underwent surgery and had slides of the preoperative endometrial biopsy and hysterectomy specimen available for review comprised the study group. The patients had received no prior therapy for endometrial cancer. Thirtysix patients (47%) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pelvic and paraaortic lymph node biopsies were performed in addition to hysterectomy and bilateral salpingo-oophorectomy in 40 patients (53%). Omentectomy was performed on ten patients with papillary serous and clear cell histology. Histological slides of the hysterectomy specimens were reviewed by one of the authors (RD) to confirm the tumor type and grade. As per the 1988 revision of the International Federation of Gynecology and Obstetrics staging system,13 endometrioid tumors were graded primarily by their architecture, with the overall grade being modified by the nuclear grade when marked discordance was present. Nuclear grading was employed for papillary serous and clear cell carcinomas. The patients’ demographic and clinical information was abstracted from the hospital charts as well as the tumor registry.

Immunohistochemical staining for E-cadherin (clone NCH-38; 1:50; DAKO, Carpinteria, CA) was performed using a streptavidin-biotin-peroxidase complex method. Briefly, formalin-fixed paraffin-embedded tissue sections were deparaffinized and rehydrated through xylene and graded alcohols. The sections were then subjected to antigen retrieval with a microwave-based heat-induced protocol. A sensitive labeled ENVISION + Peroxidase System was used on the DAKO Autostainer Immunostaining System. After using diaminobenzidine as the chromogen, the sections were counterstained with hematoxylin and coverslipped. Uterine cervical epithelium was used as an external positive control. Whenever possible, benign endometrial epithelium was used as the internal positive control.

A minimum of 25 fields were examined at x 10 magnification for each specimen. A semiquantitative scoring system was developed, and four different staining patterns for E-cadherin were identified: diffuse linear, when crisp membrane staining was seen in more than 75% of tumor cells in the absence of cytoplasmic staining (Figure 1AGo); diffuse granular, when membrane and cytoplasmic staining was seen in 26–100% of the tumor cells (Figure 1BGo); and focal granular, when membrane and cytoplasmic staining was seen in 5–25% of the tumor cells (Figure 1CGo). Staining was considered negative when less than 4% of the tumor cells were positive, irrespective of pattern (Figure 1DGo). Benign endometrial and cervical epithelium invariably stained with the diffuse linear pattern. Tumor samples expressing E-cadherin in the diffuse linear pattern were considered to have a normal pattern of expression. The level of E-cadherin staining in the remaining tumor samples decreased from diffuse granular to focal granular to negative. Structural localization and not the intensity of the reaction was taken into consideration in the scoring system.



View larger version (133K):
[in this window]
[in a new window]
  		Figure 1. Four patterns of E-cadherin staining with monoclonal antibody (clone NCH-38; 1:50; DAKO, Carpinteria, California) were identified. Diffuse linear (A): crisp membrane staining in more than 75% of cells; diffuse granular (B): membrane and cytoplasmic staining in 26–100% of cells; focal granular (C): membrane and cytoplasmic staining in 5–25% of cells; negative (D): less than 4% of cells staining, irrespective of pattern. x 40, original magnification.

Holcomb. Cadherin in Endometrial Cancer. Obstet Gynecol 2002.

 
The percentage of tumors of each histological type that expressed E-cadherin was compared by Fisher exact test. Logistic regression was used to examine the simultaneous effect of histological type and tumor grade on E-cadherin expression. Logistic regression was also used to examine the simultaneous effect of E-cadherin expression, histological type, and tumor grade on the frequency of extrauterine metastases. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL). P < .05 was considered significant for all tests.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Sixty-three endometrioid, nine papillary serous, two clear cell, and two carcinomas of mixed histology including papillary serous and clear cell components were examined. Of the endometrioid tumors, 39 (62%) were grade 1, 14 (22%) were grade 2, and ten (16%) were grade 3. All of the papillary serous, clear cell, and mixed histology tumors were nuclear grade 3. The clinical features of the endometrial carcinomas are outlined in Table 1Go. For the purposes of comparison, papillary serous, clear cell, and mixed histology carcinomas were combined into a single group. These tumors were more likely to be of advanced stage (stages III and IV) than endometrioid tumors (61% versus 11%, P < .01). As expected, papillary serous and clear cell carcinomas were more likely to have outer third myometrial invasion, adnexal spread, retroperitoneal lymph node involvement, and positive peritoneal cytology.


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical Features of Endometrial Cancers
 
Table 2Go compares the clinical features of tumors that stained positive for E-cadherin (ie, diffuse linear, diffuse granular, and focal granular patterns) with those of tumors that were negative for E-cadherin. E-cadherin negative tumors were more likely to be poorly differentiated, have cervical and adnexal spread, and have positive peritoneal cytology. We then compared E-cadherin expression between endometrioid, papillary serous, and clear cell carcinomas (Table 3Go). Papillary serous and clear cell carcinomas were significantly less likely to express E-cadherin (38%) than endometrioid tumors (95%, P < .001). This difference remained significant when grades 1 and 2 endometrioid tumors were excluded from the analysis. All ten of the grade 3 endometrioid tumors expressed E-cadherin (seven focal granular and three diffuse granular), compared with 38% of the papillary serous and clear cell carcinomas (P = .002).


View this table:
[in this window]
[in a new window]
  		Table 2. Clinical Features of Endometrial Cancers Stratified by E-Cadherin Staining
 

View this table:
[in this window]
[in a new window]
  		Table 3. E-Cadherin Expression in Endometrioid, Papillary Serous, and Clear Cell Carcinoma
 
Univariable logistic regression found tumor grade (P = .003) and histological type of cancer (P < .001) to be significant predictors of E-cadherin expression. When both variables were controlled for in multivariable analysis, however, only the histological type of tumor remained as a significant predictor of E-cadherin expression (P = .01; odds ratio [OR] 23.5; 95% confidence interval [CI] 2, 292). When tumor grade was controlled, endometrioid tumors remained 23 times more likely to express E-cadherin than papillary serous and clear cell carcinomas. Logistic regression was then used to examine the effect of tumor grade, histological type, and E-cadherin expression on extrauterine metastases. For the purposes of this analysis patients with nodal metastases, positive cytology, adnexal metastases, cervical extension, and intra-abdominal metastases were combined. E-cadherin expression (P < .01; OR 11.7; 95% CI 2, 60), tumor grade (P < .01; OR 3.5; 95% CI 2, 7), and histological type (P < .01; OR 16; 95% CI 3, 81) were all significant predictors of extrauterine metastases in univariable analysis. In multivariable analysis, however, only tumor grade remained significant (P = .02; OR 2.4; 95% CI 1, 5).


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Papillary serous and clear cell carcinomas in the present study were more likely to have positive peritoneal cytology, adnexal involvement, lymph node metastases, and lymphvascular invasion than endometrioid tumors. These observations are similar to those of Goff et al,14 who identified extrauterine metastases in 36 of 50 patients with uterine papillary serous tumors. Interestingly, depth of myometrial invasion did not significantly predict the extent of disease. Chambers et al4 found that four of 18 patients with clinical stage I uterine papillary serous carcinoma who underwent surgery had pelvic metastases and five had disease spread beyond the pelvis. Only 43% of the hysterectomy specimens, however, had greater than 50% myometrial invasion. The findings of the present study also support these observations. Sixtyone percent of the papillary serous and clear cell carcinomas had stage III or IV disease and lymph node metastases were observed in 50% of these tumors. Only 41%, however, had outer third myometrial invasion.

We also found that E-cadherin negative tumors were more aggressive than tumors expressing E-cadherin and were more likely to have positive peritoneal cytology, cervical extension, and adnexal involvement. Deep myometrial invasion was not significantly related to E-cadherin staining. This observation may be explained by the fact that 73% of the E-cadherin negative tumors were papillary serous or clear cell carcinomas in which extra-uterine metastases frequently occur without deep myometrial invasion. Only 25% of the E-cadherin negative papillary serous and clear cell carcinomas were associated with outer third myometrial invasion.

E-cadherin is found in the zonula adherens junctions of normal epithelial cells. It is a transmembrane protein with five extracellular domains and an intracellular domain that connects to the actin cytoskeleton through a complex with the cytoplasmic molecules {alpha}, ß-, and {gamma}-catenin. Decreased E-cadherin expression is associated with a loss of cell-cell cohesive forces and has been shown to precede tumor cell motility—a characteristic of tumor cell lines with high metastatic potential.15,16 Exfoliation of tumor cells due to decreased cohesiveness could potentially explain the high rates of positive intraperitoneal spread despite limited myometrial invasion, which is characteristic of papillary serous and clear cell carcinomas.17 Although E-cadherin expression was not found to be an independent predictor of extrauterine metastases in the present study, the relatively small sample size may limit the ability to detect a significant impact when tumor grade and histological type are controlled.

Sakuragi et al12 examined E-cadherin expression in 30 cases of endometrial adenocarcinoma by immunohistochemistry. They observed that E-cadherin expression decreased with loss of differentiation and was inversely correlated with the depth of myometrial invasion. A significant correlation with paraaortic nodal metastases was also noted. The present study also found a significant relationship between E-cadherin expression and tumor grade. Tumor grade was a significant predictor of E-cadherin status in univariable analysis. When histological type and tumor grade were controlled in multivariable analysis, however, only histological type remained as an independent predictor.

Our findings show that uterine papillary serous and clear cell carcinomas are significantly less likely to express E-cadherin than endometrioid carcinoma. This observation is not simply a function of tumor grade, as endometrioid tumors remained 23 times more likely to express E-cadherin when grade was controlled. It is possible that loss of E-cadherin occurs more commonly and earlier in the pathogenesis of papillary serous and clear cell carcinomas and that this explains the more aggressive nature of these tumors.

The human E-cadherin gene has been mapped to chromosome 16q22,18 a region shown to have loss of heterozygosity in 38% of informative ovarian cancers.19 Risinger et al20 examined 72 endometrial cancers and 63 ovarian cancers for alterations in the E-cadherin coding region and identified four mutations, thereby classifying E-cadherin as a tumor suppressor gene. The histological type and grade of the endometrial cancers found to have mutations in this region were not stated. Therefore it is unclear whether mutations of the E-cadherin coding region are more common in uterine papillary serous and clear cell carcinomas. Mutant E-cadherin may be resistant to the normal mechanisms of protein degradation and cause overexpression in the cytoplasm, as seen in the diffuse and focal granular patterns. Investigation of the differences in expression of {alpha}-, ß-, and {gamma}-catenin between papillary serous, clear cell, and endometrioid carcinomas is also needed to further elucidate the role of cell adhesion molecules in these tumors. Miyamoto et al21 examined the localization and expression of E-cadherin and the catenins in 30 well- and poorly differentiated endometrioid carcinomas. They observed significant differences in the patterns of expression and colocalizations between the two tumor types. The cytoplasmic molecules may play different roles in E-cadherin dysfunction in endometrioid, papillary serous, and clear cell carcinomas.

In conclusion, our results revealed that uterine papillary serous and clear cell carcinomas are significantly less likely to express E-cadherin than endometrioid carcinoma. This difference may partially account for the more aggressive behavior of papillary serous and clear cell carcinomas. Elucidating the molecular differences between these tumor types may allow for more individualized therapeutic intervention.


   Footnotes
 
All immunohistochemical analysis provided by GEMPATH Laboratories. BP is an employee of GEMPATH Laboratories.

The authors thank Tania Afonso, BS, for her contribution to the immunohistochemical analysis performed in this study.

PII S0029-7844(02)02391-8

Received January 22, 2002. Received in revised form May 9, 2002. Accepted May 30, 2002.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Lauchlan SC. Tubal (serous) carcinoma of the endometrium. Arch Pathol Lab Med 1981;105:615–8.[Medline]

2. Hendrickson M, Ross J, Eifel PJ, Cox RS, Martinez A, Kempson R. Uterine papillary serous carcinoma: A highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 1982;6:93–108.[Medline]

3. Matthews RP, Hutchinson-Colas J, Maiman M, Fruchter RG, Gates J, Gibbon D, et al. Papillary serous and clear cell type lead to poor prognosis of endometrial carcinoma in black women. Gynecol Oncol 1997;65:206–12.[Medline]

4. Chambers JT, Merino M, Kohorn EI, Peschel RE, Schwartz PE. Uterine papillary serous carcinoma. Obstet Gynecol 1987;69:109–13.[Abstract/Free Full Text]

5. Hendrickson M, Ross J, Eifel PJ, Cox RS, Martinez A, Kempson R. Adenocarcinoma of the endometrium: Analysis of 256 cases with carcinoma limited to the uterine corpus. Gynecol Oncol 1982;13:373–92.[Medline]

6. Kurman RJ, Scully RE. Clear cell carcinoma of the endometrium: Analysis of 21 cases. Cancer 1976;37:872–5.[Medline]

7. Abeler VM, Kjorstad KE. Clear cell carcinoma of the endometrium: A histopathological and clinical study of 97 cases. Gynecol Oncol 1991;40:207–17.[Medline]

8. Silverberg SG, DeGiorgi LS. Clear cell carcinoma of the endometrium: Clinical-pathological and ultrastructural findings. Cancer 1973;31:1127–30.[Medline]

9. International Federation of Gynecology and Obstetrics. Annual report on the results of treatment in gynecologic cancer. Stockholm, Sweden: FIGO, 1985.

10. Fujioka T, Takebayashi Y, Kihana T, Kusanagi Y, Hamada K, Ochi H, et al. Expression of E-cadherin and betacatenin in primary and peritoneal metastatic ovarian carcinoma. Oncol Rep 2001;8:249–55.[Medline]

11. Yoshida R, Kimura N, Harada Y, Ohuchi N. The loss of E-cadherin, alpha- and beta-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer. Int J Oncol 2001;18:513–20.[Medline]

12. Sakuragi N, Nishiya M, Ikeda K, Ohkouch T, Furth EE, Hareyama H, et al. Decreased E-cadherin expression in endometrial carcinoma is associated with tumor dedifferentiation and deep myometrial invasion. Gynecol Oncol 1994;53:183–9.[Medline]

13. Creasman WT. Announcement, FIGO stages: 1988 revisions. Gynecol Oncol 1989;35:125–7.

14. Goff BA, Kato D, Schmidt RA, Ek M, Ferry JA, Muntz HG, et al. Uterine papillary serous carcinoma: Patterns of metastatic spread. Gynecol Oncol 1994;54:264–8.[Medline]

15. Strauli P, Haemmerli G. The role of cancer cell motility in invasion. Cancer Metastasis Rev 1984;3:127–41.[Medline]

16. Volk T, Geiger B, Raz A. Motility and adhesive properties of high and low-metastatic murine neoplastic cells. Cancer Res 1984;44:811–24.[Abstract/Free Full Text]

17. Carcangui ML, Chambers JT. Early pathologic stage clear cell carcinoma and uterine papillary serous carcinoma of the endometrium: Comparison of clinicopathologic features and survival. Int J Gynecol Pathol 1995;14:30–8.[Medline]

18. Mansouri A, Spurr N, Goodfellow PN, Kemier R. Characterization and chromosomal localization of the gene encoding the human cell adhesion molecule uvomorulin.Differentiation 1988;38:67–71.[Medline]

19. Sato T, Saito H, Morita R, Koi S, Lee JH, Nakamura Y. Allelotype of human ovarian cancer. Cancer Res 1991;51: 5118–22.[Abstract/Free Full Text]

20. Risinger JI, Berchuck A, Kohler MF, Boyd J. Mutations of the E-cadherin gene in human gynecologic cancers. Nat Genet 1994;7:98–102.[Medline]

21. Miyamoto S, Baba H, Kuroda S, Kaibuchi K, Fukuda T, Maehara Y, et al. Changes in E-cadherin associated with cytoplasmic molecules in well and poorly differentiated endometrial cancer. Br J Cancer 2000;83:1168–75.[Medline]




This article has been cited by other articles:


Home page
 J. Clin. Pathol.Home page
D. S P Tan and S. Kaye
Ovarian clear cell adenocarcinoma: a continuing enigma
J. Clin. Pathol., April 1, 2007; 60(4): 355 - 360.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
K. K. Zorn, T. Bonome, L. Gangi, G. V.R. Chandramouli, C. S. Awtrey, G. J. Gardner, J. C. Barrett, J. Boyd, and M. J. Birrer
Gene Expression Profiles of Serous, Endometrioid, and Clear Cell Subtypes of Ovarian and Endometrial Cancer
Clin. Cancer Res., September 15, 2005; 11(18): 6422 - 6430.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. K. Mell, J. J. Meyer, M. Tretiakova, A. Khramtsov, C. Gong, S. D. Yamada, A. G. Montag, and A. J. Mundt
Prognostic Significance of E-Cadherin Protein Expression in Pathological Stage I-III Endometrial Cancer
Clin. Cancer Res., August 15, 2004; 10(16): 5546 - 5553.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
I. M. Stefansson, H. B. Salvesen, and L. A. Akslen
Prognostic Impact of Alterations in P-Cadherin Expression and Related Cell Adhesion Markers in Endometrial Cancer
J. Clin. Oncol., April 1, 2004; 22(7): 1242 - 1252.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Holcomb, K.
Right arrow Articles by Chambers, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Holcomb, K.
Right arrow Articles by Chambers, J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS