The Pathology of Germ Cell Tumours of the Ovary Professor Mike Wells University of Sheffield Amman, Jordan November 2013
Professor Francisco Paco Nogales
I. Primitive germ cell tumors A. Dysgerminoma B. Yolk sac tumour 1. Polyvesicular vitelline tumour 2. Glandular variant 3. Hepatoid variant C. Embryonal carcinoma D. Polyembryoma E. Nongestational choriocarcinoma F. Mixed germ cell tumour, specify components II. Biphasic or triphasic teratoma A. Immature teratoma B. Mature teratoma III. Monodermal teratoma Modified from Nogales FF et al in Tavassoli FA, Devillee P: WHO pathology and genetics of tumours of the breast and female genital organs. Lyon, France, International Agency for Research on Cancer, 2003.
Embryonic stem (ES) and induced pluripotent stem (ips) cells Regulatory network controlled by master transcriptional regulators POU5F1 (OCT3/4), SOX2, and NANOG. Further regulators include Lin28 and KLF4 BOHELER KR. J. Cell. Physiol. 221: 10 17, 2009. Somatic cells can be reprogrammed to ips cells by the expression of key pluripotency factors
OCT3/4 aka POU5F1, OCT3 or OTF3 Nuclear transcription factor - chromosome 6p21.3 Blastocyst differentiation gastrulation Embryonal stem cells of the inner cell mass epiblast Primordial germ cells Inducing pluripotency Chemically induced pluripotency of fibroblasts into embryonal stem cells
SOX2 factor SRY-box2 Nuclear transcription factor- chromosome 3q26.33 Responsible for Development of the inner cell mass epiblast Differentiation of the trophectoderm Not expressed by primordial germ cells gastrulation Neural plate cells mouse embryos that do not express the gene (knock-out) - do not progress from morula stage
SALL4 Family of three genes SALL - chromosome 20q13 Expressed by cells of epiblast Mandatory for endodermal differentiation Not implicated in trophectoderm differentiation Primordial germ cells Interacts with different other nuclear transcription factors (ie CDX2) differentiating: -Anorectal region -Kidney -Heart -Limbs -Brain
PRIMORDIAL GERM CELLS OCT3/4, SALL4 DYSGERMINOMA OCT3/4, SALL4 S O X 2 EMBRYONAL CARCINOMA SOX2, OCT3/4, SALL4 YOLK SAC TUMOUR SALL4 CHORIOCARCINOMA TERATOMA - SALL4, -SOX2, -OCT3/4 SALL4, SOX2, -OCT3/4
SALL4 14 week ovary
Ovarian dysgerminoma mutated c-kit gene usually unilateral 3% - syncytiotrophoblastic cells 5% - anaplastic granulomas in > 20%
Dysgerminoma
Dysgerminoma
Dysgerminoma
Dysgerminoma
Dysgerminoma
Dysgerminoma
Dysgerminoma Immuno 20% CK
Dysgerminoma - Immuno INESPECIFICA NON-SPECIFIC PLAP
CD117 NON-SPECIFIC
OCT3/4
Dysgerminoma - Immuno D2-40 OCT3/4 SALL4
PYS AC Day 17
AP SHYS Day 17
AFP 7th wk
Histology of yolk sac tumours Endodermal extraembryonal patterns - reticular-microcystic - endodermal sinuses (Schiller-Duval) - parietal - polyvesicular - tubular Endodermal somatic patterns - glandular - hepatic - solid YSTs with overgrown components
Murine
AFP
Tubular YST Day 33 SHYS
Histology of yolk sac tumours Endodermal extraembryonal patterns - reticular-microcystic - endodermal sinuses (Schiller-Duval) - parietal - polyvesicular - tubular Endodermal somatic patterns - glandular - hepatic - solid YSTs with overgrown components
Glypican 3 (GLP3) Expressed in 8 th and 11 th week SHYS, developing liver, lung, pancreas acinary cells, neuroectodermal epithelium and syncytiotrophoblast. + in embryonal tumours neuro-, medullo- and nephroblastoma + marker for liver cell neoplasia. Serum marker, combined with AFP levels, increases diagnostic sensitivity. GLP3 is a sensitive marker for YSTs and to a certain extent, it parallels their AFP distribution.
Yolk sac tumours - Immuno NON-SPECIFIC FOCAL >50% GLY3 GLY3 Preda O, Nicolae A, Aneiros-Fernández J, Borda A, Nogales FF. Glypican 3 is a sensitive, but not a specific, marker for the diagnosis of yolk sac tumours. Histopathology. 2011 Jan;58:312-314
Choriocarcinoma
Choriocarcinoma hcg,hpl,cd10,α-inh GLP3
Gonadoblastoma OCT3/4 α-inh
Immature teratoma of the ovary stage 1 in 70% of cases solid and cystic subjective grading preponderance of neuroectodermal tissues gliomatosis peritonei commonest complication
O Connor DM & Norris HJ Int J Gynecol Pathol 1994; 13: 283-289 Low grade (grade 1) High grade (grades 2 & 3)
GLY3
SOX2
m.wells@sheffield.ac.uk