Occult microscopic endometriosis: undetectable by laparoscopy in normal peritoneum
Open accessAbstract
STUDY QUESTION: Is there any occurrence of hidden (occult) endometriotic lesions in normal peritoneum of women with and without visible endometriosis? SUMMARY ANSWER: We detected a slightly higher occurrence of occult microscopic endometriosis (OME) in normal peritoneum of women with visible endometriosis than in control women. WHAT IS KNOWN ALREADY: Based on a small number of cases, the concept of invisible microscopic endometriosis in visually normal peritoneum has been reported for more than a decade but there is controversy regarding their tissue activity and clinical significance. STUDY DESIGN, SIZE, DURATION: This case-controlled research study was conducted with prospectively collected normal peritoneal samples from 151 women with and 62 women without visible endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Normal peritoneal biopsy specimens from different pelvic sites of were collected during laparoscopy. A histological search of all peritoneal biopsy specimens for the detection of invisible endometriosis was done by immunoreaction to Ber-EP4 (epithelial cell marker), CD10 (stromal cell marker) and Calretinin (mesothelial cell marker). Tissue expression of estrogen/progesterone receptors (ER/PR) and cell proliferation marker, Ki-67, was performed by immunohistochemistry to identify tissue activity. MAIN RESULTS AND THE ROLE OF CHANCE: Three different patterns of OME were detected based on (I) the presence of typical gland/stroma, (II) reactive hyperplastic change of endometrioid epithelial cells with surrounding stroma and (III) single-layered epithelium-lined cystic lesions with surrounding stroma. A higher tendency toward the occurrence of OME was found in women with visible endometriosis (15.2%, 23/151) compared with control women (6.4%, 4/62) (P = 0.06, χ(2) test). The epithelial cells and/or stromal cells of OME lesions were immunoreactive to Ber-EP4 and CD10 but not reactive to Calretinin. ER and PR expression was observed in all patterns of OME lesions. Ki-67 index was significantly higher in pattern I/II OME lesions than in pattern III OME lesions (P< 0.05 for each). LIMITATIONS, REASONS FOR CAUTION: Bias in the incidence rate of OME lesions in this study cannot be ignored, because we could not analyze biopsy specimens from the Pouch of Douglas of women with revised classification of the American Society of Reproductive Medicine Stage III-IV endometriosis due to the presence of adhesions in the pelvis. WIDER IMPLICATIONS OF THE FINDINGS: We re-confirmed a decade long old concept of invisible (occult) endometriosis in visually normal peritoneum of women with visible endometriosis. The existence of a variable amount of tissue activity in these occult lesions may contribute to the recurrence/occurrence of endometriosis or persistence/recurrence of pain manifestation in women even after successful ablation or excision of visible lesions by laparoscopy. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by Grants-in-aid for Scientific Research from the Japan Society for the Promotion of Science. There is no conflict of interest related to this study. TRIAL REGISTRATION NUMBER: Not applicable.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Revised American Society for Reproductive Medicine classification of endometriosis: 1996
American Society for Reproductive Medicine (1997) · Fertility and Sterility · doi:10.1016/s0015-0282(97)81391-x · Cited by 3,018 · see citing works
Sampson, J. A. (1927) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(15)30003-x · Cited by 2,334 · see citing works
Pathogenesis and pathophysiology of endometriosis
Burney, R. O., & Giudice, L. C. (2012) · Fertility and Sterility · doi:10.1016/j.fertnstert.2012.06.029 · Cited by 1,590 · see citing works
(1927) · PubMed Central · Cited by 1,008 · see citing works
Ber-EP4: new monoclonal antibody which distinguishes epithelia from mesothelial.
Latza, U., Niedobitek, G., Schwarting, R., et al. (1990) · Journal of Clinical Pathology · doi:10.1136/jcp.43.3.213 · Cited by 386 · see citing works
<i>Stem Cells and the Pathogenesis of Endometriosis</i>
Sasson, I. E., & Taylor, H. S. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1434.014 · Cited by 371 · see citing works
Balasch, J., Creus, M. T., Fábregues, F., Carmona, F., Ordï, J., Martínez‐Román, S., & Vanrell, J. A. (1996) · Human Reproduction · doi:10.1093/humrep/11.2.387 · Cited by 278 · see citing works
Aromatase and other steroidogenic genes in endometriosis: translational aspects.
Attar, E., & Bulun, S. E. (2006) · Human Reproduction Update · doi:10.1093/humupd/dmi034 · Cited by 255 · see citing works
Histologic study of peritoneal endometriosis in infertile women
Nisolle, M., Paindaveine, B., Bourdon, A., Berlière, M., Casanas‐Roux, F., & Donnez, J. (1990) · Fertility and Sterility · doi:10.1016/s0015-0282(16)53571-7 · Cited by 214 · see citing works
Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum
Murphy, A. A., Green, W. R., Bobbie, D., de la Cruz, Z. C., & Rock, J. A. (1986) · Fertility and Sterility · doi:10.1016/s0015-0282(16)49598-1 · Cited by 214 · see citing works
Endometriosis: Correlation between histologic and visual findings at laparoscopy
Walter, A. J., Hentz, J. G., Magtibay, P. M., Cornella, J. L., & Magrina, J. F. (2001) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2001.115747 · Cited by 197 · see citing works
Escherichia coli contamination of menstrual blood and effect of bacterial endotoxin on endometriosis
Khan, K. N., Kitajima, M., Hiraki, K., Yamaguchi, N., Katamine, S., Matsuyama, T., Nakashima, M., Fujishita, A., Ishimaru, T., & Masuzaki, H. (2010) · Fertility and Sterility · doi:10.1016/j.fertnstert.2010.04.053 · Cited by 195 · see citing works
Self-citationDifferential macrophage infiltration in early and advanced endometriosis and adjacent peritoneum
Khan, K. N., Masuzaki, H., Fujishita, A., Kitajima, M., Sekine, I., & Ishimaru, T. (2004) · Fertility and Sterility · doi:10.1016/j.fertnstert.2003.07.037 · Cited by 161 · see citing works
Self-citationGaetje, R., Kotzian, S., Herrmann, G., BAUMANN, R., & Starzinski‐Powitz, A. (1997) · Europe PMC (PubMed Central) · Cited by 144 · see citing works
Javert, C. T. (1952) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(16)38796-8 · Cited by 143 · see citing works
Khan, K. N., Kitajima, M., Hiraki, K., Fujishita, A., Nakashima, M., Ishimaru, T., & Masuzaki, H. (2010) · Human Reproduction · doi:10.1093/humrep/deq240 · Cited by 132 · see citing works
Self-citationKhan, K. N., Kitajima, M., Hiraki, K., Fujishita, A., Sekine, I., Ishimaru, T., & Masuzaki, H. (2008) · American Journal of Reproductive Immunology · doi:10.1111/j.1600-0897.2008.00643.x · Cited by 125 · see citing works
Self-citationStem cell theory for the pathogenesis of endometriosis
Maruyama, T. (2012) · Frontiers in Bioscience · doi:10.2741/e589 · Cited by 109 · see citing works
Khan, K. N., Kitajima, M., Hiraki, K., Fujishita, A., Sekine, I., Ishimaru, T., & Masuzaki, H. (2009) · Gynecologic and Obstetric Investigation · doi:10.1159/000212061 · Cited by 94 · see citing works
Self-citationMüllerianosis: Four Developmental (Embryonic) Müllerian Diseases
Batt, R. E., & Yeh, J. (2013) · Reproductive Sciences · doi:10.1177/1933719112472736 · Cited by 88 · see citing works
Khan, K. N., Masuzaki, H., Fujishita, A., Kitajima, M., Sekine, I., & Ishimaru, T. (2003) · Fertility and Sterility · doi:10.1016/s0015-0282(02)04535-1 · Cited by 78 · see citing works
Self-citationKhan, K. N., Masuzaki, H., Fujishita, A., et al. (2005) · Human Reproduction · doi:10.1093/humrep/dei156 · Cited by 76 · see citing works
Self-citationA serial section study of visually normal pelvic peritoneum in patients with endometriosis
Redwine, D. B., & Yocom, L. B. (1990) · Fertility and Sterility · doi:10.1016/s0015-0282(16)53823-0 · Cited by 51 · see citing works
‘Invisible’ Microscopic Endometriosis: A Review
Redwine, D. B. (2003) · Gynecologic and Obstetric Investigation · doi:10.1159/000070176 · Cited by 48 · see citing works
CA125/MUC16 Is Dispensable for Mouse Development and Reproduction
Cheon, D., Wang, Y., Deng, J. M., Lü, Z., Xiao, L., Chen, C., Bast, R. C., & Behringer, R. R. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004675 · Cited by 41 · see citing works
Is “microscopic” peritoneal endometriosis invisible?
Redwine, D. B. (1988) · Fertility and Sterility · doi:10.1016/s0015-0282(16)60205-4 · Cited by 38 · see citing works
Nonvisualized endometriosis at laparoscopy.
Nezhat, F. R., Allan, C. J., NEZHAT, C. R., & Martin, D. C. (1991) · PubMed · Cited by 35 · see citing works
Typical and subtle atypical presentations of endometriosis
Donnez, J., Squifflet, J. P., Casanas‐Roux, F., Pirard, C., Jadoul, P., & Langendonckt, A. V. (2003) · Obstetrics and Gynecology Clinics of North America · doi:10.1016/s0889-8545(02)00054-2 · Cited by 30 · see citing works
Typical and subtle atypical presentations of endometriosis
Donnez, J., & Langendonckt, A. V. (2004) · Current Opinion in Obstetrics & Gynecology · doi:10.1097/00001703-200410000-00013 · Cited by 30 · see citing works
Hey-Cunningham, A. J., Fazleabas, A. T., Braundmeier, A. G., Markham, R., Fraser, I. S., & Berbic, M. (2011) · Reproductive Sciences · doi:10.1177/1933719110397210 · Cited by 30 · see citing works
Ishimaru, T., Khan, K. N., Fujishita, A., Kitajima, M., & Masuzaki, H. (2004) · Fertility and Sterility · doi:10.1016/j.fertnstert.2003.09.037 · Cited by 27 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- Batt RE, Yeh J. Mu ¨llerianosis: four developmental (embryonic) mu ¨llerian diseases. Reprod Sci 2013;20:1030 -1037.
- Redwine DB. Mu ¨lleriosis: the single best fit model of origin of endometriosis. J Reprod Med 1988b;33:915 -920.
Cited by
Sorted by citations
Bulun, S. E., Yilmaz, B. D., Sison, C., Miyazaki, K., Bernardi, L., Liu, S., Kohlmeier, A., Yin, P., Milad, M., & Wei, J. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00242 · Cited by 844 · see citing works
Endometriosis and nuclear receptors
Yilmaz, B. D., & Bulun, S. E. (2019) · Human Reproduction Update · doi:10.1093/humupd/dmz005 · Cited by 243 · see citing works
Cancer-associated mutations in endometriosis: shedding light on the pathogenesis and pathophysiology
Guo, S.-W. (2020) · Human Reproduction Update · doi:10.1093/humupd/dmz047 · Cited by 96 · see citing works
Epidemiology of subtle, typical, cystic, and deep endometriosis: a systematic review
Koninckx, P. R., Ussia, A., Keckstein, J., Wattiez, A., & Adamyan, L. (2016) · Gynecological Surgery · doi:10.1007/s10397-016-0970-4 · Cited by 30 · see citing works
Long, Q., Zheng, H., Liu, X., & Guo, S.-W. (2019) · Reproductive Sciences · doi:10.1177/1933719119828066 · Cited by 16 · see citing works
- Authors
- Khan, K. N., Fujishita, A., Kitajima, M., Hiraki, K., Nakashima, M., & Masuzaki, H.
- Affiliations
- Nagasaki University (JP)
- Saiseikai Takaoka Hospital (JP)
- Atomic Bomb Disease Institute, Nagasaki University (JP)
- Corresponding author
- Khan, Khaleque Newaz
- Venue
- Human Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-12-18
- Volume
- 29
- Issue
- 3
- Pages
- 462-472
- ISSN
- 0268-1161 (ISSN-L)
- 1460-2350
- OpenAlex
- W2116031453
- Cited by
- 72
- References
- 31
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 9 · 2021: 5 · 2020: 6 · 2019: 9 · 2018: 6 · 2017: 2 · 2016: 6 · 2015: 5 · 2014: 4 · 2013: 1
- FWCI
- 6.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Reproduction (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Nagasaki University's Academic Output SITE (Nagasaki University) (submittedVersion, cc-by-nc-nd)
- Funders
- Japan Society for the Promotion of Science (21592101, 24592474, 23510064)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Health Sciences › Medicine › Obstetrics and Gynecology › Gynecological conditions and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ectopic Pregnancy Diagnosis and Management
- Keywords
- peritoneal biopsy, Ber-EP4, CD10, calretinin, estrogen receptor, progesterone receptor, Ki-67 proliferation index, endometriosis recurrence, laparoscopic surgery, immunohistochemistry
- MeSH terms
- Antigens, Neoplasm, Endometriosis, Female, Humans, Laparoscopy, Peritoneum, Receptors, Estrogen, Receptors, Progesterone, Biomarkers, Tumor, Neprilysin, Biomarkers, Case-Control Studies, Ki-67 Antigen, Cell Proliferation, Calbindin 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
