Expression of p63 Differs in Peritoneal Endometriosis, Endometriomas, Adenomyosis, Rectovaginal Septum Endometriosis, and Abdominal Wall Endometriosis

Omero B Poli Neto, Omero Benedicto Poli‐Neto, Hebert M Ferreira, Leandra Náira Zambelli Ramalho, Leandra N Z Ramalho, Júlio C Rosa e Silva, Francisco José Cândido dos Reis, Francisco J Candido dos Reis, Antônio Alberto Nogueira, Antonio A Nogueira
Archives of pathology & laboratory medicine · 2007 · vol. 131(7) , pp. 1099–1102 · doi:10.5858/2007-131-1099-eopdip · PMID:17616998 · W164574797
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This study used immunohistochemistry to evaluate p63 expression in various forms of endometriosis, finding significantly different positivity rates across peritoneal endometriosis, endometriomas, adenomyosis, and deep endometriosis.

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This prospective study evaluated p63 expression by immunohistochemistry in tissue from 83 consecutive surgical patients, comparing peritoneal endometriosis (n=15), ovarian endometriomas (n=22), adenomyosis (n=36), and deep endometriotic lesions of the rectovaginal septum/abdominal wall (n=10). p63 nuclear positivity was common in peritoneal endometriosis (93.3%) and endometriomas (81.8%) but much less frequent in adenomyosis (36.1%), and it was absent in rectovaginal septum/abdominal wall lesions (0%), with homogeneous staining among positive cases. The authors report no association of p63 expression with pelvic endometriosis stage, extent of accompanying peritoneal disease, age, parity, or prior cesarean delivery, but they explicitly note that it remains unclear whether negative p63 expression reflects disease extent, clinical behavior, or symptom exacerbation. This paper is centrally about endometriosis and adenomyosis — it characterizes how p63 expression differs across peritoneal endometriosis, endometriomas, rectovaginal/abdominal wall endometriosis, and adenomyosis.

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Abstract

CONTEXT: Although there is evidence that endometriosis results from basal endometrium dislocation, the underlying biology is not fully understood. One protein that plays an important role in regulating epithelial proliferation and differentiation is the 63-kDa membrane protein (p63), which is also a marker of basal and reserve cells in the female genital tract. OBJECTIVE: To determine whether p63 is expressed differently in peritoneal endometriosis, endometriomas, and adenomyosis, as well as in deep endometriotic nodules of the rectovaginal septum and abdominal wall. DESIGN: This study includes a prospective series of consecutive patients (Canadian Task Force classification II-2) from a tertiary care university hospital. Specimens collected from 83 patients (15 peritoneal endometriosis specimens, 22 endometrioma specimens, 36 adenomyosis specimens, and 10 rectovaginal septum/abdominal wall specimens) were evaluated. Diagnostic and operative laparoscopies or laparotomies were performed, and tissue samples were obtained. Immunohistochemistry was used to evaluate p63 expression. RESULTS: Positivity for p63 was detected in 93.3% of the peritoneal endometriosis specimens, 81.8% of the endometrioma specimens, 36.1% of the adenomyosis specimens, and none of the rectovaginal/abdominal wall endometriosis specimens (P < .001). Distribution of p63 immunostaining in the positive specimens was homogeneous. CONCLUSIONS: Endometriotic lesions express p63 differently, and some retain the basal/reserve cell immunophenotype. Nevertheless, it remains unclear whether the lack of p63 expression in some lesions is related to the extent of the disease, to its clinical behavior, or to exacerbation of the accompanying symptoms.
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Materials and methods

This study protocol followed the ethical guidelines established in the 1975 Declaration of Helsinki and was approved by the local ethics committee. We evaluated p63 immunoexpression in 83 biopsy specimens of endometriotic tissue from 83 consecutive patients, representing 15 cases of peritoneal endometriosis as defined by the American Society for Reproductive Medicine11 (stage I, 7 cases; stage II, 3 cases; stage III, 2 cases; stage IV, 3 cases), 22 cases of endometrioma, and 36 cases of adenomyosis, together with 10 cases of rectovaginal septum endometriosis (n = 6) and abdominal wall endometrioma (n = 4). All tissue samples were fixed in 4% formalin and embedded in paraffin. Conventional clinical features, including age, parity, and previous caesarean delivery, were evaluated and are shown in Table 1. Only specimens presenting stromal and epithelial components were analyzed. Immunohistochemistry Three-micrometer-thick sections were cut from paraffin blocks containing representative endometriosis samples. Paraffin sections were deparaffinized in xylene, rehydrated in a graded ethanol series, mounted on poly-l-lysine slides, and submitted to heat antigen retrieval in 10mM citrate buffer (pH 6.0) at 95°C using a vegetable steamer for 40 minutes. After heating, the slides were allowed to cool to room temperature and were then washed in phosphate-buffered saline. Endogenous peroxidase activity was blocked by immersing the slides in 3% hydrogen peroxide/methanol for 5 minutes. A 20-minute incubation in normal serum (Universal Quick Kit, Novocastra, Newcastle upon Tyne, UK) was used to block nonspecific immunoassaying. The sections were stained manually and incubated for 2 hours with p63 primary antibody (1:200, clone 4A4, Santa Cruz Biotechnology, Santa Cruz, Calif) at room temperature. This was followed by washing in phosphate-buffered saline and immersion in biotinylated universal secondary antibody (Universal Quick Kit) for 15 minutes. The sections were then incubated with the streptavidin-biotin complex reagent (Universal Quick Kit) for 10 minutes and developed with 3,3′-diaminobenzidine tetrahydrochloride (Novocastra) in phosphate-buffered saline (pH 7.5) with 0.036% hydrogen peroxide for 5 minutes. Subsequently, the slides were counterstained with Harris hematoxylin, dehydrated in a graded ethanol series, and mounted with Permount (Fisher Scientific, Fair Lawn, NJ). Normal skin was used as the positive control for p63. The negative controls for immunostaining were prepared by the omission of the primary antibody. Positive staining for p63 was defined as a homogeneous pattern of nuclear staining that was clearly more intense than that observed in the negative controls. Immunoreactivity to the marker was classified as continuous data, from an undetectable level (0%) to homogeneous staining (100%). The results of the immunohistochemical reaction were scored using the percentage of positive cells observed: undetectable = −; less than 30% = +/−; 30% to 80% = +; 80% to 100% = ++.12 The intensity of nuclear staining was ranked as weak (light brown), moderate (dark brown obscuring nuclear chromatin), or strong (intense brown to black).10 The slides were evaluated by 2 authors (O.B.P.N. and L.N.Z.R.). The initial interrater agreement, quantified using the kappa (κ) statistic, was 82.8%. All discordant cases were reevaluated and the result was defined by consensus. Statistical analysis was performed using the Statistica program, version 7.1 (StatSoft, Inc, Tulsa, Okla). Fisher exact test or chi-square test was used to analyze qualitative variables, and unpaired Student t test was used to analyze quantitative variables. All tests were 2-tailed. P values of <.05 were considered statistically significant.

Results

Our results are summarized in Table 2. Positivity for p63 was detected in 93.3% (14/15) of the peritoneal endometriosis specimens (8 [53.3%] were scored as + and 6 [40.0%] were scored as ++) (Figure, A), 81.8% (18/22) of the endometrioma specimens (2 [9.1%] were scored as +/ −, 3 [13.6%] were scored as +, and 13 [59.1%] were scored as ++) (Figure, B), 36.1% (13/36) of the adenomyosis specimens (12 [33.3%] were scored as +/− and 1 [2.8%] was scored as +) (Figure, C), and none (0/10) of the rectovaginal/abdominal wall endometriosis specimens (Figure, D). This difference in p63 expression among the endometriotic lesion sites was significant according to chi-square test (P < .001). Distribution of p63 immunostaining was homogeneous in the positive specimens, which presented moderate to strong nuclear staining. Positive immunostaining for p63 was detected principally in the glandular component, although sparse nuclear staining was detected in the stromal cells of rectovaginal septum specimens. The overall p63 expression was not found to be associated with the stages of pelvic endometriosis (only one stage IV peritoneal endometriosis specimen was p63 negative) (P = .50), the extent of the peritoneal disease accompanying endometriomas (the p63-negative specimens were from patients with no endometriosis, as well as from those with stage I, III, or IV peritoneal endometriosis) (P = .59), age (P = .41), parity (P = .07), or previous cesarean delivery (P = .68).

Discussion

Our results show that p63-positive cells concentrate in peritoneal endometriosis, endometriomas, and in some cases of adenomyosis. Considering that endometriosis may result from the dislocation of endometrial basal cells,5 as well as the fact that p63 immunostaining has identified a set of diseases including benign and neoplastic endometrium10 and postmenopausal endometrial polyps,13 in which the basal/reserve cell immunophenotype is maintained, we expect that most endometriotic lesions would also retain that immunophenotype. However, in the present study, the ectopic endometrial tissue in the majority of adenomyosis, rectovaginal endometriosis, and abdominal wall endometriosis specimens presented no positive immunostaining for p63. These data suggest that these former lesions are distinct from peritoneal endometriosis and endometriomas. In fact, it has been suggested recently that deep endometriosis and the other forms of this disease do not share a common pathogenetic mechanism.14 It is emphasized that peritoneal endometriosis, endometriomas, and deep endometriosis nodules (as in abdominal wall and rectovaginal septum endometriosis) must be considered as 3 separate entities with different pathogeneses. Despite the fact that peritoneal endometriosis and adenomyosis have been considered variants of the same disease,15 epidemiologic data have shown that there are differences between them. It is likely that some cases of adenomyosis are secondary to implantation of endometrial cells during surgery, especially during cesarean section.416 Therefore, the fact that cells from the eutopic endometrium, such as proliferative and secretory phase cells, do not exhibit p63 immunostaining910 might explain our results, at least partially. Furthermore, because of its clinical and histologic features, some authors consider rectovaginal septum endometriosis a distinct entity.1718 The association with chronic pelvic pain, clinically observed, underscores this hypothesis. However, the design of the present study does not allow a definitive conclusion to be drawn. Immunoreactivity to p63 suggests maintenance of the basal/reserve cell immunophenotype. However, despite the fact that p63 has shown promise as a marker of stem cells19 and that stem cells could be located in the basalis layer of the endometrium,20 it remains unclear whether these cells are true stem cells. Our results suggest that not all endometriotic lesions retain the basal/reserve cell immunophenotype. However, based on our findings, we cannot state conclusively that the lack of p63 expression seen in some lesions is related to the extent of the disease, to its clinical behavior, or to exacerbation of the accompanying symptoms. Further studies are warranted in order to make a more in-depth investigation of the role of p63 in the pathogenesis of endometriosis. Copyright: College of American Pathologists 2007 Expression of p63 in endometriosis specimens. A, p63-positive peritoneal endometriosis (original magnification ×400). B, p63-positive endometrioma (original magnifications ×200 and ×400 [high power, inset]). C, p63-negative adenomyosis (original magnification ×200). D, p63-negative rectovaginal septum endometriotic nodule (original magnification ×200) Contributor Notes Reprints: Omero B. Poli Neto, MD, Bandeirantes Ave 3900, 9o andar, Ribeirão Preto, Brazil 14049-900 ([email protected])

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Condition tags

endometriosisadenomyosisendometrioma

MeSH descriptors

Endometriosis Membrane Proteins Peritoneal Diseases Rectal Diseases Vaginal Diseases Abdominal Wall Adult Aged Endometriosis Female Humans Immunohistochemistry Immunophenotyping Membrane Proteins Middle Aged Peritoneal Diseases Prospective Studies Rectal Diseases Vaginal Diseases

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