International Journal of Gynecological Pathology:
Pathology of the Lower Genital Tract: Original Articles
Mammaglobin Expression in the Female Genital Tract: Immunohistochemical Analysis in Benign and Neoplastic Endocervix and Endometrium
Onuma, Kazuya M.D., Ph.D.; Dabbs, David J. M.D.; Bhargava, Rohit M.D.
Department of Pathology, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA
Dr Kazuya Onuma is currently affiliated with the Department of Pathology and Molecular Medicine, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada.
Address correspondence and reprint requests to Kazuya Onuma, MD, PhD, Department of Pathology and Molecular Medicine, McMaster University Faculty of Health Sciences, 1200 Main St W 2N25, Hamilton, Ontario, Canada L8N 3Z5. E-mail: email@example.com; firstname.lastname@example.org
Mammaglobin (MGB), a secretory protein belonging to the uteroglobin/Clara cell protein family, is a sensitive marker for breast carcinoma, but is also reported to be expressed in the female genital tract and its neoplasms. Details of MGB expression pattern and its pathologic significance in the female genital tract have not been systematically studied. To investigate the potential use of MGB in gynecologic pathology practice, we tested MGB expression by immunohistochemistry on 47 endocervical adenocarcinomas (whole tissue sections of 13 invasive and 35 in situ) and 55 endometrial carcinomas (39 endometrioid and 16 nonendometrioid represented on a single tissue microarray). Nonneoplastic endocervical and endometrial tissues were also evaluated for MGB expression. MGB expression was detected in thirty (77%) of 39 of endometrioid endometrial adenocarcinomas compared with 4 (31%) of 13 endocervical adenocarcinomas. MGB was mostly negative in nonendometrioid endometrial carcinoma (negative in 14 [88%] of 16). Endocervical adenocarcinoma in situ (AIS) showed either weak (predominantly) or moderate (occasionally) expression in about 40% of the cases in comparison with strong positivity in benign endocervical glandular epithelium. Reduction of MGB staining was seen in transition from benign epithelium to AIS. These results confirm that MGB is not specific for breast carcinoma, but is also variably expressed in nonneoplastic and neoplastic endocervical and endometrial tissues. Frequent MGB expression in endometrioid endometrial adenocarcinoma is significantly different from nonendometrioid carcinoma. Hormone receptor status is not associated with MGB expression in endometrial carcinomas. Most endocervical adenocarcinomas are negative for MGB, in contrast to mostly positive endometrioid endometrial adenocarcinomas, however, MGB expression alone is not specific enough to distinguish these 2 tumor types. MGB expression is altered in neoplastic endocervical epithelium compared with normal, and may indicate its decreased expression in the process of early carcinogenesis. MGB may be a promising new adjunctive marker in gynecologic pathology.
Mammaglobin (MGB) is a secretory protein with a similar sequence to that of epithelial secretory proteins belonging to the uteroglobin family (1), including rabbit uteroglobin (2), rat prostatic steroid–binding protein subunit C3 (3), and human Clara cell 10-kd protein (4). Watson and Fleming (5) reported that MGB messenger RNA (mRNA) expression was increased in breast carcinomas at least 10-fold relative to normal breast tissue. MGB expression was also detected by immunohistochemistry in a high percentage of breast carcinomas (6). These findings suggested that MGB was a promising sensitive marker for breast carcinoma. MGB was initially also reported as a breast-specific marker. Recently, however, its expression has also been detected in nonbreast tissue and its neoplasms, including ovary, endometrium, cervix, and prostate (7). Our previous study of MGB immunohistochemical expression in various carcinomas also demonstrated higher sensitivity of MGB expression for breast carcinoma than Gross Cystic Disease Fluid Protein-15, but we simultaneously identified its expression in about 40% of endometrial adenocarcinoma. This expression was significant compared with endocervical adenocarcinoma, none of which showed positive expression (8). Furthermore, different expression patterns were observed in nonneoplastic endocervix, endocervical adenocarcinoma in situ (AIS), and invasive endocervical adenocarcinoma. These observations led us to conduct further immunohistochemical analysis of MGB expression in endocervical and endometrial tissues to investigate its potential use as a new immunohistochemical marker in gynecologic pathology. The purpose of this study was: 1) to evaluate MGB expression in a large number of endometrial carcinomas; 2) to assess the use of MGB as a marker in the distinction between endocervical and endometrial adenocarcinomas; and 3) to investigate MGB expression in nonneoplastic endocervix, AIS, and invasive endocervical adenocarcinoma.
MATERIALS AND METHODS
This study was approved by the institutional review board of the University of Pittsburgh. Endocervical and endometrial tissues were retrieved from the surgical pathology archives at Magee-Womens Hospital of University of Pittsburgh Medical Center. The endocervical tissues included 33 endocervical AIS, 13 endocervical adenocarcinomas (11 usual types, 1 minimal deviation, and 1 adenosquamous carcinoma). Endometrial tissues included 55 endometrial carcinomas (39 endometrioid and 16 nonendometrioid), 8 endometrial complex hyperplasia with atypia, 22 benign endometrial tissues (6 proliferative-phase endometrium, 5 secretory-phase endometrium, 1 simple hyperplasia without atypia, 2 complex hyperplasia without atypia, 1 disordered proliferative endometrium, and 7 endometrial polyps). Of 33 AIS cases, 6 had coexistence of invasive carcinoma, and both AIS and invasive components were subjected for MGB staining evaluation in these cases. Among 39 endometrioid endometrial adenocarcinomas, 20 cases were the Fédération Internationale de Gynécologie Obstétrique (FIGO) Grade 1, 12 were Grade 2, and 7 were Grade 3. Sixteen nonendometrioid carcinoma cases consisted of 8 serous carcinomas, 3 clear cell carcinomas, 1 mixed serous and clear cell carcinomas, 3 undifferentiated carcinomas, and 1 malignant mixed müllerian tumor. All endometrial carcinomas were also evaluated for estrogen receptor (ER) and progesterone receptor (PR) status by immunohistochemistry.
For endometrial tissues, a tissue microarray (TMA) was constructed using 0.6-mm tissue cores. A hematoxylin and eosin-stained section was evaluated for the presence of specific diagnosis, and the area to be used for creation of TMA was marked on the slide and the donor block. Three cores from different areas of a single formalin-fixed paraffin-embedded tissue block were used on each case.
For endocervical tissues, whole tissue sections were obtained from the tissue block of each representative lesion.
Immunohistochemical Analysis for MGB
Four-micron-thick sections of TMA and whole tissue were immunostained with anti-MGB cocktail antibody (Zeta Corporation, Sierra Madre, CA) on the Benchmark XT automated stainer (Ventana Medical Systems, Tucson, AZ). The protocol consisted of pretreatment with CCl, pH 8.0 (Ventana Medical Systems) followed by incubation with MGB mouse (clone 304-1A5) and rabbit (clone 31A5) monoclonal cocktail (Zeta Corporation) with 1:25 dilution.
Immunohistochemical staining for nonneoplastic endocervix and endometrium, AIS, endocervical adenocarcinoma, and endometrial carcinoma on each slide was evaluated in a semiquantitative fashion and scored from Scores 0 to 3. This scoring was defined as 0, nonreactive; 1, weak staining and/or only patchy moderate staining; 2, diffuse moderate staining or patchy strong staining; and 3, diffuse strong staining (Fig. 1). For endometrial tissues, staining on each of three TMA cores was evaluated, and the average score was assigned as the final staining score for each tumor. Evaluation was conducted on a multiheaded microscope by 2 pathologists.
Hormone Receptor Status
Immunohistochemical analysis for ER was performed using the 6F11 antibody and IVIEW detection on the Benchmark XT (Ventana). Immunohistochemical analysis for PR was performed using the 1A6 antibody (Ventana) and IVIEW detection on the Benchmark XT. Any staining was considered as positive for ER and PR.
MGB immunohistochemical staining was seen in the cytoplasm with patchy or diffuse pattern of variable intensity. The staining was evaluated according to the criteria described above.
MGB Expression in Endocervical Tissue
The results of MGB immunohistochemical expression in the endocervical tissues are summarized in Table 1. The normal endocervical glandular epithelium consistently showed moderate or diffuse strong MGB staining in almost 100% of the cases (Figs. 2A, B). In comparison, both AIS and invasive endocervical adenocarcinomas showed reduced MGB expression. Fourteen of 33 AIS cases were completely negative for MGB, and about one half of the cases (51%) showed weak staining, and occasional cases showed moderate staining. The glands partially involved by AIS showed reduced MGB staining in AIS and diffuse strong staining in the normal portion of the glands (Figs. 2A, B). About 70% (9 of 13 cases) of invasive endocervical adenocarcinomas were negative for MGB (Figs. 2C, D). Of the 4 positive cases, 3 were usual-type adenocarcinomas, and 1 was adenosquamous carcinoma. Only adenocarcinomatous component was positive for MGB in the adenosquamous carcinoma. One case of minimal deviation adenocarcinoma was negative for MGB.
MGB Expression in Endometrial Tissue
The results of MGB immunohistochemical expression in the endometrial tissues are summarized in Table 2. MGB expression was detected in all of benign endometrial epithelium with moderate to strong staining (Scores 2 and 3) in 72% of the cases and weak staining (Score 1) in the remainder 27%. In normal endometrium, MGB staining appeared to be stronger in secretory-phase endometrium (Fig. 3A). The endometrial stroma was negative for MGB. Six of 7 endometrial polyps showed moderate to strong staining (Scores 2 and 3) in the glandular epithelium, and 1 was Score 1. One disordered proliferative endometrium showed moderate staining (Score 2). One simple hyperplasia showed weak staining (Score 1), and 2 cases of complex hyperplasia without atypia showed moderate and strong staining, respectively. Most (88%) complex hyperplasia with atypia showed MGB expression, with greater than 60% showing moderate to strong staining (Scores 2 and 3). Endometrioid-type adenocarcinomas demonstrated moderate to strong staining (Scores 2 and 3) in 41% (Fig. 3B) and weak staining (Score 1) in 36% of the cases. In comparison, 88% of nonendometrioid carcinomas showed negative staining (Fig. 3C), and only 2 cases exhibited weak to moderate staining (Score 1-2). These 2 cases were 1 serous carcinoma with Score 2 and an undifferentiated carcinoma with Score 1. In the endometrioid adenocarcinoma cases, 18 (90%) of 20 of FIGO Grade 1 tumor showed positive staining (Score 1-3), with 45% showing moderate to strong staining. In 12 cases of Grade 2 tumor, positive staining (Score 1-3) was seen in 8 (67%) cases, but weak staining was more predominant. There were only 7 cases of Grade 3 tumor available for this evaluation. Among these, 4 cases showed a Score of 2, one showed a Score of 1, and 2 were negative (Score 0).
Relationship Between MGB Expression and Hormone Receptor Status
Endometrioid adenocarcinomas (n=39): 24 (61%) endometrioid adenocarcinomas were positive for both ER and PR, and 10 (26%) were positive only for ER. Five (13%) endometrioid adenocarcinomas were negative for both ER and PR. Among the hormone receptor–positive tumors, 14 tumors showed Score 2 or 3 staining of MGB, 14 showed Score 1 staining, and 6 were negative for MGB expression. Two hormone receptor–negative tumors showed Score 2 staining, and 3 were negative for MGB expression.
Nonendometrioid carcinomas (n=16): 3 (19%) nonendometrioid carcinomas were positive for both ER and PR, and 6 (37%) were positive only for ER, and seven (44%) were negative for both ER and PR. One ER-positive tumor showed Score 2 staining of MGB, and 1 tumor positive for both ER and PR showed Score 1 staining. All other tumors were negative for MGB expression regardless of hormone receptor status. Relationship between MGB expression and hormone receptor status is summarized in Table 3. In summary, no significant association between MGB expression and hormone receptor status was observed.
Comparison of MGB Expressions Between Endocervical and Endometrial Adenocarcinomas
Thirty (77%) of 39 endometrioid endometrial adenocarcinomas demonstrated positive MGB staining (Score 1-3). In comparison, only 4 (31%) of 13 invasive endocervical adenocarcinomas were positive for MGB. The results are summarized in Table 4.
MGB was originally discovered and named by Watson and Fleming (5), who isolated a full-length complementary DNA clone and demonstrated significantly increased MGB expression in breast carcinomas compared with benign breast tissue by mRNA level. The same group and others demonstrated its expression being restricted to the normal breast gland and carcinoma (5,6,9,10). Since then, a number of studies evaluated and suggested its potential clinical use to detect breast carcinoma and as an immunotherapeutic target because of its high breast specificity (11,12). However, recent studies have shown that it is also expressed in nonbreast tissue (7,8,13–15). Among various nonbreast tissues expressing MGB, the female genital tract has drawn much attention because of its high MGB expression. Grunewald et al. (7) demonstrated frequent expression of MGB in the female genital tract and its neoplasms. They found MGB expression by nested reverse transcriptase polymerase chain reaction in 100% of normal tissue and adenocarcinomas of the endometrium, and in 90% of the uterine cervix. Zafrakas et al. (14) reported much higher MGB mRNA in the normal cervical tissue than the breast tissue. The same group also demonstrated MGB expression on the tissue sections of the normal endocervical gland, endometrium, and endometrial adenocarcinoma by RNA in situ hybridization and immunohistochemistry. Bhargava et al. (8) also demonstrated relatively frequent expressions of MGB in endometrioid adenocarcinomas in their comprehensive immunohistochemical study of MGB expression in breast carcinomas and nonbreast malignant neoplasms. Endocervical adenocarcinoma did not show MGB expression in their study.
In the current study, we investigated MGB expression by immunohistochemistry in a number of benign and malignant endocervical and endometrial tissues. Our findings confirmed that MGB is not a breast-specific marker, and is also highly expressed in normal endocervical epithelium and endometrium. In the normal endocervix and endometrium, the glandular epithelium exhibits strong cytoplasmic staining with anti-MGB antibody. The stromata of both endocervix and endometrium are completely negative for MGB staining. The restricted expression of this secretory protein in the glandular epithelium is as reported in the breast tissue by Watson and Fleming (5) and Leygue et al. (16). Constant strong MGB staining of the endocervical glandular epithelium is consistent with high levels of mRNA expression as reported previously (8,14).
Endometrial carcinoma is the most common malignant tumor of the female genital system in developed countries. Endometrial carcinoma is currently divided into 2 distinct types, endometrioid adenocarcinoma and nonendometrioid carcinoma on the basis of their different pathogeneses. Endometrioid adenocarcinomas are far more common, generally estrogen dependent, and better differentiated. In contrast, nonendometrioid carcinomas are estrogen independent and high-grade tumors. Our study demonstrated distinctly stronger MGB expression in endometrioid adenocarcinomas compared with nonendometrioid carcinomas. In endometrioid adenocarcinomas, MGB expression was stronger and more frequent in Grade 1 tumor than Grades 2 or 3 tumors. This finding may suggest a possible association of MGB expression and tumor grade. In breast carcinoma, several studies analyzing association between MGB expression and tumor grade have been reported with contradictory results. Some studies have reported higher MGB expressions associated with low-grade hormone receptor–positive tumors and better prognosis (17,18), whereas others have shown no relationship with tumor grade (8,15). Hormone receptor status is also associated with tumor grade of endometrioid adenocarcinoma. Hormone receptor positivity is correlated with FIGO stage, FIGO grade, and the nuclear grade of endometrioid adenocarcinoma (19,20). We investigated the relationship between MGB expression and hormone receptor status in endometrial carcinomas. We analyzed the data separately for endometrioid adenocarcinomas and nonendometrioid carcinomas. In each category, no significant association was identified between hormone receptor status and MGB expression.
Uterine serous carcinoma is usually morphologically distinguishable from endometrioid adenocarcinoma. However, morphologic overlap does exist, leading to controversy and diagnostic difficulty. Immunohistochemical stain of p53 protein has been used for this distinction and diagnostic confirmation (21). p53 mutation is the most frequent genetic alteration in serous carcinoma, and occurs in its putative precursor lesion, endometrial intraepithelial carcinoma (22). Serous carcinoma usually expresses p53 in a strong and diffuse fashion. However, a subset of endometrioid adenocarcinoma may show p53 expression (23), and a minority of serous carcinoma may be negative for p53 expression (24,25). These reports indicate the limitation of p53 staining in the differential diagnosis. With respect to MGB expression between endometrioid adenocarcinoma and nonendometrioid carcinoma, five (71%) of seven FIGO Grade 3 endometrioid adenocarcinoma showed positive MGB staining (Score 1-2), and in contrast, seven (88%) of eight serous carcinomas showed negative MGB staining. The 1 positive tumor showed weak staining (Score 1). Although the number is too small to draw definite conclusions, these results suggest the promising role of MGB as another adjunctive marker for such clinically important distinction.
One of our objectives in this study was to explore the possibility of MGB as a marker to distinguish invasive endocervical adenocarcinoma and endometrial adenocarcinoma. Our previous study demonstrated that all endocervical adenocarcinomas were negative for MGB expression, and this was distinctly different from endometrial adenocarcinoma, 40% of which showed MGB positivity (8). In the current study, although 31% of invasive endocervical adenocarcinoma cases (including 1 adenosquamous carcinoma) exhibited moderate to strong MGB staining, it is still much less frequent than endometrial endometrioid adenocarcinoma, 77% of which showed MGB expression. Among previous studies of MGB expression in nonbreast tissue, Zafrakas et al. (14) demonstrated upregulation of MGB in endocervical adenocarcinoma and confirmed MGB expression by dot blot hybridization, reverse transcriptase polymerase chain reaction, RNA in situ hybridization, and immunohistochemistry. However, it was tested on only 2 cases, leading to a limited conclusion. In contrast, Sasaki et al. (15) found no MGB expression in all of 4 endocervical adenocarcinoma cases by immunohistochemistry.
Differential MGB expression between endometrial and endocervical adenocarcinomas suggests that MGB can be used as another marker in addition to the useful panel of vimentin, carcinoembryonic antigen, ER, and p16 (26–29).
Another interesting finding in our study was the negative MGB expression in minimal deviation adenocarcinoma. Minimal deviation adenocarcinoma is an extremely well-differentiated carcinoma with the tumor cells similar to the normal endocervical glandular cells, and the diagnosis can be difficult or even impossible in a small biopsy. Although our finding was a limited observation on just one case, this aspect is worth studying in more detail with a larger number of cases. Weak to negative MGB staining in AIS and in most of invasive adenocarcinomas in comparison with strong staining in the normal endocervical glands may indicate reduced MGB expression in the process of carcinogenesis of endocervical adenocarcinoma. MGB may be applied to biopsy or cytology materials to distinguish nonneoplastic and neoplastic endocervical glands.
In this study, we have used TMA for endometrial tissues, whereas whole tissue sections were used for endocervical tissues. The TMA is a relatively new technique and enables rapid analysis of hundreds of samples on a single slide. It also has an advantage that all samples are processed at one time in identical conditions. However, because of the reduced amount of tissue analyzed from a whole tissue to a 0.6-mm tissue core, it may be of concern to some investigators that TMA is not representative for the protein expression pattern of the entire tumor, leading to a possible study bias between endometrial and endocervical tissues in this study. However, several recent studies have shown a high concordance of protein expression pattern between TMA and whole tissue section, and 2 or 3 cores from different areas of tumor are generally accepted to represent the entire tumor (30,31). Feasibility of TMA has also been proven for gene amplification studies (32). In this study, TMA was created using 3 cores from each tumor.
In conclusion, our study demonstrated that MGB is variably expressed in benign and neoplastic endocervix and endometrium by immunohistochemistry. Different intensity and frequency of MGB expression in various types of tumors in these sites suggest the possibility of MGB as an adjunct marker in gynecologic pathology.
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