Clinical Controversies in Endometriosis

Clinical Controversies in

EndometriosisAmerican Society of Reproductive Medicine

Baltimore, Maryland

October 21, 2015

Dan C. Martin, M.D.Interim Director Gynecology

Director Minimally Invasive Surgery

Director Reproductive Endocrinology and Infertility

Department of Obstetrics and Gynecology

University of Tennessee Health Science Center

Memphis, Tennessee

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Disclaimer

Abbvie – Consultant on a new product not to be

discussed today.

Subject matter expert for Epic EHR for Baptist Memorial

Health Care Corporation

------------------------------------------------

Please confirm that you have the right to use copy

righted material.

Permission to use slides from

The Laparoscopic Appearance of Endometriosis

http://www.danmartinmd.com/files/coloratlas1990.pdf

is on page iii of the PDF

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http://www.danmartinmd.com/files/coloratlas1990.pdf

Subjects

Classical Appearance

Laparoscopic Appearances

Histology

Why biopsy?

Empirical therapy

Intentional delayed diagnosis

Is mild endometriosis a disease?

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RV Pouch of Douglas

The RV Pouch

of Douglas is to

the middle third

of the vagina in

93% of women.

– Kuhn 1982

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5

Greek Architecture Slide

Kleinhan 1904Futh 1903

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Cullen 1917

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Cullen 1917

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Sampson 1921

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Sampson 1921 & 1924

Blebs

Red Raspberries

Purple Raspberries

Blueberries

Deep Infiltration

Chocolate Cysts

Peritoneal Pockets

Unseen Endometriosis in

Adherent Surfaces

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Adamyan Classification

Adamyan 1993, Martin & Batt 2001 11

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Rectovaginal Septum

Adamyan 1993, Martin & Batt 2001 13

Dark Scarred 1990

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Dark Scarred 1990

Carbon

Endometriosis deep

in fibromuscular scar →

Powder Burn

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Old Blood →

Fibro-muscular scar →

Stroma →

Glandular Epithelium →

Muscle →

Masson’s Trichrome Stain

Muscle →

Fibrous Scar →

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1,000 hours1,000 hours

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Ericsson 1993, Gladsto20

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Statistics

There are three kinds of lies: lies, damned

lies, and statistics– Benjamin Disraeli (1804–1881)

– Mark Twain (1835-1910)

Statistics don’t lie just statisticians.

Politicians use statistics in the same way

that a drunk uses lamp-posts —

for support rather than illumination – Andrew Lang (1844-1912)

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Recognition

Recognition of small lesions (180 – 800 microns) is

dependent on the viewing distance (magnification).

Redwine Gynecol Obstet Invest 2003

Murphy 1986

Nisolle 1990

Redwine 1988, 1990

Nezhat 1991

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Confirmation in 495 Consecutive Cases

Cancer Surveillance Study 1982-1986

Year 1982 1983 1984 1985 1986.1 1986.2

Positive for Endo 8 17 59 84 48 68All Patients 8% 19% 65% 87% 96% 99%

If Excised 62% 50% 91% 93% 96% 99%

Martin 1987, Stripling 1988, Martin 1990

1,000 hours

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Confirmation in 495 Consecutive Cases

Cancer Surveillance Study 1982-1986

Year 1982 1983 1984 1985 1986.1 1986.2

Positive for Endo 8 17 59 84 48 68All Patients 8% 19% 65% 87% 96% 99%

If Excised 62% 50% 91% 93% 96% 99%

Martin 1987, Stripling 1988, Martin 1990

1,000 hours

NOTE: 14% “false” negative tissue in 1986

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Martin 1990 26

Confirmation at a Research Level

Requirements

• Pathologist must be requested to perform several sections.

• A large number of tissue samples must be taken for histologic confirmation of the diagnosis, and each one should be submitted in a separate container.

• An average of 1.2 samples/patient is not sufficient.

Buchweitz 2003 27

Confirmation at a Research LevelNo Expectation of Appearance

Biopsy Techniques–Power density of 4,000 to 26,000 watt/cm2 (0.2 to 0.5 cm spot, 110 watt laser)

–Alignment for TEM00 mode

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

Require a Histologic DescriptionA 1 mm lesion requires histology compatible with a 1 mm lesion.

Histologic Criteria (Batt 1989)

Reviewing Slides

Surgeon Experience

Fixed Protocol* Protocol in yellow may not be compatible with STARD.

This level of concern for accuracy

can be attained in research.

There is no documentation that

this is useful outside of a research

setting.

A STARD level research protocol

would not allow communications

or review. The protocol would

need to clarify the procedures.

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Confirmation – Time Intervals

Cumulative Cases

100 500

100

90

80

70

60

50

40

30

20

10

200 300 400

Pe

rce

nt

Po

sit

ive ●

●●

●

●

Martin 1987, Stripling 1988, Martin 1989, Martin 1990

495 Cases, 99%


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Confirmation – Time Intervals

Cumulative Cases

100 500

100

90

80

70

60

50

40

30

20

10

200 300 400

Pe

rce

nt

Po

sit

ive ●

●●

●

●


Stratton 2002, Stegmann 2008, 179 Cases

●●●

Dulumba 2012

● 280 Cases, 80%

495 Cases, 99%

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Confirmation – Research v Clinical

100

90

80

70

60

50

40

30

20

10

Pe

rce

nt

Po

sit

ive

●

●

●

●

ClinicalResearch

Stripling 1988, Martin 1990

Webb, Martin 2005

Buchweitz 2003

Buchweitz, 2003

99%

88% with 10% false negative87%

56%

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What Can We Do with a Biopsy?

Rule out cancer

Determine a histological diagnosis

Guide therapy in some casesThis does not include deciding on therapy of endometriosis with non-specific histology.

– Therapeutic conclusions in the literature are based on appearance, “appearance or histology” or history but not on histology only.

– The literature says to treat it like endometriosis if it looks like endometriosis.

– Histology is used to clarify other concerns.

Research32

Histologic Grading System

Grade 1: possible residua of resorbed endometriosis, i.e., hemosiderin, calcium, nerve, blood vessels, and smooth muscle.

Grade 2: consistent with endometriosis, i.e., hemosiderin, characteristic glands, or stroma.

Grade 3: definite endometriosis, i.e., characteristic glands and stroma with hemosiderin.

Grade 4: grade 3 with structures conveying an organoid pattern, i.e., glandular-stromal layer with overlying well-developed smooth muscle layer.

Batt RE, et al. 1989

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Histologic Grading System

Grade 2: consistent with endometriosis, i.e., hemosiderin, characteristic glands, or stroma.

Grade 3: definite endometriosis, i.e., characteristic glands and stroma with hemosiderin.

Batt, et al. 1989

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Premenarcheal “Endometriosis”Marsh and Laufer. Fertil Steril 2005

Inflammatory lesions

Left

Ovary Uterosacral

Ligament

Broad Ligament

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All 5 Inflammatory

Grade 2

Grade 3

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Marsh 2005

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Drs. Tasuku Harada , Fuminori Taniguchi and Yukihiro Azuma

Tottori University School of Medicine, Yonago, Japan 39

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Tadpole who thinks they

are a sperm slide

Delayed Diagnosis

Majority of adults with endometriosis had

severe dysmenorrhea as teeagers.

Data on what percent of adults with no

diagnosis of endometriosis had severe

dysmenorrhea as a teen?

Data on what percent of women with mild

endometriosis as a teen have severe

endometriosis 20 years later.

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Empirical Therapy

Dysmenorrhea – Oral Contraceptives

Pelvic Pain – NSAIDs

Combined OC & NSAID therapy

Persistent Pain

– Depo-MPA

– Depo-GnRH agonist

– Narcotics

– Laparoscopy

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Delayed Diagnosis

Natural Course?

Suppressive Therapy?

Surgical Therapy?

Physical Therapy?

Acupuncture?

Meditation?

…

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Is Superficial Implantation a Disease?

Is Transient Occurrence a Disease?

“Disease exists with aggressive infiltration or cystic ovarian endometriosis.”

Koninckx PR. Is mild endometriosis a condition occurring intermittently in all

women? Human Reproduction. 1994;9:2202-5.

“Endometriotic disease is not simply the finding of glands and stroma

(endometriosis) as these findings can be the result of retrograde

menstruation with early peritoneal implantation. Early implantation may be

recognized and eradicated by the immune system.”

Evers JLH. Endometriosis does not exist; all women have endometriosis.

Human Reproduction. 1994;9(12):2206-9.

Compare with the Pimple Model

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Pimple Model

Pimples come and go.

Most get better.

Some get worse.

Few develop acne vulgaris.

Pimples decrease with aging.

You can see what looks bad.

You cannot see what causes pain.

You cannot tell what will grow.

You cannot tell what will scar.

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All M.C. Escher works (c) 2013 The M.C. Escher Company - the Netherlands.

All rights reserved. Used by permission. www.mcescher.com

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Escher Relativity Slide

http://www.mcescher.com/gallery/back-in-holland/relativity/



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Retrograde Menstruation

Dispersion, Attachment, Infiltration, Growth

Sigmoid Colon

Uterine Fundus

Ovary

Ovary

Tube

Rectovaginal

Pouch of Douglas

Bladder

Fimbriae

Tube

Nisolle 1997

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What % of women have retrograde menstruation?

37%

51%

76%

87%

97%

100%

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What % of women have retrograde menstruation?

37% - D’Hooghe, et al. 1996* – Recurrent

51% - D’Hooghe, et al. 1996 – Single

76% - Liu and Hitchcock 1986 – All Women

87% - D’Hooghe, et al. 1996 – Stage I

97% - Liu and Hitchcock 1986 – Endometriosis

100% - D’Hooghe, et al. 1996 – Stage II to IV

* * Higher prevalence and recurrence with spontaneous endometriosis.

** Less than 100% Mayer-Rokitansky-Küster-Hauser.

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When is the

immune

response

mature?

Nisolle 199752

Immune Response?

Size of Lesion?

Shakiba et al. Obstet Gynecol. 2008

Age Range 7 Year Reoperation

19-29 72%

29-39 56%

≥ 40 24%

Dan Martin 1981-c1995

Age Reoperation

≤18 80% at 2 years

26 50% at 5 years

≥42 15% lifetime

Nisolle 199753

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“Not normal” peritoneum

Redwine 1988, Albee 200855

Visually Normal Peritoneum

Criteria for selection of visually normal peritoneum by near-contact

laparoscopy.

Peritoneal surface perfectly smooth with no texture irregularity or

specular light reflections

No abnormal vascular patterns

Transparent peritoneum without associated color

No suggestion of subperitoneal cystic structures

No superficial fibrosis

Redwine 1988, Albee 2008

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Clinical Controversies in Endometriosis

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