Richard J. Zaino, MD Hershey Medical Center Penn State University Hershey, PA

Transcription

1 2008 ISGP Symposium Morphology and prognostic factors in endometrial adenocarcinoma Richard J. Zaino, MD Hershey Medical Center Penn State University Hershey, PA

2 Objectives 1) Review the biology of the major types of endometrial adenocarcinoma 2) Examine the application of and significance of the CAP template for endometrial cancer 3) Examine the utility and limitations of the FIGO staging scheme for endometrial cancer 4) Examine prognostic factors in endometrial carcinoma

3 CAP approved (so it must be good for us) Surgical Pathology Cancer Case Summary (Checklist) Protocol revision date: January 2005 Based on AJCC/UICC TNM, 6th edition and FIGO 2001 Annual Report ENDOMETRIUM: Hysterectomy, With or Without Other Organs or Tissues

4 MACROSCOPIC Specimen Type Hysterectomy Radical hysterectomy (includes parametria) Pelvic exenteration *Tumor Site *Specify location(s), if known: Tumor Size Greatest dimension: cm *Additional dimensions: x cm Cannot be determined (see Comment) Other Organs Present (check all that apply) None Right ovary Left ovary Right fallopian tube Left fallopian tube Urinary bladder Vagina Rectum Other(s) (specify):

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10 Significance of maximum size of endometrial adenocarcinoma Relative few studies addressing prognostic significance Mariani et al, 2001 and 2002 size > 2cm is a predictor of lymphatic failure and distant failure by univariate analysis but not by multivariate analysis

11 MICROSCOPIC Histologic Type Endometrioid adenocarcinoma, not otherwise characterized Endometrioid adenocarcinoma, secretory (variant) Endometrioid adenocarcinoma, ciliated cell (variant) Endometrioid adenocarcinoma, with squamous metaplasia Adenosquamous carcinoma Serous adenocarcinoma Clear cell adenocarcinoma Mucinous adenocarcinoma Squamous cell carcinoma Mixed carcinoma (specify types and percentages): Undifferentiated carcinoma Histologic Grade (if applicable) (Grading system below applies primarily to endometrioid carcinoma) Not applicable GX: Cannot be assessed G1: 5% or less nonsquamous solid growth G2: 6% to 50% nonsquamous solid growth G3: More than 50% nonsquamous solid growth

12 Pathologic classification of endometrial adenocarcinomas adenocarcinoma endometrioid adenoacanthoma endometrioid w squamous diff adenosquamous villoglandular clear cell secretory mucinous serous (UPSC) clear cell mixed

13 Endometrioid adenocarcinoma

14 Smooth luminal border

15 Estrogen receptor

16 Villoglandular adenocarcinoma

17 Secretory adenocarcinoma

18 Adenocarcinoma with squamous differentiation

19 Mucinous adenocarcinoma

20 Papillary serous carcinoma (UPSC)

21 Clear cell adenocarcinoma

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23 Carcinoma with clear cells

24 Carcinoma with clear cells

25 Two types of endometrial adenocarcinoma (Bokhman, 1981) Type I Type II With hyperplasia No hyperplasia (EIN) (EIC) Hyperestrinism No hyperestrinism Endometrioid Serous/CC Well differentiated Poorly differentiated Steroid receptor + Steroid receptor /+ Good prognosis Poor prognosis PTEN null/msi p53 overexpression

26 uterine papillary serous carcinoma papillae

27 Scalloped luminal border

28 Gaping glands

29 Frayed or scalloped luminal border

30 polyp Serous carcinoma

31 p53

32 MIB1

33 ER

34 Survival in endometrial adenocarcinoma (all stages) Tumor type 5 yr survival Endometrioid 80 90% UPSC 10 30%

35 UPSC patterns of spread Author Carcangiu Mallipeddi Lee Gitsch Carcangiu Cirisano Wheeler Goff Sherman Geisler sites of disease intrabdominal/small bowel nodes, bowel, omentum, cyto ovaries, nodes, peritoneum cyto, nodes, omentum, liver, dia adnexa, peritoneum, omentum, nodes nodes, ovaries, peritoneum, omentum ovary, omentum, bowel ovary, nodes, omentum, peritoneum nodes, cyto, ovary, omentum omentum, cyto, peritoneum, nodes

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39 MICROSCOPIC Histologic Type Endometrioid adenocarcinoma, not otherwise characterized Endometrioid adenocarcinoma, secretory (variant) Endometrioid adenocarcinoma, ciliated cell (variant) Endometrioid adenocarcinoma, with squamous metaplasia Adenosquamous carcinoma Serous adenocarcinoma Clear cell adenocarcinoma Mucinous adenocarcinoma Squamous cell carcinoma Mixed carcinoma (specify types and percentages): Undifferentiated carcinoma Histologic Grade (if applicable) (Grading system below applies primarily to endometrioid carcinoma) Not applicable GX: Cannot be assessed G1: 5% or less nonsquamous solid growth G2: 6% to 50% nonsquamous solid growth G3: More than 50% nonsquamous solid growth

40 Grade 1

41 Grade 1

42 Grade 2

43 Grade 2

44 Grade 3

45 Grade 3

46 Grade 1 (architecture)

47 Grade 3 (nuclei) Overall grade 2

48 Grade 3 nuclei Overall grade 2

49 Stage I adenocarcinoma of the endometrium (FIGO 2003) Grade 5 year survival 1 92% 2 88% 3 75%

50 Grading endometrial adenocarcinoma Two grades versus three FIGO 3 grades, architecture +/- nuclear GOG 3 grades, architecture Hachisuga -3 grades, nuclear (quantitative) Taylor et al 2 grades, architecture (10% solid) Scholten 2 grades, architecture (50% solid) Lax 2 grades, architecture (solid, pattern, necrosis) Alkushi 2 grades, architecture and nuclear Each prognosticates well

51 Reproducibility of grading Inter-observer kappa 2 grade 3 grade Alkushi (arch+nuclear) Nielsen (arch) 0.70 Nielsen (nuclear) 0.55 Zaino (arch) 0.49 Zaino (nuclear) 0.57 Taylor (arch) Lax (arch) Scholten (arch, using Lax)

52 Lymphatic invasion

53 lymphatic invasion

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55 vascular pseudo-invasion

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57 Pathologic Staging (ptnm [FIGO]) Primary Tumor (pt) ptx [--]: Primary tumor cannot be assessed pt0 [--]: No evidence of primary tumor ptis [0]: Carcinoma in situ pt1 [I]: Tumor confined to corpus uteri pt1a [IA]: Tumor limited to endometrium pt1b [IB]: Tumor invades less than one-half of the myometrium pt1c [IC]: Tumor invades one-half or more of the myometrium pt2 [II]: Tumor invades cervix, but does not extend beyond uterus pt2a [IIA]: Tumor limited to the glandular epithelium of the endocervix. There is no evidence of connective tissue stromal invasion. pt2b [IIB]: Invasion of the stromal connective tissue of the cervix pt3 [III]: Local and/or regional spread as specified in T3a, T3b, N1, and FIGO IIIA, IIIB, and IIIC pt3a [IIIA]: Tumor involves serosa, parametria, and/or adnexa (direct extension or metastasis) * pt3a [IIIA]: Tumor involves serosa and/or adnexa (direct extension or metastasis) and/or cancer cells in ascites or peritoneal washings pt3b [IIIB]: Involvement of vagina (direct extension or metastasis), rectal or bladder wall (without mucosal involvement), or pelvic wall(s) (frozen pelvis) pt4 [IVA]: Tumor invades bladder mucosa and/or bowel mucosa Regional Lymph Nodes (pn) pnx: Cannot be assessed pn0: No regional lymph node metastasis pn1 [IIIC]: Regional lymph node metastasis Specify: Number examined: Number involved: Distant Metastasis (pm) pmx: Cannot be assessed pm1 [IVB]: Distant metastasis

58 Pathologic Staging (ptnm [FIGO]) Primary Tumor (pt) ptx [--]: Primary tumor cannot be assessed pt0 [--]: No evidence of primary tumor ptis [0]: Carcinoma in situ pt1 [I]: Tumor confined to corpus uteri pt1a [IA]: Tumor limited to endometrium pt1b [IB]: Tumor invades less than one-half of the myometrium pt1c [IC]: Tumor invades one-half or more of the myometrium pt2 [II]: Tumor invades cervix, but does not extend beyond uterus pt2a [IIA]: Tumor limited to the glandular epithelium of the endocervix. There is no evidence of connective tissue stromal invasion. pt2b [IIB]: Invasion of the stromal connective tissue of the cervix pt3 [III]: Local and/or regional spread as specified in T3a, T3b, N1, and FIGO IIIA, IIIB, and IIIC pt3a [IIIA]: Tumor involves serosa, parametria, and/or adnexa (direct extension or metastasis) * pt3a [IIIA]: Tumor involves serosa and/or adnexa (direct extension or metastasis) and/or cancer cells in ascites or peritoneal washings pt3b [IIIB]: Involvement of vagina (direct extension or metastasis), rectal or bladder wall (without mucosal involvement), or pelvic wall(s) (frozen pelvis) pt4 [IVA]: Tumor invades bladder mucosa and/or bowel mucosa Regional Lymph Nodes (pn) pnx: Cannot be assessed pn0: No regional lymph node metastasis pn1 [IIIC]: Regional lymph node metastasis Specify: Number examined: Number involved:

59 Stage I Corpus Cancer 1) Is the distinction of non-invasive from inner half invasion reliable? 2) Should invasion be assessed in thirds or halves of myometrial thickness?

60 Superficial myometrial invasion

61 endometrium myometrium

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63 Superficial myometrial invasion

64 Stage I Corpus Cancer significance of invasion Stage 5 year survival rates (FIGO, 2003) IA 92% inability to distinguish inter- IB 91% digitations from myo invasion IC 81% either outer third or outer half invasion highly significant (insufficient data to distinguish which is superior)

66 Stage II Corpus Cancer Significance of true surgical pathologic staging: a GOG study (Creasman et al, 1999) 148/1180 with clinical stage II (+ECC) 66/148 with disease in the cervix 31/66 with extrauterine disease 35 (24%) with surgical stage II Recurrence rates at 5 years: IIA 18% IIB 21%

67 Stage II Corpus Cancer 5 year survival - 75%, lower than Stage I (FIGO results, 2003) More often associated with higher grade, deep myometrial invasion, and lymphatic invasion than Stage I Insufficient data to determine whether Stage II is a significant prognosticator by multivariate analysis (probably not)

68 IIA IIB Stage II Corpus Cancer endocervical gland involvement cervical stromal invasion Definitions applied in various publications: IIA - surface epithelium only (Jordan) IIA gland involvement only (Fanning, Eltabbakh, Prat) IIA confined to endocervical epithelium (mucosa) (Clement and Young) -but endocervix lacks a mucosa diagnostic reproducibility probably low (never tested) how does it involve glands only?

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72 Pathologic Staging (ptnm [FIGO]) Primary Tumor (pt) ptx [--]: Primary tumor cannot be assessed pt0 [--]: No evidence of primary tumor ptis [0]: Carcinoma in situ pt1 [I]: Tumor confined to corpus uteri pt1a [IA]: Tumor limited to endometrium pt1b [IB]: Tumor invades less than one-half of the myometrium pt1c [IC]: Tumor invades one-half or more of the myometrium pt2 [II]: Tumor invades cervix, but does not extend beyond uterus pt2a [IIA]: Tumor limited to the glandular epithelium of the endocervix. There is no evidence of connective tissue stromal invasion. pt2b [IIB]: Invasion of the stromal connective tissue of the cervix pt3 [III]: Local and/or regional spread as specified in T3a, T3b, N1, and FIGO IIIA, IIIB, and IIIC pt3a [IIIA]: Tumor involves serosa, parametria, and/or adnexa (direct extension or metastasis) * pt3a [IIIA]: Tumor involves serosa and/or adnexa (direct extension or metastasis) and/or cancer cells in ascites or peritoneal washings pt3b [IIIB]: Involvement of vagina (direct extension or metastasis), rectal or bladder wall (without mucosal involvement), or pelvic wall(s) (frozen pelvis) pt4 [IVA]: Tumor invades bladder mucosa and/or bowel mucosa Regional Lymph Nodes (pn) pnx: Cannot be assessed pn0: No regional lymph node metastasis pn1 [IIIC]: Regional lymph node metastasis

73 Stage III Corpus Cancer: Are all forms of Stage IIIA disease equivalent? Positive peritoneal cytology Direct invasion to uterine serosa Adnexal spread or metastases

74 Stage IIIA Corpus Cancer + peritoneal cytology Milosevic et al, 1992, pooling of literature 17 studies, 3800 patients; incidence 11% Often associated with adnexal or nodal spread, high grade, deep invasion Univariate analysis increased risk of recurrence in most studies Multivariate analysis (5 studies) decreased survival in 3/5 + cyto as an isolated poor prognostic factor is rare

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76 Stage IIIA Corpus Cancer + adnexal involvement (Connell et al, 1999) 5 year DFS 37% overall Often associated with higher grade, lymphatic invasion, other extrauterine disease 5 year DFS - 71% without other extrauterine spread

77 Stage IIIA Corpus Cancer + serosal involvement (SI) (Ashman et al, 2001) 5 year DFS 29% 5 year DFS 20%, SI + other extrauterine sites 5 year DFS 42%, SI only

78 Are all forms of Stage IIIA disease equivalent? 5 year recurrence free survival (Mariani et al, 2002) + cytology only 79% + adnexa/uterine serosa 57% (p = 0.04) (Tebeu et al, 2004) + cytology only 91% + adnexa/uterine serosa 50%

79 Stage III Corpus Cancer Stage IIIB vaginal metastases Very rare, (less than 1% of corpus cancer and about 2% of stage III pts) Vaginal mets often associated with nodal or distant metastases Prognosis poor 5 year survival about 25%

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82 Stage III Corpus Cancer Stage III C pelvic/paraaortic nodal mets (Mariani et al, 2002) Stage IIIC often are also Stage IIIA/IIIB 5 year DFS 33% Stage IIIC with IIIA/B mostly extranodal failures 5 year DFS 68% Stage IIIC without IIIA/B mostly nodal failures

83 Stage III Corpus Cancer Stage III C pelvic/paraaortic nodal mets 5 year DFS about 65-80% + pelvic node 5 year DFS about 30% + paraaortic node Significant survival differences between microscopic and grossly positive nodes, resected vs non-resected disease, radiated vs non-irradiated nodal beds, and capsular invasion and desmoplasia

84 Tentative staging conclusions Stage IA cannot reliably be distinguished from Stage IB pathologically in many cases Stage IIA and IIB are poorly defined pathologically and may not differ prognostically Stage II is probably not prognostically significant Stage III disease is very heterogeneous Stage IIIA alone is heterogeneous + cytology alone is rare and probably significant but with small effect (85%) + adnexa is more significant (70%) + uterine serosa carries a poor prognosis (30%)

85 Tentative staging conclusions Stage IIIB (vaginal mets) very rare, poor prognosis (25%) Stage IIIC + pelvic nodes significant (70%) + paraaortic nodes significantly worse (30%) grossly positive nodes; capsular invasion and desmoplasia; other extrauterine sites associated with a much worse outcome (Stage IIIC limited to nodes usually fails in nodal area)

86 Surgical Staging of Corpus Cancer (EGO, 2008) Stage IA G123 IB G123 IIA IIB IIIA1 IIIA2 IIIB1 IIIB2 IVA IVB Characteristics invasion to endometrium/inner half of myometrium invasion to outer half of myometrium positive peritoneal cytology uterine serosa, adnexal or other pelvic spread pelvic nodal metastasis (micro) pelvic nodal metastasis (gross) paraaortic nodal metastasis (micro) paraortic nodal metastasis (gross) vaginal metastases, invasion of bladder or bowel mucosa distant, intraabdominal or inguinal node metastases

87 Additional prognostic factors Flow cytometry Steroid receptors Markers of apoptosis (BCL-2) Markers of proliferation Tumor suppressor genes and oncogenes Markers of angiogenesis

88 Demonstrated utility FIGO stage Histologic grade Cell type Depth of myometrial invasion Lymphatic invasion Tumor ploidy p53

89 Potential utility Steroid receptors BCL-2 MIB1 Her2/neu Microvessel density

90 Unlikely utility PCNA S-phase fraction AgNOR count

91 Objectives 1) Review the biology of the two major types of endometrial adenocarcinoma 2) Examine the application of and significance of the CAP template for endometrial cancer 3) Examine the utility and limitations of the FIGO staging scheme for endometrial cancer 4) Examine prognostic factors in endometrial carcinoma