Approach to endometrial biopsy

Endometrial biopsy interpretation for post graduate students in Pathology.

1. Approach to Endometrial Biopsy Dr.CSBR.Prasad , MD., Professor & HOD Deptt . of Pathology Sri Devaraj Urs Medical College Kolar-563101

2. What do you think of this EM biopsy?

3. What is the finding here?

4. What is your impresion on this biopsy? http://www.webpathology.com/image.asp?n=1&Case=568

5. Some fundamentals Only endometrium from the fundus is suitable for diagnosis The functionalis layer is particularly ideal Basalis layer is generally of little diagnostic value except in two conditions: Carcinoma Irregular shedding Irregular development is best detected in larger fragments of tissue where structural units retain their relationship EM from the isthmic region is unsuitable for functional diagnosis as they fail to respond to hormonal changes

6. Some fundamentals Proliferative phase may fluctuate between 10-20days – Dating is not possible Secretory phase is fixed and hence dating is possible Cystic dilatation of an occasional gland is not necessarily a sign of hyperplasia Ovulation may recur sporadically, even years after menopause, the associated corpus luteum is insufficient

7. EM Biopsy Different methods of obtaining endometrial sample Curetting (D&C) Pipelle biopsy or other equivalent technique Hysteroscopy and direct biopsy Endometrial cytology

8. Adequacy There are no definitive guidelines / agreements * If you can make a diagnosis, it is adequate Clinical details are very important Eg : Strips of endometrium in a post menopausal woman Don’t write “inadequate” Sign out No stroma Proliferative without definite stroma No endometrium No tissue *Phillips V, McCluggage WG. Results of a questionnaire regarding criteria for adequacy of endometrial biopsies. J Clin Pathol 2005;58:417–9.

9. EM biopsy, Post menopausal

10. Algorithm for assessment of the adequacy of an endometrial biopsy specimen McCluggage WG. My approach to the interpretation of endometrial biopsies and curettings . J Clin Pathol 2006;59:801–12.

11. Indications for EM Biopsy* 4 Main INDICATIONS Other Indications Determine the cause of AUB AGC /EM cells in PAP smear Assessment of response of the EM to hormone Tx Finding thickened EM in US in post menopausal women Status of EM in infertile patients / dating Evacuation of POC (Spontaneous or MTP) *Diagnosis of Endometrial Biopsies and Curettings : A Practical Approach By Michael Mazur, Robert J. Kurman

12. DDs for presence of adipose tissue in EM samples Uterine Perforation (Critical value) Lipoleiomyoma

13. Myometrium in the curettings Notify the clinician how much myometrium was there in the curettings This helps in two ways: Gives info regarding the consistency of myometrium Gives information about the technique of curettage

14. Artefacts Telescoping (glands within glands) Artefactual crowding and compression of glands Pseudopapillary architecture of superficial strips of EM Crushed endometrial glands and stroma may be extremely cellular and can cause concern

15. Telescoping (gland within gland)

16. Crushed endometrial glands

17. Pseudopapillary architecture of superficial strips of EM

18. Normal EM

19. Proliferative endometrium

20. Proliferative endometrium

21. Mitosis - indicator of proliferative activity Non-reactive endometrium (No mitosis) Mitosis in post menopausal EM May be associated with hyperplasia If there is no hyperplasia: Continued estrogen stimulation Prolapse EM polyp

22. EM – Status Post menopusal

23. Secretory endometrium

24. Endometritis Common components in EM : Lymphocytes, including natural killer cells and lymphoid aggregates PMNs: Premenstrual and menstrual phases Plasma cells : * Plasma cells: Is it always endometritis ? Other morphological features that favour endometritis : Disturbance in maturation—focal areas that are out of cycle with other areas Stromal edema and Characteristically, a spindle-cell alteration of the stroma, especially around glands Glandular architectural complexity and cytological atypia *Bayer-Garner IB, Korourian S. Plasma cells in chronic endometritis are easily identified when stained with syndecan-1. Mod Pathol 2001;14:877–9

25. Lymphoid aggregate

26. Spindle-cell alteration of the stroma, especially around glands

27. Endometritis In the absence of other morphological features exhaustive search for plasma cells is unnecessary

28. Endometritis Focal necrotising endometritis * Granulomatous endometritis Tuberculosis Sarcoidosis Others *Bennett AE, Rathore S, Rhatigan RM. Focal necrotizing endometritis : a clinicopathologic study of 15 cases. Int J Gynecol Pathol 1999;18:220–5.

29. EM polyp 40-50yrs (rare before menarche, can occur after menopause) Site: Fundus and cornua Often pedunculated Histology: Composed of glands and stroma Mostly proliferative changes (cyclical changes are rare) Foci of squamous metaplasia Smooth muscle may form a component Blood vessels are thick walled and tortuous Rarely carcinoma can arise (3%) Through examination of polyp / stalk is important Atypicalities in a post menopausal woman warrants hysterectomy

30. EM polyp Proliferative activity is common in endometrial polyps, even in postmenopausal women A diagnosis of simple hyperplasia should not be made in the case of an endometrial polyp Carcinomas may arise in endometrial polyps Endometrial polyps are particularly common in association with tamoxifen There is a peculiar tendency for serous carcinoma and EIC to arise within endometrial polyps whether sporadic or associated with tamoxifen * *Silva EG, Jenkins R. Serous carcinoma in endometrial polyps. Mod Pathol 1990;3:120–8.

31. EM polyp

32. Metaplasias - Epithelial Epithelial metaplasias : Squamous or mucinous Associated with hyperplasia / carcinoma Ciliated metaplasia: Applicable only when extensive resembling fallopian tube Papillary syncytial metaplasia: May be a reparative response When florid, this may be suggestive of a serous carcinoma or an EIC Mucinous metaplasia Benign papillary proliferations

33. Squamous metaplasia

34. Tubal metaplasia

35. Benign papillary proliferation

36.  Simple mucinous metaplasia in the basalis of an atrophic endometrium

37. Include ichthyosis uteri

38. Metaplasias - Stromal Formation of smooth muscle, cartilage and bone Importance : May be it difficult to assess myometrial invasion in carcinoma. What are the differentials for stromal metaplasia? Retained fetal parts Int J Gynecol Pathol 2007;26:115

39. Metaplasias - Stromal Endometrial stromal nodule with smooth muscle metaplasia

40. Effects of Tamoxifen on the Endometrium Tamoxifen is widely used as adjuvant therapy in the management of breast cancer Tamoxifen may exert a proliferative effect on the endometrium The risk increases with increasing duration and dosage of tamoxifen EFFECTS : Benign polyps (most common) Stromal fibrosis Stromal condensation around glands (DD Adenosarcoma ) Endometrial hyperplasia Endometrioid and Non- Endometrioid carcinomas Tamoxifen -associated polyps should be extensively sampled

41. EM Hyperplasia Def : Endometrial proliferation with an increase in gland to stroma ratio (from 2:1 to 3:1). Classification of endometrial hyperplasia: WHO 1994 - Four tier system WHO 2014 – Two tier system Atypia : Vesicular nuclei Prominent nucleoli Rounding of nuclei Increased cytoplasmic eosinophilia

42. New WHO classification of endometrial hyperplasias - 2014 New term Synonym Genetic changes Coexistent invasive endometrial carcinoma Progression to invasive carcinoma Hyperplasia  without atypia Non-atypical EM hyperplasias Low level of somatic mutations < 1 % RR: 1.01–1.03 Atypical hyperplasia/ endometrioid intraepithelial neoplasia Atypical EM hyperplasias , EIN Many of the genetic changes typical for endometrioid endometrial cancer are present 25–33 %  2 59 %  1 RR: 14–45 1.  Antonsen S L, Ulrich L, Hogdall C. Patients with atypical hyperplasia of the endometrium should be treated in oncological centers.  Gynecol Oncol . 2012;125:124–128 2.  Zaino R, Carinelli S G, Ellenson L H, Lyon: WHO Press; 2014. Tumours of the uterine Corpus: epithelial Tumours and Precursors; pp. 125–126.

43. EM hyperplasia

44. Simple hyperplasia without atypia http://www.webpathology.com/image.asp?n=1&Case=568

45. Complex hyperplasia without atypia http://www.webpathology.com/image.asp?n=1&Case=568

46. Complex hyperplasia without atypia

47. Atypical hyperplasia

48. Atypical hyperplasia

49. Atypical hyperplasia

50. Complex hyperplasia without nuclear atypia & Carcinoma

51. Complex hyperplasia with atypia Regresses in about 57%  of cases Progression to adenocarcinoma occurs in about 30%  of cases Hysterectomy soon after biopsy : between  23% and 48%  harbor EM adenocarcinoma http://www.webpathology.com/image.asp?n=8&Case=568

52. Benign mimics of EM hyperplasia Artefacts Endometritis Endometrial polyp Arias-Stella reaction Disordered proliferative endometrium Benign papillary proliferations Lower uterine segment endometrium

53. Disordered proliferative endometrium

54. Immunohistochemical staining of FOXA1 and AR in normal endometrium, atypical hyperplasias , and endometrial cancer Qiu , Meiting , Bao , Wei, Wang, Jingyun , Yang, Tingting , He, Xiaoying , Liao, Yun , Wan, Xiaoping . FOXA1 promotes tumor cell proliferation through AR involving the Notch pathway in endometrial cancer BMC Cancer 2014; 14:78 · 

55. Cyclin D1 staining 1-Surface epithelium 2-Complex hyperpasia 3-Endometrioid adenocarcinoma (+) and adenomyosis (-)

56. Arias – Stella reaction

57. Extensive regions of necrosis in curettings - Causes Degenerating carcinoma Septic abortion Infarcted polyp Degenerated submucosal leiomyoma

58. Extensive regions of necrosis better microscopic evidence must be sought before making a definitive diagnosis of carcinoma

59. Adenocarcinoma of endometrium Criteria helpful in distinguishing carcinoma from hyperplasia: The tumor is probably malignant if : Glands are closely packed without intervening stroma for at least half the low power field If gland Lumina containing multiple thin branching papillary projections with a collagenous core with neoplastic epithelium occupying more than half of low-power field If sheets of squamous cells occupy more than half of low-power field Bridging between the adjacent glands – Cribriform pattern Luminal necrosis with PMN infiltration If stroma between the glands is collagenous

60. Some tips Interact with your clinician / History is important for interpretation Separate the endometrial tissue proper from the blood clots for processing Endometrium with surface epithelium is best for interpretation. Absence of surface epithelium compromises interpretation Do not report hyperplasia on secretory endometrium In all cases of abnormal uterine bleeding, consider the possibility of polyp Finding fat in EM curetting is a critical value . It should be intimated to the clinician Aware of the mimics All endometrial cancers should be typed and, if appropriate, graded, even for small biopsy specimens

61. Thank you