McKenney, Jesse K. MD; Balzer, Bonnie L. MD, PhD; Longacre, Teri A. MD

1. Lymph Node Involvement in Ovarian Serous Tumors of Low Malignant Potential (Borderline Tumors)pathology, prognosis, and proposed classification McKenney, Jesse K. MD; Balzer, Bonnie L. MD, PhD; Longacre, Teri A. MD American Journal of Surgical Pathology. 30(5):614-624, May 2006 Intern:簡世杰

2. Serous borderline Tumours(SBT) • Histological criteria for the diagnosis of serous borderline tumours.(WHO) • Epithelial hyperplasia in the form of stratification , tufting, cribriform and micropapilary arrangements • Atypia (usually mild to moderate) • Detached cell clusters • Variable and usually minimal mitotic activity • Absence of destructive stromal invasion

3. Introduction • Ovarian serous tumors of low malignant potential (S-LMP) may be associated with lymph node involvement (LNI) in 21% to 29% of patients who undergo a formal lymph node sampling at the initial staging surgery Gynecol Oncol. 1991;42:124-130 Am J Surg Pathol. 2005;29:707-723

4. Purpose • Evaluate the specific histologic patterns of nodal involvement • Criteria for classifying LNI into prognostic groups(Although criteria have been proposed for invasive and noninvasive implants in the peritoneum and outcome data have been linked to these subtypes.) • nodal involvement by S-LMP may in some cases arise independent of the ovarian tumor via neoplastic transformation from preexisting endosalpingiosis. Am J Surg Pathol. 2000 the definition and the relative prognostic and therapeutic implications?

5. Materials and Methods • Database：Stanford University Medical Center Division of Surgical Pathology or the Stanford Pathology Consultation Service from the years 1958 to 1998 • Patient Numbers：approximately 540 S-LMP . 74 patients who underwent a surgical staging procedure that included retrieval of lymph node. • Classification：according to the current World Health Organization criteria into two types: typical S-LMP (serous borderline tumor) and S-LMP with micropapillary features (serous borderline tumor with micropapillary features). Lyon, France: IARCPress; 2003

6. Materials and Methods • Stage：the International Federation of Gynecology and Obstetrics system • Statistical analysis：Fisher exact test • Significance leve was set at P<0.05 • All tumors with micropapillary or cribriform features were classified on the basis of the modified Burks criteria • The presence of stromal microinvasion was determined using the criteria of Bell and Scully • Ovarian autoimplants were not classified as stromal invasion. • Extra-ovarian epithelial implants were classified as invasive, noninvasive, or indeterminate

7. Materials and Methods • Lymph nodes were classified as positive or negative based on the presence or absence of involvement by S-LMP • The positive lymph nodes were further evaluated for the following features: • Architectural pattern and degree of cytologic atypia • Mitotic figures • Presence of tumor in sinuses or parenchyma • Greatest linear dimension of epithelial aggregates without intervening lymphoid tissue (nodular aggregate) • Number of foci involved in an individual lymph node • Stroma reaction • Extranodal extension

8. Materials and Methods • Four morphologic patterns were identified: • Individual cells, cell clusters, and simple papillae • Intraglandular aggregates • Cell with prominent cytoplasmic eosinophilia(“eosinophilic cells”) • Micropapillary (criteria provided by Bell et al)

9. Materials and Methods • disease status was defined as follows • Dead of disease(DOD)：patient died as a result of persistent, progressive, or recurrent serous disease • Alive with disease (AWD)：patient alive with clinical and/or radiographic evidence of persistent, progressive, or recurrent serous disease at last follow-up visit • Dead of intercurrent disease (DID), patient died of an unrelated cause with no clinical or radiographic evidence of persistent, progressive or recurrent serous disease • No evidence of disease (NED)：no clinical or radiographic evidence of persistent, progressive, or recurrent serous disease at last follow-up visit

10. Result no LNI or endo-salpingiosis only No significant different between 2 groups

11. Follow-up Status for S-LMP Patients With and Without Lymph Node Involvement (LNI)

12. Result Follow- up • An additional 10 patients developed recurrent disease (5 with LNI and 5 without LNI) with an interval from initial surgery to recurrence ranging from 7 to 158 months (mean, 49 months; median, 35.5 months). • Five of the patients with recurrent disease were alive with disease at last follow-up. • One patient with stage IV disease and axillary lymph node involvement had persistent, but otherwise stable, disease at 11 months of follow-up.

13. Result • Anatomic site of lymph node(total=31) • in pelvic (18; 58%) • mesenteric/omental (9; 29%) • paraaortic (8; 26%) • supradiaphragmatic (2; 6%) • There was no correlation between anatomic site of involvement and overall or disease-free survival.

14. Cytologic & Histologic Patterns • Cytologic patterns • Mild cytologic atypiamost cases • Moderate cytologic atypia9 cases • Mitotic figures7 cases(4/7 combined with moderate atypia) • Individual cells, clusters of cells, and simple papillae individual cells, clusters of cells, and simple papillae (28 of 31; 90%) • intraglandular pattern (21 of 31; 68%) • prominent cytoplasmic eosinophilia (16 of 31; 52%) • micropapillary architecture (5 of 31; 16%).

15. Individual cells, clusters of cells, and simple papillae

17. Individual Cells, Clusters of Cells, and Simple Papillae • The most common pattern of LNI by S-LMP(28/31) • 5 of these patients had stromal microinvasion and 4 had micropapillary architecture in the primary ovarian tumor. • 16 patients with this pattern of LNI had noninvasive peritoneal implants, whereas 6 had invasive implants and 2 had implants that were indeterminate for invasion. • Follow-up information : 2 DOD at 8 and 74 months, 3 AWD (11, 61, and 230 months), 15 NED, and 8 with no available follow-up data • Disease-free survival versus LNI without this pattern ：75% and 50%, respectively (P=0.42).

18. Intraglandular pattern

20. Intraglandular Pattern • 21/31 • 3 cases consisted entirely of the intraglandular pattern, one of which formed nodular aggregates with associated stromal reaction. • 3 patients with intraglandular LNI had stromal microinvasion in the primary ovarian tumor and 3 had micropapillary architecture. • All patients with intraglandular LNI had intraperitoneal implants (3 invasive and 18 noninvasive). • Follow-up information ：11 NED and 3 AWD at 11, 38, and 230 months • Disease-free survival versus LNI without this pattern ：79% and 71% respectively

21. Prominent Cytoplasmic Eosinophilia

23. Prominent Cytoplasmic Eosinophilia • 16/31 • 3 patients had lymph nodes diffusely infiltrated by eosinophilic cells with a sinus and parenchymal distribution, one with nodular aggregates. • 5 patients with LNI featuring eosinophilic cells had stromal microinvasion in the primary ovarian tumor • 11 patients with eosinophilic cell LNI had peritoneal implants. 2 had invasive peritoneal implants (no significance) • Follow-up information ：6 NED ;2 NED following recurrence at 12 and 74 months, 1 AWD at 11 months, and 1 DOD. • Disease-free survival versus LNI without this pattern ： No significant difference

24. Micropapillary Architecture

26. Micropapillary Architecture • 5/31 • The number of nodes involved：2 to 11 (mean, 4.6), others :mean of 2.1 (range, 1–12) • 3 of the 5 (60%) lymph nodes with micropapillary architecture also had an associated stromal reaction, compared with 2 of 26 (8%) without micropapillary architecture (P=0.02). • 4 of the 5 (80%) micropapillary cases had nodular aggregates (size from 2 to 8 mm), whereas only 2 of the 26 (8%) nonmicropapillary cases formed a nodular aggregate (1 mm in size) (P<0.001). • 3 (60%) were associated with endosalpingiosis, compared with 16 of 26 (62%) nonmicropapillary cases.

27. Micropapillary Architecture • All 5 patients with micropapillary LNI had peritoneal implants. (2/5 invasive) • Follow-up information：2 AWD ,1 NED at 87 months following an abdominal wall recurrence at 74 months, and 1 was NED with no evidence of recurrent disease at 77 months, 1 LFU • Disease-free survival versus LNI without this pattern ：50% vs. 82%not reach statistical significance (P=0.22).

28. Stromal Response

30. Stromal Response in Lymph Node Involvement • 5/31 (16%) cases with LNI had an associated stromal reaction. • Each of the 5 cases with intranodal stromal reaction had nodular aggregates (P=0.0001) • 3 had micropapillary architecture (P=0.02), and 1 had a diffuse “eosinophilic cell” pattern • Follow-up information：2 AWD, and 1 NED, 3 LFU • Disease-free survival versus LNI without this pattern ：33% versus 68%(not significant?)

31. Extent and Location of Lymph Node Involvement • Disease-free survival for patients with only one involved node versus patients with greater than one involved node was 73% and 80%, respectively. (one vs many) • There was no significant difference in overall survival or disease-free survival in patients with diffuse LNI versus patients without diffuse LNI. • Disease-free survival for LNI with parenchymal involvement compared with no parenchymal involvement was 69% and 77%, respectively (P=0.61).

32. Nodular aggregate

34. Extent and Location of Lymph Node Involvement • Nodular aggregate：was defined as a collection of epithelium without intervening lymphoid tissue measuring greater than 1 mm in linear dimension Ps:diffuse LNI was characterized by epithelial cells of any morphologic pattern scattered throughout the lymph node (ie, not focal), but with intervening lymphoid tissue. • Nodular aggregates were strongly associated with desmoplastic fibrous stromal reaction (P=0.001) and micropapillary architecture (P=0.02). • Disease-free survival versus LNI without this pattern ：25% versus 87% (P=0.02)significience

35. Endosalpingiosis

37. Association of Lymph Node Involvement With Endosalpingiosis • 18/31(58%) versus 15/43(35%) (P=0.06) • 4 mild cytologic atypia；1 moderate cytologic atypia • no significant difference in overall survival for patients with and without LNI • there was a trend for improved survival among patients with endosalpingiosis only (93%) compared with patients with LNI and endosalpingiosis (85%) and patients with LNI but no associated endosalpingiosis (56%).

38. YOKOHAMA COSMO WORLD

39. Disscussion • lymph node status does not appear to be an independent prognostic factor for patient survival in patients with S-LMP. • the presence of nodular aggregates is associated with a statistically significant adverse prognosis independent of histologic pattern. • The relatively high incidence of LNI in this study (42%) ? • LNI was commonly associated with peritoneal implants (87% of cases): (Leake et al) • LNI was also associated with a higher incidence of disease recurrence ?not meet statistical significance.

40. Histologic Patterns of S-LMP Lymph Node Involvement • admixture of individual epithelial cells, clusters of l cells, and simple papillae frequently coexisted with an intraglandular pattern • Distinguished from LNI by metastatic low grade carcinoma • Comparaticely low volume of epithelium • Minimal to at most moderate cytologic atypia • Rare mitotic figures

41. Histologic Patterns of S-LMP Lymph Node Involvement • Primary ovarian S-LMP with micropapillary epithelial overgrowth are more often bilateral, exophytic, and associated with extraovarian implants than S-LMP without this appearance • micropapillary architecture was strongly associated withdisease progression over time and decreased overall survival on univariate analysis. Longacre et al • the micropapillary pattern was more frequently associated with several other histologic features Ex: stromal reaction (60% vs. 12%), diffuse nodal involvement (60% vs. 38%), nodular aggregates (33% vs. 12%), and extranodal extension (20% vs. 0%).

42. Histologic Patterns of S-LMP Lymph Node Involvement • This eosinophilic cell pattern of LNI was associated with stromal microinvasion in the primary ovarian tumor in almost one third of the cases in this series. • the association between eosinophilic cell LNI and adverse outcome is not statistically significant • Differential diagnosis：intranodal hyperplastic mesothelial cells Immunohistochemistery：BER-EP4；calretinin P.S. S-LMP is characterized by cytoplasmic reactivity with Ber-EP4 but no nuclear calretinin expression

43. Nodular Aggregates of LNI Are Associated With Adverse Prognosis, Regardless of Histologic Pattern • nodular aggregates of epithelium greater than 1 mm, without intervening lymphoid tissue ,predicted a statistically significant ： • decreased disease-free survival • strongly associated with micropapillary architecture and nodal stromal reaction • invasive peritoneal implants in 3 of 6 casesshould probably be classified separately from other patterns of LNI ? • Nodular aggregates did not occur in association with any specific lymph node group in this study

44. Nodular Aggregates of LNI Are Associated With Adverse Prognosis, Regardless of Histologic Pattern • In our experience, the presence of nodular aggregates is more commonly encountered in recurrent disease and delayed lymph node involvement than at initial presentation • Nodular Aggregates should be regarded as a high-risk lesion ? transformation to low-grade serous carcinoma ?

45. At Least Some S-LMP May Arise Primarily in Foci of Endosalpingiosis • identical K-ras mutations in S-LMP and adjacent benign müllerian inclusions. (Alvarez et al) • support the concept that S-LMP may arise in endosalpingiosis in at least a subset of cases. • a trend for decreased survival among patients without associated endosalpingiosis (not meet statistical significance) • endosalpingiosis only (93%) • LNI and endosalpingiosis (85%) • LNI but no associated endosalpingiosis (56%).

46. Conclusion • no single histologic pattern of LNI is entirely predictive of adverse outcome • nodular aggregates of S-LMP is associated with decreased disease-free survival independent of implant type. • nodular aggregates more common in cases with a micropapillary pattern and an associated stromal reaction in the intranodal tumor. • This high-risk pattern of LNI may be analogous to invasive peritoneal implants in terms of prognostic significance and deserves independent assessment in future studies of S-LMP.

47. Thanks your attention