1	Endometrial carcinoma Prognostic factors Dr. G. Jacomen AZ St Jozef Malle
2	Prevalence Flanders 1997-1999: 670 new cases/year 5,3 % of all malignancies in women third after breast (35,3 %) and colorectum (13,5 %) Increase !! 2000-2001 761 new cases/year
3	Prognostic factors Stage Type Grade Lymphovascular permeation
4	Stage Figo TNM not on biopsy or curettings
5	Endometrial Ca: stage FIGO I: limited to corpus IA: only EM IB: <50% MM IC: ³50% MM TNM pT1 pT1a pT1b pT1c
6	Endometrial Ca: stage (2) FIGO II: in cx but not beyond IIA: endocx glands IIB: in stroma cx TNM pT2 pT2a pT2b
7	Endometrial Ca: stage (3) FIGO III: pelvic extension IIIA: in serosa, adnex or + cytology IIIB: in vagina IIIC: meta in lymph nodes: pelvic, paraAo TNM pT3a pT3b pN1
8	Endometrial Ca: stage (4) FIGO IV: spread beyond pelvis IVA: in mucosa of bladder or bowel IVB: distant meta TNM pT4 pM1
9	Problems with stage I Irregular border between endometrium and myometrium Distinction between IA and IB; and between IB and IC is difficult
10	pT1a or pT1b ?
11	pT1b !
12	Can CD 10 assist ? CD 10 + in endometrial stromal cells Prove of endometriosis If + round tumour : stage IA ?
13	Limited use of CD 10 Carcinoma cells can induce CD 10 + cells round the tumour Only CD 10 negativity is helpful: prove of invasion in myometrium
14	pT1b or pT1c: often difficult Use arcuate vascular plexus as cut off In doubt: use thickness of opposite uterine wall Williams: Assessment of uterine wall thickness and position of the vascular plexus in the deep myometrium: Implications for the measurement of depth of myometrial invasion of endometrial Ca I J Gynecol Pathol (2006) 25: 59-64
15	Invasion or extension in adenomyosis ? Extension in adenomyosis without invasion does not have the same negative prognosis as deep invasion Extension in adenomyosis more often associated with stage IC What about invasion originating from adenomyosis ???
16	Alternative for subdividing stage I Lindauer: Is there a prognostic difference between depth of myometrial invasion and the tumour-free distance from the uterine serosa in endometrial cancer? Gynecol Oncol 2003; 91(3): 547-551 TFD but not DOI is predictive of recurrence and is more significant predictor of DOD Tumour free distance: 1 cm Combination of DOI and TFD ? Combined with myometrial thickness?
17	Problems with stage II On curettings: only stage II if endometrial carcinoma in a clearly cervical fragment Do not trust your clinician !!! Difficult assessment of stromal invasion
18	Are all stage II really stage II ? Reisinger: Preoperative radiation therapy in clinical stage II endometrial carcinoma Gynecol Oncol 1992, 45(2): 174-178 Survival in Stage IIA is significantly higher than in Stage IIB (86% vs 46%)
19	Frequency of stage IIA Mariani: Endometrial cancer: predictors of peritoneal failure Gynecol Oncol 2003; 89(2): 236-242 Superficial implants in cervix with no or minimal stromal invasion occurs in 40%
20	Etiology of stage IIA Implants are due to settling of tumour on endocervical mucosa following curettage Stage II is induced by curettage !!!!
21	Therapeutical implication Stage IIB : radiotherapy Stage IIA : no radiotherapy
22	pT2a ?
23	Continous extension in cervix
24	pT2b
25	Remarks on stage III Extension to adnex does not have to be continuous Para-aortic nodes have worse prognosis than pelvic nodes Specimen for cytologic examination should be obtained at the start of the operation
26	Adnexal and endometrial involvement in cancer 3 possible scenarios: 1) Primary endometrial 2) Primary ovarian 3) 2 concurrent malignancies
27	Primary endometrial metastatic to adnex Deeply invasive type 1 Ca Lymphovascular spread Often bilateral adnexal involvement Often small separate nodules in adnexes
28	Primary ovarian metastatic to endometrium Rare Only if small, discrete plaques of tumour in an otherwise normal endometrium
29	2 synchronous primaries Younger patients If both are endometrioid: good prognosis Presumed to arise from endometriosis è high stage cancers can be separate primaries with excellent prognosis
30	Frequency of lymph node metastasis Inner third MM 5 % Middle third MM 23 % Outer third MM 33 % Grade 1 inner third None Grade 1 outer third 25 %
31	pN1 stage IIIA
32	Lymph node metastasis: predicting prognosis High metastatic ratio: worse Extranodal extension: worse Desmoplasia in + nodes: worse Yasunaga: Endometrial carcinoma with lymph node involvement: novel histopathologic factors for predicting prognosis I J Gynecol Pathol 2003, 22(4): 341-346
33	IHC on lymph nodes? Gonzalez: CK staining of resected lymph nodes may improve the sensitivity of surgical staging for endometrial cancer Gynecol Oncol 2003; 91(3): 518-525 Using CK the detection of tumour cells is increased: 12,5% (2/16) have micrometastasis, 50% of them will DOD
34	Are they important? Yabushita: Occult lymph node metastases detected by CK IHC predict recurrence in node-negative endometrial cancer Gynecol Oncol 2001; 13(1): 38-41 Stage I with no nodal involvement : 0/22 recurrence vs 5/14 with CK + cells Related to lymphovascular permeation
35	Should we do it? Not (yet) recommended on routine basis If you consider it: type II Ca or grade 3 type I deeply invasive lymphovascular permeation
36	Müllerian inclusions Glands ¹ metastasis Difficult on frozen sections Often in capsule
37	Müllerian inclusions: diagnosis Flat or cuboidal cells No atypia Compare with tumour
38	Stage III by cytology If stage III only because of + cytology: prognosis does not equal that of other stage III + cytology remains stage III, but other therapy
39	Importance of + cytology Kadar: Positive peritoneal cytology is an adverse risk factor in endometrial carcinoma only if there is other evidence of extrauterine disease Gynecol Oncol 1992, 46: 145-149 Tebeu: Impact of peritoneal cytology on survival of endometrial cancer patients treated with surgery and radiotherapy Br J Cancer 2003 89(11): 2023-2026
40	Recent evidence Slomowitz: Heterogeneity of stage IIIA endometrial carcinomas: implications for adjuvant therapy Int J Gynecol Cancer 2005, 15(3): 510-516 Fadare: Upstaging based solely on positive peritoneal washing does not affect outcome in endometrial cancer Mod Pathol 2005, 18: 673-680
41	Prognostic factors Stage Type Grade Lymphovascular permeation
42	Type WHO Type 1: estrogen-related : endometrioid Ca, mucinous Ca Type 2: serous or clear cell Ca Carcinosarcoma Undifferentiated carcinoma Endometrial stromal sarcoma
43	Type 1 Type 2
44	Prognostic factors Stage Type Grade Lymphovascular permeation
45	Endometrioid Ca: grading Mostly based on architectural grade Nuclei only important if grade 3
46	Architectural grade Depends on the extent of solid zones in comparion to the glands Do not consider squamous zones !!
47	Architectural grade Grade1: Max 5 % solid Grade 2: 6-50 % solid Grade 3: > 50 % solid
48	Architectural grade 1
49	Papillae = glands !
50	Architectural grade 2
51	Architectural grade 3
52	Do not forget the tumour in the curettage !!! If little amount of tumour in the hysterectomy: grading should be performed together with the material of the curettage
53	Cytological grade Nuclei grade 1: oval slightly enlarged fine dispersed chromatin Nuclei grade 3: strongly pleomorphic strongly enlarged unregular coarse chromatin prominent eosinophilic nucleoli
54	Cytological grade Nuclei grade 2: between 1 and 3 Number of mitosis not important
55	Nuclear grade 1
56	Nuclear grade 3
57	Nuclear grade 2
58	Determination of grade Architectural grade primordial Cytologic grade 3 augments architecturale grade 1 or 2 by 1 If really discordant: think of Serous Ca Clear cell Ca
59	Examples Arch 1 + Cyt 1 or 2 è Grade 1 Arch 1 + Cyto 3 è Grade 2 Arch 2 + Cyt 1 or 2 è Grade 2 Arch 2 + Cyt 3 è Grade 3
60	Grade can be very heterogenic 1 tumour with zones grade 1 and zones grade 3
61	Grading Heterogeneity in grade very often Reason for discordance between curettage and hysterectomy Grade 1 remains grade 1 in 45%
62	Grade 1 + undifferentiated Ca Silva: Association of low-grade endometrioid Ca of the uterus and ovary with undifferentiated Ca: a new type of dedifferentiated Ca? I J Gynecol Pathol (2006) 25: 52-58 Indicates aggressive behavior In asynchronous cases: can explain absence of second primary
63	Grading mucinous carcinoma No rules !!! By convention : rules of endometrioid Most are grade 1
64	Grading type II Ca Always Grade 3!
65	Is grading reproducible ? Architectural grading: kappa 0.70 Nuclear grading: kappa 0.55 Combined FIGO grading: kappa 0.65
66	Other systems Lax: A binary architectural grading system for uterine endometrial endometrioid Ca has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis Am J Surg Pathol (2000) 24: 1201-1208 Alkushi: Description of a novel system for grading of endometrial Ca and comparison with existing grading systems Am J Surg Pathol (2005) 29: 295-304
67	Lax (2000) > 50% solid growth (squamous and non-squamous) Tumour cell necrosis Diffusely infiltrative pattern of invasion (versus pushing) ³ 2/3 features : high-grade £ 1/3 features : low-grade Only for endometrioid type
68	Alkushi (2005) Predominantly papillary or solid growth Mitotic index ³ 6/10 HPF Severe nuclear atypia ³ 2/3 features : high-grade £ 1/3 features : low-grade For all types of tumour
69	Comparison of the 3 systems Alkushi: most prognostic power when applied to all tumours (regardless of cell type) FIGO: superior when only endometrioid type is considered Binary system with combining FIGO grade 1 and 2 is most prognostically system
70	Prognostic factors Stage Type Grade Lymphovascular permeation
71	Lymphovascular permeation Not on biopsy or curettings Cave retraction !!! Typical feature of type II Ca
72
73	Vascular invasion as a prognostic marker Definite vascular invasion is a independent prognostic factor
74	Other prognostic factors Age : ³ 70 y MELF K-Ras Ploidy ER, PR MSI: 5y survival 20% better PTEN Angiogenesis Proliferation: Ki67 bCatenin: + in subset of less-aggressive tumours bcl2 C-Erb-B2 P53 cyclinA CA 125
75	Age Prognosis worse if ³ 70 years, even if treated in similar fashion Intrinsically more aggressive in older patients Alektiar: Is endometrial Ca intrinsically more aggressive in elderly patients? Cancer (2003) 98: 2368-77
76	MELF Microcystic Elongated Fragmented Higher incidence of lymphatic invasion
77	K-ras Oncogene Mutations in 10-15 % Little if any significance
78	Ploidy Ploidy is strong predictor of outcome Stage 1: Diploid: 94 % progression-free survival Aneuploid: 64 %
79	ER, PR Type 1 Ca: mostly + Type 2 Ca: - Conflicting results Not independent risk factor: correlated with stage and grade
80	MSI in EmCa Related with HNPCC 20-30 % In mucinous Ca, not in USC
81	Angiogenesis Tumour > 1mm needs new vessels VEGF in high concentration in neoplastic cells High microvessel counts are significant predictor of decreased survival
82	Proliferation markers: Ki67 Ki67 is expressed in all non-resting nuclei High expression is significant independent prognosticator
83	bcl-2 bcl-2 inhibits apoptosis Normally highly expressed in proliferative phase, downregulation in secretory phase Simple hyperplasia: high level persists Diminishes progressively in atypical hyperplasia and with increasing grade in Ca Expression is significantly related to probability of lymph node metastasis or tumour recurrence
84	c-Erb-B2 (Neu-oncogen) Amplification occurs in 20-40 % Associated with aggressive cell types: clear cell Associated depth of invasion, grade
85	p53 Overexpression related to higher grade, aggressive type (USC), higher stage
86	CA 125 Preoperative serum level correlates significantly with survival £ 13 U/ml versus > 13 U/ml
87	Endometrial carcinoma: conclusion on prognosis Classical factors most important New markers and genetic factors will have impact on therapy