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Pathology of gynecological cancer.What do we need to know

(Case 2)Luca Mazzucchelli

Istituto cantonale di patologiaLocarno

SAMO Interdisciplinary Workshop on Gynecological TumorsLucern, October 22-23

Case 2

32 years old woman with bilateral ovarian tumors and numerousnodules (> 2cm) in the peritoneal cavity and omentum

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Final diagnosis:Low grade serous adenocarcinomaFIGO: IIICMüllerian inclusion cysts in periaortal LNs

Discussion points:

� High-grade versus low-grade serous carcinoma

� Defining the cut point between low-grade and high grade ovarian serous carcinoma

� Defining the significance of a micropapillary pattern

� Identify potential diagnostic pitfalls

Low-grade serous-papillary or endometrioidcarcinomas

� 25% of ovarian cancers� 10% of ovarian cancer deaths� affect younger women

compared to high grade carcinomas

� Slow growing and attain a large sizre while still confinedto the ovary

� Esily detected by pelvicexamination and/ortransvaginal ultrasound

� Develop in a stepwise fashionfrom borderline tumors

� Almost all advanced stagedisease

� Relatively indolent diseasecourse with prolonged survivaltime (median 82 months)

Low-grade serous-papillary or endometrioidcarcinomas

� Small, uniform nuceli withminimal atypia and low mitoticactivity

� Low proliferative rate (ki67)� They contain KRAS, BRAF, or

ERBB2 mutation in 2/3 of thecases

� They rarely harbor p53 mutations

� Relative resistance to platinum-based chemotherapy

High grade serous,undifferiated, and carcinosarcomas

� 70-80% of ovarian cancers� 50-80% of ovarian cancer

deaths� Frequently affecting women in

the perimenopausal orpostmenopausal age-group

� Clinically aggressive neoplasms

� Very chemosensitive� Median survival of 30 months

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High grade serous,undifferiated, and carcinosarcomas

� Papillary or solid growth pattern

� Marked atypical large pleomorphic nuclei withfrequent mitotic figures

� They frequently contain TP53 mutation (80%) and PIC3K mutaion (40%)

� They rarely harbor KRAS, BRAF, and ERBB2 mutations

Defining the cut point between low grade and high grade ovarian serous carcinoma Grading systems

Am J Surg Pathol 2004Nuclear grade. Mitoticactivity

G1-22-tier system

Cancer 1998Architectural, nuclearfeatures. Mitotitc activity

G1-G3Silverberg

WHO classification of tumorsof the breast and femalgenital organs 2003

Cytologic and architectural

G1-G3WHO

Acta Obstet Gynecol Scand1971; 50:1-7

architectureG1-G3FIGO

Does Grad 2 ovarian carcinoma exist?

� Frequeny has been estimated to be approximately 4% of all serous carcinomas

� All patients presented with stage IIIC� Survival time varied from 6 to 30 months� 10/11 carried TP53 mutations� None of the tumors carried KRAS, BRAF or ERBB2

mutatons

Ayhan A et al: Am J Surg Pathol 2009, 33:1220

K-Ras

BRAF

MEK

ERK1,2

PI3K

Akt

mTOR

PTEN

changesin gene expression

out

nucleus

cytoplasm

EGFR

� Low grade are notchemosensitive

� New target therapiesmay be effective

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Micropapillary pattern

� Fine papillary structuresarising directly from plump papillae

� Some authors suggest moreaggressive disease comparewith borderline tumors withoutMP (carcinoma)

� Other authors find no convincing evidence thatpatients with MP pattern havepoorer prognosis than patientswith conventional borderlinetumors

� Carefully staging and samplingare crucial to establish a correct diagnosis

Am J Surg Pathol 1999, 23:397; Virchows Arch 2000, 436:403

Desmoplastic non-invasive implants

� Cell complexes or gland likestructures plastered on thesurface of the peritoneum

� Dense fibroblastic orgranulation tissue-like stromalreaction

� Associated inflammatorychanges in the peritonealcavity a frequent

� Numerous psammoma bodiescan be present

� Frequently found in Stage IC borderline tumors

Nodal staging?

� Müllerian inclusion cysts are common in patients withborderline tumors (up to 50%) and low gradeadenocarcinoma

� Incidental finding rather thanmetastatic disease

� Benign “flat” to proliferative features

� No desmoplastic response� Nodal involvement apperas to

affect intra-abdominalrecurrence rates but not long-term clinical outcome