Ecografia e marcatori/Ultrasound and Markers

Daniele L. SpagnoloOspedale San RaffeleUniversità Vita e SaluteMILANO

Ephraim McDowell

first to successfully remove an ovarian tumor.

November 11, 1771 – June 25, 1830

On December 13, 1809

physicians thought that Mrs. Crawford was beyond term pregnant.

On Christmas morning, 1809, Dr. McDowell began his operation.

The tumor Dr. McDowell removed weighed 22.5 pounds (10.2 kg)

Robert Meyer coined the term 'disgerminoma’ for the ovarian tumor that had been described in detail by the French investigator Marcel Chenot 5 years after Chevassu had mentioned the tumor in his paper describing the seminoma.(1911)

Epidemiology 1

• Ovarian germ cell tumours (OGCT) principally affect young women.

• Derived from primitive germ cells• They include both benign (predominantly) and malignant

subtypes.• Germ cell tumours (GCT) account for 15-20% of all ovarian

neoplasms,

Epidemiology 2

• GCT predominantly affect young women, but they do sometimes occur in infants and older women.

• GCT account for over 60% of ovarian neoplasms in children and adolescents,

• One-third are malignant. • The frequency of OGCT is invariable throughout the world.

There does not appear to be a racial predisposition, in contrast to epithelial ovarian cancers.

• The incidence of OGCT increases in incidence from the age of 8-9 years, and peaks at 18 years

Clinics

• Most GCT are benign and unilateral, with the exception of dysgerminomas.

• Abdominal pain (10%) is the commonest presenting symptom of GCT, however they may be asymptomatic. (85%)

• The mass may cause acute pain due to torsion, rupture, or haemorrhage. Patients may also have abdominal distension , vaginal bleeding or fever.

• Teratomas are usually diagnosed in premenopausal women without presenting symptoms.

• Only 1-2% of dermoid cysts become malignant, usually in postmenopausal women

Cellular Classification of Ovarian Germ Cell Tumors

• Dysgerminoma.• Other germ cell tumors:

– Endodermal sinus tumor (rare subtypes are hepatoid and intestinal)– Embryonal carcinoma.– Olyembryoma.– Choriocarcinoma.– Teratoma:

• Immature.• Mature:

– Solid.– Cystic:

» Dermoid cyst (mature cystic teratoma).» Dermoid cyst with malignant transformation.

• Monodermal and highly specialized:– Struma ovarii.– Carcinoid.– Struma ovarii and carcinoid.– Others (e.g., malignant neuroectodermal and ependymoma).

– Mixed forms.

Serov SF, Scully RE, Robin IH: International Histologic Classification of Tumours: No. 9. Histological Typing of Ovarian Tumours. Geneva: World Health Organization, 1973.  

OGCT

An interesting tale• Girls and Young• Rare• Low stage • Excellent cure rate and prognosis• high fertility expectancy• Feasible fertility sparing surgery• Concern about chemotherapy long-term

effects

Markers

• CA 125

Aumentato in caso di cancro ovarico, polmonare, linfomi non-Hodgkin (40% dei casi), e affezioni benigne: endometriosi, cisti ovariche, mastopatia fibrocistica, cirrosi epatica, pancreatite acuta, e gravidanza

• ALFA-FETOPROTEINA (alfa-FP)

Aumentato in caso di: carcinoma epatocellulare ,cancro testicolare di tipo non-seminoma tumori ovarici, dello stomaco, e del colon.

• BETA-HCG

aumentato in caso di: cancri testicolari di origine germinale, coriocarcinoma dell’utero, gravidanza normale. Assente negli uomini

• CA 19-9

Aumentato in caso di: cancro pancreatico, gastrico, colorettale, melanoma, e patologie benigne (malattie epatobiliari e polmonari). L’1% dei soggetti normali ha un CA 19-9 costituzionalmente elevato, per motivi genetici.

• CEA

Aumentato in caso di: cancro colorettale, di mammella,

polmone, stomaco, pancreas, fegato, e molti altri.

Hystology

Markers

A FP Beta HCG LDH Ca125 Ca19.9 CEA

Dysgerminoma - +- + + - -

Endodermal sinus tumor

+ - + +- +- +-

Mixed tumor +- +- +- +- +- +-

Immature teratoma

+- +- +- - +- +

Choriocarcinoma - + +- - - -

Embryonal carcinoma

+- + +- - - -

Polyembrioma +- + - - - -

Seven tumor markers in benign and malignant germ cell tumors of the ovary

Michiyasu Kawai M.D. , *, Takeo Kano M.D.*, Fumitaka Kikkawa M.D.*, Yoshimitsu Morikawa M.D.*, Hidenori Oguchi M.D.*, Nobuo Nakashima M.D.†, Takao Ishizuka M.D.‡, Kazuo Kuzuya M.D.§, Masahiro Ohta M.D. , Yoshitaro Arii M.D.* and Yutaka Tomoda M.D.*,#

135 patients

35 Yolk Sac24 Immature teratoma28 Dysgerminoma9 MCT with malignant defeneration

Germ cell tumor Markers

+ Yolk Sac ImmatureTeratoma

Mature Cystic Teratoma

Dysgerminoma

α FP 100% 61.9% 0 11.8%

Ca 125 100% 90.9% 23.7% 54.5%

Ca 19-9 20% 57.1% 48.6% 0

CEA 10.3% 22.2% 0 0

β HCG 27.3% 10% - 100%

LDH 83.3% 28.6% - 95%

α FP > 1000 ng/ml discrimina tra Yolk Sac e Teratoma Immaturo

Malignant Ovarian Germ Cell Tumors: Identification of Novel Prognostic Markers and Long-Term Outcome After Multimodality TreatmentN. Murugaesu, P. Schmid ,M.Seckl et al. 2006

• Pretreatment Levels of AFP o β HCG taken alone failed to predict survival

• Elevation of both markers is a strong predictor

89.6% vs 50.4%

Malignant Ovarian Germ Cell Tumors: Identification of Novel Prognostic Markers and Long-Term Outcome After Multimodality TreatmentN. Murugaesu, P. Schmid ,M.Seckl et al. 2006

• Tumour markers play a vital role in the diagnosis

• Elevated preoperative levels of A FP and Beta HCG virtually diagnostic of an OGCT

• Should be performed in all young women with pelvic mass

• Monitoring of A FP and beta HCG useful in monitoring relapse

• Ca 125 less reliable in premenopausal women

Controversies in the management of germ cell tumours of the ovary – Patterson,Rustin Curr Opin Onc 2006

• Tumour markers do not exclude malignancy

when not elevated• Are not definitive preoperatively , but are of

value in the ability of monitoring debulking and relapse

• Owing long half lives of A FP and beta HCG better US immediately postoperatively

Follow – upCharing Cross Hospital

1st year Every 2 wks x 6 months

1st year Monthly x 6 months

2nd year Every 3 months

3rd year Every 4 months

4th year Every 6 months

Ultrasound scan Every 3rd visit for the first 2 years then annual pelvic US

Diagnosi per immagini

Task of ultrasonographer:• See• Measure• Give information about mass• Try to define if benign or not• Monitoring postoperatively• Long term follow-up

Mission impossible?

?

Sassone AM, Timor-Tritsch IE, Artner A, et al: Transvaginal sonographic characterisation of ovarian disease: Evaluation of a new scoring system

to predict ovarian malignancy. Obstet Gynecol 78:70-76, 1991[

Bourne T, Campbell S, Steer CV, et al: Transvaginal colour flow imaging: A possible new screening technique for

ovarian cancer. BMJ 299:1367-1370, 1989

Timmerman D, Verrelst H, Bourne TH, et al: Artificial neural network models for the pre-operative discrimination between malignant and benign adnexal masses. Ultrasound Obstet Gynecol 13:17-25, 1999

Simple cyst of ovary

clot retraction within small hemorrhagic cyst septations in hemorrhagic cyst and

peripheral vasculature

fallopian tubes in chronic salpingitis

endometrioma with associated acoustic enhancement

τέρας, -ατος, τ  ὸmostro

τερατώδης, -ες 

Straordinario, prodigioso 

• Teratomas

Teratomas develop from totipotential germ cells, and consequently contain all three germ cell layers: ectoderm, mesoderm and endoderm. Teratomas are classified into immature (malignant), mature (dermoid cyst) and monodermal (struma ovarii, carcinoid).

• Dermoid cysts contain mature tissue, and skin, teeth, bone, hair, sebaceous glands and neural tissue predominate; whilst cartilage, respiratory and intestinal epithelium are also common. They are cystic tumours with a firm capsule

• Monodermal teratoma comprise mainly one tissue element. For example the most common type of monodermal teratoma, Struma ovarii, is comprised of at least 50% mature thyroid tissue (of any type.

• Immature teratomas account for approximately 20% of all malignant GCT. Immature teratomas are solid tumours containing immature or embryonal tissues. Immature neuroepithelium is the predominant immature tissue found.

Teratomi

• I Teratomi Ovarici includono

A- Teratomi Cistici Maturi ( Cisti Dermoidi )

B- Teratomi Immaturi

C- Teratomi Monodermici ( Struma Ovari,Carcinoide, Tumore Neurale)

US Findings in MCT

Modified from Saba et al.:Eur.J.Rad. 2009

Rokitansky nodule with acousticattenuation nodule in dermoid

Rokitansky nodule with acousticattenuation and fat–fluid level

Hyperechoic fat–fluid level

Hyperechoic lines and punctuate dotsrepresenting hair in dermoid tumor (Dermoid Mesh)

teratoma cistico maturo massa prevalentemente iperecogena attenuazioni del segnale presenza di un Tubercolo di Rokitansky capelli ( Dermoid Mesh)

Teratoma cistico maturo massa iperecogena con “sbarramento” materiale sebaceopresenza di grasso

MR T1 e T2 “spheres floating” teratoma cistico maturo

MR infarto da torsione di teratoma cistico maturo

US Performance in diagnosis of MCT

Author Year N Cases MCT Sens Spec PPV NPV

Kurijak 1997 887 102 93.1% 99.4% 95% 99.1%

Ekici 1996 1035 147 94% 99% ns Ns

Patel 1998 252 74 85% ns 98% Ns

Guerriero 1997 83 14 93% 100% 100% 99%

Tan 2007 187 30 90%

Modified from Saba et al.:Eur.J.Rad. 2009

Teratoma immaturo Teratoma immaturo con calcificazioni

Benign MCT vs Malignant degeneration

• The appearence of malignant degeneration is similar to benign but with more solid components

• Surface of dermoid is smooth whereas m.d. has septa

Take home

Color Doppler image of vascularity in solid papillary

intratumoral blood flow on color

Doppler

Dysgerminomi US

Doppler and color positive

Solid mass with hypoechoid and irregular septa

Lobelike divided

Markers

Ultrasound characteristics can be used

to categorize ovarian and adnexal masses,

and pattern recognition can accurately diagnose

some of the classic-appearing nonneoplastic

entities, benign neoplasms, and malignancies.

Often, however, the sonographic appearance of an ovarian mass is not pathognomonic

IOTA group

CONCLUSION. Ultrasound characteristics can be used to diagnose the classic-appearing nonneoplastic entities, benign neoplasms and malignancies. In cases in which the appearanceof an ovarian mass is not classic, assignment of relative risk of malignancy using a multiparametric model is appropriate and beneficial for patient management.

Conclusioni

Collaborative Trial of Ovarian Cancer Screening (UKCTOCS),

the largest study of its kind to date. 202 638 post-menopausalwomen aged 50–74 years were randomly assigned to no treatment (control), annual multimodal screening by serum CA125 assay and transvaginal ultrasound (MMS), and transvaginal ultrasound screening alone (USS).

From these preliminary results it might be speculatedthat MMS will be the preferred screening strategy, ifthe completed UKCTOCS study shows that it has hada signifi cant eff ect on mortality when it is concludedin December, 2014.

Hopefully in the near future new molecular markers for early stage ovarian cancer will be discovered

Ignace Vergote*, Frédéric Amant, Lieveke Ameye,Dirk Timmerman

When the going gets tough, the toughs get going!

John BelushiAnimal House , 1980

EpidemiologiaM.O.G.T.s (malignant ovarian germ cell tumors)

• 1-2% di tutte la patologie maligne ovariche• 20-25% di tutte le forme ovariche ma solo 3-5% sono maligne• 58% delle forme sotto i 20 anni

Tra 1973 e 2002 :1262 casi di MOGTs di cui

32.8% disgerminomi

35.6% teratomi immaturi con deg. Maligne

28.7% forme misti

MCT

• 10-20% di tutte le neoplasie ovariche• Spesso asintomatici e casualmente repertati• 20% di complicanze anche gravi: torsione,

rottura, infezione trasformazione maligna

• I teratomi cistici maturi superiori a 6 cm hanno maggiore probabilità di andare incontro a torsione

• Influenzano anche la posizione dell’utero “stirato” verso la torsione

Teratomi immaturi

• I teratomi immaturi hanno dimensioni medie superiori 14-25 mm

• Sono misti con aree solide e cave• Spesso perforazione della capsula• Spesso associati con teratomi cistici maturi• Quadri US aspecifici

The ultimate approach to prospectively predicting ovarian malignancy by ultrasound should include a universal consensus of the clinical and sonographic risk parameters among radiologists and gynecologists and gynecologic oncologists with a multiparametric model that has an organized, coordinated template that is generally used, easily applied, and offers clear interpretations of relative risk.

Disgerminomi

• 45% di tutti i GCT• 1% delle forme maligne dell’ovaio• 10-20% bilaterali• Prognosi buona

US e patologia ovarica

Conclusioni

• Should be recommended use of preoperative investigations, including US and Markers

• Masses exceeding 8 cm, US solid are suspect

Fetiform Teratoma (Homunculus)Jason R. Weiss, DO, Jeanette R. Burgess, MD, and Keith J. Kaplan, MD

Color Doppler Flow: mixed tumor

Classificazione Tumori Germinali

• Teratoma Maturo Cistico• Yolk Sac• Teratoma Immaturo• Disgerminoma• Teratoma Cistico Maturo con trasformazione

maligna

Diagnosi diff

• Coaguli endoluminali in cisti emorragiche• Anse intestinali• Appendici perforate• cistoadenofibromi

Manifestazioni Eco dei teratomiApparenza cistica 73% dei teratomi maturi

Apparenza cistica 18% dei teratomi immaturi

Apparenza solida e mista 82% dei teratomi immaturi

Non ausilio diagnostico da età,lato, dimensioni massime

Imaging of Ovarian TeratomaCan Ass of Radiologist Journal ;2010, 61

Origine dei markers

• Ca125 deriva da epitelio celomatico( Mulleriano, peritoneale, pleurico, pericardico) Ca 19-9 deriva dal Gruppo Lewis del sangue

• I tumori germinali dell’ovaio contengono cellule di derivazione ovarica

• Molti markers quindi sono attesi positivi• Seppure la diagnostica per immagini può fare diagnosi

della massa , l’uso dei markers può essere di grande aiuto o dirimente nell’analisi della origine del tumore

• I GCT hanno una incidenza dello 0,41/10000• 40 volte meno dei tumori epiteliali• Sono dunque molto rari

MAPoiché sono spesso curabili e quasi sempre giovanili

questo li rende molto importanti ed interessanti Sotto ai 25 anni rappresentano tra il 46 e il 58% di tutte le

forme ovariche

….. e l’1-2% di tutte le forme maligne

Young Patients • excellent prognosis• high fertility expectancy• Feasible fertility sparing surgery• Concern about chemotherapy long-term

effects

Teratomi cistici maturi 1

• La maggior parte dei teratomi cistici maturi possono essere diagnostiati agli U.S. ma hanno una grande varietà di quadri ecografici

• Gli aspetti ecografici dei teratomi immaturi sono aspecifici , lesioni parzialmente solide di solito con calcificazioni sparse

Teratomi cistici maturi 2

Manifestazioni tipiche :

• Lesione cistica ben delineata con area iperecogena solida , tubercolo di Rokitansky

• Livelli di grasso liquido• Massa parzialmente ecogena con un’area che determina

“sbarramento” agli ultrasuoni• Dermoid Mesh : sottili linee iperecogene mobili ( capelli)• Icerberg sign : iperecogenicità con ombra acustica posteriore

• A teratoma is an encapsulated tumor with tissue or organ components resembling normal derivatives of all three germ layers.

• teratomas have been reported to contain hair, teeth, bone and very rarely more complex organs such as eye,[1][2] torso,[3][4] and hands, feet, or other limbs.[5]

• A mature teratoma is typically benign and found more commonly in females, while an immature teratoma is typically malignant and is more often found in males.

• Teratoma qualifies as a rare disease, but is not extremely rare.

disposizione dei vasi all'interno delle ovaie (pericistica, periferica, centrale, o all'interno di setti e vegetazioni); tipo di vascolarizzazione (nessuna evidenza di vasi, vasi ad andamento lineare, vasi di piccole dimensioni distribuiti in maniera disordinata); valutazione dell'indice di resistenza (8),infatti,analizzando la resistance index (RI) e la pulsatility index (PI) e the peak systolic velocità (PSV) si osserva una significativa riduzione nei teratomi maligni.

doppler