Borderline tumors. Borderline tumors. Serous borderline tumor are NOT benign. Low grade serous carcinoma: pathogenesis. Serous carcinoma: pathogenesis

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1 Serous borderline tumor are NOT benign Robert A. Soslow, MD Memorial Sloan-Kettering Cancer Center Borderline tumors Serous BTs and seromucinous BTs are both histopathologically borderline and clinically borderline. Borderline tumors Serous BTs and seromucinous BTs are both histopathologically borderline and clinically borderline. Intestinal mucinous, endometrioid and transitional BTs are only histopathologically borderline ; they are not clinically borderline. They are instead clinically benign. Serous carcinoma: pathogenesis Familial Inclusion cyst BRCA-1 mutation Dysplasia BRCA-1 LOH Sporadic BRAF KRAS Surface Epithelium Borderline tumor (BT) Low grade serous carcinoma: pathogenesis TP53 mutation TP53 mutation Micropapillary BT High grade carcinoma Low grade carcinoma 1

2 Prognosis Confirmed Stage Success of debulking Implant invasion Prognosis Confirmed Stage Success of debulking Implant invasion Probable (considered confirmed by many) Architecture i.e. micropapillary/cribriform Microinvasion Prognosis Confirmed Stage Success of debulking Implant invasion Probable (considered confirmed by many) Architecture i.e. micropapillarity Microinvasion Not Lymph node involvement Significance of micropapillary (MP) architecture in a non-invasive ovarian tumor Established: MP tumors are more frequently associated with invasive implants (~20%) MP tumors are more frequently bilateral (70% vs 20%) MP tumors more frequently involve the ovarian surface (60% vs 30%) MP tumors are more aggressive because of their association with invasive implants Significance of micropapillary (MP) architecture in a non-invasive ovarian tumor Established: MP tumors are more frequently associated with invasive implants MP tumors are more frequently bilateral (70% vs 20%) MP tumors more frequently involve the ovarian surface (60% vs 30%) MP tumors are more aggressive because of their association with invasive implants Probable: MP tumors present at higher stage MP tumors recur more frequently Significance of micropapillary (MP) architecture in a non-invasive ovarian tumor Does this justify classification as carcinoma? 2

3 Significance of micropapillary (MP) architecture in a non-invasive ovarian tumor Does this justify classification as carcinoma? I think it does! Noninvasive MP tumors are like low grade DCIS Invasive MP tumors are low grade invasive carcinomas Significance of MP architecture in an ovarian tumor Analogy: MP tumors are akin to low grade carcinomas in situ. 1) If they re non-invasive and organ confined, they behave like other low grade, non-invasive tumors. Significance of MP architecture in an ovarian tumor Analogy: MP tumors are akin to low grade carcinomas in situ. 1) If they re non-invasive, they behave like other low grade, non-invasive tumors. 2) If they re invasive (anywhere), they behave like low grade carcinoma. Significance of MP architecture in an ovarian tumor Analogy: MP tumors are akin to low grade carcinomas in situ. 1) If they re non-invasive, they behave like other low grade, non-invasive tumors. 2) If they re invasive (anywhere), they behave like carcinoma. 3) If they re incompletely excised, they can progress to carcinoma and/or might be associated with occult invasion. Significance of MP architecture in an ovarian tumor Analogy: MP tumors are akin to low grade carcinomas in situ. Serous borderline tumor 1) If they re non-invasive, they behave like other low grade, non-invasive tumors. 2) If they re invasive (anywhere), they behave like carcinoma. 3) If they re incompletely excised, they can progress to carcinoma. 4) If you don t know whether they re invasive, you must investigate further. Benign (non-mp) Cancer (SBT-MP) 3

4 Serous borderline tumor Benign Cancer Just because Dr Kurman has provided (compelling) evidence that some borderline tumors (SBT-MP) are carcinomas, does NOT mean that all of the remaining tumors are benign Borderline Significance of MP architecture in a non-invasive ovarian tumor If SBT-MP tumors are carcinomas, are there non-mp tumors that behave like carcinomas?? Significance of MP architecture in a non-invasive ovarian tumor Are there non-mp tumors that invade, metastasize and kill patients? YES Serous borderline (non-mp) tumors are not all benign Unfavorable outcomes are associated with non-mp SBTs Unresected non-invasive implants may progress to invasive low grade serous carcinoma or be associated with occult invasive foci Unfavorable outcomes are associated with non-mp SBTs Non-invasive implants may progress to invasive low grade serous carcinoma 4

5 1/5 non-mp tumors with follow-up was associated with invasive implants and death 17% non-mp tumors were associated with invasive implants vs 8% SBT-MP Eichhorn JH, Bell DA, Young RH, Scully RE. Am J Surg Pathol Apr;23(4): Prat J, de Nictolis M. Am J Surg Pathol Sep;26(9): /13 patients who died of disease had noninvasive implants and non-mp tumors at presentation 74% of patients suffering recurrence had non-mp tumors and 83% of patients with recurrence developed serous carcinoma Deavers MT, Gershenson DM, Tortolero-Luna G, Malpica A, Lu KH, Silva EG. Am J Surg Pathol Sep;26(9): Silva EG, Gershenson DM, Malpica A, Deavers M. Am J Surg Pathol Nov;30(11): /12 patients who died with 5-year follow up had non-mp tumors BUT: only 2/12 lacking both MP and microinvasion (MI) died Longacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR. Am J Surg Pathol Jun;29(6): /12 patients who died with 5- year follow up had non-sbt tumors BUT: only 2/12 lacking both MP and microinvasion (MI) died MP and MI together might be stronger predictors of carcinoma than either alone Longacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR. Am J Surg Pathol Jun;29(6):

6 Non-MP Many unfavorable outcomes are associated with non-mp tumors Caveat: extensive sectioning of many, but not all SBTs associated with invasive implants reveal invasive foci (upgraded 3/8) 5/8 tumors had neither MP nor MI on extensive sectioning (> 1 section per cm) Longacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR. Am J Surg Pathol Jun;29(6): Seidman JD, et al. Mod Pathol 22; 236A (abstract 1078), 2009 Unfavorable outcomes are associated with non-mp SBTs Unresected non-invasive implants may progress to invasive low grade serous carcinoma or be associated with occult invasive foci 13/17 patients who died of disease and had serous carcinoma at recurrence had noninvasive implants at presentation 6/13 had non-mp tumors Deavers MT, Gershenson DM, Tortolero-Luna G, Malpica A, Lu KH, Silva EG. Am J Surg Pathol Sep;26(9): Serous borderline tumor: 5/10 yr follow up Serous borderline tumors: 10/20 yr follow up SBT 70% Stage I 30% >Stage I 90-95% Non-Inv 5-10% Inv 70% No Rec 30% Recur 70% Inv** 30% Non-Inv SBT 70% Stage I 30% >Stage I 90-95% Non-Inv 5-10% Inv 56% No Rec 44% Recur 83% Inv** 17% Non-Inv ** ~50% of patients died Gershenson DM, Silva EG. Cancer 1990;65: **75% of patients died Silva EG, et al. Am J Surg Pathol 2006;30:

7 Serous borderline tumors: 10/20 yr follow up Invasive implant study 61 cases diagnosed as SBT with invasive implants from 6 institutions Histologic consensus Clinical outcomes Minimum follow up: 48 months Recurrence Survival Silva EG, Vang R, Kurman R, Soslow R, Prat J, Longacre T. Mod Pathol 19; 197A, 2006 (abstract 914) Silva EG, Gershenson DM, Malpica A, Deavers M. Am J Surg Pathol Nov;30(11): Consensus review Invasive implants (n=49) 60% DOD 29 DOD, 7 AWD, 13 NED Mean time to death: 94 m Median: 63 m MSKCC review Invasive implants (n=29) 62% DOD 18 DOD, 4 AWD, 7 NED Mean time to death: 69 m Median: 61 m Invasive implant study What does this mean? Some noninvasive implants remain histologically stable, but progress clinically Indeterminate implants (n=17) 50% DOD 7 DOD, 4 AWD, 3 NED Mean time to death: 161 m Median: 130 m Invasive implant study What does this mean? Some noninvasive implants remain histologically stable, but progress clinically Some noninvasive implants remain histologically stable, but death results from intestinal obstruction or overzealous therapy Invasive implant study What does this mean? Some noninvasive implants remain histologically stable, but progress clinically Some noninvasive implants remain histologically stable, but death results from obstruction or overzealous therapy Some noninvasive implants progress histologically and clinically over extended periods of time 7

8 2/14/2011 Ovary-confined SBT without surface involvement, regardless of MP: BENIGN Ovary-confined SBT with surface involvement: BENIGN, with recurring potential Intestinal mucinous, endometrioid and Brenner BT: BENIGN SBT-MP, unstaged: UNCERTAIN MALIGNANT POTENTIAL (unstaged noninvasive low grade serous ca) SBT-MP with noninvasive implants or indeterminate implants: SBT with noninvasive implants: LOW MALIGNANT POTENTIAL SBT with invasive implants: MALIGNANT (invasive low grade serous ca) LOW MALIGNANT POTENTIAL with possibility of transformation to low grade ca 8

9 Summary Serous BTs as a group are neither benign nor overtly malignant (although the group harbors benign, low malignant potential and malignant tumors) Summary Serous BTs as a group are neither benign nor overtly malignant Prognosis depends on stage, debulking, implant type, microinvasion and micropapillary/cribriform architecture Summary Serous BTs as a group are neither benign nor overtly malignant Prognosis depends on stage, debulking, implant type, microinvasion and, possibly, micropapillary architecture Tumors with invasive implants are morphologically and clinical similar to low grade serous carcinoma Summary Serous BTs as a group are neither benign nor overtly malignant Prognosis depends on stage, debulking, implant type, microinvasion and, possibly, micropapillary architecture Tumors with invasive implants are similar to low grade serous carcinoma Tumors with non-invasive implants may recur as invasive implants/low grade serous carcinoma Summary Serous BTs as a group are neither benign nor overtly malignant Prognosis depends on stage, debulking, implant type, microinvasion and, possibly, micropapillary architecture Tumors with invasive implants are similar to low grade serous carcinoma Tumors with non-invasive implants may recur as invasive implants/low grade serous carcinoma Many unfavorable outcomes are associated with nonmicropapillary SBTs Conclusion tumors can invade, metastasize and kill patients Serous borderline (non-mp) tumors are not all benign 9

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