Ovarian TumoursOvarian Tumours

Kapila GunawardanaKapila GunawardanaM.B.B.S.,M.S.(Obs & Gyn), F.R.C.O.G.,F.C.O.C.(S.L )M.B.B.S.,M.S.(Obs & Gyn), F.R.C.O.G.,F.C.O.C.(S.L )

Consultant Obstetrician and GynaecologistConsultant Obstetrician and GynaecologistTeaching Hospital,Teaching Hospital,Peradeniya.Peradeniya.

Ovarian Ovarian TumoursTumours EpidemiologyEpidemiology EmbryologyEmbryology AetiologyAetiology Risk factorsRisk factors WHO classificationWHO classification Staging Staging Pathology of ovarian Pathology of ovarian

tumourstumours ScreeningScreening Natural historyNatural history

Prognostic factorsPrognostic factors Management (diagnosis & Management (diagnosis &

management)management) SurgerySurgery RadiotherapyRadiotherapy ChemotherapyChemotherapy HRT for post treatmentHRT for post treatment Immune therapyImmune therapy Gene therapy Gene therapy

WhyWhy is it important? is it important? Accounts for nearly 4% of all cancers occurring in womenAccounts for nearly 4% of all cancers occurring in women Leading cause of death from malignancies arising in the Leading cause of death from malignancies arising in the

female genital tractfemale genital tract Life time riskLife time risk in the general population is 1.5%in the general population is 1.5% with one affected family member is 4%with one affected family member is 4% with two affected family members is 7%with two affected family members is 7% with BRCA-1 & BRCA-2 gene mutation 16-65%with BRCA-1 & BRCA-2 gene mutation 16-65% Most fatal and most feared cancerMost fatal and most feared cancer The risk could be reducedThe risk could be reduced

EmbryologyEmbryology of the ovary of the ovary

Primitive gonads appear around the 5Primitive gonads appear around the 5thth week of IUL as the week of IUL as the gonadal ridge from the coelomic epithelium on the medial gonadal ridge from the coelomic epithelium on the medial aspect of the urogenital ridge.aspect of the urogenital ridge.

In the xx embryo , the cortex develop as the ovary and the In the xx embryo , the cortex develop as the ovary and the medulla regress to a small area.medulla regress to a small area.

The ovarian serosa is the direct descent of the coelomic The ovarian serosa is the direct descent of the coelomic epithelium and it give rises to epithelium and it give rises to endocervical,endometrial,endosalphinx and the endocervical,endometrial,endosalphinx and the epithelium of the urogenital system.epithelium of the urogenital system.

The undifferentiated serosal cells can undergo neoplastic The undifferentiated serosal cells can undergo neoplastic changes and lead to tumours of the above tissues. changes and lead to tumours of the above tissues.

Development of the ovaryDevelopment of the ovary

1. Cortical cords2. Degenerating mesonephric tubule3. Mesonephric duct4. Paramesonephric duct5. Degenerating medullary cords6. Surface epithelium

WHO Classification of ovarian tumoursWHO Classification of ovarian tumours

1.Epithelial tumours1.Epithelial tumours Benign,Boarderline tumours and Benign,Boarderline tumours and

Carcinomas Carcinomas 2.Sex cord and Mesenchymal tumours2.Sex cord and Mesenchymal tumours Benign,Boarderline tumours and Benign,Boarderline tumours and

carcinomascarcinomas3.Germ cell tumours3.Germ cell tumours Benign,Boarderline tumours and Benign,Boarderline tumours and

carcinomascarcinomas

WHO Classification,contWHO Classification,cont

1.EPITHELIAL TUMOURS1.EPITHELIAL TUMOURS

Serous tumoursSerous tumours Mucinous tumoursMucinous tumours Endometroid tumoursEndometroid tumours Clear cell tumoursClear cell tumours Brenner tumoursBrenner tumours Mixed tumoursMixed tumours Undifferentiated tumoursUndifferentiated tumours Unclassified epithelial tumoursUnclassified epithelial tumours Metastatic tumours Metastatic tumours

1.Epithelial tumours1.Epithelial tumours

ClassificationClassification Pathway of differentiation Pathway of differentiation Potential biologic behaviourPotential biologic behaviour

Epithelium of fallopian tube(serous tumours)

Endocervix (mucinous tumours)

Endometrium (endometroid tumours)

Urinary bladder (Brenner tumours)

Serous tumours – Serous cystadenomaSerous tumours – Serous cystadenoma

Reproductive yearsReproductive years

10% bilateral10% bilateral

Cystic and unilocularCystic and unilocular

No solid areasNo solid areas

Smooth inner and outer cystic Smooth inner and outer cystic

linings and clear serous linings and clear serous

contentscontents

Serous cystadenofibromaSerous cystadenofibroma

Size 1 - 20 cmSize 1 - 20 cm

Similar appearance to Similar appearance to

serous cystadenoma with serous cystadenoma with

clusters of small firm clusters of small firm

whitish noduleswhitish nodules

Serous tumour of low malignant potentialSerous tumour of low malignant potential (LMP, borderline tumours) (LMP, borderline tumours)

Mostly cystic Mostly cystic

Exuberant papillary projections Exuberant papillary projections

on inner/outer surfaceson inner/outer surfaces

Usually no necrosis or Usually no necrosis or

haemorrhagehaemorrhage

20-40% of cases have omental 20-40% of cases have omental

implantsimplants

Also pelvic, peritoneum, Also pelvic, peritoneum,

mesosalpinxmesosalpinx

Serous carcinomaSerous carcinoma

Commonest primary Commonest primary

malignant ovarian malignant ovarian

neoplasmneoplasm

40-60 years40-60 years

50% bilateral50% bilateral

Serosanguinous fluid, Serosanguinous fluid,

friable haemorrhagic friable haemorrhagic

cyst contentscyst contents

Mucinous tumours – Mucinous Mucinous tumours – Mucinous cystadenomacystadenoma

Reproductive age

5% bilateral

Cystic and

multilocular, smooth

lining, thick mucinous

contents

Large in size : 1 - 50 cm

WHO Classification - contWHO Classification - cont

2 .2 .SEX CORD STROMAL(GONADAL) TUMOURSSEX CORD STROMAL(GONADAL) TUMOURS

Granulose theca cell tumoursGranulose theca cell tumours Sertoli-Leydig cell tumourSertoli-Leydig cell tumour Malignant thecomas(Gynandroblastomas)Malignant thecomas(Gynandroblastomas)

SCST with ovarian differentiationSCST with ovarian differentiation Adult granulosa cell tumoursAdult granulosa cell tumours

95% post pubertal95% post pubertal 50% post menopausal50% post menopausal 5% bilateral5% bilateral Frequently associated with Frequently associated with

hyperoestrogenismhyperoestrogenism(DUB, endometrial (DUB, endometrial hyperplasia and even hyperplasia and even carcinoma)carcinoma)

Prognostic factors- Prognostic factors- size(<5cm-100%, 6-size(<5cm-100%, 6-

15cm- 60%,>15cm- 15cm- 60%,>15cm- 50%)50%)mitotic activitymitotic activitystage- best prognostic stage- best prognostic

indicatorindicatortumour rupturetumour rupture

SCST with testicular differentiationSCST with testicular differentiation

Sertoli leydig cell tumourSertoli leydig cell tumour Mixed cell typesMixed cell types 0.2% of ovarian tumours0.2% of ovarian tumours Reproductive ageReproductive age 50% androgenized, rare 50% androgenized, rare

estrogenic effectsestrogenic effects 1.5% bilateral1.5% bilateral Well differentiated tumours Well differentiated tumours

– good prognosis– good prognosis

FibromaFibroma

WHO Classification - ctdWHO Classification - ctd

3.3.GERM CELL TUMOURSGERM CELL TUMOURS DysgerminomasDysgerminomas Embroyonal (tumours of totipotential cells) carcinomasEmbroyonal (tumours of totipotential cells) carcinomas -Embroyonic-Teratomas(mature/immature)-Embroyonic-Teratomas(mature/immature) -Extra embryonic –Endodermal sinus tumours-Extra embryonic –Endodermal sinus tumours .Yolk sac and non-gestational choriocarcinomas.Yolk sac and non-gestational choriocarcinomas .Mixed germ cell tumours.Mixed germ cell tumours

2nd most common germ cell tumour2nd most common germ cell tumour Elevated AFP (alpha feto protein)Elevated AFP (alpha feto protein) MalignantMalignant RadioresistantRadioresistant UnilateralUnilateral

Endodermal sinus tumour (yolk sac tumours)

Large, solid and lobulatedLarge, solid and lobulated Grey white with necrosisGrey white with necrosis Schiller-Duvall bodies Schiller-Duvall bodies

(glomeruloid tufts)(glomeruloid tufts) Microscopic patterns- Microscopic patterns-

papillary, alveolar, papillary, alveolar, microcystic, cystic, solidmicrocystic, cystic, solid

Myxomatous, polyvesicularMyxomatous, polyvesicular PAS positive hyaline PAS positive hyaline

globulesglobules

Endodermal sinus tumour

(yolk sac tumours) cont.

TeratomaTeratoma

Derived from all three Derived from all three germ layers; ectoderm, germ layers; ectoderm, mesoderm and mesoderm and endodermendoderm

Variable according to Variable according to the degree of “maturity”the degree of “maturity”

Immature elements Immature elements show features of show features of primitive embryonic primitive embryonic tissuestissues

Metastatic carcinoma of the ovary

AetiologyAetiology Hereditary cancersHereditary cancers 10% occurs in women who carry mutations in cancer 10% occurs in women who carry mutations in cancer

susceptibility genes BRCA-1,BRCA-2(these are susceptibility genes BRCA-1,BRCA-2(these are tumour suppressor genes)tumour suppressor genes)

AetiologyAetiology - ctd - ctd Sporadic cancersSporadic cancers

-90% of the cases-90% of the cases -alteration of the p53 tumour suppressor is the most -alteration of the p53 tumour suppressor is the most

frequent genetic event frequent genetic event (amplification,overexpression,mutation and deletion)(amplification,overexpression,mutation and deletion)

Aetiology Aetiology

Incessant ovulationIncessant ovulation Gonadotrophin and sex hormone therapyGonadotrophin and sex hormone therapy -Inclusion cyst formation-Inclusion cyst formation -Repair of the germinal epithelium following -Repair of the germinal epithelium following

ovulationovulation -Persistent stimulation and exposure to -Persistent stimulation and exposure to

gonadotrophinsgonadotrophins and sex hormones(proliferation and mitotic activity)and sex hormones(proliferation and mitotic activity) -Theoretical risk of artificial ovulation induction -Theoretical risk of artificial ovulation induction

Risk factorsRisk factors Advanced age(average age is 60 yrs)Advanced age(average age is 60 yrs) -90%of the tumours occur among post menapausal -90%of the tumours occur among post menapausal femalesfemales -<40 yrs infrequent -<40 yrs infrequent -<30 yrs fewer than 3/100,00-<30 yrs fewer than 3/100,00 Caucasian 1Caucasian 1stst degree relative with Ca-3.5 fold risk degree relative with Ca-3.5 fold risk BRCA-1, BRCA-2 mutant genes (17q,13q)BRCA-1, BRCA-2 mutant genes (17q,13q) NulliparityNulliparity Early age of menarcheEarly age of menarche Late age of menopauseLate age of menopause Non usage of contraceptivesNon usage of contraceptives Personal or family history of breast, ovarian or colonic Ca Personal or family history of breast, ovarian or colonic Ca

(hnpcc)(hnpcc)

PREVENTION (FACTORS REDUCING THE PREVENTION (FACTORS REDUCING THE RISK FOR OVARIAN CANCER)RISK FOR OVARIAN CANCER)

““Reduction of ovarian cancer predominantly are associated Reduction of ovarian cancer predominantly are associated with reduction in the number of ovulatory cycleswith reduction in the number of ovulatory cycles

Prolong use of OCPProlong use of OCP Multiparity Multiparity Breast feeding Breast feeding Tubal legations Tubal legations Place of prophylactic oophorectomy (performed when she is Place of prophylactic oophorectomy (performed when she is

still in the reproductive age-specially with a family history of still in the reproductive age-specially with a family history of ovarian cancer. There is reduction in the incidence of ovarian ovarian cancer. There is reduction in the incidence of ovarian and breast cancer)and breast cancer)

Use of vitamin A derivativesUse of vitamin A derivatives ScreeningScreening

SCREENING FOR OVARIAN TUMOURSSCREENING FOR OVARIAN TUMOURSWHO CRETERIA FOR A SCREENING PROGRAMMEWHO CRETERIA FOR A SCREENING PROGRAMME

The condition should an important health problemThe condition should an important health problem There should be an accepted treatment for the patients with There should be an accepted treatment for the patients with

recognized diseaserecognized disease Facilities for diagnosis and treatment should be availableFacilities for diagnosis and treatment should be available There should be a recognized early stage of the diseaseThere should be a recognized early stage of the disease There should be a suitable testThere should be a suitable test The test should be acceptable to the populationThe test should be acceptable to the population The natural history of the condition should be well understoodThe natural history of the condition should be well understood There should be an agreed policy on whom to screen There should be an agreed policy on whom to screen It should be cost effectiveIt should be cost effective Case finding should be a continuning process Case finding should be a continuning process

OVARIAN TUMOUR SCREENING MULTI OVARIAN TUMOUR SCREENING MULTI MODELMODEL

ca 125 and vaginal scanning ca 125 and vaginal scanning Ca 125 >30 u\ml is abnormalCa 125 >30 u\ml is abnormalCa 125 is an antigen found in the foetal amniotic and coelomic epithelium.in Ca 125 is an antigen found in the foetal amniotic and coelomic epithelium.in

adults it is found in mesothelial cells of pleuraadults it is found in mesothelial cells of pleuraPericardium and tubal, endometrial, endocervical and the ovary.Pericardium and tubal, endometrial, endocervical and the ovary.The surface epithelium of normal foetal and adult ovaries does not express The surface epithelium of normal foetal and adult ovaries does not express

the antigen , except in inclusion cysts, papillae or metaplasiathe antigen , except in inclusion cysts, papillae or metaplasiaAn elevated level is found in 50% of stage 1 and >90% in women with An elevated level is found in 50% of stage 1 and >90% in women with

advanced disease.advanced disease.Sensitivity is 97%Sensitivity is 97%Specificity is 96%Specificity is 96%False positive in ca endometrium ca colon, endometriosis, fibroid, PID, False positive in ca endometrium ca colon, endometriosis, fibroid, PID,

pregnancy and menstruation pregnancy and menstruation

OVARIAN TUMOUR SCREENINGOVARIAN TUMOUR SCREENING-ctd-ctd

Ovarian volume >20ml in reproductive age, and Ovarian volume >20ml in reproductive age, and >8-10ml in post menopausal are abnormal.>8-10ml in post menopausal are abnormal.

Ultrasound findings (scoring system)Ultrasound findings (scoring system) VolumeVolume Thick wallThick wall SeptaeSeptae Solid areaSolid area Cystic areas with solid areasCystic areas with solid areas PapillaePapillae AscitisAscitis Secondary Secondary

Microscopic features suggestive of Microscopic features suggestive of Malignancy Malignancy

HyperchromaciaHyperchromacia PolychromasiaPolychromasia Nuclear atypiaNuclear atypia Increased nuclear Increased nuclear

cytoplasmic ratiocytoplasmic ratio Invasion of basement Invasion of basement

membranemembrane

Macroscopic features suggestive Macroscopic features suggestive of malignancyof malignancy

Cystic and solid areasCystic and solid areas Hemorrhagic areasHemorrhagic areas Necrotic areasNecrotic areas Increased vascularityIncreased vascularity Bilateral tumoursBilateral tumours Associated ascitisAssociated ascitis

SURGICAL STAGINGSURGICAL STAGING

Stage 1-growth limited to ovariesStage 1-growth limited to ovaries 1a growth limited to one ovary1a growth limited to one ovary 1b growth limited to both ovaries1b growth limited to both ovaries 1c tumour either 1a or 1b with any of the1c tumour either 1a or 1b with any of the followingfollowing - tumuor on the surface- tumuor on the surface - capsular rupture- capsular rupture - Ascitis containing malignant cells- Ascitis containing malignant cells - Positive peritoneal washings - Positive peritoneal washings

SURGICAL STAGING-ctdSURGICAL STAGING-ctd

Stage ii growth involving one or both ovaries with Stage ii growth involving one or both ovaries with pelvic extensionspelvic extensions

ii a extension or metastasis to the uterus or tubesii a extension or metastasis to the uterus or tubes ii b extension to other pelvic tissues ii b extension to other pelvic tissues ii c tumour either 1a or 1b with any of the following ii c tumour either 1a or 1b with any of the following -tumour on the surface-tumour on the surface -capsular rupture-capsular rupture -ascitis containing malignant cells-ascitis containing malignant cells -positive peritoneal washings-positive peritoneal washings

SURGICAL STAGING- ContSURGICAL STAGING- Cont

Stage iii growth involving one or both ovaries withStage iii growth involving one or both ovaries with peritoneal implants out side the pelvis or positive peritoneal implants out side the pelvis or positive

inguinal or retro-peritoneal nodes (superficial liver inguinal or retro-peritoneal nodes (superficial liver metastasis or histologically proven omental or bowel metastasis or histologically proven omental or bowel metastasis)metastasis)

iii a limited to true pelvis with negative nodes but iii a limited to true pelvis with negative nodes but with microscopically positive seedings with microscopically positive seedings

iii b tumour implants in the abdominal cavity<2cmiii b tumour implants in the abdominal cavity<2cm iii c tumour implants in the abdominal cavity >2cm iii c tumour implants in the abdominal cavity >2cm

with positive nodes with positive nodes

SURGICAL STAGING- ContSURGICAL STAGING- Cont

Stage iv growth involving one or both ovaries Stage iv growth involving one or both ovaries with distant metastasiswith distant metastasis

If pleural effusion is present there must be If pleural effusion is present there must be positive cytologypositive cytology

PROGNOSTIC FACTORSPROGNOSTIC FACTORS

Pathological factorsPathological factors -architecture and grade of lesion-architecture and grade of lesion -differentiation and anaplasia-differentiation and anaplasia Biological factors Biological factors - flow cytometry- flow cytometry - diploidy/anaploidy- diploidy/anaploidy Clinical factorsClinical factors

NATURAL HISORYNATURAL HISORY

2/3 of the patients present with advanced disease 2/3 of the patients present with advanced disease Pattern of spread-trans-coelomicPattern of spread-trans-coelomic -lymphatic-lymphatic -haematogenic-haematogenic stage i-5 years survival 90%stage i-5 years survival 90% stage ii-5 year survival 70%stage ii-5 year survival 70% stage iii& iv – 5 year survival 30%stage iii& iv – 5 year survival 30% Most of them succumb following anorexia, vomiting Most of them succumb following anorexia, vomiting

and catchexia and catchexia

MANAGEMENT MANAGEMENT DIADNOSIS, PRE-OPERATIVE DIADNOSIS, PRE-OPERATIVE ASSESMENT &TREATMENTASSESMENT &TREATMENT

DiagnosisDiagnosis -History-History -Examination-Examination -Investigation -Investigation Treatment optionTreatment option -Surgery-Surgery -Chemotherapy-Chemotherapy -Radiotherapy-Radiotherapy -Immunotherapy-Immunotherapy -Gene- therapy -Gene- therapy

DIAGNOSISDIAGNOSIS

HISTORYHISTORY -most women with epithelial tumours are -most women with epithelial tumours are

asymptomatic for a long duration asymptomatic for a long duration -often the symptoms are vague-often the symptoms are vague -irregular menstruation-irregular menstruation -bowel and urinary symptoms -bowel and urinary symptoms -distention, bloating,constipation,nausea,vomiting -distention, bloating,constipation,nausea,vomiting

and anorexia in advanced stagesand anorexia in advanced stages

DIAGNOSISDIAGNOSIS

EXAMINATION EXAMINATION - information about the tumour and the - information about the tumour and the

fitness for surgeryfitness for surgery - post-menopausal palpable ovary syndrome - post-menopausal palpable ovary syndrome - the presence of a pelvic mass (fixed, - the presence of a pelvic mass (fixed,

irregular, solid ,cystic and solid, bilateralirregular, solid ,cystic and solid, bilateral - if in additional, an upper abdominal mass - if in additional, an upper abdominal mass

or ascitis is present, the diagnosis of ovarian or ascitis is present, the diagnosis of ovarian malignancy is certain.malignancy is certain.

INVESTIGATIONSINVESTIGATIONS

Routine investigationRoutine investigation- Hb- Hb- UFR- UFR- FBS- FBS- BU\SE- BU\SE- LFT- LFT- ECG- ECG- CXR- CXR

INVESTIGATIONSINVESTIGATIONS

Special investigation Special investigation - Ca 125- Ca 125- Alpha feto protein- Alpha feto protein- Ultrasound scan- Ultrasound scan- CT scan- CT scan- MRI scan- MRI scan

PRE-OPERATIVE ASSESMENTPRE-OPERATIVE ASSESMENT

Optimize the healthOptimize the health- Correction- Correction- Medical fitness- Medical fitness- Anti-coagulation- Anti-coagulation

SURGICALSURGICAL MANAGEMENT MANAGEMENT

THE CORNER STONE OF THEREPY FOR OVARIAN THE CORNER STONE OF THEREPY FOR OVARIAN MALINANCY IS SURGERYMALINANCY IS SURGERY

SURGICALSURGICAL MANAGEMENT MANAGEMENT Conservative surgeryConservative surgery

-stage 1a-stage 1a-if the patient has not completed her family -if the patient has not completed her family

Radical surgeryRadical surgery-stage 1b-c-stage 1b-c

Cytoreductive surgeryCytoreductive surgery-advanced stage -advanced stage

Second look laparotomy/laparoscopySecond look laparotomy/laparoscopy Second cytoreductivesurgerySecond cytoreductivesurgery Salvage therapySalvage therapy

SURGICALSURGICAL MANAGEMENT MANAGEMENT ProcedureProcedure

- vertical abdominal incision- vertical abdominal incision- collect peritoneal fluid- collect peritoneal fluid- systematic exploration- systematic exploration- biopsies- biopsies- TAH+BSO- TAH+BSO- omentectomy- omentectomy- appendicetomy- appendicetomy- pelvic and para-aortic lymph node sampling- pelvic and para-aortic lymph node sampling

CHEMOTHERAPYCHEMOTHERAPY

Alkylating agents Alkylating agents -interfere with base pairing leading to inhibition of -interfere with base pairing leading to inhibition of DNA,RNA and protein synthesis (Cyclophoshamide, DNA,RNA and protein synthesis (Cyclophoshamide, melphalan, chlorambucil)melphalan, chlorambucil)

Anti-tumour antibiotics Anti-tumour antibiotics -Inserted between DNA base pairs -Inserted between DNA base pairs

(Bleomycin,Mitomycin)(Bleomycin,Mitomycin) Ante-metabolites(Methotrexate,5FU)Ante-metabolites(Methotrexate,5FU) Plant alkaloidPlant alkaloid -bind to vital intra-cellular micro-tubular proteins -bind to vital intra-cellular micro-tubular proteins

(Vincristine , vinblastine , paclitaxel)(Vincristine , vinblastine , paclitaxel)

CHEMOTHERAPYCHEMOTHERAPY

Early stage Early stage -stage 1a,1b,grade 1&2-stage 1a,1b,grade 1&2-no further adjuvant therapy is needed-no further adjuvant therapy is needed

Early stageEarly stage -1c or poorly differentiated-1c or poorly differentiated

-low risk-low risk-alkylating agents and plant alkaloids-alkylating agents and plant alkaloids

Advanced ovarian caAdvanced ovarian ca-carboplatin and paclitaxel – 3H every 3 weeks for 6 cycles-carboplatin and paclitaxel – 3H every 3 weeks for 6 cycles-single agent carboplatin-single agent carboplatin

RADIORADIO THERAPY THERAPY

Intra peritoneal radio-colloids (p53)Intra peritoneal radio-colloids (p53)

Whole abdominal radiationWhole abdominal radiation

IMMUNOTHERAPYIMMUNOTHERAPY

Biological response modifier therapyBiological response modifier therapy (corynebacterium parvum,BCD)(corynebacterium parvum,BCD)

-enhancement of host immune response & tumour rejection-enhancement of host immune response & tumour rejection Cytokines therapyCytokines therapy

-interferons,tumour necrosis factor-alpha, interleukin-2.-interferons,tumour necrosis factor-alpha, interleukin-2. Adaptive immunotherapyAdaptive immunotherapy

-infusion of LAK cells-infusion of LAK cells Intra-peritoneal gene therapy Intra-peritoneal gene therapy

-expression of cytokine genes or genetic -expression of cytokine genes or genetic immunopotentiation (enhancement of anti-tumour immune immunopotentiation (enhancement of anti-tumour immune response)response)

GENEGENE THERAPY THERAPY

Potential intervention at the molecular levelPotential intervention at the molecular level

Genetic immuno–potentiation Genetic immuno–potentiation