Mutually Exclusive Expression of PAX8 and P63 in Transitional Cell Tumors of the Ovary: The Diagnostic and Histogenetic Significance

Research Article

J Pathol & Microbiol.2016; 1(1): 1004.

Mutually Exclusive Expression of PAX8 and P63 in Transitional Cell Tumors of the Ovary: The Diagnostic and Histogenetic Significance

Tong GX¹*, Hawver M¹, Wei JJ², Chen XW¹ and Bena DH¹

¹Department of Pathology and Cell Biology, Columbia University Medical Center, USA

²Department of Pathology, Northwestern University, USA

*Corresponding author: Guo-Xia Tong, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10305, USA

Received: November 25, 2015; Accepted: February 12, 2016; Published: February 19, 2016

Abstract

Ovarian epithelial tumors with transitional cell features are well-recognized. They morphologically resemble urothelium or urothelial carcinomas of the urinary tract and are classified as transitional cell tumors of the ovary which currently includes Brenner tumors and transitional cell carcinomas of the ovary. Brenner tumors are further classified as benign, borderline and malignant subtypes. The clinical and biological features of transitional cell tumors of the ovary are not well defined and the histogenesis of Brenner tumors is still uncertain. We report here our Immunohistochemistry (IHC) findings of PAX8 and p63 on transitional cell tumors of the ovary, the cell lineage specific transcription factors for Mullerian and urothelial epithelial cells, respectively. We show here that PAX8 and p63 were mutually exclusively expressed in Brenner tumors (PAX8-/p63+) and transitional cell carcinomas of the ovary (PAX8+/p63-), underlying a cell lineage difference between these two tumors. We also report that transitional metaplasia is a common phenomenon of the fallopian tube epithelium in the fimbriae and may represent an additional innate differentiation potential of the fallopian tube epithelium. The metaplastic transition type epithelium closely resembles immature urothelial cells and Brenner tumors on IHC, but not transitional cell carcinoma of the ovary. We thus suggest an alternative histogenesis for Brenner tumors arising from fallopian tube epithelium derived ovarian inclusion cysts. The cell lineage difference between Benner tumors and transitional cell carcinomas justifies the use of PAX8 and p63 to accurately diagnose transitional cell tumors of the ovary and separation of these two tumors in future classification of epithelial ovarian tumors.

Keywords: Immunohistochemistry; Bilateral salpingo-oophorectomy

Introduction

Tumors histologically similar to benign urothelium or urothelial carcinomas of the urinary tract are well-recognized in the ovary and are classified as transitional cell tumor of the ovary, which currently includes Brenner tumors and transitional cell carcinomas of the ovary [1]. The Brenner tumors are further classified into benign, borderline and malignant types. The differential diagnosis of primary malignant transitional cell tumors of the ovary can be challenging because they are morphologically indistinguishable and have been traditionally dependent on the identification of benign or borderline components of Brenner tumors. When the benign or borderline components are present, the malignant transitional cell tumor is diagnosed as malignant Brenner tumor, otherwise, as transitional cell carcinomas of the ovary [2]. However, it is conceivable that the benign or borderline components may be overlooked or misinterpreted and thus leads to the misclassification of transitional cell tumors of the ovary.

Recent evidences have indicated that transitional cell carcinomas of the ovary may have distinct clinical and biological features. The transitional cell morphologies are reported more frequently seen in BRCA gene mutation related ovarian carcinomas [3]. Transitional cell carcinomas of the ovary were reported to have better response to the cisplatin-based chemotherapy and May response to the Poly- ADP Ribose Polymerase (PARP) inhibitors which are under clinical try for BRCA related ovarian carcinomas [4-6]. Thus, it is imperative to have an accurate diagnosis of transitional cell tumors of the ovary for proper chemotherapy and evaluation of the treatment effects. In addition, the histogenesis of Brenner tumors still is puzzling because of the unique histologic features [7].

In this study, we investigated the expression of PAX8, p63, as well as cytokeratin 5/6, 7, and 20 in transitional cell tumors of the ovary utilizing IHC. We also studied the expression of these markers in the recently recognized metaplastic transitional epithelium of the fallopian tube [8-10]. We report here that fallopian tube epithelium frequently undergoes transitional (or urothelial) cell differentiation in the fimbriae. The metaplastic transitional type epithelium closely resembles immature urothelium and Brenner tumors on IHC. We suggest that Brenner tumors arise in the ovary from the metaplastic transitional epithelium of the fallopian tube epithelium derived cysts and therefore have a unified histogenesis as other ovarian epithelial tumors, i.e., a direct Müllerian epithelial origin. We also suggest that a cell lineage-related approach with IHC including PAX8 and p63 is more reliable to distinguish transitional cell tumors of the ovary and hence will facilitate to further define these tumors.

Material and Methods

The tissues used in this study included 5 cases of fallopian tube with metaplastic transitional epithelium, 27 Brenner tumors (25 benign, 1 borderline, and 1 malignant), and 23 transitional cell carcinomas of the ovary. The H&E sections of tumor cases were reviewed and the corresponding diagnoses were confirmed. A Tissue Microarray (TMA) was assembled with three 0.6 mm cores of representative tissues from each benign Brenner tumor or ovarian transitional cell carcinoma for IHC study. The cases of metaplastic transitional epithelium were selected from the prophylactic sapingo-ovulectomy specimen for patients with BRCA 1 or 2 germline mutations or family history of breast and ovarian carcinomas. A TMA with 41 invasive urothelial carcinomas of the urinary bladder was used as control in this study.

IHC with PAX8 (Proteintech, Chicago, IL), p63 (Ventana, Tuscon, AZ) as well as CK5/6, CK7 and CK20 was performed in a Dako autostainer utilizing avidin-biotin peroxidase method after appropriate antigen retrieval according to the manufacture manual. Only distinct nuclear staining was considered to be positive for PAX8 and p63. The staining intensity was graded as negative, weak (1+), moderate (2+) and strong (3+).

Results

The metaplastic transitional epithelium of the fallopian tube is defined as areas of stratified epithelium composed of multiple layers of uniform epithelial cells with round or oval nuclei and nuclear grooves morphologically resembling the urothelium in the fallopian tube epithelium. We have reviewed the H&E sections of fallopian tubes from 30 RRSO specimens performed for patients with high risk of developing ovarian carcinomas either confirmed BRCA1 or BRCA2 germline mutation or strong family history of breast and ovarian carcinomas. The patients varied from 30 to 52 year old (an average of 41 years). All fallopian tubes were submitted entirely for histologic examination according to the recently proposed protocol which generated 8 to 12 sections (an average of 10 sections) for each case. Areas of transitional-like epithelium were found in five cases which were readily identified because of its stratification of multiple layers of epithelial cells distinct from the single layer of ciliated fallopian tube epithelium. The transitional type epithelium usually were present bilaterally (4/5), multifocal, and varied from 1 to 5 mm in width and 5 to 10 cell layers. The transitional type epithelium was found in the fimbriae either franked by or growing under the ciliated serous epithelium (5/5) as well as in the peritoneal-tubal junctions (2/5). The transitional-like areas are uniform and small and the cells in the superficial layers appeared to be larger and flatten, but there were no typical umbrella-like cells present (Figure 1). In addition to areas of transitional type epithelium, one with high grade serous intraepithelial carcinoma, one with endometrial metaplasia, and one with mucinous metaplasia (endocervical type) were also identified in these 30 cases (data not shown).