Endometriosis Dan C. Martin, M.D. University of Tennessee Health .

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Slide 1 :

Endometriosis Dan C. Martin, M.D. University of Tennessee Health Science Center Memphis, Tennessee

Slide 2 :

Learning Objectives Following the presentation “Endometriosis” participants should be able to: Understand definitions of endometriosis. Contrast pain and fertility. Describe medical therapy. Understand the use of surgery. Have a knowledge of endometriosis research.

Slide 3 :

Disclosure Baxter BioSurgical Production of Educational Material Presentations on 4% Icodextrin (Adept ®) and Adhesions Ethicon Endo-Surgery Education Grant for UTHSC Resident Education Covidien (formerly Valley Lab and Autosuture) Expenses of Monitoring Dr. Nezhat’s Course. Several Companies Pens, dinners, dinner speakers, etc

Slide 4 :

Off-Label Discussion Pain and Endometriosis Oral Contraceptives Provera / Depo-Provera

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Definition Histologic Glands and Stroma Hemosiderin Laden Macrophages Laparoscopic Dark Scarred Lesions Subtle “Atypical” Lesions Clinical Dysmenorrhea not responsive to NSAIDs / OCs

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Occurrence Maximum Minimum Theoretical 99% ? Family Practice 15% 1% Gyn Practice 72% 30% Infiltrating 25% 5% Bowel* 12% 0.5% Vaginal* 4% 0.17% Deep Vaginal* 0.04% 0.00015% * Increased chance of colostomy if surgery

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Theories Implantation Mullerian Tissue Present at Birth Coelomic Metaplasia Vascular Metastasis Lymphatic Metastasis

Slide 8 :

Theories Implantation

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Theories Present at Birth (Mullerian Remnants)

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Natural Progression i f P r o g r e s s i n g Implantation Clear Blisters Red Polypoid Blisters Scarring and Blood Trapping Collection of Old Blood More Scar Deep Infiltration

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Histological Diagnosis 400 / 200 µm circled

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Histological Diagnosis 400 / 200 µm circled O O O O O O O O

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Histological Diagnosis

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Dilated Gland ? Histological Diagnosis Ovary ? Right Tube ? ? Hemosiderin and stroma Dilated Gland ? Right Tube ? ? Hemosiderin and stroma Dilated Gland ? Hemosiderin and stroma ? Ovary ? Dilated Gland ?

Slide 15 :

Dilated Gland ? Histological Diagnosis Ovary ? Right Tube ? ? Hemosiderin and stroma Dilated Gland ? Right Tube ? ? Hemosiderin and stroma Dilated Gland ? Ovary ? Edematous Glands and Stroma ?

Slide 16 :

Histological Diagnosis

Slide 17 :

Histological Diagnosis

Slide 18 :

Histological Diagnosis Trichrome Stain H&E Stain Muscle ? Fibrous Scar ? Glands and Stroma Fibromuscular Scar

Slide 19 :

Histological Diagnosis Fibromuscular Scar ? Stroma ? Glandular Epithelium ? Old Blood ?

Slide 20 :

Presentation Pelvic Pain Mass Infertility Uncommon and Rare Problems Diaphragmatic Pain Catamenial Pneumothorax Bowel Obstruction

Slide 21 :

Pain - Clinical Behavior Endometriosis should be viewed as a chronic disease that requires a life-long management plan with the goal of maximizing the use of medical treatment and avoiding repeated surgical procedures. Gastrointestinal, urinary, musculoskeletal and psychological conditions can mimic the symptoms of endometriosis and should be excluded before pursuing aggressive therapy for endometriosis in all patients, particularly those who fail to respond to standard medical treatments. ASRM 2006

Slide 22 :

Pain - Clinical Behavior Laparoscopy remains the cornerstone of accurate diagnosis. Both medical and surgical treatments are effective. In women with symptoms of pelvic pain, visible endometriosis observed during surgery should be treated. Surgical treatment for endometriosis, followed by medical therapy, offers longer symptom relief than surgery alone. Definitive treatment of endometriosis should be reserved for women with debilitating symptoms that can reasonably be attributed to the disease who have completed childbearing and have failed to respond to alternative treatments. ASRM 2006

Slide 23 :

Treatment Medical Therapy (Empirical?) Oral Contraceptives NSAIDs Norethindrone 5 to 15 mg Daily Depo-Provera GnRH Analogs Aromatase Inhibitors Surgery Diagnostic Laparoscopy Therapeutic Laparoscopy Laparotomy

Slide 24 :

Are These FDA Approved? Pain Infertility NSAIDs Oral Contraceptives Norethindrone Depo-Provera GnRH Analogs Aromatase Inhibitors Laparoscopy Laparotomy

Slide 25 :

Provera® Indications Provera® (medroxyprogesterone acetate) is indicated for: Treating secondary amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. Reducing the incidence of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving daily oral conjugated estrogens 0.625 mg tablets.

Slide 26 :

Provera® Contraindications Provera® Contraindications Undiagnosed abnormal genital bleeding Known, suspected, or history of cancer of the breast Known or suspected estrogen- or progesterone-dependent neoplasia Active deep vein thrombosis, pulmonary embolism or a history of these conditions Active or recent (within the past year) arterial thromboembolic disease (for example, stroke and myocardial infarction) Known liver dysfunction or disease Missed abortion As a diagnostic test for pregnancy Known hypersensitivity to the ingredients in Provera® tablets Known or suspected pregnancy - Pregnancy Category X

Slide 27 :

Aygestin® Indications Aygestin® is indicated for the treatment of secondary amenorrhea, endometriosis, and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. NOTE: Pregnancy Category X

Slide 28 :

Lupron Depot 3.75 mg® Lupron Depot 3.75 mg® is indicated for: Endometriosis: Pain relief and reduction of endometriotic lesions. In combination with norethindrone acetate 5 mg daily is also indicated for initial management and for management of recurrence of symptoms. Duration of initial treatment or retreatment should be limited to 6 months. Uterine Leiomyomata (Fibroids): Concomitantly with iron therapy for preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata. The clinician may wish to consider a one-month trial period on iron alone inasmuch as some of the patients will respond to iron alone.

Slide 29 :

Lupron Depot 3.75 mg® Pregnancy Category X When administered on day 6 of pregnancy to rabbits, Lupron Depot 3.75 mg® produced a dose-related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with higher doses of Lupron Depot 3.75 mg® in rabbits and with the highest dose in rats.

Slide 30 :

Pain, Endometriosis and GnRH Frank Ling et al. Obstet Gynecol 1999 Chronic, non-cyclic pelvic pain not NSAID responsive. 78 (82%) of 95 patients with endometriosis Endometriosis diagnosed laparoscopically Pain relief with GnRH agonists 82% (27 of 33) with Endometriosis 73% (8 of 11) with No Endometriosis Pain relief with placebo 39% (15 of 38) with Endometriosis 16% (1 of 6) with No Endometriosis

Slide 31 :

Pain, Endometriosis and Suppression Todd Jenkins et al. AAGL 2007 Chronic pelvic pain 87 (84%) of 104 patients had endometriosis Endometriosis diagnosed laparoscopically 87% (41 of 47) with pain relief 81% (46 of 57) with no pain relief Endometriosis diagnosed histologically 67% (31 of 46) with pain relief 68% (39 of 57) with no pain relief

Slide 32 :

Indications for Surgery Generally Accepted Indications Bowel Stenosis Ureteral Obstruction Mass of Uncertain Nature Relative Indications Pain Infertility Vercellini, ASRM 2005

Slide 33 :

Superficial or Deep Coagulation vs Excision

Slide 34 :

Superficial or Deep Coagulation vs Excision Bowel Bowel

Slide 35 :

Tissue Diagnosis Research Standard? Diagnostic Standard? Exclude Other Diagnoses Clear Vesicles Endometriosis Endosalpingiosis Psammoma Bodies Low Malignant Potential Tumor Subtle Lesions White Nodules

Slide 36 :

Tissue Effect of Electrosurgery 5 cm monopolar in bowel Wheeless 1978 0.1 mm @ 60,000 watt/cm2 monopolar Luciano 1987 Visual Appearance to 5 mm with bipolar Ryder 1993 Lateral spread to 20 mm with bipolar at 6 seconds exposure. Phipps 1994

Slide 37 :

Tissue Diagnosis The clinical purpose of biopsy is to exclude other pathology. If the histology is uncertain, the clinical diagnosis is maintained. In research, biopsy are often avoided as they may modify the behavior of the process.

Slide 38 :

rASRM 1996

Slide 39 :

Who Needs a Biopsy? Dark Scarred Puckered Pigmented Mixed Color - > No biopsy needed. Dark Scarred Puckered Pigmented and Vesicles. - > Biopsy! Asymptomatic patient having tubal sterilization. (Moen)

Slide 40 :

Who Needs a Biopsy? Endometriosis Endosalpingiosis Psammoma Bodies - > Biopsy needed? Same plus LMPT and Cancer - > Biopsy! Asymptomatic patient having tubal sterilization. (Moen)

Slide 41 :

Who Needs a Biopsy? Psammoma Bodies Endosalpingiosis - > Biopsy needed? Same plus LMPT and Cancer - > Biopsy! Asymptomatic patient having tubal sterilization. (Moen)

Slide 42 :

Histological Diagnosis

Slide 43 :

Histological Diagnosis

Slide 44 :

Histological Diagnosis

Slide 45 :

Histological Diagnosis Tube ? Ovary ?

Slide 46 :

Histological Diagnosis Tube ? Ovary ?

Slide 47 :

Histological Diagnosis

Slide 48 :

Histological Diagnosis

Slide 49 :

Histological Diagnosis

Slide 50 :

Histological Diagnosis

Slide 51 :

Histological Diagnosis

Slide 52 :

Histological Diagnosis

Slide 53 :

Biopsy White nodules Clusters of vesicles Mixed color endometriosis. Anything you do not recognize in a reasonable anatomic area.

Slide 54 :

Confirmation at a Research Level No Expectation of Appearance Biopsy Techniques Adequate Number of Biopsies Signal to Noise Ratio Tagging the Specimen Location Marking the Specimen Side Notations on Pathology Request Uniform Specimen Size in Container Cell Block Transferring the Specimen to Container Processing by the Surgeon Communications with the Cutters Communications with the Pathologist Re-cutting Specimens Requiring Histologic Description Histologic Criteria (Batt 1989) Reviewing Slides Surgeon Experience Fixed Protocol if for STARD

Slide 55 :

Confirmation at a Research Level Year 1982 1983 1984 1985 1986.1 1986.2 Cumulative Number 97 188 279 376 426 495 of Patients by One Gyn Positive for Endo 62% 50% 91% 93% 96% 99% when Excised 99% in last 69 of 495 cases over 60 months (8.2 per month) Martin 1987, Stripling 1988, Martin 1990 45% Positive Predictive Value in 44 cases over 20 months (2.2.per month) Walter, 2001 61% of lesions in first 46 cases over 34 months (1.4 per month) 68% of lesions in next 56 cases over 36 months (1.6 per month) Stratton 2003, Stegmann 2005, the NIH group 88% in 2004 Memphis study in 72 cases over 7 months (10.1 cases per month) Pathologists found an additional 10% in 2004 compared with 14% in 1986.

Slide 56 :

What Can We Do with a Biopsy? Rule Out Cancer Determine a Histologic Diagnosis Research Guide therapy in some cases This does not include deciding on therapy of endometriosis. Therapeutic conclusions in the literature are based on appearance or history but not histology. The literature says to treat it like endometriosis if it looks like endometriosis. Histology is used to clarify other concerns. See $100 reward at www.memfert.com/reward.htm.

Slide 57 :

Endometriosis Clinical Care Laparoscopy is the gold standard for diagnosing endometriosis Exceptions Vaginal Endometriosis Sciatic, pulmonary, etc. endometriosis Research Laparoscopy has been the gold standard Histology is needed

Slide 58 :

Ilium

Slide 59 :

Retrocervical Endometriosis RV Pouch is to the middle third of the vagina in 93% of women. Kuhn 1982

Slide 60 :

Ring Forceps Test

Slide 61 :

Ring Forceps Test

Slide 62 :

Retrocervical Endometriosis Rectovaginal endometriosis is more rectocervical than rectovaginal. Martin 2001, 2005

Slide 63 :

Rectovaginal Pouch Obliteration

Slide 64 :

Rectovaginal Pouch Obliteration

Slide 65 :

Conclusions Endometriosis is a complex process that includes formation, progression and regression in what may be a random and unpredictable fashion or may be dependant on genetics or the environment. This is another “Watch This Space” story.

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The clinical purpose of biopsy is to exclude other pathology.Pathologists found an additional 10% i more The clinical purpose of biopsy is to exclude other pathology.Pathologists found an additional 10% in 2004 compared with 14% in 1986. …www.emsc.info/southbend30jan08.ppt less
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