1	Other carcinomas Non-type 1 Ca
2	WHO-classification of EM-Ca Endometrioid adenoCa Mucinous Ca Serous Ca Clear cell Ca Undifferentiated Ca Mixed cell adenoCa Squamous cell Ca Transitional cell Ca Small cell Ca Others
3	Serous carcinoma (USC) Formerly: papillary serous Ca Celltype is important, not the architecture Other types can have papillary architecture Can be solid or glandular Type II carcinoma often lymphatic permeation !!!
4	Serous carcinoma Postmenopausal, mean age 10 y older than endometrioid type Estrogens less involved, p53 is important Incidence is increasing ? Macro: often small uterus !!
5	Serous carcinoma Great architectural diversity papillary: short thick broad fibrotic > 50 % : also long slender papillae glandular solid zones
6	Serous carcinoma: cytology Polygonal cells clear or eosinophilic cytoplasm hobnailcells striking atypia: no diagnosis of USC without nuclei grade 3 Discordance: architectural grade 1 cytological grade 3
7	Serous ca: cohesion Cells on papillae form micropapillae with limited cohesion Non-attached cells frequent
8	USC: broad fibrotic papillae
9	USC: typical pattern
10	USC: slender papillae !
11	USC: irregular contour
12	USC: discohesive cells
13	USC: solid pattern
14	USC: glandular pattern
15	USC: glandular pattern
16	USC: fibrous stroma
17	USC: hobnail cells
18	USC: IHC Ki67 p53
19	Serous Ca: surrounding Em Atrophic hyperplasia only in 10 %, often without atypia EIC
20	USC: endometrial intraepithelial carcinoma
21	USC: neoplastic glands and atrophic glands
22	Serous Ca: DD Papillary pattern: Villoglandular Ca Solid or glandular zones: endometrioid Ca Primary ovarian Ca: even with only EIC primary USC è bilateral, small nodules
23	Glandular USC/endometrioid Ca USC nuclei grade 3 Hobnail cells Unregular luminal border Discohesive cells in lumen Ki67 ++, p53 ++ Endometrioid nuclei often grade 1-2 rather regular luminal border Cells are more cohesive ER +, Vim +
24	WHO-classification of EM-Ca Endometrioid adenoCa Mucinous Ca Serous Ca Clear cell Ca Undifferentiated Ca Mixed cell adenoCa Squamous cell Ca Transitional cell Ca Small cell Ca Others
25	Clear cell carcinoma Type II carcinoma
26	Clear cell carcinoma: architecture Solid: clear or eosinophilic cells papillary: hobnail cells tubular cystic Stroma : dens fibrotic
27	Clear cell ca: cytology large polygonal cells with clear cytoplasm Severe atypia: nuclear grade 3 Central nuclei glycogen in cytoplasm PAS+, disappears after diastasis hyalin bodies: intra- and extracellular PAS+, diastasis resistent
28	Clear cell Ca: solid
29	Clear cell Ca: papillary pattern with hobnail cells
30	Clear cell Ca: cytology
31	Clear cell Ca: PAS D
32	Clear cell Ca + EIC
33	Clear cell Ca
34	Clear Cell Ca: DD Secretory Ca USC stroma, cytology Eosinophilic globules Yolk sac tumour: younger patients, aFP, Schiller-Duval
35	WHO-classification of EM-Ca Endometrioid adenoCa Mucinous Ca Serous Ca Clear cell Ca Undifferentiated Ca Mixed cell adenoCa Squamous cell Ca Transitional cell Ca Small cell Ca Others
36	Undifferentiated carcinoma Rare (1-2 % ?) Underrecognition Lack of diagnostic criteria
37	Undifferentiated carcinoma: definition WHO : “... are those lacking any evidence of differentiation” too poorly differentiated to be placed in any other category of carcinoma FIGO grade 3: > 50 % of tumour is solid è overlap
38	Undifferentiated carcinoma: proposed criteria Altrabulsi: Undifferentiated carcinoma of the endometrium Am J Surg Pathol 2005; 29: 1316-1321 No glandular differentiation FIGO grade 3 : 50 % > glandular > 1 %
39	Undifferentiated Ca
40	Endometrioid Ca grade 3
41	Undifferentiated Ca
42	Undifferentiated carcinoma: cytology Medium-sized cells Monotonous epithelial cells Solid growth No identifiable pattern (except for vague cords or trabeculae)
43
44	Undifferentiated carcinoma: IHC Keratinstains only focally + in 5 - 10 % of cells DD with grade 3: diffuse + If negative: repeat on other block Intensity of + cells is marked Neuro-endocrine markers - or minimal expressed
45	Undifferentiated Ca: keratin Keratin stain focal + Majority of cells -
46	Undifferentiated carcinoma: epidemiology 9 % of EM-Ca has a component of undifferentiated Ca 29 % pure 71 % mixed with endometrioid type
47	Undifferentiated carcinoma: DD Endometrioid Ca grade 3 High-grade sarcoma Carcinosarcoma
48	Undifferentiated carcinoma: importance Grade 3 DOD 39,4 % DOD <5y: 36,4 % 70% stage I-II Undifferentiated Ca DOD 75 % DOD <5y: 62,5 % 46 % stage I-II
49	WHO-classification of EM-Ca Endometrioid adenoCa Mucinous Ca Serous Ca Clear cell Ca Undifferentiated Ca Mixed cell adenoCa Squamous cell Ca Transitional cell Ca Small cell Ca Others
50	Mixed Ca MD Anderson: most non-endometrioid cancers have endometrioid component USC 64 % CC 62 % Undifferentiated 71 % Report each type > 10 % present
51	Carcinosarcoma WHO: “ ... admixture of malignant epithelial and mesenchymal components” Carcinomatous component Sarcomatous component MMMT
52	Carcinosarcoma: origin Conversion: carcinoma becomes in part sarcoma Collision: 2 separate tumours
53	Carcinosarcoma: monoclonality Thompson: Monoclonal origins of CS. Evidence for a divergent histogenesis AJSP 1996, 20: 277-285 Monoclonality of epithelial and mesenchymal component in 3 tumours, using 3 different methods for determining clonality
54	Carcinosarcoma: molecular pathology Wada: Molecular evidence that most but not all CS of the uterus are combination tumours Cancer Res 1997, 57: 5379-5385 Identical pattern of chromosome X inactivation Same mutations in K-ras or p53 (if present) 3/25 cases: collision tumours
55	Carcinosarcoma: genetics Fuji: Frequent genetic heterogeneity in the clonal evolution of gynecological CS and its influence on phenotypic diversity Cancer Res 2000, 60: 114-120 Shared allelic losses and retentions among multiple individual carcinomatous and sarcomatous foci within 16/17 CS
56	CS: sum of molecular data Monoclonal origin of CS with subsequent divergent differentiation Not a sarcoma !!! Metaplastic carcinoma
57	CS: epithelial component Most frequent: endometrioid with squamous differentiation
58	CS: sarcomatous component Homologous: sarcomatous component has normal counterpart in endometrium Heterologous: normal counterpart of sarcomatous component not normally present in endometrium
59	CS: homologous type ESS Leiomyosarcoma Fibrosarcoma Undifferentiated sarcoma Usually high-grade
60	CS: homologous type: LMS
61	CS: heterologous type Chondrosarcoma Rhabdomyosarcoma Osteosarcoma Liposarcoma
62	CS: heterologous type
63	CS: to the exotic ! Amant: Uterine CS with melanocytic differentiation Int J Gynecol Pathol 2001, 20: 186-190
64	CS with melanocytic differentiation
65	CS: metastasis, only sarcoma
66	Carcinosarcoma: prognosis Past: sarcomatous component was determinant Heterologous was worse Present: epithelial component is important Type II Ca is worse Sarcomatous component is not important
67	Carcinosarcoma: prognosis Prognosis is worse than for grade 3 Ca or type II Ca Other pattern of metastasis
68	Sarcomas uterus (Carcinosarcoma) Endometrial stromal sarcoma Leiomyosarcoma Others
69	Endometrial stromal sarcoma High grade = undifferentiated sarcoma Low grade
70	Endometrial stromal sarcoma Monotonous proliferation of stromal cells Infiltrative growth Young patients 30-50 y
71	ESS: cytology Bland cytology Little atypia Rare mitoses
72	ESS: cytology
73	ESS: bland cytology
74	Ki 67
75	ESS: architecture Infiltrative growth between muscle fibers Cellular zones Round arterioles and smaller vessels Typical lymphovascular permeation
76	ESS: cellular zones
77	ESS: infiltrative pattern
78	ESS: in vesselwall
79	ESS: intravascular
80	ESS: diagnosis Rarely pre-op Not well known by pathologists on hysterectomy
81	ESS F. Amant (KUL) : The diagnostic problem of ESS: report on 6 cases Gynecol Oncol 2003, 90(1): 37-43 6/15 initially missed this is 40 % !!
82	ESS: DD Endometrial stromal nodule Carcinosarcoma with few carcinomatous zones Adenomyosis with rare glands
83	Endometrial stromal nodule Very well circumscribed Some irregularities at border are allowed No intravascular tumour
84	ESN: sharp demarcation
85	ESN: minor irregularities
86	ESS: IHC CD 10 + Actin focally + Desmin - (not always) ER, PR +
87	SMA
88	"CD 10" CD 10
89	Typing of endometrial tumours: conclusion WHO Type is major prognostic factor Think of type II Ca CS is not a sarcoma ESS