title: Serous carcinomatous component championed by heparin-binding EGF-like growth factor (HB-EGF) predisposing to metastasis and recurrence in stage I uterine malignant mixed mullerian tumor.
abstract: The stage I uterine malignant mixed mullerian tumor (MMMT) shows different potential for progression. We reason that MMMTs with high-grade carcinomatous component and positivity for HB-EGF are prone to recurrence/metastasis in the early stage. A retrospective clinical and histopathologic review with immunohistochemical staining for HB-EGF, EGFR, and integrin-α5 was performed for 62 surgically staged MMMT cases. Recurrence/metastasis (RM) is 6/18 (33%) in stage I disease. Of all the clinicopathologic variables and biomarkers analyzed for stage I MMMT, serous carcinomatous component (83% [5/6] versus 17% [1/12], P = .0015) and HB-EGF expression (100% [6/6] versus 50% [6/12], P=.0339) were significantly different between groups with RM and without RM. The presence of serous carcinoma in all stages was 83% (5/6) in stage I with RM, 8% (1/12) in stage I without RM, 20% (1/5) in stage II, 36.4% (8/22) in stage III and 64.7% (11/17) in stage IV; this was paralleled by HB-EGF expression of 100% (6/6), 50% (6/12), 40% (2/5), 50% (11/22) and 71% (12/17) with a correlation coefficient r=0.9131 (P=.027). HB-EGF and integrin-α5 were highly expressed in MMMTs bearing serous carcinoma component, compared to endometrioid and unclassifiable/miscellaneous subtypes (84.6%/47.6%/33.3%, P=.025 for HB-EGF; and 61.5%/42.9%/20.0%, P=.021 for integrin-α5). The EGFR positivity was comparable among the three subtypes (48.1%, 47.6% and 26.7%, P=.326). This study indicates that serous carcinomatous component championed by expression of HB-EGF predisposes to recurrence/metastasis in stage I MMMT. This process might involve integrin-α5 and does not seem to require overexpression of EGFR. Further study is required.
authors.affiliation: The Department of Pathology, John A. Burn School of Medicine, the University of Hawaii, Honolulu, HI 96813; The Clinical Informatics Fellowship Program, University of California at Los Angeles, Los Angeles, CA 90095. Electronic address: lei_248@hotmail.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Department of Pathology, John A. Burn School of Medicine, the University of Hawaii, Honolulu, HI 96813; The Department of Pathology, the Queen's Medical Center, Honolulu, HI 96813. Electronic address: Dshimizu@queens.org.
authors.forename: David
authors.initials: D
authors.lastname: Shimizu
authors.affiliation: The Department of Pathology, John A. Burn School of Medicine, the University of Hawaii, Honolulu, HI 96813; The Department of Pathology, Kapi'olani Medical Center for Women and Children, Honolulu, HI 96826. Electronic address: jeffrey.killeen@hawaiilabs.com.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Killeen
authors.affiliation: The Department of Pathology, John A. Burn School of Medicine, the University of Hawaii, Honolulu, HI 96813; Department of Pathology, Kaiser Permanente, Honolulu, HI 96819. Electronic address: stacey.honda@kp.org.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Honda
authors.affiliation: The Department of Pathology, University of California at Irvine, Irvine, CA 92868. Electronic address: lud5@uci.edu.
authors.forename: Di
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Mathematics, California State University-Dominguez Hills. Electronic address: astanoyevitch@csudh.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Stanoyevitch
authors.affiliation: The Department of Pathology, University of California at Irvine, Irvine, CA 92868. Electronic address: flin@uci.edu.
authors.forename: Fritz
authors.initials: F
authors.lastname: Lin
authors.affiliation: The Department of Pathology, University of California at Irvine, Irvine, CA 92868. Electronic address: bevwang@uci.edu.
authors.forename: Beverly
authors.initials: B
authors.lastname: Wang
authors.affiliation: The Department of Pathology, University of California at Irvine, Irvine, CA 92868. Electronic address: Emonuki@uci.edu.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Monuki
authors.affiliation: The Department of Pathology, John A. Burn School of Medicine, the University of Hawaii, Honolulu, HI 96813; Cancer Center, University of Hawaii, Honolulu, HI 96813. Electronic address: Mcarbone@cc.hawaii.edu.
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002465:Cell Movement; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D039482:Integrin alpha5 / Q000032:analysis; D008875:Middle Aged; D018198:Mixed Tumor, Malignant / Q000737:chemistry* / Q000556:secondary / Q000601:surgery; D018200:Mixed Tumor, Mullerian / Q000737:chemistry* / Q000556:secondary / Q000601:surgery; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000737:chemistry* / Q000556:secondary / Q000601:surgery; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D014594:Uterine Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor; D066257:Heparin-binding EGF-like Growth Factor; D039482:Integrin alpha5; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: AJCC stage; Epidermal growth factor receptor (EGFR); Heparin-binding epidermal growth factor-like growth factor (HB-EGF); Integrin-α5; Malignant mixed mullerian tumor (MMMT); Serous carcinoma; Tissue microarrays (TMA)