Borderline ovarian tumours - AHN€¦ · Borderline ovarian tumours Robert A. Soslow, MD...

04/13/2017

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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

Serous

Intestinal

mucinous

Sero-

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

Fimbria?

Dysplasia

High grade

carcinoma

BRCA-1

mutation

TP53

mutation

Familial Sporadic

TP53

mutation

Serous Epithelium

Borderline tumor (BT)

Micropapillary BT

Low grade carcinoma

BRAF

KRAS

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

** ~50% of patients died Gershenson DM, Silva EG.

Cancer 1990;65:578-85

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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• 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.


• 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



– Probable

• Architecture i.e. micropapillarity

• Microinvasion

Prognosis

– Confirmed

• Stage



– 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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• Fat or muscle invasion: invasive

• Diffuse high grade cytologic atypia: carcinoma




• 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

Fat invasion

Invasive Cytologic atypia

Carcinoma Micropapillary

?Invasive Non-invasive

Yes

Yes No

No

Yes No

Implant assessment

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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


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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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.


Analogy: MP tumors are akin to low grade carcinomas in situ.


2) If they’re invasive (anywhere), they behave like low grade carcinoma.

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2) If they’re invasive (anywhere), they behave like carcinoma.

3) If they’re incompletely excised, they can progress to carcinoma.




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.


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. 4) If you don’t know whether they’re invasive, you must

investigate further. 5) 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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• 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%)

– Clear cell (50%)

– RED= mean size >10 cm



Small numbers


• Serous tumors: importance of micropapillary architecture

– Serous BT, no MP: 96% accuracy

– Serous BT with MP: 57% accuracy



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Serous carcinoma: pathogenesis

Fimbria?

Dysplasia

High grade

carcinoma

BRCA-1

mutation

TP53

mutation

Familial Sporadic

TP53

mutation

Serous epithelium

Borderline tumor (BT)

Micropapillary BT

Low grade carcinoma

BRAF

KRAS

MEK inhibitors

Nature.com

Managerial classification of SBT

• BENIGN:

– Ovary-confined SBT (with or without MP)

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• BENIGN:


• UNCERTAIN MALIGNANT POTENTIAL:

– Unstaged SBT-MP


• BENIGN:



– Unstaged SBT-MP

• (S)LOW MALIGNANT POTENTIAL:

– SBT (with or without MP) with noninvasive implants


• BENIGN:



– 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)


• 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)


• 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)


• Many might represent progression from SBT and SBT with micropapillary features

Summary (2)


• Many might represent progression from SBT and SBT with micropapillary features

• They rarely progress to a high-grade neoplasm

Borderline ovarian tumours - AHN€¦ · Borderline ovarian tumours Robert A. Soslow, MD...

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