Non-epithelial Ovarian Cancers

This blog post is based on the points taken from TOG article Non-epithelial Ovarian Cancers published in July 2021. This article provides a detailed review to understand the classification, diagnosis and management of all NEOCs with focus on MOGCTs and SCSTs. 

I hope you find this post helpful.

To access the original article : Click Here

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Introduction

Ovarian Cancer in UK

•   6th commonest cancer in women                     

•   Causes 4000 deaths per annum

Non-epithelial ovarian cancers NEOCs

•   uncommon form of ovarian tumor         

•   10% of all ovarian malignancies

•   NEOCs can present at ANY age

•   Classified into

•   Malignant Ovarian Germ Cell Tumors - MOGCTs

•   Sex Cord-Stromal Tumors - SCSTs

•   Ovarian Sarcoma

•   Small cell carcinoma of the ovary

Pathophysiology

•   Ovaries divided into cortex and medulla

•   Cortex made of ovarian follicles, interstitial gland cells & stroma

•   Surrounded by dense capsule and surface covered with surface epithelium (coelomic)

•   Epithelial ovarian tumors occur due to neomataplasia of surface epithelial cells

•   SCSTs arise from different cell types from primitive sex cords and stromal cells

•   Stromal cells include→ Theca cells, Fibroblasts & Leydig cells

•   Primitive sex cords include→ Granulosa & Sertoli cells

•   Germ cells arise from endodermal layer of the yolk sac

•   Most non-epithelial ovarian tumors arise from these above specific cells (germ cells, granulosa cells, theca cells, stromal fibroblasts and steroid cells)

 

Clinical Presentation

•   The commonest presenting symptoms — persistent abdominal distention, pelvic or abdominal pain, urinary urgency or frequency & menstrual irregularities

•   In female of ANY age presenting with complex ovarian mass — must consider NEOC as differential diagnosis

 

Classification of Non-epithelial Ovarian Cancer

Ref: TOG

MOGCTs    

•   Usually occur in premenopausal women

•   80% of preadolescent ovarian malignancies

•   Incidence    3.7 per 100 000 women per year

SCSTs                          can present at ANY age

•   Adult-type granulosa cell tumors mainly in peri-menopausal & postmenopausal 

•   Sertoli-Leydig cell tumor occur in young

•   Incidence    2.1 per 100 000 women per year

Malignant Germ Cell Tumors 

Dysgerminomas — nests of polygonal cells with prominent nucleoli and clear glycogen-filled cytoplasm

Immature teratomas — elements from all 3 germ layers

Yolk sac tumors — microscopically large, with extensive areas of necrosis and hemorrhage; Schiller-Duval bodies is pathognomic

Sex Cord-Stromal Tumors 

Granulosa cell tumors —large tumors with cystic/solid areas          associated with mutations in FOXL2 gene

Sertoli-Leydig tumors — resemble embryonic testis & cause virilisation   22% have heterozygous elements (mucinous glands)            60% exhibit DICER1 mutation

 

Diagnosis and Tumor Markers

•   TVS is the first line investigation for detecting malignancy

•   CT used for staging

•   MRI used when USG is inconclusive

•   Serum CA125, Lactic Dehydrogenase (LDH), Alphafetoprotein (AFP) & Human Chorionic Gonadotropin (HCG) should be measured in ALL women <40 years presenting with complex ovarian masses

•   CA125 to be checked in all postmenopausal 

•   Carcinoembryonic antigen (CEA) and CA19-9 can help in diagnosis of  mucinous or endometrioid epithelial ovarian tumors or Krukenberg Tumors

•   These are non-specific markers but their level correlates with staging and survival rates

Ref: TOG

CA125

•   Usually raised in epithelial ovarian cancers but only in 50% of early disease

•   Can also be raised in endometriosis, fibroids and pelvic infections

•   Not recommended for premenopausal women with simple ovarian cysts 

•   If taken level >200 U/ml to be discussed with gynaecological oncologist

•   In postmenopausal RMI to be calculated                  

•   Any score ≥200 CT abdomen & pelvis to be done     

•   Refer to MDT

SCSTs can present with hormone-mediated syndromes 

Hyper-estrogenic SCSTs — may present with precocious puberty, abnormal uterine bleeding or endometrial hyperplasia

Hyper-androgenic SCSTs — may present with defiminisation, hirsutism, irregular menstruation, hoarse voice or male-pattern baldness

Inhibin B

•   Expensive   

•   Not commonly used for diagnosis         

•   Part of follow-up protocols 

Staging and Prognosis

Ref: TOG

•   FIGO staging is used for classification

•   Full staging is done by surgical approach which includes omentectomy, biopsies of peritoneum and pelvic/para-aortic lymph nodes along with pelvic washings

•   In suspected NEOC — fertility-sparing surgery should be initial approach in girls, adolescents and women wanting to preserve fertility. 

•   Pre-operative investigations include TVS; CT thorax, abdomen & pelvis; CXR and blood tests (including appropriate tumor marker)

•   PET used in selected cases of germ cell tumors in case of inadequate surgical staging or for restating after adjuvant chemotherapy.

•   Must perform endometrial curettage in women with granulosa cell tumors

•   MOGCTs and SCSTs — highly sensitive to chemotherapy            

•   Can be successfully treated even in the advanced stage disease

•   Over-all 5 year survival >80% (despite lung or lymph node metastasis)

Ref: TOG

Ref: TOG

Management

•   Surgery & chemotherapy are cornerstones for treatment of NEOCs

•   Aim of surgery — to remove all visible deposits  

Fertility-conserving Surgery

•   As NEOCs are common in young so unilateral salpingo-oophorectomy is a common practice

•   Gold standard of management — full surgical staging

•   Surgery often carried out through open route — midline laparotomy

•   Laparoscopy may be useful in some cases—controversial (risk of spillage, inadequate staging and risk of port site metastasis)

•   After surgery, the quantity of ovarian reserve is affected but successful pregnancies rates comparable to women with both ovaries intact

•   Earlier menopause by one year in women with one ovary

 

Management of Malignant Germ Cell Tumors

•   MGCTs 1.5% of ovarian cancers in EU            100 cases per year in UK

•   60-70% diagnosed in early stage & treated with surgery ± chemotherapy

•   More sensitive to chemotherapy than SCSTs

•   As most patients are young — more focus on fertility-sparing surgery along with chemotherapy

•   Full staging can be associated with higher morbidity (if full lymphadenectomy done)

•   More recently focus on lesser degree of surgical staging 

Ref: TOG

•   Stage I cancer can be managed without chemotherapy Discuss with women the pros & cons of chemotherapy 

•   Relapse of stage 1a dysgerminoma      20% — most cured with salvage chemotherapy

Common adjuvant chemotherapy regimens

•   Standard treatment regimen: 3-4 cycles of EP or BEP

•   Etoposide & Cisplatin (EP) used in >40 yrs old

•   Bleomycine, Etoposide and Cisplatin (BEP) used in <40 yrs old

•   Side effects of BEP: ototoxicity & hearing loss, nephrotoxocity, pulmonary dysfunction, Raynaud’s phenomenon, avascular necrosis and secondary malignancies (especially Acute Myeloid Leukaemia)

•   Risk of gonadal dysfunction leading to iatrogenic menopause & sterility — POF 3% 

•   Possible to have successful pregnancies after chemotherapy 

 

Management of Sex Cord-Stromal Tumors

•   60-95% of all SCSTs diagnosed at early stage - Focus of treatment is surgery & chemotherapy

•   Advanced stage— more extensive surgery & adjuvant chemotherapy

•   SCSTs less chemo sensitive than MOGCTs 

•   Most with SCSTs are perimenopausal or postmenopausal

•   Full staging surgery recommended (including hysterectomy + BSO)

•   Fertility-sparing considered in individual bases

•   Chemotherapy regimens — same like MOGCTs    can also be treated with Carboplatin and Palitaxel 

Ref: TOG

 

Small Cell Carcinoma of Ovary- Hypercalcaemic Type (SCCOHT)

•   Aggressive tumors          Malignant Rhabdoid Tumors

•   Associated with deleterious mutations of SMARCA4 remodeling genes

•   Median age at presentation 24 years

•   Serum calcium increased in 2/3 of patients

•   Mostly unilateral  

•   50% have extra ovarian spread @ diagnosis

•   Chemosensitive but high risk of relapse

•   No clear recommendations for management 

•   Cisplatin and Etoposide are agents of choice

•   5-year survival 10% -most die within 2 years of diagnosis 

 

Ovarian Sarcoma

•   Very rare

•   Adenosarcoma & Carcinosarcoma - mixed epithelial and mesenchymal tumors (managed as epithelial ovarian cancers)

•   Carcinosarcoma is the most common subtype 

•   Non-epithelial ovarian sarcoma — angiosarcoms, leiomyosarcoma, liposarcoma and osteosarcoma

•   80% occur in postmenopausal            

•   Median age @diagnosis 63 years

•   Aggressive tumors & most present with distant disease

•   Commonly spread to liver, lungs and retroperitoneal lymph nodes

•   NICE recommends to manage in specialist sarcoma units which improves outcome           MDT

•   No clear consensus for treatment         localized manage with surgery      distant managed with chemotherapy (palliative)

•   Agents used are Cisplatin, Doxorubicin, Ifosfamide

•   Poor prognosis 

 

Active Surveillance and Follow-up

Ref: TOG

Germ Cell Tumors

•   Recurrence of MOGCTs usually occur early

•   Highest relapse in first 2 years 

•   Must follow active surveillance plan - 10 years  

•   Avoid pregnancy for first 2 years post-treatment 

 

Sex Cord-Stromal Tumors

 

Ref: TOG

•   Standard follow-up regimens to be followed - history, examination (including pelvic), serum markers

•   SCST relapse LATE        

•   Regular follow-up starts in 3rd year and continues indefinitely 

•   If lung metastasis suspected - CT chest abdomen & pelvis to be done

•   All patients with fertility-sparing surgery to have 6 monthly pelvic USGs

 

Hormone Replacement

•   In SCSTs → Avoid HRT  

•   In MOGCTs → Safe to use HRT & hormonal contraception

 

Psychological Support

•   Early involvement of Teenage and Young Adult services

•   Keep a holistic approach

 

Conclusion

·  NEOCs are a broad group of malignancies

·  Important to consider it as DD in young females with complex ovarian mass

·  MDT involvement is essential

·  Fertility-sparing surgery to be considered in those wishing to retain fertility

·  Referral for oocyte preservation to be considered and discussed