Female genital tract II.

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1 Female genital tract II. Pathology of the uterine corpus Lilla Madaras 2 nd Department Of Pathology Semmelweis University Budapest 9 th April 2018

2 Anatomy 2

3 The normal endometrium Histology Regulation of the endometrial cycle Dating the endometrium Assesment techniques of the endometrium 3

4 The normal endometrium Regulation of the endometrial (and ovarial) cycle Proliferative phase, secretory phase, menstrual phase Proliferative phase Early proliferative phase Midproliferative phase Late proliferative phase Secretory phase-day by day changes dating the endometrium 4

5 Ovarian and endometrial (menstrual) cycles and their regulation

6 Dating the endometrium 6

7 Dating the endometrium 7

8 Early proliferative phase- ( blue doughnuts glands)

9 Day 17-subnuclear vacuoles (piano key morphology) within endometrial glands 9

10 Day 18-tortuous endometrial gland with sub-, and supranuclear vacuolization 10

11 Day 24 11

12 12 Exhausted secretory glands, predecidual changes around spiral arterioles

13 Exhausted secretory glands, predecidual changes within the stroma- Day 26

14 Menstrual phase

15 Menstrual phase

16 How do we assess the endometrium? 1. By sampling procedures 2. In hysterectomy specimens (from TAH with or without BSO, laparoscopic hysterectomy, Chrobak surgery, Wertheim surgery ) 16

17 Endometrium Sampling Techniques 1. Dilatation and Curettage(D&C) 2. Fractional curettage (separate sampling of the endometrium and endocervix) 3. Hysteroscopy+ polyp/endometrium ablation 4. Endometrial biopsy (Pipelle) 17

18 Endometrial sampling-when? AUB (abnormal uterine bleeding) Abortion Dating the endometrium in cases of infertility Hormone replacement therapy, Tamoxifen 18

19 Pathology of the endometrium 19

20 Inflammation Clinical terms AUB Endometrial hyperplasia Adenomyosis end endometriosis Tumors of the endometrium 20

Inflammation Acute endometritis in abortion, in a postpartum state group A hemolytic streptococci, staphylococci Chronic endometritis after retained gestational tissue in PID due to an IUD

21 Inflammation Acute endometritis in abortion, in a postpartum state group A hemolytic streptococci, staphylococci Chronic endometritis after retained gestational tissue in PID due to an IUD (actinomyces!) tuberculosis (from tubercolous salpingitis)- rare in the western world chlamydial infection- plasma cells! Pyometra Asherman s syndrome (intrauterine adhesion resulting in amenorrhea) Semmelweis Ignác ( ) 21

22 Clinical terms (still in your book and in use) amenorrhea- primary or secondary Oligomenorrhea polymenorrhea hypomenorrhea menorrhagia metrorrhagia dysmenorrhea 22

23 Clinical terms Dysfunctional uterine bleeding Oligomenorrhea, polymenorrhea hypomenorrhea menorrhagia Metrorrhagia, metropathia haemorrhagica Dysmenorrhea Abnormal Uterine Bleeding (AUB) 20

24 AUB facts Premenop AUB- 1/3 of gynecological consultations Peri- and postmenop AUB- 70% of gynecological consultations FIGO Menstrual Disorders Working Group-2011 American College of Obstetricians and Gynecologists (ACOG)

25 AUB definitions AUB: bleeding from the uterine corpus that is abnormal in volume, regularity, and/or timing Heavy menstrual bleeding (HMB) Intermenstrual bleeding (IMB) 25

26 AUB definitions (cont.) Chronic AUB: bleeding from the uterine corpus that is abnormal in volume, regularity, and/or timing, and has been present for 6 months Acute AUB: was defined as an episode of heavy bleeding that, in the opinion of the clinician, is of sufficient quantity to require immediate intervention to prevent further blood loss Intermenstrual bleeding (IMB): occurs between clearly defined cyclic and predictable menses 26

27 AUB in reproductive ages PALM/COEIN 27

28 PALM Polyp-AUB-P Adenomyosis AUB-A Leiomyoma AUB-L Malignancy and hyperplasia AUB-M These lesions are detected by imaging and assessed by histology 28

29 Causes of Abnormal Uterine Bleeding by Age Group Prepuberty Adolescence Reproductive age Perimenopausal Precocious puberty (hypothalamic, pituitary or ovarian origin) Anovulatory cycle Complication of pregnancy (abortion, trophobl.disease, ectopic pregnancy) Organic lesions (leiomyoma, polyp, adenomyosis, endometrial hyperplasia, carcinoma) Anovulatory cycle Anovulatory cycle Organic lesions (carcinoma, hyperplasia, polyp) Postmenopausal Organic lesions (carcinoma, hyperplasia, polyp) Endometrial atrophy 29

30 Dysfunctional endometrial bleeding (now AUB-COEIN group) Inadequate proliferative phase discrepancy between the observed and the expected endometrial pattern in the proliferative phase Inadequate luteal phase low progesteron level infertility amenorrhea or abnormal bleeding sampling 2 days before expected menstruation! Irregular shedding of the endometrium menstruation lasts longer than 7 days without prolongation of the cycle sampling on the 5th day of the menstruation demonstrates menstruation type and late secretory type endometrium and 30

31 Dysfunctional endometrial bleeding Anovulatory cycle (AUB-O) in adolescence and premenopausa most commonly due to slight hormonal imbalances and no apparent causes Less commonly: endocrine causes: thyroid, adrenal or pituitary disease ovarian causes: PCO, granulosa-theca cell tumor systemic metabolic causes: obesity, malnutrition (anorexia nervosa!), chronic systemic diseases etc. no ovulation prolonged unopposed estrogenic stimulation persistant proliferative endometrium endometrial hyperplasia or unsheduled breakdown of the stroma abnormal bleeding if ~ is suspected diagnostic D&C in the secretory phase (2 days before the expected menstruation) will show proliferating endometrium 31

32 Endometrial hyperplasia result of unopposed, prolonged estrogenic stimulation (due to anovulation or increased estrogen production- PCO, Stein-Leventhal sy, cortical stromal hppl, estrogen replacement therapy, functioning granulosa cell tumor) Inactivation of PTEN tumor suppressor gene (normally blocks the PI3K growth-regulatory pathway) Simple hyperplasia (without or with atypia) Complex hyperplasia (without or with atypia) 32

33 Simple hyperplasia Without atypia (Glandular cystic hppl) diffuse alteration increased amount of glands and stroma Mildly increased ratio of glands and stroma differences in glandular size and shape cystically dilated glands glandular epithelium: proliferative Usually no progression to adenocarcinoma (1%) With atypia the previous features + cytological atypia Uncommon Progression to adenocarcinoma 8% 33

34 Simple hyperplasia 34

35 Simple hyperplasia- endometrium 35

36 Complex hyperplasia Without atypia focal alteration irregular glands increased ratio of glands to stroma (less intervening stroma, back-to-back placed glands) Progression to adenocarcinoma 3% With atypia with cytological atypia differentiating from endometrial adenocarcinoma may be difficult Usually hysterectomy is done Progression to adenocarcinoma 25-30% 36

37 Complex hppl 37

38 Diagnostic problems with endometrial hyperplasia Assessment of cellular atypia highly subjective Complex hyperplasia with atypia (CHA)- distinction from adenocc may be highly difficult (in 25-45% of cases if hysterectomy is performed after CHA diagnosis, adenocarcinoma is found in the specimen) If metaplasia is present (common) assessment of atypia is difficult CHA may occur in young women- management? 38

39 Metaplasias different forms: squamous,tubal, eosinophilic, mucinous, etc. frequently associated with hyperplasia 39

40 Tubal metaplasia 40

41 Adenomyosis and endometriosis Adenomyosis: endometrial glands and stroma deep within the myometrium (by at least 2-3 mm from endometrium) Endometriosis: endometrial tissue outside the uterus made of functional endometrium undergoing cyclic changes origin from müllerian rests? implantation?lymphatic or hematogenous spread? most commonly within the ovaries, uterine ligaments, on the pelvic peritoneum, bowel, appendix, cervix, fallopian tube, laparotomy scars pelvic pain, dysmenorrhea, infertility Deep infiltrating endometrosis (DIE) 41

42 Adenomyosis and endometrial polyp 42

43 Adenomyosis 43

44 Adenomyosis 44

45 Endometriosis of ovary- cyst formation (chocolate cyst) 45

46 Peritoneal endometriosis 46

47 Endometrial polyps not true neoplasms, exophytic mass may occur after Tamoxifen (SERM) administration asymptomatic or may produce abnormal bleeding (AUB-P) MA: projects into the body cavity MI: cystically dilated glands, fibrous stroma and thick-walled vessels adenocarcinoma arising in ~ is possible 47

48 Tumors of the uterine corpus Arising from Benign Malignant Endometrium Endometrial glands Endometrial stroma - Endometrioid carcinoma Serous cc Clear cell cc Stromal nodule Stromal sarcoma Endometrial glands and stroma Adenofibroma Adenomyoma Carcinosarcoma Adenosarcoma Myometrium Leiomyoma Leiomyosarcoma 48

49 WHO, 4th edition,

50 Endometrial carcinoma The most common invasive cancer in the female genital tract 7% of all (non-skin)cancers in women mainly in postmenopausal woman ( y) If it affects women 40 y Lynch syndrome should be excluded SY: usually postmenopausal bleeding 50

51 Endometrial carcinoma Two main types (by pathogenesis): Endometrioid carcinoma on a background of endometrial hyperplasia Obesity, diabetes, hypertension, infertility, Stein- Leventhal sy, longstanding estrogen users, breast cancer patients treated with Tamoxifen more favorable prognosis usually well differentiated mutations in PTEN, microsatellite instability, k-ras, PIK3CA, B-cathenin genes In poorly differentiated carcinoma TP53 mutations may occur Variants: Squamous, Villoglandular 51

52 52

53 Endometrial carcinoma Endometrioid carcinoma (cont) Grading Grade 1: if<5% solid growth, Grade 2:if < 50% solid growth Grade 3: if > 50% solid growth 53

54 Endometrial carcinoma Serous Carcinoma not associated with endometrial hyperplasia Usually in the setting of atrophy Poorly differentiated, aggressive high grade cytologic features, necrosis, lymphovascular invasion Papillary, glandular mutation of TP53 Precursor lesion: serous endometrial intraepithelial carcinoma 54

55 Endometrial carcinoma Spread and metastases local spread: myometrium and cervix extrauterine spread: pelvic and paraaortic lymph nodes, ovaries serous carcinoma: early spread to the peritoneum TNM, 8th edition 55

56 Endometrioid carcinoma 56

57 Endometrioid carcinoma 57

58 Endometrioid carcinoma 58

59 Endometrioid carcinoma 59

60 Serous carcinoma 60

61 Papillary structures-high grade cytomorphology- Serous carcinoma 61

62 Clear cell carcinoma 62

63 Tumors of the uterine corpus Arising from Benign Malignant Endometrium Endometrial glands Endometrial stroma - Endometrioid carcinoma Serous cc Clear cell cc Stromal nodule Stromal sarcoma Endometrial glands and stroma Adenofibroma Adenomyoma Carcinosarcoma Adenosarcoma Myometrium Leiomyoma Leiomyosarcoma 63

64 WHO, 4th edition,

65 Endometrial stromal tumors middle- aged (average 45 y) women tumor cells mimicking endometrial stromal cells Endometrial stromal nodule Endometrial stromal sarcomas low and high grade group 65

66 Endometrial stromal sarcoma 66

67 Endometrial stromal sarcoma 67

68 Tumors of the uterine corpus Arising from Benign Malignant Endometrium Endometrial glands Endometrial stroma - Endometrioid carcinoma Serous cc Clear cell cc Stromal nodule Stromal sarcoma Endometrial glands and stroma Adenofibroma Adenomyoma Carcinosarcoma Adenosarcoma Myometrium Leiomyoma Leiomyosarcoma 68

69 Mixed epithelial and mesenchymal tumors Adenomyoma Atypical polypoid adenomyoma Adenofibroma Adenosarcoma Carcinosarcoma (formerly malignant mixed müllerian tumor) 69

70 Carcinosarcoma (formerly: malignant mixed müllerian tumor) postmenopausal patients uterine enlargement and bleeding MA: large, soft, polypoid masses MI: admixture of carcinoma and sarcoma-like elements carcinoma: high grade, undifferentiated, necrosis, hemorrhage sarcoma: homologous or heterologous (skeletal muscle, cartilage, bone or fat) 70

71 Carcinosarcoma-uterus 71

72 Carcinosarcoma with heterologous elements (cartilage) 72

73 Adenosarcoma generally regarded as low grade MA: large polypoid growth filling the uterine cavity MI: abnormally shaped glands (but no cytologic atypia!) and malignant stroma (the whole resembling phyllodes tumor of the breast) 73

74 Adenosarcoma- reminescent of phyllodes tumor of the breast 74

75 Myometrium 75

76 Tumors of the uterine corpus Arising from Benign Malignant Endometrium Endometrial glands Endometrial stroma - Endometrioid carcinoma Serous cc Clear cell cc Stromal nodule Stromal sarcoma Endometrial glands and stroma Adenofibroma Adenomyoma Carcinosarcoma Adenosarcoma Myometrium Leiomyoma Leiomyosarcoma 76

77 Tumors of the Myometrium Leiomyoma in 40% of women over the age of 50 years location: submucosal, intramural, subserosal symptoms: abnormal bleeding, pain, spontaneous abortion, impaired fertility, compression of the urinary bladder ( frequency) MA: well circumscribed, round, grayish-whitish nodule(s) with a whorling pattern MA: uniform spindle shaped cells, no atypia, scanty mitoses 77

78 78

79 Tumors of the Myometrium Leiomyosarcoma in older patients ( average 55 years) MA: fleshy with necrosis and hemorrhage MI: hypercellular, nuclear atypia, pleomorphism, increased mitotic index, atypical mitoses, necrosis Metastases: pelvis, lung, bone, brain but lymph node metastases exceptional! 79

80 Leiomyosarcoma-uterus 80

81 Leiomyosarcoma 81

5 Mousa Al-Abbadi. Ola Al-juneidi & Obada Zalat. Ahmad Al-Tarefe

5 Mousa Al-Abbadi. Ola Al-juneidi & Obada Zalat. Ahmad Al-Tarefe 5 Mousa Al-Abbadi Ola Al-juneidi & Obada Zalat Ahmad Al-Tarefe Abnormal Uterine Bleeding (AUB) AUB is a very common scenario or symptom where women complain of menorrhagia (heavy and/or for long periods),