Clinical Presentation and Management of Endometriosis-Related Hemorrhagic Ascites: A Case Report and Systematic Review of the Literature.

This study aims to analyze the patient profile and presentation of endometriosis-related hemorrhagic ascites and review its management to raise awareness among gynecologists and improve treatment strategies. We present a case report and engage in a systematic review involving human cases of histologically proven endometriosis with hemorrhagic ascites. Keywords were searched in PubMed/MEDLINE, Cochrane Library, EMBASE, and Ovid Discovery databases from inception until December 2018. Studies that did not include a description of ascites or histopathologic results confirming endometriosis or those that involved patients with other conditions that may contribute to ascites were excluded. The review yielded 73 articles describing 84 premenopausal women with histologically proven endometriosis-related hemorrhagic ascites. Of note, 83% (65/78) of the patients were nulliparous and 69.35% (43/62) were of African descent. The most common chief complaint was abdominal enlargement (58.33%, 49/84) but a host of other symptoms were also reported. Pleural effusion was reported in 32.14% (27/84), and elevated CA-125 was seen in 74.42% (32/43). The majority (64.29%, 54/84) of the patients underwent laparotomy, and an increasing trend of minimally invasive surgical approaches (p<0.001) and fertility-sparing techniques (p<0.001) was observed. The mean ascites volume was 4228.27 mL (SD: 2625.66). Moderate to severe endometriosis was seen in 97.44% (76/78) of cases. The majority of the patients who received medical treatment were given gonadotropin-releasing hormone (GnRH) agonists (63.79%, 37/58). The rate of recurrence after termination or suppression of ovarian function was 8.33% (7/84), and there was a mortality rate of 1.19% (1/84). Diagnosis of endometriosis-related hemorrhagic ascites may be challenging because it mimics several disease entities that cause ascites, thereby warranting a heightened clinical suspicion. Minimally invasive techniques are usually employed to establish a histologic diagnosis. The prevention of recurrence involves the recognition of endometriosis-related hemorrhagic ascites as a manifestation of severe endometriosis, which should prompt therapies directed at suppressing ovarian function. Since affected women are of childbearing age, ovary-preserving surgeries are generally preferred. The rate of recurrence is low after appropriate surgical and medical interventions.

Introduction

Hemorrhagic ascites is a rare complication of endometriosis. The first description of endometriosis-related ascites has been attributed to Brews in 1954 [1]. However, it was not until 1957 that Charles first chronicled a case of blood-stained ascites in association with endometriosis [2]. Since then, fewer than 100 reports of hemorrhagic ascites related to endometriosis have been published in the literature.

Endometriosis-related hemorrhagic ascites may manifest with varying symptoms. Recognizing it may be difficult as it may present with similar disease processes such as malignancy, infection, cirrhosis, or trauma [3-6]. In light of this, we conducted this study to examine and elucidate the patient profiles and presentation of the disease to raise clinical awareness among gynecologists regarding the diagnosis of hemorrhagic ascites associated with endometriosis.

Case presentation

A 34-year-old Taiwanese nulligravida woman presented to the outpatient department with a one-year history of irregular dysmenorrhea that was 5/10 in severity. She had no other associated complaints such as weight loss, anorexia, dyspareunia, urinary changes, or heavy menstrual bleeding. On further probing, the patient revealed having mild bloating that did not cause discomfort. Her menstruation occurred at regular monthly intervals. On physical examination, she had clear breath sounds and mildly distended flanks. Pelvic examination showed a corpus enlarged to 8-10 weeks' size without adnexal masses or tenderness. Fullness at the cul-de-sac was palpated. Pelvic ultrasound revealed multiple small leiomyomas with massive ascites and a heterogeneous right ovarian tumor. A CT scan showed a multicystic right ovary with soft tissue seeding to bilateral paracolic gutters, omentum, and recto-uterine pouch, with massive ascites (Figures 1, 2). CA-125 was elevated (819.1 U/mL). With the working diagnosis of a possible malignant ovarian tumor, laparotomy was performed with staging surgery in mind.

Figure 1

Abdominal CT scan – sagittal view showing massive ascites (asterisk)

CT: computed tomography

Figure 2

Abdominal CT scan – axial view showing massive ascites (asterisk), right adnexal mass (arrow), and soft tissue seeding

CT: computed tomography

Intraoperatively, 2 liters of dark-red ascitic fluid was drained (Figure 3a). Both adnexa were plastered to the posterior uterine wall. An ovarian tumor could not be identified. Friable soft tissue lesions were found on the uterine surface (Figure 3b). The cul-de-sac was obliterated. Multiple gray soft tissue nodules were scattered about the contracted omentum, mesentery, and the appendix (Figures 3c, 3d). Minimal manipulation of the pelvic organs provoked bleeding. The frozen section and final histopathological report of the implants were consistent with endometriosis. A diagnosis of stage IV endometriosis was made.

Figure 3

Operative findings

a. Hemorrhagic fluid. b. Friable soft tissue lesions on the uterine surface. c. Granular lesions on intestines, soft tissue nodules at the base of the appendix. d. Contracted omentum with numerous gray soft tissue nodules

The patient had an uncomplicated postoperative course and was started on leuprorelin injections once a month for six months. After two months, a repeat ultrasound showed mild ascites (~100 mL). The patient remained otherwise asymptomatic on her monthly follow-up visits.

Discussion

Methods

Literature Search Strategy

An extensive literature search of all case reports, case series, and letters to the editor was performed. PubMed/MEDLINE, Cochrane Library, EMBASE, and Ovid Discovery were searched with the keywords, “endometriosis” OR “endometriotic “OR “endometrioma” AND “ascites” OR “bloody ascites” OR “hemorrhagic ascites” OR “serosanguinous “OR “chocolate” OR “brown fluid” OR “chocolate ascites” OR “brown ascites” OR “serosanguinous ascites”. Human studies involving women with biopsy-proven endometriosis published in any language were included, from inception until December 2018.

Eligibility Criteria

Studies with no available full-texts, non-histologically proven cases of endometriosis, non-hemorrhagic ascites, or those without a description of ascites were excluded. Patients with conditions that may cause ascites or hemorrhage (current tuberculosis, malignancy, other infections, ovulation induction, end-stage renal disease, HIV), history of trauma, pregnancy, were likewise excluded.

Screening and Data Extraction

Two independent reviewers (MCT and WTC) reviewed all titles and abstracts of articles obtained through the online database search. The full-text articles of abstracts that were deemed relevant were retrieved online or by manual searching. Reviewed articles were entered into a standardized data collection matrix. Information on authors, country/continent of origin, year of publication, patient characteristics such as age, parity, and ethnicity were entered into the data matrix. Chief complaint, character and volume of the ascites, interventions, intraoperative findings, severity of endometriosis, and outcomes were likewise recorded. In cases where the exact volume of ascites was not stated in a study, ascites was quantified based on the definitions from the existing literature and consensus reports [7-9]. The severity of endometriosis was recorded in each case or assessed based on intraoperative descriptions vis-a-vis the revised American Society for Reproductive Medicine (ASRM) classification of endometriosis [10].

Quality Assessment of Case Reports

MCT and WTC independently assessed the quality of individual studies based on the checklist for case reports and case series from the Joanna Briggs Institute Critical Appraisal tools for systematic reviews [11].

The literature search strategy was summarized in a flow diagram based on the protocol laid out by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement [12] (Figure 4).

Figure 4

PRISMA flow diagram

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses

Statistical Analysis

Descriptive statistics were used to report study and patient characteristics, including symptoms and peritoneal involvement. Spearman rank correlation was used. Analyses were done using the Stata software version 16.0 (StataCorp, College Station, TX).

Results

The literature search initially yielded 1,341 citations for review. After a screening based on the inclusion and exclusion criteria, 73 case reports involving 84 women of endometriosis-related hemorrhagic ascites were included in the final analysis. These were published from 1957 to 2018. The patient demographics, clinical presentation, and management as described in these reports are summarized in Table 1.

Table 1

Case reports of endometriosis-related hemorrhagic ascites

A: Asian; AFR: of African descent; B: brown/dark brown/brownish/chocolate-colored; BS: bilateral salpingectomy; BSO: bilateral salpingo-oophorectomy; C: Caucasian; COC: combined oral contraceptive pills; coffee: coffee-colored; distension: abdominal distension; DMPA: depot medroxyprogesterone acetate; Dysm: dysmenorrhea; GnRH: gonadotropin-releasing hormone agonists; H: hemorrhagic/bloody; mass: abdominal mass; MPA: medroxyprogesterone acetate; pain: abdominal pain; SS: serosanguinous/blood-stained/haemoserous; TAHBSO: total abdominal hysterectomy with bilateral salpingo-oophorectomy; USO: unilateral salpingo-oophorectomy; RSO: right salpingo-oophorectomy

Study

Patient age (years)

Race

Parity

Chief complaint

CA-125 (U/mL)

Ascites volume (mL)

Ascites color

Pleural effusion

Surgery

Main procedure

Medical management

Recurrence

1

Soyman et al., 2018 [13]

31

0

Pain

<35

3000

H

No

Laparotomy

Biopsy

GnRH

No

2

Mendes et al., 2018 [14]

31

AFR

0

Distension

192

8500

H

No

Laparoscopy

BS, excision of peritoneum

GnRH, then COC

Yes

3

Mendes et al., 2018 [14]

26

C

0

Distension

86

≥2000

H

Yes

Laparoscopy

Biopsy

GnRH, then desogestrel

No

4

Mendes et al., 2018 [14]

37

AFR

0

Distension

5700

H

No

Laparoscopy

Biopsy, excision of nodules

GnRH for 3 months, then desogestrel

No

5

Walker et al., 2018 [15]

33

A

0

Distension

239

6000

SS

Yes

Laparotomy

Biopsy

GnRH, then dienogest

Yes

6

O'yandjo et al., 2018 [16]

31

AFR

0

Distension

5000

H

Yes

Laparotomy

Cyst excision

GnRH

No

7

Magalhães et al., 2018 [17]

28

AFR

0

Weight loss

889.6

8000

H

No

Laparoscopy

Biopsy

GnRH for 6 months

Yes

8

Petrosellini et al., 2018 [18]

44

AFR

0

Mass

89.8

2000

B

No

Laparotomy

Partial cystectomy

None

No

9

Pereira et al., 2018 [19]

21

0

Distension

4000

H

No

Laparoscopy

Biopsy

Monophasic COC

Yes

10

N'Guessan et al., 2017 [20]

26

AFR

0

Distension

63

6000

H

No

Laparoscopy

Biopsy

GnRH, then COC

No

11

Varun and Tanwar, 2016 [21]

26

A

0

Distension

36.3

3000

H

No

Laparotomy

Cystectomy

GnRH

No

12

Dun et al., 2016 [22]

26

AFR

0

Distension

7800

H

No

Laparoscopy

Biopsy, peritoneal stripping

None

Yes

13

Hinduja et al., 2016 [23]

34

1

Distension

<35

4500

SS

No

Laparotomy

TAHBSO

GnRH 250mcg/day for 6 weeks

Yes

14

Setubal et al., 2015 [24]

26

C

0

Dysm

100

3500

H

No

Laparoscopy

Biopsy

COC

Yes

15

Bignall et al., 2014 [25]

36

AFR

0

Pain

1123

3500

H

No

Laparoscopy

Biopsy

GnRH + tibolone

Yes

16

Cosma et al., 2014 [26]

36

0

Dysm

184

4200

B

No

Laparoscopy

Biopsy, excision of all lesions

None

Yes

17

Hasdemir et al., 2015 [27]

32

0

Distension

41.7

2500

H

Yes

Laparoscopy

Biopsy

GnRH for 6 moths, then dienogest

Yes

18

Park and Kim, 2014 [28]

44

0

Pain

>10000

≥2000

B

No

Laparotomy

USO, cystectomy

NR

No

19

Asano et al., 2014 [29]

35

A

0

Dysm

22

5500

H

No

Laparoscopy

Biopsy

GnRH, then dienogest 2 mg PO OD

Yes

20

Appleby et al., 2014 [30]

34

AFR

0

Distension

4000

H

No

Laparoscopy

Biopsy

GnRH for 6 months

No

21

Mumtahana et al., 2014 [31]

36

A

0

Distension

5009

3000

H

No

Laparoscopy

Bilateral cystectomy

GnRH

No

22

Packard and Adamson, 2013 [32]

22

AFR

0

Dyspnea

61

2700

B

Yes

Paracentesis

Biopsy

GnRH, then DMPA

No

23

Akinola et al., 2012 [33]

26

AFR

0

Cough

72.5

≥1000

H

Yes

Laparotomy

Ovarian mass excision

GnRH 3.6 mg

No

24

Akintomide et al., 2012 [34]

22

AFR

0

Distension

5900

H

No

Laparotomy

Biopsy

Danazol

Yes

25

Queirós et al., 2011 [35]

36

C

0

Infertility

73

1500

H

No

Laparoscopy

Cystectomy

COC

26

Queirós et al., 2011 [35]

30

AFR

0

Infertility

192

12000

B

Yes

Laparoscopy

Biopsy

GnRH, then GnRH + COC

27

Shabeerali et al., 2012 [36]

40

4

Distension

<35

3000

B

No

Laparoscopy

Biopsy

GnRH for 6 months

Yes

28

Shabeerali et al., 2012 [36]

30

2

Distension

96

≥1000

B

No

Laparotomy

SubTAH + BSO

None

No

29

Shabeerali et al., 2012 [36]

28

0

Distension

≥800

H

No

Laparotomy

TAHBSO

None

Yes

30

Ferrero and Remorgida, 2011 [37]

36

Distension

89.4

4800

H

No

Laparoscopy

Biopsy, excision of nodules

Norethindrone acetate 2.5 mg PO OD

No

31

Cordeiro Fernandes et al., 2011 [38]

28

AFR

0

Distension

<35

9400

H

No

Laparoscopy

Biopsy

GnRH for 3 months, then COC

No

32

Suchetha et al., 2010 [39]

36

1

Ascites

>5000

6000

Coffee

No

Laparotomy

TAHBSO

None

No

33

Ignacio et al., 2010 [40]

38

AFR

0

Distension

50

7000

B

Yes

Laparoscopy

Cystectomy

GnRH + add-back therapy

No

34

Day et al., 2009 [41]

24

0

Pain

2500

H

No

Laparoscopy

Biopsy

GnRH

Yes

35

Park et al., 2009 [42]

34

0

Pain

548.1

2000

B

No

Laparoscopy

USO

GnRH + tibolone add-back therapy for 6 months

No

36

Lodha et al., 2008 [43]

30

AFR

0

Distension

4000

H

No

Laparoscopy

Biopsy

COC

No

37

Ussia et al., 2008 [44]

23

C

0

Dysm

1500

H

Yes

Laparoscopy

Biopsy

GnRH + intermittent steroids

Yes

38

Ussia et al., 2008 [44]

26

C

0

Pain

2000

H

No

Laparotomy

USO

GnRH

Yes

39

Sait, 2008 [45]

26

AFR

0

Distension

3140

5000

H

No

Laparotomy

Bilateral cystectomy

GnRH for 6 months, then COC

No

40

Santos et al., 2007 [46]

40

C

0

Pain

≥2000

SS

No

Laparotomy

Biopsy

None, mortality

No

41

Palayekar et al., 2007 [47]

AFR

1

Distension

33.6

4000-6000

H

No

Laparotomy

TAHBSO

None

No

42

Goumenou et al., 2006 [3]

46

C

0

Dyspnea

3504

4000

H

Yes

Laparotomy

TAHBSO

None

No

43

Baykal et al., 2006 [48]

30

0

Distension

2540

≥1000

B

No

Laparotomy

USO

NR

No

44

Ekoukou et al., 2005 [49]

28

AFR

0

Infertility

10000

H

No

Laparoscopy

Biopsy

GnRH

Yes

45

Fortier et al., 2005 [50]

33

AFR

0

Infertility

257

4000

SS

Yes

Laparoscopy

Cystectomy

GnRH

Yes

46

Zeppa et al., 2004 [51]

34

500

H

No

Paracentesis

Paracentesis

NR

No

47

Francis et al., 2003 [52]

2

Dyspnea

<35

≥2000

B

Yes

Laparotomy

TAHBSO

None

No

48

Cheong and Lim, 2003 [53]

40

A

1

Distension

<35

5600

H

Yes

Laparotomy

Biopsy

NR

No

49

Moffatt and Mitchell, 2002 [54]

37

AFR

0

Dyspnea

<35

≥2000

B

Yes

Laparotomy

TAHBSO

GnRH

Yes

50

Dias et al., 2000 [55]

41

AFR

0

Distension

10000

B

No

Laparotomy

USO

GnRH for 6 months

Yes

51

Bhojawala et al., 2000 [56]

34

AFR

0

Distension

9000

B

Yes

Laparotomy

TAHUSO

None

No

52

El Khalil et al., 1999 [57]

36

Distension

3500

H

No

Laparoscopy

Biopsy

COC

Yes

53

Samora-Mata and Feste, 1999 [58]

43

C

3

Pain

2000

B

No

Laparotomy

TAHRSO

None

No

54

Fletcher et al., 1999 [59]

27

AFR

1

Distension

8000

B

No

Laparotomy

Biopsy

GnRH monthly for 6 months

No

55

Muneyyirci-Delale et al., 1998 [60]

26

AFR

Pain

455

2000

H

Yes

Laparotomy

Bilateral cystectomy

Danazol 600 mg PO daily for 6 months, then norethindrone acetate

Yes

56

Muneyyirci-Delale et al., 1998 [60]

31

AFR

0

Shortness of breath

10000

B

Yes

Laparotomy

TAHBSO

None

Yes

57

Muneyyirci-Delale et al., 1998 [60]

32

AFR

0

Distension

4900

H

No

Laparotomy

Ovarian wedge resection

GnRH

No

58

Muneyyirci-Delale et al., 1998 [60]

35

AFR

1

Dysm

266

3000

H

No

Laparotomy

Adnexal mass resection

GnRH for 6 months, then norethindrone acetate

No

59

Mejia et al., 1997 [61]

44

AFR

0

Distension

<35

10000

H

No

Laparotomy

TAHBSO

None

No

60

Flanagan and Barnes, 1996 [62]

30

AFR

Distension

49

2000

B

Yes

Laparotomy

USO, ovarian wedge resection

GnRH

Yes

61

el-Newihi et al., 1995 [63]

32

AFR

0

Distension

118

4000

B

Yes

Laparotomy

TAHBSO

GnRH IM monthly for 6 months

No

62

Schlueter and McClennan, 1994 [64]

20

AFR

0

Distension

5000

H

No

Laparoscopy

Biopsy

GnRH monthly

No

63

Jose et al., 1994 [65]

30

0

Distension

5000

B

Yes

Laparotomy

USO

Danazol 200 mg TID

No

64

London and Parmley, 1993 [66]

29

AFR

0

Distension

3000

B

No

Laparotomy

TAHBSO

None

No

65

Chen et al., 1992 [67]

20

A

0

Distension

46

5600

B

Yes

Laparotomy

USO

Danazol 400 mg PO daily + Duphaston 10 mg PO OD for 6 months

No

66

Tsvelev et al., 1990 [68]

31

Pain

8000

B

No

Laparotomy

USO

NR

No

67

Yu and Grimes, 1991 [69]

26

A

0

Pain

3000

H

Yes

Laparotomy

USO

GnRH for 6 months

No

68

Hattori et al., 1990 [70]

50

A

2

Distension

36

3800

B

No

Laparotomy

TAHBSO

MPA

Yes

69

Taub et al., 1989 [6]

32

AFR

1

Distension

3400

H

Yes

Laparotomy

BSO

DMPA

No

70

Olubuyide et al., 1988 [71]

19

AFR

0

Distension

4600

H

No

Laparotomy

Biopsy

Norethisterone acetate 5 mg PO TID for 1 week, then 10 mg BID

No

71

Chichareon and Wattanakitkrailert, 1988 [72]

31

0

Distension

1800

H

No

Laparotomy

TAHUSO

DMPA

Yes

72

Iwasaka et al., 1985 [73]

35

A

0

Distension

17

2500

B

No

Laparotomy

TAHBSO

None

No

73

Iwasaka et al., 1985 [73]

25

A

0

Pain

150

H

No

Laparotomy

USO, Ovarian wedge resection

Danazol 400 mg PO daily for 3 months

No

74

Naraynsingh et al., 1985 [74]

24

AFR

0

Distension

6000

H

No

Laparotomy

Biopsy

DMPA IM q2 weeks for 6 months

No

75

Halme et al., 1985 [75]

23

AFR

0

Distension

7500

SS

No

Laparotomy

Biopsy

Danazol 400 mg PO BID

No

76

Jenks et al., 1984 [76]

33

AFR

0

Distension

5000

H

No

Laparotomy

TAHBSO

None

No

77

Gaulier et al., 1983 [77]

22

AFR

0

Pain

≥2000

B

Yes

Laparotomy

Ovarian resection

Danazol

No

78

Chervenak et al., 1981 [78]

20

0

Distension

1500

B

No

Laparotomy

BSO

None

No

79

Chervenak et al., 1981 [78]

26

AFR

0

Distension

4000

B

No

Laparotomy

BSO

Danazol 400 mg daily for 10 months

No

80

Irani et al., 1976 [79]

32

AFR

0

Distension

2000

H

Yes

Laparotomy

TAHBSO

None

No

81

Collier et al., 1962 [80]

34

AFR

0

Distension

4000

B

No

Laparotomy

TAHBSO

None

Yes

82

Bernstein et al., 1961 [81]

29

AFR

1

Distension

3900

B

No

Laparotomy

TAHBSO

None

No

83

Ripstein et al., 1959 [82]

24

AFR

0

Chest discomfort

100-150

B

Yes

Laparotomy

Biopsy

COC

No

84

Charles, 1957 [2]

33

0

Pain

3000

H

Yes

Laparotomy

USO

Deep X-ray therapy

Yes

Patient characteristics are shown in Table 2. The mean age of the patients at diagnosis was 31.16 years (SD: 6.57; range: 19-50). There was no relationship between the year of publication/presentation and age (p=0.193) or age distribution (p=0.600).

Table 2

Endometriosis-related hemorrhagic ascites – patient characteristics

SD: standard deviation

Characteristics	Values
Age, years, mean (SD)	31.16 (6.57)
Age range, years	19-50
Age distribution, number (%), N=82
<20 years	1 (1.22)
20-29 years	31 (37.80)
30-39 years	40 (48.78)
40-49 years	9 (10.98)
≥50 years	1 (1.22)
Parity, number (%), N=78
Nulliparous	65 (83.33)
Parous	13 (16.67)
Race distribution, number (%), n=62
African	43 (69.35)
Asian	10 (16.13)
Caucasian	9 (14.52)
Ascitic fluid volume, mL, mean (SD)	4228.27 (2625.66)

The most common presenting symptom was abdominal distension (Table 1). Other initial complaints reported by patients are presented in Table 3. The majority (91.67%, 77/84) of the symptoms were gradual in onset. Pleural effusion was reported in 32.14% (27/84) of cases. The ascitic fluid was predominantly massive with a mean volume of 4228.27 mL (SD: 2625.66; range: 100-10000). CA-125 was elevated in 32 out of 43 patients, with a median value of 86 U/mL (range: 17->10000 U/mL).

Table 3

Symptoms of hemorrhagic ascites associated with endometriosis (N=84)

Symptom	Number (%)
Abdominal distension	66 (78.57)
Dysmenorrhea	47 (55.95)
Abdominal pain	28 (33.33)
Weight loss	18 (21.43)
Primary infertility	17 (20.24)
Nausea and/or vomiting	13 (15.48)
Anorexia	11 (13.10)
Dyspnea	9 (10.71)
Deep dyspareunia	6 (7.14)
Fatigue/malaise	6 (7.14)
Chronic pelvic pain	5 (5.95)
Constipation	5 (5.95)
Shortness of breath	4 (4.76)
Early satiety	4 (4.76)
Cough	3 (4.57)
Dyschezia	3 (3.57)
Menorrhagia	3 (3.57)
Right-sided chest discomfort	3 (3.57)
Weight gain	2 (2.38)
Loose stools	2 (2.38)
Dysuria	2 (2.38)
Orthopnea	1 (1.19)
Abdominal mass	1 (1.19)
Thoracic pain	1 (1.19)

Moderate to severe endometriosis (ASRM stage III to IV) was seen in 97.44% (76/78) of the cases, and adhesions were described in 78.05% (64/82). In 43.90% (36/82) of the cases, an ovarian cyst was identified; 11.11% (4/36) of the cases were ruptured. Peritoneal implants scattered about the abdominopelvic cavity in 42.68% (35/82), while peritoneal nodules were seen in 20/82 (24.39%). Other abdominopelvic areas involved are shown in Table 4.

Table 4

Peritoneal involvement in endometriosis-related hemorrhagic ascites (N=82)

Organ involved	Number (%)
Intestines	52 (63.41)
Recto-sigmoid	27 (32.93)
Omentum (caking/nodule/retraction/implants)	25 (30.49)
Cul-de-sac	23 (28.05)
Liver	10 (12.20)
Diaphragm	7 (8.54)
Appendix	6 (7.32)
Rectovaginal area	5 (6.10)
Umbilicus (nodule/mass/cyst)	4 (4.88)

At the time of presentation, 64.29% (54/84) underwent laparotomy, and laparoscopy was performed in 33.33% (28/84). Two cases (2/84) had paracentesis. Almost half (44.05%, 37/84) of the cases had repeat abdominal surgeries, while 76.19% (64/84) required multiple procedures that included repeat abdominal surgeries (laparoscopy and/or laparotomy), paracentesis, thoracostomy, or thoracotomy. On the other hand, less invasive surgical approaches (p<0.001) and fertility-sparing procedures (p<0.001) are observed to be increasingly favored in recent years.

A cure was reported in 95.45% (21/22) who went through definitive surgery via hysterectomy with bilateral salpingo-oophorectomy. Medical treatment was not given to 68.18% (15/22) after surgery. Four patients tolerated stripping or excision of the peritoneum of all endometriotic implants with no recurrence. Two of these received no additional medical therapy.

Patients who were offered medical therapy post-surgery received gonadotropin-releasing hormone (GnRH) agonists (63.79%, 37/58), either alone, with add-back therapy, or as a preliminary treatment that was eventually transitioned to either a progestogen or a combined oral contraceptive (COC) pill. In 86.49% (32/37) who received GnRH agonists, no recurrences were observed. Other therapies included danazol (13.79%, 8/58), progestogens alone (10.34%, 6/58), or COC alone (10.34%, 6/58). The cure rate with danazol was 100% (eight out of eight), while COC and progestogens were equally effective, each with an 83.33% (five out of six) cure rate.

The recurrence rate observed at the time of presentation or after initial management was 36.90% (31/84), while that after definitive surgery and/or ovarian function suppression was 8.33% (7/84). Five of these cases reported significant ascites upon the cessation of GnRH therapy [35,49,50,62] or upon shifting from GnRH to progestogen therapy [15]. The other two had reaccumulating minimal ascites while on oral COC [35] or oral progestogen [70]. Of note, 71.42% (five out of seven) of recurrences had undergone ovary-preserving procedures (oophorocystectomy or biopsy) prior to medical therapy. Mortality was reported in one case. The Median follow-up period was eight months.

Analysis

Very little is known about the pathogenesis of endometriosis-related hemorrhagic ascites. One putative mechanism is peritoneal irritation from the rupture of ovarian cysts. The endometrial cells from this spillage propagate the spread of implants in the pelvic cavity and cause inflammation, which in turn leads to adhesions and ascites [81]. This theory assumes the presence of ovarian cysts. However, in this review, less than half of the study population were found to have ovarian endometriotic cysts, and only four out of 36 of these cysts were ruptured. Alternative hypotheses such as alterations in vascular permeability, lymphatic channel obstruction, as well as individual variations in susceptibility to the disease may be explored [44,49,83,84].

The rubor of ascites may be due to increased angiogenesis seen in endometriosis. Erosions from affected friable soft tissue, serosal, peritoneal surfaces, and implants cause micro-bleeding or frank bleeding, leading to the hemorrhagic character of ascites [49,84]. Pleural effusions associated with the hemorrhagic ascites may be due to several mechanisms. However, based on the presentation of massive ascites in the majority of cases, the most plausible cause is anatomic defects in the diaphragm that allow for the passage of hemorrhagic fluid into the pleural space [85,86].

Endometriosis-related hemorrhagic ascites may affect any woman of reproductive age but is more common in women in their twenties and thirties, without any significant increase or decrease with respect to the age of onset. This finding differs from what was previously described [44]. Many patients may seek a consult for abdominal distension or symptoms secondary to abdominal distension such as pain or pulmonary discomfort in the background of dysmenorrhea or worsening dysmenorrhea. Dysmenorrhea accounted for only 5.95% (5/84) of the chief complaints in this review but is most commonly elicited on history as an accompanying symptom. Massive ascites usually predominate in clinical evaluation.

The utility of CA-125 in the diagnosis of this condition is arguable due to its non-specificity. While the majority presented with CA-125 >35 U/mL, similarly increased levels have been described in various benign gynecologic diseases [87]. Mesothelial cells that line the peritoneum secrete CA-125. Since mesothelial hyperplasia and hypertrophy are associated with endometriosis, CA-125 release is greater, and hence elevated in this condition. However, the same holds true for other diseases of the peritoneum such as malignancy and tuberculosis [84,88,89]. Its clinical use, therefore, is limited to determining whether a patient has peritoneal disease in general.

Management of the condition relies critically on establishing a histologic diagnosis. Surgery is thus warranted, although several studies have achieved cytological confirmation through paracentesis [32,51]. With the case presented, a clinically presumptive diagnosis of ovarian cancer was made, which led to the decision to perform a laparotomy. This is supported by studies on ovarian cancer [90]. However, with the availability of minimally invasive techniques and increasing technical confidence among surgeons, there is a growing trend favoring their use in the management of potentially malignant ovarian tumors [90,91]. The current recommendation for laparoscopy in suspected ovarian tumors is to establish a histologic diagnosis through a frozen section and, if tumors are found malignant, to assess their resectability [91-93]. Since it is difficult to differentiate it from a malignant etiology, surgical management of endometriosis-related hemorrhagic ascites may follow this approach.

Moderate to severe (ASRM stage III to IV) endometriosis almost always presents intraoperatively and with adhesions and implants in the abdominopelvic cavity. Peritoneal involvement can be related to small implants, nodules, or varying degrees of adhesions. Thus, the presence of hemorrhagic ascites, as seen in 97.44% of cases and in the index case, may correlate with the severity of endometriosis.

Since the ascites in this review was found mostly in moderate to severe endometriosis, it seems logical to follow the principles of endometriosis treatment. Termination or suppression of ovarian function is the cornerstone of management. The importance of this cannot be overemphasized as many women undergo multiple surgeries for recurrence or for the treatment of an existing endometriosis. Surgical sterility via hysterectomy with removal of bilateral ovaries is the definitive form of management [19,36 59,61,63,68]. However, fertility-sparing surgeries are currently performed in patients who wish to realize their reproductive potential.

Medical therapy consists of GnRH agonists, which have been used with success in achieving ovarian suppression. Danazol, progestogens, and COC pills are likewise given as primary treatment or upon completion of GnRH agonist therapy for long-term control of the disease. Danazol, an antigonadotropic, anti-estrogenic synthetic steroid, is effective in suppressing ovarian function. However, its various androgenic effects preclude its use [94,95]. In the majority of cases and especially in more recent studies, GnRH agonists have been used more frequently. These are effective in achieving ovarian suppression and increasing fertility rates but their side effect profile limits their long-term use [94,95]. Progestogens and COC pills were effective as medical treatments in this review, but current evidence has failed to demonstrate any benefit of COC in managing pelvic pain in endometriosis [96]. On the other hand, oral medroxyprogesterone acetate has been shown to be effective in decreasing chronic pelvic pain [97]. Other medications of interest are the levonorgestrel-releasing intrauterine system and mifepristone, which were not used in the studies included in this review. Nonetheless, their clinical utility may be explored as these have been shown to be effective in suppressing the menstrual cycles and relieving pain associated with endometriosis [98,99].

Conclusions

Hemorrhagic ascites is a rare manifestation of endometriosis that can present in any premenopausal woman. The most common initial complaint is abdominal distension, but a host of other symptoms may also be associated with the condition. Diagnosis can be challenging because it mimics several disease entities that cause ascites, thus warranting a heightened clinical suspicion. Minimally invasive techniques may be employed to establish a histologic diagnosis. Recognition of hemorrhagic ascites as a manifestation of severe endometriosis is essential for recurrence prevention, which should prompt therapies directed at suppressing ovarian function. Ovary-preserving surgeries are preferred because affected women are of childbearing age. Recurrence is low after appropriate surgical and medical interventions.