04/13/2017
Borderline ovarian tumours
Robert A. Soslow, MD
[email protected]
Outline
• Orientation
• Ovarian tumor overview
• Serous and seromucinous borderline tumors
– Clinical summary
– Morphologic description
– Prognostic indices
• Low grade serous carcinoma
Borderline tumors
• Synonyms:
– Tumor of borderline malignancy
– Borderline tumor (BT)
– Tumor of low malignant potential (LMP)
– Atypical proliferative tumor
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Borderline tumors
• Borderline: Neither clinically benign nor
malignant
– Recurrence is common, but death is uncommon
Borderline tumors
• Borderline: Neither clinically benign nor
malignant
– Recurrence is common, but death is uncommon
• Borderline: Neither morphologically benign
nor malignant
– Architectural complexity without malignant
cytologic features or invasion
“Borderline” tumors
Seromucinous
Serous
Intestinal
mucinous
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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.
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Serous carcinoma: pathogenesis
Familial
Sporadic
Fimbria?
Serous Epithelium
BRAF
KRAS
BRCA-1
mutation
Borderline tumor (BT)
Dysplasia
TP53
mutation
TP53
mutation
High grade
carcinoma
Micropapillary BT
Low grade carcinoma
Low grade serous carcinoma: pathogenesis
Putative precursor to SBT and LGSC:
Papillary tubal hyperplasia (PTH)
Kurman RJ, et al. Am J Surg Pathol 2011 Nov;35(11):1605-14
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Clinical
•
•
•
•
•
•
Fifth decade
Pelvic discomfort
+/- elevated CA125
70% stage I (30% of total are bilateral)
30% have extraovarian, peritoneal disease
95% 5-year survival
Serous borderline tumor:
5/10 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
Gershenson DM, Silva EG.
Cancer 1990;65:578-85
** ~50% of patients died
Serous borderline tumors:
10/20 yr follow up
SBT
70% Stage I
30% >Stage I
90-95% Non-Inv
5-10% Inv
56% No Rec
44% Recur
83% Inv**
17% Non-Inv
**75% of patients died
Silva EG, et al. Am J Surg
Pathol 2006;30:1367-1371
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Seromucinous borderline tumor
• Synonyms
– Mullerian mucinous borderline tumor
– Endocervical-type mucinous borderline tumor
– Mixed epithelial borderline tumor
• “True” borderline tumor, akin to serous
borderline tumor
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Seromucinous borderline tumor
• Similarities with serous borderline tumor
– Growth pattern
• Assessment of micropapillary architecture
– Association with implants
• Assessment for invasion
– Possibility of malignant behavior (very rare!)
Shappell HW, et al. Am J Surg Pathol. 2002 Dec;26(12):1529-41.
Seromucinous borderline tumor
• Similarities with serous borderline tumor
– Growth pattern
– Association with implants
– Possibility of malignant behavior (very rare!)
• Differences with serous borderline tumor
– Association with endometriosis
– Morphologic similarities to endometrial cancers
with mucinous metaplasia
– Malignant potential is lower
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Seromucinous BT: further
evidence supporting kinship to
endometrioid neoplasia
• Lack or paucity of WT1 staining
• Presence of ARID1A mutation in
approximately 1/3 of cases
Vang R, et al. Int J Gynecol Pathol. 2006 Jan;25(1):83-9.
Wu DH, et al. Int J Gynecol Pathol. 2012 Jul;31(4):297-303
Prognosis
– Confirmed
• Stage
– Success of debulking
– Implant invasion
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Prognosis
– Confirmed
• Stage
– Success of debulking
– Implant invasion
– Probable
• Architecture i.e. micropapillarity
• Microinvasion
Prognosis
– Confirmed
• Stage
– Success of debulking
– Implant invasion
– Probable
• Architecture i.e. micropapillarity
• Microinvasion
– Not
• Lymph node involvement
Implant terminology (historical)
• Ovarian borderline tumor + peritoneal disease
= borderline tumor with implant
• Ovarian carcinoma + peritoneal disease =
metastatic ovarian carcinoma
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Implant terminology (future)
• Ovarian borderline tumor + noninvasive
peritoneal disease = borderline tumor with
noninvasive implant
• Ovarian borderline tumor + invasive peritoneal
disease = metastatic low grade serous carcinoma
(with associated serous borderline tumor)
• Ovarian carcinoma + peritoneal disease =
metastatic carcinoma
Significance of implant type
Non-invasive implant survival (10 yr): ~95%
Invasive implant survival (10-20 yr): 33-50%
Stage III low grade serous carcinoma survival (10-20 yr): 25-50%
Implant morphology
• No invasion WITHOUT diffuse high grade cytologic atypia or
micropapillary architecture: non-invasive
• Tumor stroma prominent WITHOUT fat or muscle invasion,
diffuse high grade cytologic atypia or micropapillary
architecture: non-invasive
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Implant morphology
• No invasion WITHOUT diffuse high grade cytologic atypia or
micropapillary architecture: non-invasive
• Tumor stroma prominent WITHOUT fat or muscle invasion,
diffuse high grade cytologic atypia or micropapillary
architecture: non-invasive
• Fat or muscle invasion: invasive
• Diffuse high grade cytologic atypia: carcinoma
Implant morphology
• No invasion WITHOUT diffuse high grade cytologic atypia or
micropapillary architecture: non-invasive
• Tumor stroma prominent WITHOUT fat or muscle invasion, diffuse
high grade cytologic atypia or micropapillary architecture: noninvasive
• Fat or muscle invasion: invasive
• Diffuse high grade cytologic atypia: carcinoma
• Endophytic micropapillary architecture WITHOUT fat or muscle
invasion or diffuse high grade cytologic atypia: indefinite for
invasion/probably invasive/may progress and then invade
No invasion AND no diffuse high grade cytologic
atypia or micropapillary architecture:
non-invasive epithelial implant
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Exophytic micropapillary architecture WITHOUT fat or
muscle invasion or diffuse high grade cytologic atypia:
controversial entity
Tumor stroma prominent AND no fat or muscle
invasion, diffuse high grade cytologic atypia or
micropapillary architecture:
non-invasive “desmoplastic” implant
Tumor stroma prominent AND no fat or muscle
invasion, diffuse high grade cytologic atypia or
micropapillary architecture:
non-invasive “desmoplastic”
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Fat or muscle invasion: invasive implant
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Endophytic micropapillary architecture WITHOUT fat or muscle
invasion or diffuse high grade cytologic atypia:
indeterminate/probably invasive/may progress and then invade
Diffuse high grade cytologic atypia:
high grade serous carcinoma
Implant assessment
Fat invasion
Yes
No
Invasive
Cytologic atypia
Yes
Carcinoma
No
Micropapillary
Yes
?Invasive
No
Non-invasive
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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
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 tumor recur more frequently
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Significance of micropapillary (MP)
architecture in a non-invasive ovarian
tumor
• Does this justify classification as “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.
Significance of MP architecture in an
ovarian tumor
Analogy: MP tumors are akin to low grade carcinomas in situ.
1)
2)
If they’re non-invasive, they behave like other low grade,
non-invasive tumors.
If they’re invasive (anywhere), they behave like low grade
carcinoma.
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Significance of MP architecture in an
ovarian tumor
Analogy: MP tumors are akin to low grade carcinomas in situ.
1)
2)
3)
If they’re non-invasive, they behave like other low grade,
non-invasive tumors.
If they’re invasive (anywhere), they behave like carcinoma.
If they’re incompletely excised, they can progress to
carcinoma.
Significance of MP architecture in an
ovarian tumor
Analogy: MP tumors are akin to low grade carcinomas in situ.
1)
2)
3)
4)
If they’re non-invasive, they behave like other low grade,
non-invasive tumors.
If they’re invasive (anywhere), they behave like carcinoma.
If they’re incompletely excised, they can progress to
carcinoma.
If you don’t know whether they’re invasive, you must
investigate further.
Significance of MP architecture in an
ovarian tumor
Analogy: MP tumors are akin to low grade carcinomas in situ.
1)
2)
3)
4)
5)
If they’re non-invasive, they behave like other low grade,
non-invasive tumors.
If they’re invasive (anywhere), they behave like carcinoma.
If they’re incompletely excised, they can progress to
carcinoma.
If you don’t know whether they’re invasive, you must
investigate further.
Avoid unequivocal diagnosis of borderline tumor at FS when
MP architecture is present
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Microinvasion
• Definition
– One or more foci
– <5mm in any one dimension or <10mm2
• Description
– Pink cells in spaces
– Micropapillary or cribriform nests
• Associations: pregnancy
• Significance (not pregnancy-associated)
– Over-represented in high stage cases
– Possible adverse outcome (Longacre)
McKenney JK, Balzer BL, Longacre TA. Am J Surg Pathol 30:1209-21, 2006
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Lymph nodes
• ~30% of stage III SBTs have involved LNs
• Prognostic implication: none
• Differential diagnosis:
– Carcinoma
• Nodular aggregates > 1mm
– Benign Mullerian inclusions (endosalpingiosis)
– Mesothelial hyperplasia
McKenney JK, Balzer BL, Longacre TA. Am J Surg Pathol 30:614-24, 2006
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Therapy
• Surgical disease
• Hormonal therapy
• Cytotoxic chemotherapy
– 4% complete response to platinum and taxol*
• Targeted therapy
– MEK inhibitors for invasive implants/low grade serous
carcinoma
*Schmeler KM, et al. Gynecol Oncol. 2008 Mar;108(3):510-4.
Borderline tumors at frozen section
• When and why do gynecologists perform
staging operations?
– Detect extraovarian disease
• Serous and seromucinous BT
– Concern that BT diagnosis will be “upgraded” to
carcinoma on permanent sections
• Micropapillary serous, intestinal mucinous,
endometrioid and clear cell
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Borderline tumors at frozen section
• BTs at frozen section at MSKCC
– Serous (67%)
– Seromucinous (11%)
– Gastrointestinal mucinous (17%)
– Endometrioid (4%)
– Clear cell (2%)
– RED= mean size >10 cm
Shih KK, Garg K, Soslow RA, Chi DS, Abu-Rustum NR, Barakat RR.
Gynecol Oncol. 2011 Dec;123(3):517-21.
Borderline tumors at frozen section
• FS is 87% accurate for BT diagnosis at MSKCC
• “Undercalls”
– Serous (6%)
– Seromucinous (0%)
– Gastrointestinal mucinous (25%)
– Endometrioid (80%)
Small numbers
– Clear cell (50%)
– RED= mean size >10 cm
Shih KK, Garg K, Soslow RA, Chi DS, Abu-Rustum NR, Barakat RR.
Gynecol Oncol. 2011 Dec;123(3):517-21.
Borderline tumors at frozen section
• Serous tumors: importance of micropapillary
architecture
– Serous BT, no MP: 96% accuracy
– Serous BT with MP: 57% accuracy
Shih KK, Garg K, Soslow RA, Chi DS, Abu-Rustum NR, Barakat RR.
Gynecol Oncol. 2011 Dec;123(3):517-21.
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Serous carcinoma: pathogenesis
Familial
Sporadic
Fimbria?
Serous epithelium
BRAF
KRAS
BRCA-1
mutation
Borderline tumor (BT)
Dysplasia
TP53
mutation
Micropapillary BT
TP53
mutation
High grade
carcinoma
Low grade carcinoma
MEK inhibitors
Nature.com
Managerial classification of SBT
• BENIGN:
– Ovary-confined SBT (with or without MP)
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Managerial classification of SBT
• BENIGN:
– Ovary-confined SBT (with or without MP)
• UNCERTAIN MALIGNANT POTENTIAL:
– Unstaged SBT-MP
Managerial classification of SBT
• BENIGN:
– Ovary-confined SBT (with or without MP)
• UNCERTAIN MALIGNANT POTENTIAL:
– Unstaged SBT-MP
• (S)LOW MALIGNANT POTENTIAL:
– SBT (with or without MP) with noninvasive implants
Managerial classification of SBT
• BENIGN:
– Ovary-confined SBT (with or without MP)
• UNCERTAIN MALIGNANT POTENTIAL:
– Unstaged SBT-MP
• (S)LOW MALIGNANT POTENTIAL:
– SBT (with or without MP) with noninvasive implants
• MALIGNANT
– SBT (with or without MP) with invasive implants
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Summary (1)
• Serous and seromucinous BTs as a group are
neither benign nor overtly malignant
Summary (1)
• Serous BTs as a group are neither benign nor
overtly malignant
• Prognosis depends on stage, debulking,
implant type, microinvasion and, probably,
micropapillary/cribriform architecture
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Summary (1)
• 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 non-invasive implants may recur
as invasive implants/low grade serous
carcinoma
Summary (1)
• 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 non-invasive implants may recur
as invasive implants/low grade serous
carcinoma
• Tumors with invasive implants are similar to
low grade serous carcinoma
Summary (2)
• Low-grade serous carcinomas (LGSC) are
clinically, biologically and morphologically
distinct from HGSC
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Summary (2)
• Low-grade serous carcinomas (LGSC) are
clinically, biologically and morphologically
distinct from HGSC
• Many might represent progression from SBT
and SBT with micropapillary features
Summary (2)
• Low-grade serous carcinomas (LGSC) are
clinically, biologically and morphologically
distinct from HGSC
• Many might represent progression from SBT
and SBT with micropapillary features
• They rarely progress to a high-grade neoplasm
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