At age 23, this medical student presented with a multicystic mass in the right ovary. The patient had

an apparently unrelated clinical history of tumours in other organs

Case

RSO MacroscopyMulticystic ovary 6 X 8 X 6cmCysts varying from 0.3-3cmOcassional solid yellow areaContralateral ovary normal

p53

What is this lesion?

Is it sensu stricto neoplastic?

Multifocal coexisting with normal follicles

Contralateral ovary is normal

Papillary projections, angiogenesis

What is this lesion?

Is it a granulosa cell lesion?:

All cell markers present: InhA, CLRT, dot keratins

Inh A

CAM 5.2

AAT

CAM 5.2

Calretinin

Inhibin

Melan A

What is this lesion?

Can granulosa cells be so atypical ?

Similar atypia can be found in

juvenile granulosa cell tumours

Surprise !!!!!

AGE SITE HISTOLOGIC TYPELOCAL

RECURRENCE

METAST. TREATMENT

10 Lt tibia Telangiectatic Osteosarcoma 6 months Pulmonar

yAmputation andchemotherapy

15 Lt breast Fibroadenoma - - Local excision

18 Bothbreasts

Rt.Malignant Phyllodes tumour

Lt. Phyllodes tumour3 & 5 years -

Extensive local excision followed

by bilateral mastectomy at

25yrs

21 Skin (nose) Reticulohistiocytoma Local excision

23 Lt breast Intraductal Carcinoma - - Local excision

23 RT OVARY

GRANULOSA CELL LESION - - RSO

Possibility of mutational syndrome ??

Li-Fraumeni syndrome ?

Clinical considerations

Autosomal dominant familial disorderMultiple primary neoplasmsYoung patients < 45 yrs70% germline mutation of exons 5-8 of p53

Associations (usual):Sarcomas Breast CancerCNS tumoursAdrenocortical CarcinomaLeukaemia

Li-Fraumeni Syndrome

Patient’s Blood:P53 gene mutation @ exon 10 [exons

5-8 no change] T insertion in codon 336 (ATG to TAT) generating a stop codon in the oligomerization domain of the protein (E336X).

Genetic analysis

E336X

P53

E336XE336X

Family: (Parents, 2 siblings, uncle): P53 gene normal

Tumour tissue: T insertion (ATG to TAT) in codon 237 of exon 7

Genetic analysis

Multifocal intrafollicular granulosa

cell tumor of the ovary associated

with an unusual exon 10, codon 336

[non familial] germline p53 mutation

Case 2 Diagnosis

F o l l o w u p

24 Retroperit. Well differentiated Liposarcoma - - Local excision

24 Rt breast Invasive ductal Carcinoma

3 axillary nodes

Rt mastectomy and axillary dissection

25 Myometrium Leiomyomas - - TAH-LSO

25 Endometrium

Intramucosal endometrioid

adenocarcinoma with atypical hyperplasia

- - TAH-LSO

AGE SITE HISTOLOGIC TYPELOCAL

RECURRENCE

METASTAST. TREATMENT

25 Iliac bone. Leiomyosarcoma - - Biopsy

AGE SITE HISTOLOGIC TYPELOCAL

RECURRENCE

METASTAST. TREATMENT

In childhood malignant adrenocortical tumor where a similar mutation occurs in the same dimerization domain of TP53, exon 10 codon 337, an altered apoptotic function may be responsible for tumorigenesis. Varley et al, 2003

Epithelial ovarian Ca.Teratoma, YST, DysgerminomaEndometrial CaCervical CaLeiomyomas

Li-Fraumeni Syndrome and the female genital

tract

Exon 10 mutation most unusual

Cellular appearance of the previous mesenchymal

tumours was identical (atypia, globules: continuum?)

Li Fraumeni Syndrome does not include any sex

cord stromal tumours of the ovary

Granulosa Cell Tu. are asociated with mesenchymal

tumours (Ollier, Mafucci, etc....)

Pertinent questions

6 year old girlMultiple right side

enchondromas in phalanxes, scapula, pelvis, femur, tibia, tarsal bones

Spontaneous fracture in femur

Vaginal bleeding Precocious pseudopuberty 12cm right ovarian tumour

Ollier’s Disease associated to JGCT

Velasco et al, Cancer 62:222-225; 1988

Case has typical clinical presentation of a full blown LFS

In LFS there is usually a relationship between the type of mutation (mutational genotype) and the number and type of cancers and age of presentation (tumor phenotype)

Childhood malignant adrenocortical tumor is characteristically associated with LFS and usually involves mutations at exon 10 at “hot spot” 337 only. Here mutation was at codon 336

Mutation occurred in a domain which is characteristically related to the childhood malignant adrenocortical tumor reported in Brazilian children with LFS, a neoplasm with which it shares a common embryogenesis.

More pertinent questions

Velasco A, Alonso A, Blanco A, Nogales FF. Ollier's disease associated with ovarian juvenile granulosa cell tumor. Report of a case and literature review. Cancer 1988; 62:222-225.

Kleihues P et al. Tumors associated with p53 germline mutations. A synopsis of 91 families. Am J. Pathol 150:1-13, 1997

Varley JM et al. Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. Am J Hum Genet 1999;55:995-1006

Ribeiro RC, et al . An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. PNAS 2001;98:9330-9335

Varley JM. Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat 2003;21:313-320.

www.iarc.fr/P53/Germline.html

References