Various types of endometrial carcinoma

Endometrial Ca classification and histopathological features , CAP protocol for reporting , grading and staging tumors
Reference - Robbins , Rosai & Ackerman , Sternberg ,Fletcher ,WHO classification of tumors of female reproductive system, CAP

1. Various Types Of Endometrial Carcinoma Grading and Staging Presented by – Dr. Pritika Nehra SMS Medical College , Jaipur

2. OUTLINE WHO Classification Precursor Lesions Molecular Pathogenesis Endometrial Ca and Variants Tumor like lesions Spread & Metastasis Prognostic Factors Treatment CAP Protocol Grading and Staging

3. Precursor Lesions Hyperplasia without Atypia : exaggerated proliferation of glands of irregular size and shape increase in the gland to stroma ratio without significant cytological atypia Progression to well-differentiated E ndometrial C a :1–3 %

4. Differential Diagnosis Disordered Proliferative Phase : Proliferation of glands displaying no cytological atypia that exceeds that of normal proliferative endometrium but falls short of the crowding seen in hyperplasia abnormal glands should be focal qualitatively similar to those seen in simple hyperplasia, but limited in extent and interspersed among glands with a normal proliferative phase pattern .

5. Atypical Hyperplasia aka Endometrioid Intraepithelial Neoplasm Cytological atypia superimposed on endometrial hyperplasia Genetic changes & Hereditary susceptibility parallels that of heritable syndromes associated with an increased risk for endometrioid carcinoma 25% likelihood of concurrent adenocarcinoma at hysterectomy, and a 14-fold elevated prospective risk of future adenocarcinoma.

6. Endometrial carcinoma Endometrioid carcinoma Mucinous carcinoma Serous endometrial intraepithelial carcinoma Serous carcinoma Clear cell carcinoma Neuroendocrine tumours Mixed cell adenocarcinoma Undifferentiated carcinoma Dedifferentiated carcinoma TYPE i TYPE ii

7. RISK FACTORS : Type I EC : Postmenopausal with unopposed estrogen action , PCOS, oestrogen-producing ovarian tumours , early menarche, Late menopause, nulliparity , obesity, diabetes mellitus Type II EC : multiparous, current smokers , post tubal ligation, h/o breast carcinoma and/or tamoxifen use and are thin Pathogenesis

8. MOLECULAR PATHOGENESIS Endometrioid Ca (Type 1) – MC Mode - increase signaling through PI3K/AKT pathway augments expression of estrogen receptor-dependent target genes in endometrial cells UNIQUE - individual tumors may harbor multiple mutations that increase PI3K/AKT signaling , suggesting that tumor development and progression is fostered by successive increases in signal strength

9. TP53 mutation - 30 % of grade 3 endometrial carcinoma inactivation of PTEN (> 50%) mutations in PIK 3CA (30%) PIK3R1 (20–43 %) ARID1A (40%) KRAS (20–26%)

10. Hypermutated Endometrial Carcinomas – Defects involving DNA mismatch repair genes - 20% of sporadic tumors ,particularly in endometrial carcinomas arising in women from families with HNPCC (Lynch Syndrome ) Mcc by epigenetic silencing ( promoter methylation ) Testing for defective DNA mismatch repair proteins by IHC is the most cost-effective method Loss of MSH2 or MSH6 expression essentially always indicates Lynch syndrome.

11. Ultramutated endometrial carcinomas 10-fold more mutation than the hypermutated tumors , and the molecular basis for this is mutations in the polymerase epsilon (POLE ) gene , resulting in loss of the exonuclease proofreading function and increased mutation rates associated with a very favorable prognosis , even though they are often higher grade

12. Serous Carcinoma (Type 2) – loss of p53 function (seen as aberrant protein accumulation on IHC) (86 %) , also found in approximately 75% of serous endometrial intraepithelial carcinoma Recent identified mutations – P13K & PP2A gene Clear cell carcinomas - 30% rate of inactivation of the chromatin- remodeling complex factor Baf250a (ARID1A)

13. PROTECTIVE FACTORS : later age at first birth and last birth, continuous combined HRT, OCPs (high progestin potency), Inj. progestins , IUD’s, smoking and tubal ligation CLINICAL FEATURES : Present in 60’s. vaginal discharge, usually bleeding (post menopausal bleeding) malignant glandular cells may be found in cervical cytology Advanced disease - abdominal distension, pelvic pressure or pain

14. Endometrioid Carcinoma : Type 1 Endometrial carcinoma ( Bokhman ) Most common type (80%) G landular neoplasm displaying an acinar , papillary or partly solid configuration, lacking the nuclear f/o endometrial serous carcinoma MACROSCOPY : one or more discrete , tan nodules,diffuse and exophytic . Variable necrosis & h’ge

15. MICROSCOPY : glandular or villoglandular architecture, lined by stratified columnar epithelium crowded , complex,branching architecture smoothly contoured glandular lumen,eosinophilic granular cytoplasm Nuclear atypia is usually mild to moderate, with inconspicuous nucleoli, except in poorly differentiated carcinomas. Variable mitotic index FIGO Notable nuclear atypia , which exceeds that which is routinely expected for the architectural grade, increases the tumor grade by 1

16. Squamous differentiation – 10- 25% of endometrioid ca keratin pearl formation, intercellular bridges or solid masses of cells with abundant , polygonally shaped, dense eosinophilic cytoplasm and distinct cell membranes not included in the estimation of solid growth for grading Secretory differentiation - < 2% columnar cells that have single, large, sub/ supranuclear vacuoles of glycogen rather than eosinophilic cytoplasm resemble endometrial glands of the secretory phase almost always well differentiated Less frequent patterns : villoglandular , sertoliform and microglandular

17. GRADE ???

18. Differential Diagnosis Atypical hyperplasia/EIN vs well differentiated endometrial ca presence of stromal invasion , loss of intervening stroma (a confluent glandular/ cribriform pattern) an altered endometrial stroma ( desmoplastic reaction) or a papillary architecture ( villoglandular pattern) E ndocervical vs well differentiated endometrial carcinoma

19. Serous Carcinoma prototypical type II tumour complex papillary and/or glandular architecture with diffuse, marked nuclear pleomorphism MACROSCOPY: uterus is usually small tumour is often inconspicuous , arising on the surface of an endometrial polyp

20. MICROSCOPY : Serous endometrial intraepithelial carcinoma ( SEIC) develops directly on a polyp or in atrophic endometrium lesion is confined to the epithelium, even in the absence of demonstrable invasion, can shed cells and metastasize widely to extra-uterine sites. Distinction of SEIC from early stromal invasion by serous carcinoma is often impossible , it is recommended that these lesions in biopsies be termed “ minimal uterine serous carcinoma”

21. Uterine serous carcinoma Complex papillary architecture is characteristic Papillae vary from short,branching & hyalinized,to long, thin & delicate Each lined by epithelial cells with large atypical nuclei, prominent nucleoli and scant cytoplasm . Scalloped /frayed luminal surface Numerous mitotic figures Myometrial invasion - gaping glands

22. IHC – P53 STAIN

23. Differential Diagnosis H igh-grade glandular endometrial adenocarcinomas with serous differentiation: Variable p53 stain in <75% of the neoplastic cells -- wild type TP53, H igh-grade endometrioid carcinoma Aberrant p53 expression (intense and diffuse staining of at least 75% of the tumour cells -- TP53 mutation and very high Ki-67 - more typical of Serous carcinoma may represent an unusual pattern of serous carcinoma or a true, mixed serous and endometrioid carcinoma. Because of the highly aggressive nature of serous carcinoma, clinicians regard even a relatively minor component as tantamount to a pure serous carcinoma Serous ca ovary -

24. Clear Cell Carcinoma uncommon (2 %) ,one of the type II endometrial carcinomas Multiparity and cigarette smoking are more common Arises in background of atrophic endometrium or endometrial polyps HISTOPATHOLOGY : Polygonal/ hobnail shaped cells with clear cytoplasm tubulocystic , papillary or solid architecture papillae -short and branching, with hyalinized stroma Nuclear atypia is prominent Mitotic figures are usually numerous . 2/3 rd clear cell carcinomas: extracellular globules or hyaline bodies

25. clear cytoplasm with hobnail cells. papillae with hyalinized cores papillary and solid patterns tubulocystic pattern. protrusion of apical cytoplasm containing nuclei into the lumen.

26. IHC Clear cell carcinoma is usually ER and PR negative and rarely overexpresses p53. Ki-67 labelling index -25–30%. Tumour cells express HNF-1B in most cases. L ow-grade endometrioid carcinoma - strongly positive for ER and PR and negative for p53 S erous carcinoma - negative or weakly positive for ER and PR and diffusely positive for p53

27. Mucinous carcinoma > 50% of the neoplasm is composed of mucinous cells 1–9% of endometrial carcinomas almost always stage I ,well differentiated and have a good prognosis MACROSCOPY : can be suspected by their gelatinous/ mucoid texture MICROSCOPY : glandular or villoglandular architecture uniform , mucinous, columnar cells with minimal stratification Mucin - basophilic globules or slightly pale, granular cytoplasm M ucicarmine and CEA + ve Mild to moderate nuclear atypia

28. Differential Diagnosis Endocervical carcinoma : IHC can be helpful in this distinction Proliferative mucinous lesions vs atypical hyperplasia and well differentiated endometrial carcinoma : presence of a confluent or cribriform architecture with even minimal cytological atypia – carcinoma Proliferations that do not display these features should be classified as atypical mucinous glandular proliferations Frequently associated with an underlying low-grade carcinoma

29. Neuroendocrine tumours Share a morphological neuroendocrine phenotype < 1% of endometrial cancers Low-grade neuroendocrine tumour -Carcinoid tumour (grade 1) High-grade neuroendocrine carcinoma –Small & Large cell (grade 3) SCNEC : resembles small cell carcinoma of the lung composed of ovoid, poorly cohesive cells, with condensed chromatin and scant cytoplasm frequent nuclear moulding, numerous mitotic figures necrosis and apoptotic bodies LCNECs : well demarcated nests , trabeculae or cords with peripheral palisading tumour cells are large, polygonal, with vesicular or hyperchromatic nuclei and a prominent nucleolus high mitotic activity and extensive geographic necrosis

30. Mixed C arcinomas two or more different histological types of endometrial carcinoma, atleast one of which is of the type II category MC encountered: endometrioid and serous carcinoma Min % of 2 nd component : 5 % IHC : combination of PTEN, p53, and p16 helps to discriminate between endometrioid and serous carcinoma Correlates with highest grade component A threshold of as little as 5% of a serous component in a mixed carcinoma adversely influences outcome

31. Undifferentiated and Dedifferentiated carcinomas Undifferentiated carcinoma-malignant epithelial neoplasm with no differentiation. Dedifferentiated carcinoma - undifferentiated carcinoma and a second component of either FIGO grade 1 or 2 endometrioid carcinoma

32. Carcinosarcomas (Malignant Mixed Müllerian Tumors ) biphasic tumour( high grade carcinomatous + sarcomatous elements) <5% of all uterine malignancies Association with tamoxifen therapy or long-term unopposed estrogen long-term complication of pelvic radiotherapy (10-20 yrs ) C/F : one-third have evidence of extra-uterine spread at the time of diagnosis, often uterine enlargement or a pelvic mass, prolapses through the cervix in about one-half of patients

33. MACROSCOPY characteristically large and polypoid , filling the entire uterine cavity often protruding through the cervical os typically soft, with areas of haemorrhage, necrosis and cystic degeneration frequent myometrial invasion and sometimes cervical involvement MICROSCOPY typically an intimate admixture of high-grade epithelium & mesenchyme; one or the other may predominate usually sharply demarcated but merging can be observed

34. Epithelium is most often of endometrioid or serous types mesenchymal component is mostly a high-grade, non-specific sarcoma heterologous elements including rhabdomyosarcoma , chondrosarcoma , rarely, osteosarcoma are seen in 50% of cases commonly exhibit deep myometrial and lymphovascular invasion

35. Similar molecular profile to high-grade endometrial carcinomas TP53 mutation- most common molecular alteration 50 % -mutations of the PI3K / AKT and/or RAS/RAF pathways Poor outcome and have a pattern of spread similar to high-grade endometrial carcinoma A high proportion of patients with apparently clinically stage I disease have evidence of extrauterine spread at the time of diagnosis. Metastatic spread – pelvic and para -aortic lymph nodes Mcc death- local pelvic/abdominal recurrence Risk of advanced stage disease - closely related to depth of myometrial invasion Serous and clear cell carcinomatous elements are associated with a higher frequency of other adverse prognostic features R habdomyosarcomatous component - WORST prognosis.

36. TUMOR LIKE LESIONS POLYP : disorganized proliferation of benign glandular & stromal elements that is usually elevated above the surface of the adjacent endometrium LYMPHOMA LIKE LESIONS : typically superficial and non-mass forming dense infiltration of the endometrium by lymphoid cells with a predominance of large cells with features of immunoblasts a poptotic debris and tingible body macrophages may result in a starry-sky pattern typically b/g of chronic endometritis , including small lymphocytes , plasma cells and neutrophils

37. METAPLASIA : change from one mature histological cell type to another, composed of cells that have cytoplasmic, nuclear and/ or architectural differentiation that differ from that of normal endometrioid glands can be secondary to non-specific endometrial breakdown, chronic inflammation or an abnormal hormonal state

38. ARIAS-STELLA REACTION: Striking cellular and nuclear atypia of cells within endometrial glands occurring in association with gestation, GTD’s, treatment with gonadotropins or high doses of progestins

39. Accreditation Requirements Core data elements required in reports to adequately describe appropriate malignancies, MUST be reported in all instances, even if the response is “not applicable” or “cannot be determined.” Conditional data elements are only required to be reported if applicable. Ex- total no of LN’s examined must be reported, but only if present in the specimen Optional data elements are identified with “+” and although not required , may be considered for reporting as determined by local practice standards. NOT required for recurrent and metastatic tumors NOT required for pathology reviews performed at a second institution

40. Surgical Pathology Cancer Case Summary

41. Spread & Metastasis Related to the microscopic grade of the tumour Modes : 1 . Direct spread- myometrium ( upto 50% or >50 %) and cervix 2 . Lympho -vascular invasion 3 . Transtubal invasion Most common site for extra uterine spread - Pelvic , para aortic lymph nodes, ovaries Papillary serous carcinomas-propensity to lymph vessel permeation Most common site of recurrence is the vaginal vault and pelvis . Distant metastasis-lung, liver, bone, CNS, skin.

42. Myometrial invasion in the form of jagged, irregular branching glands inflamed granulation tissue often forms around invasive foci

43. In a large number of cases, not straightforward task because the normal endometrial– myometrial junction is irregular , and the normal endometrium often interdigitates deeply with the myometrium. As a result, the basalis can lie deep in the myometrium . If deeply lying basalis is involved by carcinoma, difficult to distinguish this from superficial myoinvasion . Unless a granulation tissue host inflammatory reaction is identified, we withhold a diagnosis of myoinvasion .

44. Involvement of adenomyosis by carcinoma should be distinguished from myoinvasion , former does not imply a worse prognosis Thorough sectioning to identify residual benign endometrial glands and/or endometrial stroma in suspected foci usually have a blunted advancing front often surrounded by hyperplastic struts of myometrium

45. Lynch syndrome in patients with LUS endometrial carcinoma (29 %) Involvement of the surface endocervical epithelium and/or endocervical glands (either by direct extension or drop metastases) does not have any prognostic significance and is not T2/Stage II

46. Prognostic Factors Tumor stage – strongest indicator Myoinvasion Grade of differentiation Age – consistent important prognostic factor Histotype – Grade 3 endometrioid , serous and clear cell ca Lymph vessel invasion – poor sign Molecular subtypes Others - F avorable : absence of L1CAM expression,absence of β-catenin mutation and diploid cellular DNA content

47. Treatment T otal abdominal hysterectomy with bilateral salpingo -oophorectomy S upplemented by S urgical staging ( including biopsies of pelvic and para -aortic lymph nodes) if any of the following is present: greater than 50% myometrial invasion, grade III tumor , cervical involvement, extrauterine spread, unfavorable histologic component (serous , clear cell, or undifferentiated)or palpably enlarged nodes Progestational agents for early stage, low-grade tumors , and in more advanced tumors - temporary regressions in the primary tumor as well as in the metastases Serous carcinoma –TAH with BSO , omentectomy , and surgical staging , including peritoneal cytology and pelvic and para -aortic lymph node sampling,followed by adjuvant therapy Tumor relapse may appear in the form of local recrudescence(50 %), distant metastases (28%), or both (21%)

48. Endometrioid carcinoma: Stage I ( grade 1 or 2 ) – 90% Stage I (grade 3 ) – 75% Stage II and stage III – 50% Serous carcinoma : 18-27% 5 year survival rates

49. REFERENCES WHO Classification of Tumours of Female Reproductive Organs,4 th edition, 2014 Robbins and Cotran Pathologic Basis of Disease.9 th edition,2015 Rosai And Ackerman’s Surgical Pathology,11 th edition,2018 Fletcher’s Diagnostic Histopathology of Tumors,4 th edition,2013 Sternberg’s Diagnostic Surgical Pathology.6 th edition,2015 2018 College of American Pathologists (CAP ) www.cap.org/cancerprotocols