Clinical Focus on Endometriosis Jaideep Malhotra, Rohan Palshetkar, Narendra Malhotra, Neharika Malhotra, Aruna Suman, Panchampreet Kaur, Kalyan B Barmade
Page numbers followed by f refer to figure, fc refer to flowchart, and t refer to table
Adnexa 30
American Association of Gynecologic Laparoscopists 6, 24
classification 12, 12f
American Society for Reproductive Medicine 7, 8t, 16, 21, 21f, 44, 60, 68
revised classification of endometriosis 7, 8t
Angiogenesis 18
Anti-Müllerian hormone 53
Aromatase inhibitors 37, 51
Assisted reproductive technology 44, 47, 60, 68
indications for 54
Atorvastatin 58
Autoantibodies 18
Bladder 24, 30
anterior compartments of 32f
endometriosis 16
posterior compartments of 32f
Blood biomarkers 18
Bone mineral density 77
Bowel 30
Brain-derived neurotrophic factor 68
Cabergoline 38, 58
antigen 3, 18
benign 1
ovarian 1, 2fc
Cervix 30
Clomiphene citrate 62,63,63t, 64, 65
Coelomic metaplasia 7
Computed tomography scan 20
Conservative surgery, outcomes of 42
Controlled ovarian
hyperstimulation 60
stimulation 61
C-reactive protein 18
Cyst, endometriotic 19f, 20f
Cystectomy 41
laparoscopic 52
Cytokines, inflammatory 18
Danazol 37, 51
Deep infiltrating endometriosis 15, 26, 29, 52f, 53
Enzian classification of 27f
Deoxyribonucleic acid 1
Diarrhea 47
Dienogest 51
Douglas pouch 17, 29, 30
Dyschezia 28, 47
Dysmenorrhea 28, 47, 75
Dyspareunia 28, 47, 75
Dysuria 28, 47
Embryo transfer 67
Endocrine abnormalities 47
Endometrial stromal tissue 19
Endometrioma 15, 21, 30, 52f
Endometriosis 1, 2fc, 6, 12f, 15, 17, 24, 25f, 36, 44, 47, 48f, 52, 53, 57, 58, 60, 67, 68f, 69, 75
bowel deep infiltrating 33f
classification for 47, 49f
deep 7, 24, 28, 41
infiltrating 15, 26, 29, 52f, 53
development 45
diagnosis of 17, 22, 24
enigma 1
Enzian classification of 11f
epidemiology of 46f
fertility index 7, 26, 48, 70, 74
classification 9t, 10t
lesions, evolution of 2fc
malignant transformation of 1
medical management of 36
mild 60, 63
mild to moderate 61f
minimal 60, 63
moderate 60
ovarian 7, 24, 41
pathogenesis of 45, 45f
pelvic 67
peritoneal 41
premenarchal 6
recurrent 75, 76, 77t, 78f
Research Foundation 27f
revised classification of 21f, 25f
scoring systems 24
severe 60
staging for 47, 49f
superficial 24, 28, 52f
surgical management of 40
symptoms of 47, 47t
therapy 51
treatments for 74fc
Endometrium 47, 62
Enzian classification 7, 11f, 12, 26, 27f
revised 9
Epiphenomenon 1
Epithelial cells 57
Estradiol 63
Estrogen receptor 77
European Society for Gynaecological Endoscopy 6, 24
European Society of Human Reproduction and Embryology 6, 17, 24, 41, 44, 60
guidelines 70
Federation of Obstetric and Gynaecological Societies of India 44
Fibroblast growth factor-2 188
Follicle-stimulating hormone 6264, 71
Follicular fluid 68
Follistatin 18
Frozen embryo transfer 53
Genetics 7
Glycodelin A 18
Glycoproteins 18
Gonadotropin-releasing hormone 38, 41, 70
agonists 37, 51, 61
antagonists 38
Hematochezia 28, 47
Hematuria 28
macroscopic 47
microscopic 47
Heme 1
Hemoglobin, extracellular 1
growth factor 18
nuclear factor 1-beta 2
Human chorionic gonadotropin 61
Human endometrial stromal cells 58
Human menopausal gonadotropin 62, 64
Hysterectomy 42
In vitro fertilization 26, 52, 62, 67
Infertility 47, 60
endometriosis-related 48
male 54
Inflammatory disease 6
International deep endometriosis analysis 28
International ovarian tumor analysis 29, 30
Intracytoplasmic sperm injection 71
Intrauterine insemination 53, 60, 63
clinical impact 65
protocols 60
Iron 1
Kirsten rat sarcoma viral oncogene homolog 2
Laparoscopic uterine nerve ablation 42
Laparoscopy 20, 28
surgery 40
Lesions, endometriotic 15
Letrozole 62, 63t
Leuprolide acetate 37
Levonorgestrel-releasing intrauterine system 80
Lovastatin 58
Luteinizing hormone 61, 63, 68
Magnetic resonance imaging 19, 26
Malignancy, endometriosis-associated 1
Malignant transformation
early detection of 3
mechanism of 1, 2fc
Matrix metalloproteinases 46
Menstrual pain, severe 47
Menstrual stem cells 57
Mesenchymal epithelial transition factor 2
Microembolization 6
Mifepristone 37
Monocyte chemoattractant protein-1 18
Morphological uterus sonographic assessment 30
Multidetector computerized tomography enema 26
Nafarelin 37
National Institute for Health and Care Excellence 61
Nonsteroidal anti-inflammatory drugs 37, 78
Nuclear factor kappa B 46
donation 70
quality of 69t
Oophorectomy 42
Oral contraceptive
combined 36, 51, 74
low-dose 80
pills 77, 81
Ovarian cancer pathogenesis, endometriosis-associated 2fc
Ovarian clear cell cancer 3
Ovarian endometrioma 15, 28, 29, 41, 52
size of 30
Ovarian endometriosis 7, 24, 41
cysts 21
Ovarian hyperstimulation syndrome 65, 74
Ovarian masses 30
Ovarian suppression 51
Ovulatory dysfunction 69
Pelvic adhesions 20f
Pelvic nerve pathways, interruption of 42
Pelvic pain, chronic 28, 47, 75
Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha 2
Platelet-derived growth factor 18
Pollakiuria 47
Pregnancy 76
Presacral neurectomy 42
Progesterone-containing contraceptives 36
Progestins 51
Proteomics 19
Radical surgery 42
Randomized controlled trial 51, 71
Rapamycin, mammalian target of 2
Reactive oxygen species 46
Rectosigmoid junction 30, 31
Rectovaginal nodules 31
Rectovaginal septum 9, 30, 31
Rectum 24, 30, 31
Retrograde menstruation, Sampson's theory of 6
Revised American Society for Reproductive Medicine 7, 26
classification 7
Sampson's theory 6
Selective estrogen receptor modulators 51
Selective progesterone receptor modulators 37
Sigmoid 31
colon 30
Simvastatin 58
Society of Obstetricians and Gynaecologists of Canada 44
Soluble epidermal growth factor 18
Sorafenib 58
Stem cell 3, 57, 58
therapy 57, 58
Steroidogenesis 67
Superficial peritoneal lesions 15
Superovulation 53
Tenesmus 47
Transvaginal scan 19
Transvaginal sonography 26
Tubal factor 69
Tuboovarian complex 10
Tumor necrosis factor alpha 46, 60
Ulipristal acetate 37
Ultrasound 19
Ureteric lesions 41
Ureters 30
Urine biomarkers 19
Uterine adenomyosis 16
Uterosacral ligaments 24, 30, 31
Uterovesical region 30
Uterus 30, 57
anteverted 31f
retroverted 31f
Vagina 24
Vaginal fornix, posterior 30
Vaginal septum 9
Vaginal wall 31
Vascular endothelial growth factor 18, 46, 60
World Endometriosis Society 24, 44
Zona pellucida 68f
Chapter Notes

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Endometriosis an Enigma, a Benign Cancer: An EpiphenomenonCHAPTER 1

Aarti Chitkara Wadhawan,
Narendra Malhotra,
Neharika Malhotra
Endometriosis is a common disease in women, causing pelvic pain and infertility. It is characterized by the presence of endometrial tissue, composed of epithelial glands and endometrial stromal cells, outside the uterus. It is an extremely heterogenous clinical entity with regard to etiopathogenesis, clinical features, and treatment.
Although benign, endometriosis has cancer-like features, a mutation profile similar to that of an ovarian cancer (OC), and an increased risk of OC.13 They result in local and distant metastasis, invasion and destruction of adjacent structures, unrestricted growth, resistance to apoptosis, development of new blood vessels, etc.
The lifetime risk of OC among women with endometriosis is 1.80%, fewer than 2 women in 100,4,5 thereby suggesting a very low overall risk of developing OC.
Sampson in 19256 proposed three criteria for the diagnosis of endometriosis-associated OC (EOAC):
  1. Evidence of endometriosis close to the tumor
  2. Exclusion of invasion from other sources
  3. Presence of tissue resembling endometrial stroma surrounding characteristic epithelial glands.
Scott in 19537 revised the criteria and added the fourth criterion:
  1. Histological proof of transitions from benign changes in endometriosis to malignant changes.
Endometriosis is associated with genetic instability and several genetic alterations. Few mutations shared by both endometriosis and endometriosis-associated malignancy (EAM) are loss of heterozygosity at 10q23, PTEN (phosphatase and tensin homolog deleted on chromosome 10), ARID1A (AT-rich interactive domain-containing protein 1A), and p53 mutations.8
A proposed mechanism of pathway postulated for EAM is depicted in Flowchart 1.
Two potential mechanisms leading to EOAC have been proposed:
  1. Extracellular hemoglobin, iron, and heme (from the repeated hemorrhages occurring in the endometriosis) causing cellular oxidative damage via increased reactive oxygen species with subsequent deoxyribonucleic acid (DNA) damage and resulting mutations
  2. The second mechanism involves persistent production of antioxidants, which would favor a tumor-potentiating environment.2
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Flowchart 1: Mechanism of malignant transformation in endometriosis.(ARID1A: AT-rich interactive domain-containing protein 1A; HNF-1B: hepatocyte nuclear factor 1-beta; MET: mesenchymal-epithelial transition factor; PIK3CA: phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha)
Both of these result in a double-edged sword redox imbalance milieu.9,10
Flowchart 2 illustrates the potential process of establishment and evolution of endometriosis lesions to ovarian cancer.
Risk factors that lead to transformation of endometriosis from benign to borderline (atypical) and then to EOAC involve molecular genomic alteration, inflammation, hyperestrogenism, oxidative stress, and obesity. Molecular alterations such as mutations of ARID1A, PI3KCA (phosphoinositide 3-kinases), loss of heterozygosity of PTEN, HNF-1b (hepatocyte nuclear factor-1b), and mutation of CTNNb1 (catenin beta 1) are illustrated in Flowchart 3.11
Endometroid and clear cell carcinoma are the most common types of ovarian carcinoma of EAOC with an incidence of 32% and 28%, respectively. Other less common types of malignancies encountered are the endocervical type of mucinous borderline tumor, endometrial stromal sarcoma, and Mullerian adenosarcoma.12,13
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Flowchart 2: Potential process of the establishment and evolution of endometriosis lesions to ovarian cancer.
zoom view
Flowchart 3: Molecular pathways involved in endometriosis-associated ovarian cancer pathogenesis.(AKT: AK strain transforming protein; BRAF: ERK 1/2: extracellular signal-regulated kinases; KRAS: Kirsten rat sarcoma viral oncogene homolog; MEK 1/2: mTOR: mammalian target of rapamycin; RTK: receptor tyrosine kinases)
3The diagnostic dilemma between endometriosis and OC is further perplexed by raised cancer antigen (CA)-125 in both the entities. Human epididymis protein 4 (HE4) is a useful differentiating tumor marker, specifically for ovarian malignancy.
Some recent suggestions propose that endometriotic lesions originate from ectopic endometrial stem cell progenitors. This is supported by the fact that some Hox genes are involved in both eutopic endometrium and OC.1417 However, research in this area is far from offering any direct evidence; therefore, we can only hypothesize about the possible role of stem cells, and the calls of direct targeting as a therapeutical tool are yet to be established.
Early detection of malignant transformation is of paramount importance to improve the prognosis of EOAC. One should be cautious in women diagnosed with endometriosis at an early age, long-standing history, large endometrioma, and endometriosis-associated infertility.
With advancement in ultrasound and rising expertise in detecting subtle features on ultrasound, this can be a useful modality to diagnose early features of a malignant transformation of endometriosis. A unilocular cyst with papillary projection without ascites has been detected in most instances of EAOC in a multicenter study involving 239 women on ultrasound.18 On T1-weighted images of contrast-enhanced magnetic resonance imaging (MRI), unilateral cystic mass containing hemorrhagic fluid and mural nodule is characteristic of malignant transformation of endometrioma. The disappearance of shading on T2-weighted images with enlargement of endometrioma is suggestive of malignant transformation.19
Many experts observed a better prognosis compared with non-EOAC probably due to early stage and grade of the disease.20 In a large population-based cohort study, longer survival was observed in OC patients with histologically proven endometriosis than those without endometriosis even after adjusting stage, grade, type, age at diagnosis, treatment protocol, and residual tumor after surgery.21
A recent meta-analysis demonstrated that EOAC patients had better overall survival (OS) as compared to non-EOAC patients in both OC and ovarian clear cell cancer (OCCC) cohorts. The meta-analysis also found that EOAC patients had better progression-free survival (PFS) than non-EOAC patients.22
A Swedish study of over 64,000 women found that patients with endometriosis have an increased risk of certain malignancies (ovarian, endocrine, non-Hodgkin lymphoma, and brain tumors), and this risk increases with early diagnosed or long-standing disease.23 A study of 45,000 Danish women confirmed not only the increased risk of OC, but also the increased risks of endometrial and breast cancers.24 In addition, the risk of colorectal cancer was increased 13-fold in women with internal endometriosis.25
Studies are underway to identify specific biomarkers to identify endometriosis with oncogenic potential where specific targeted therapy can be offered. It has been 4observed that the risk of EOAC results in a 20–30% reduction with 5 years of use of oral contraceptives.26
No clear evidence exists that transvaginal ultrasound or CA-125 measurements can detect OCs early or that risk-reducing salpingo-oophorectomy can save lives. Generally, to improve health and reduce the risk of cancer, a balanced diet with a low intake of alcohol, regular exercise, healthy weight, and refraining from smoking is advisable.
There appears to be an increased risk of OC, particularly endometrioid and clear cell types, in individuals with ovarian endometriosis but not in patients with peritoneal or deeply infiltrating endometriosis. Some ovarian endometriosis lesions harbor genetic mutations in ARID1A, PTEN, HNF-1b and K-Ras that may also be found in ovarian cancer lesions. Future molecular analysis of surgical ovarian endometriosis specimens may help to identify patients at the highest risk of developing OC. While the relative risk of OC may be increased, the absolute risk of developing OC from ovarian endometriosis remains low, with approximately two additional cases per 10,000 women-years of follow-up for individuals with ovarian endometriosis compared with those without endometriosis.27
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