BORDERLINE TUMORS OF THE OVARY:

ADDITIONAL THOUGHTS

Steven G. Silverberg, M.D., FRCPathUniversity of Maryland, American Registry

of Pathology

BORDERLINE

Definition: Tumors with known behavior intermediate between fully benign and fully malignant

Example: Serous borderline tumor of ovary

LOW MALIGNANT POTENTIAL (LMP)

Definition: Minimally aggressive cancersExamples: Granulosa cell tumor of ovary

Papillary carcinoma of thyroid

ATYPICAL PROLIFERATING (APT)

Definition: In the ovary, used as a synonym for borderline tumors that are assumed to be really benign; in other organs, usually refers to non-neoplastic reactive processes.

Examples: Regeneration of mucosa after biopsy/curettage “Pseudosarcomatous” polyps of nasal mucosa, vagina, etc. Lymph nodes in infectious mononucleosis

UNCERTAIN MALIGNANT POTENTIAL (UMP)

Definition: “I don’t know” if benign or malignant (BUT the tumor knows – so not a true entity – all UMPs are either benign or malignant

Example: Uterine smooth muscle tumor of uncertain malignant potential (STUMP)

PERCENTAGES OF BENIGN, BORDERLINE, AND INVASIVE CARCINOMATOUS OVARIAN TUMORS BY

HISTOLOGIC SUBTYPE

5≠95951023Carcinoma

<1<1<11012Borderline

955*5*8065Benign

BrennerClear CellEndometrioidMuinous (G-I)Serous

*Excluding endoemetriosis, including atypical adenofibromas≠malignant Brenner tumor, transitional cell carcinoma

Notes: 1. Proportions unknown for mucinousendocervical/müllerian/seromucinous tumors, but probably mostly benign and borderline;

2. Undifferentiated epithelial tumors are by definition carcinomas, but

3. Unclassified and mixed epithelial tumors may be benign, borderline or carcinoma

IMMUNOHISTOCHEMISTRY OF MUCINOUS BOT

(Vang et al, IJGP 25:83, 2006)

50%(5)0%Mesothelin

91%0%CA-125

33%(4)0%PR

64%(3)0%ER

0%32%(2)CK20

100%71%(1)CK7

EndocervicalIntestinal

(1) 21% focal; (2) 54% focal; (3) 36% focal; (4) 33% focal; (5) 33% focal

ATYPICAL ADENOFIBROMAS / CYSTADENOFIBROMAS

• Defined as architecturally benign but cytologically atypical

• Most commonly endometrioid and clear cell• Should be sectioned extensively to rule out the

coexistence of an obvious carcinoma or borderline tumor

• If no CA or BT, the behavior should be benign, but relatively few cases have been reported

ENDOMETRIOID BORDERLINE TUMOR: PROPOSED CRITERIA FOR CARCINOMA

Glandular confluence or stromaldisappearance, penetrating stromal invasion, non-intracysticvilloglandular or sertoliform (rare) pattern

Roth et. al. (AJSP 27: 1253, 2000)

Glandular confluence or (13%) destructive stromal invasion

Bell and Kurman(AJSP 24:1465, 200)

Disorderly penetration of usually reactive stroma or back-to-back glands

Scully et. al.

Epithelial component complex and irregular, with desmoplastic stroma

Russell(in Haines and Taylor, 1995)

> 5 mm atypical epithelial proliferation uninterrupted by stroma

Snyder et. al.(AJSP 12:661, 1988)

OVARIAN ENDOMETRIOID NEOPLASIA: MY CRITERIA

AbsentEndometrial carcinoma* ≥ 5 mmInvasive Carcinoma

AbsentEndometrial carcinoma* but <5 mm in greatest linear measurement

Borderline with Microinvasion

AbsentEndometrial hyperplasia/atypical hyperplasia

Borderline Tumor

AbsentDispersed glands with/without squamous metaplasia, in fibrotic(not desmoplastic) stroma

Adenofibroma

PresentHyperplastic and/or cytologicallyatypical endometrium

Atypical Endometriosis

PresentNormal/metaplasticendometrium

Endometriosis

ENDOMETRIAL STROMAEPITHELIUM LOOKS LIKE DIAGNOSIS

*Confluent/cribriform mazelike, desmoplastic or necrotic stroma, villoglandular or sertoliform pattern

BRENNER TUMOR CLASSIFICATION

• Benign – small cell nests, uniform small cells without nuclear atypia

• Proliferating – large cell nests, papillae, minimal atypia

• Borderline/LMP – large cell nests, papillae, moderate to marked atypia, no stromal invasion

• Carcinoma – any tumor with stromal invasion: Malignant Brenner tumor if benign/borderline elements present – Transitional cell carcinoma if benign/borderline elements absent

SUMMARY OF BRENNER/TCC CATEGORY

• Benign Brenner tumor ≥ 95% - usually small, incidental –small nests with minimal atypia, often include mucinousepithelium (“metaplastic Brenner tumor”) – stromanormal/fibrotic/hormonally active

• Borderline Brenner tumor (rare, ?1%) – average 14 cm, often cystic – usually characterized by papillary growth, mild to moderate atypia, resembling low grade urothelialcarcinoma of bladder, but may show solid or cystic nested pattern (“atypical adenofibroma”) or severe atypia(? “intraepithelial carcinoma”) – usually have foci of benign BT – microinvasion not reported, but probably occurs

• Malignant Brenner tumor – invasive transitional cell CA accompanied by benign or borderline BT

• Transitional cell carcinoma – same tumor without benign or borderline BT

• Mixed transitional cell carcinoma –invasive TCC plus one or more other cell types (serous, endometrioid, etc) – more common than pure TCC or MBT

372 PRIMARY OVARIAN NEOPLASMS IN GILDA RADNER FAMILIAL OVARIAN CANCER

REGISTRY(Piver, et al., Gynecol Oncol 78:166, 2000)

0.8%3Others

1.1%4Carcinosarcoma

1.3%4BORDERLINE

96.8%359ALL CARCINOMAS

4.9%18Undifferentiated/other carcinoma

3.5%13Mucinous carcinoma

4.6%17Clear cell carcinoma

5.4%20Endometrioid carcinoma

13.5%50Carcinoma NOS65.2%242Serous carcinoma

TUBAL INVOLVEMENT IN PELVIC SEROUS CARCINOMA (Kindelberger et al, AJSP 31:161-169, 2007)

• 55 Consecutive cases of pelvic serous CA• Classified as ovarian (43), peritoneal (7), or

tubal (5)• 41 of 55 (75%) had TIC (tubal intraepithelial

carcinoma) when tubes were entirely sectioned and examined (93% in fimbriae)

• Same p53 mutations in TIC and ovarian CA• Can TIC be precursor of some (? Most) ovarian

and 1º peritoneal CA?