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Endometriosis

Authors: Lisa Han, M.D., Rochelle Garcia, M.D., Aurelia Busca, M.D., Ph.D., Carlos Parra-Herran, M.D.

Editorial Board Member: Gulisa Turashvili, M.D., Ph.D.

Last author update: 13 October 2020

Last staff update: 21 November 2022 (update in progress)

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Table of Contents

Cite this page: Han L, Garcia R, Busca A, Parra-Herran C. Endometriosis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/ovarynontumorendometriosis.html. Accessed June 8th, 2023.

Definition / general

Presence of endometrial tissue outside of endometrium and myometrium, consisting of both endometrial glands and stroma

Essential features

Ectopically located endometrial tissue consisting of both endometrial type glands and stroma
Endometriosis is associated with ovarian clear cell carcinoma and endometrioid carcinoma and shares similar molecular alterations
Endometriosis in patients without cancer harbors oncogenic mutations in ARID1A, PIK3CA, KRAS and PPP2R1A, suggesting a neoplastic nature in some cases (N Engl J Med 2017;376:1835)
CD10 immunohistochemistry can be used to confirm the presence of endometrial stroma

Terminology

Endometriotic cyst / endometrioma: cystic form of endometriosis
Atypical endometriosis: endometriosis with cytologic atypia or gland crowding lined by atypical epithelium resembling endometrial atypical hyperplasia (Adv Anat Pathol 2007;14:241)

ICD coding

ICD-10: N80 - Endometriosis of uterus
- N80.0 - Endometriosis of uterus
- N80.1 - Endometriosis of ovary
- N80.2 - Endometriosis of fallopian tube
- N80.3 - Endometriosis of pelvic peritoneum
- N80.4 - Endometriosis of rectovaginal septum and vagina
- N80.5 - Endometriosis of intestine
- N80.6 - Endometriosis in cutaneous scar
- N80.8 - Other endometriosis
- N80.9 - Endometriosis, unspecified

Epidemiology

Affects 5 - 15% women of reproductive age
Peak incidence: 30 - 45 years of age
Estrogen dependent; rarely affects men taking large doses of estrogen (Fertil Steril 2012;98:511)

Sites

Ovary (67%) > anterior and posterior cul de sac > posterior broad ligaments, uterosacral ligaments > uterus > fallopian tubes > sigmoid colon and appendix > round ligaments (Eur J Obstet Gynecol Reprod Biol 2018;230:36)
Also seen in bladder and cervix
Rarely in remote sites such as lung, regional lymph nodes and skin

Pathophysiology

Retrograde menstruation theory: endometrial lining cells travel backwards through fallopian tubes during menses to reach peritoneal cavity, proliferate and cause chronic inflammation with formation of adhesions (Nat Rev Endocrinol 2014;10:261)
Coelomic metaplasia theory: metaplastic transformation of coelomic cells lining the pelvic peritoneum (J Lab Physicians 2010;2:1)
Induction theory: a combination of the first 2 theories (N Engl J Med 1993;328:1759)
Development of malignant neoplasm occurs in < 1% of cases; 75% of malignant neoplasms arise in ovarian endometriosis (J Lab Physicians 2010;2:1)

Etiology

Organochlorine pollutant exposure

Clinical features

Pelvic pain (Arch Gynecol Obstet 2015;292:1295)
Dyspareunia
Dysmenorrhea
Infertility
Rarely, infection or rupture of an endometriotic cyst with ascites or hemoperitoneum

Diagnosis

Laparoscopy required for definitive diagnosis, although ~ 50% laparoscopic biopsy specimens contain microscopic endometriosis (Am J Obstet Gynecol 2001;184:1407)
Endometriosis in pelvis categorized as superficial peritoneal, ovarian and deeply infiltrating

Radiology description

Ultrasound mostly used for ovarian endometriotic cysts
Typically multilocular cysts with septations and hyperechoic mural nodules (Radiology 1999;210:739)

Prognostic factors

Risk of development of malignant neoplasm estimated at 1% for premenopausal women and up to 2.5% for postmenopausal women
~ 75% neoplasms complicating endometriosis arise within ovary; most common extraovarian site is rectovaginal septum
- Increased risk of endometrioid carcinoma followed by clear cell carcinoma (Clin Chim Acta 2019;493:63)
- Other associated neoplasms include seromucinous neoplasms (mainly borderline), endometrioid adenofibromas and borderline neoplasms, adenosarcomas and endometrial stromal sarcomas (Histopathology 2020;76:76)
Women with carcinoma arising in endometriosis tend to be premenopausal, obese and with history of unopposed estrogens (Gynecol Oncol 2000;79:18)
Endometriosis associated carcinomas (other than clear cell) tend to be lower grade and stage than similar ovarian carcinoma without associated endometriosis (Gynecol Oncol 2001;83:100)

Case reports

35 year old woman presenting with hematuria and abdominal pain (BMJ Case Rep 2018;11)
37 year old woman with history of pelvic surgery presenting with pelvic pain (Medicine (Baltimore) 2018;97:e0376)
40 year old woman with elevated CA125 and pelvic mass (Medicine (Baltimore) 2019;98:e15741)
49 year old Japanese woman with abnormal vaginal bleeding and adenocarcinoma diagnosed by cervical cytology (J Obstet Gynaecol Res 2020;46:536)
55 year old woman with peritoneal endometriosis and smooth muscle metaplasia (Int J Clin Exp Pathol 2015;8:3370)
62 year old woman presented with hematuria (Pathology 2017;49:441)

Treatment

Pain treated with NSAIDs, hormonal contraceptives, GnRH analogues and aromatase inhibitors (Arch Gynecol Obstet 2015;292:1295)
Surgical resection

Gross description

Ovarian endometriotic cysts (endometriomas) have fibrotic walls, a smooth lining and dark brown cyst contents (chocolate cyst), often adherent to adjacent organs
Polypoid endometriosis has a polypoid configuration that raises the differential diagnosis of a neoplasm on gross and intraoperative examination (Am J Surg Pathol 2004;28:285)
Red, brown, white plaques, sometimes with a gelatinous appearance (Arch Gynecol Obstet 2015;292:1295, Taiwan J Obstet Gynecol 2019;58:328)

Gross images

Contributed by University of Washington Medical Center and AFIP images

Uterus with shaggy hemorrhagic adhesions

External surfaces of the ovarian wedges show red, blue and brown areas, some associated with fibrotic puckering

Cyst contains chocolate colored fluid

Cyst has dark brown discoloration

Images hosted on other servers:

Small foci resembling powder burns

"Chocolate" cyst

Frozen section description

Presence of endometrial glands or endometrial stroma (Taiwan J Obstet Gynecol 2019;58:328)
- Sometimes only macrophages and hemosiderin present (diagnose as "consistent with clinical impression of endometriosis" as other causes are possible)
Can be associated with fibrous adhesions
Negative for neoplastic features such as glandular complexity

Frozen section images

Contributed by University of Washington Medical Center

Endometriosis involving omental nodule

Endometriosis in peritoneal nodule

Microscopic (histologic) description

At least 2 of the following 3 features
- Endometrial type glands:
  - Müllerian type epithelium (can be atrophic to cycling endometrium)
  - Can show degenerative atypia (enlarged smudgy nuclei) or metaplasia
- Endometrial type stroma:
  - Often contains fine capillary network
  - May undergo smooth muscle metaplasia, fibrosis (longstanding), decidual change
  - May be myxoid (particularly in pregnancy)
  - Stroma may be only identifiable component (stromal endometriosis)
- Evidence of chronic hemorrhage (hemosiderin laden or foamy macrophages)
Other rare findings:
- Necrotic pseudoxanthomatous nodules: central necrosis surrounded by histiocytes and outer fibrous zone
- Liesegang rings: eosinophilic acellular rings within necrotic tissue (Histopathology 2020;76:76)
- Burnt out endometriosis: this term has been proposed for changes suggestive of endometriosis, such as central necrosis with surrounding fibrosis and pseudoxanthoma cells but lacking confirmatory features as listed above
- Atypical endometriosis: this has been reported in 1.7 - 4.4% of endometriotic lesions and is considered the precursor lesion for endometriosis associated carcinomas (clear cell or endometrioid); may be in continuity with these tumors
  - Includes cytologic atypia in the epithelial lining of the glands or gland crowding lined by atypical epithelium resembling endometrial atypical hyperplasia (Histopathology 1997;30:249, Case Rep Oncol 2013;6:480)

Microscopic (histologic) images

Contributed by University of Washington Medical Center

Uterine serosa with endometriosis

Endometriosis, partially denuded

Endometriosis with hemosiderin

Endometriosis involving appendix

CD10

Virtual slides

Images hosted on other servers:

Ovarian endometriotic cyst

Cytology description

Reported in peritoneal fluid and fine needle aspiration of scar tissue following gynecologic procedure (e.g. Caesarean section) (J Cytol 2017;34:61)
Variably sized 3 dimensional spherules with periphery of polygonal endometrial cells with larger, hyperchromatic nuclei and moderate amount of cytoplasm, often with center of stroma cells with hyperchromatic nuclei, scant cytoplasm and indistinct cytoplasmic borders (Cancer Cytopathol 2013;121:582)
May have admixed hemosiderin laden macrophages

Cytology images

Contributed by Carmen Luz, M.D.

FNA from abdominal wall

Positive stains

CD10 is positive in endometrial stroma
ER, PR and PAX2 are often positive in endometrial glands and stroma (Am J Surg Pathol 2013;37:1342)

Molecular / cytogenetics description

Endometriosis and synchronous carcinoma share similar genetic alterations including ARID1A, PTEN and PIK3CA
Mutations in ARID1A, a tumor suppressor gene, identified in up to 57% of ovarian endometrioid carcinoma and up to 30% of clear cell carcinoma
- Multiple studies suggest ARID1A mutation occurs at early stage of canceration of endometriosis (Oncol Rep 2016;35:607)
- Endometriosis occurring distant from ARID1A deficient carcinomas are more likely to retain ARID1A expression
Other associated genetic alterations include loss of BAF250a, ER and PR and upregulation of hepatocyte nuclear factor - beta and Skp2
In one study, loss of DNA mismatch repair protein expression was found in 10% of patients with endometriosis associated ovarian carcinoma (Int J Gynecol Pathol 2012;31:524)

Videos

Causes, symptoms, diagnosis, treatment, pathology

Histopathology - ovary

Sample pathology report

Uterus, hysterectomy:
- Proliferative endometrium negative for hyperplasia or malignancy
- Unremarkable cervix
- Myometrium with leiomyomata
- Uterine serosa with multifocal endometriosis
Right ureterosacral peritoneum, excision:
- Fibrous tissue with focal endometrial type stroma and hemorrhage, suggestive of endometriosis

Differential diagnosis

Endocervicosis:
- Glandular component is endocervical mucinous type, no endometrial stroma, no hemorrhage
Endosalpingiosis:
- Glandular component is tubal (ciliated with peg / intercalated) cells, no endometrial stroma, no hemorrhage
Adenomyosis:
- Endometrial glands and stroma in myometrium
Endometrioid adenocarcinoma:
- Complex glandular growth and cytologic atypia
Metastatic carcinoma:
- Morphology varies by site of origin; however, no endometrial stroma
- Other features of neoplasm present, including crowded irregular glands, nuclear atypia or elevated mitotic activity

Additional references

Annu Rev Pathol 2020;15:71, Pathology 2018;50:190, Mutat Res 2018;809:1

Board review style question #1

A 39 year old woman presents with pelvic pain and menorrhagia. Hysterectomy was performed and the histologic findings shown in this photomicrograph were present on the serosal surface and right ovary. What malignant neoplasm is most associated with the lesion?

Immature teratoma
Ovarian endometrioid carcinoma
High grade serous carcinoma
Clear cell sarcoma
Endometrial stromal sarcoma

Board review style answer #1

B. Ovarian endometrioid carcinoma. Endometriosis can be associated with endometrioid and clear cell carcinoma, with the greatest association identified in the former neoplasm. Rare endometrial stromal sarcomas and adenosarcomas have also been reported to arise in association with endometriosis. There is no reported link between germ cell tumors and clear cell sarcomas with endometriosis.

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Reference: Endometriosis

Board review style question #2

Which of the following genes is most commonly altered in endometriosis associated carcinomas?

PTEN
CDKN2A (p16)
BRAF
ARID1A
TP53

Board review style answer #2

D. ARID1A. Of the 5 genes listed, mutations in tumor suppressor gene ARID1A are most commonly identified in endometriosis and endometriosis associated carcinomas. Many studies suggest that loss of ARID1A expression is an early driver mutation. Other common molecular alterations include mutations in PTEN, PIK3CA, KRAS and to a lesser extent, microsatellite instability with MMR protein loss. TP53 and CDKN2A mutations are rare. BRAF mutations are not associated with endometriosis.

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Reference: Endometriosis

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