GERM CELL TUMOURS OF OVARY BY DR SREELASYA KAKARLASri Siddhartha Medical College And Research Hospital , Tumkur

• Germ cell-• A germ cell is any biological cell that gives rise to the gametes of an organism

that reproduces sexually.

• Germ cell tumors are composed of a number of histologically different tumor types derived from the primitive germ cells of the embryonic gonad.

Basis of germ cell tumors 1. The common histogenesis of these neoplasms.2. The relatively frequent presence of histologically different

neoplastic elements within the same tumor.3. The presence of histologically similar neoplasms in

extragonadal locations along the line of migration of the primitive germ cells from the wall of the yolk sac to the gonadal ridge.

4. The remarkable homology between the various tumors in the male and the female. Eg.seminoma to dysgerminoma.

• Germ cell tumors presumed to derived from the pathogenic transformation of ovarian germ cells being unique in the fact that they recreate, however imperfectly, aspects of human development.

• Germ cell tumors• Germ cell tumors arise from the ovary's germinal elements

and comprise a third of all ovarian neoplasms.• The mature cystic teratoma, also called dermoid cyst, is by

far the most common subtype. • This accounts for 95 percent of all germ cell tumors and is

clinically benign

• Seen most frequently from the first to the sixth decades(even during fetal life). • In children and adolescents, more than 60% of ovarian neoplasms are of germ

cell origin, and one third are malignant. • Malignant ovarian germ cell tumors occur in the first four decades and are

rare thereafter.• 90% are pure type and rest are mixed.

• Three features typically distinguish malignant germ cell tumors from epithelial ovarian cancers.• 1) Individuals typically present at a younger age, usually in their teens

or early twenties. • 2) most have stage I disease at diagnosis. • 3) prognosis is excellent—even for those with advanced disease—due

to exquisite tumor chemosensitivity.

Primitive germ cell tumors

Dysgerminoma • Most common of the primitive germ cell tumors / most common

malignant ovarian germ cell neoplasm• 0.9 and 2% of all ovarian malignancies.• Three quarters of the patients are between 10 – 30 years old• Median age is about 20 yrs.• Few occur under age6 or over age 60• Only 4% of the patients are over 40 yrs.

• It is rare in infants but it is the most common ovarian malignancy of children, adolescents and pregnant women• 17% of dysgerminomas are associated with pregnancy.• It is the most common associated with gonadoblastoma in dysgenetic

gonads.• Bilateral ovarian involvement is seen in 15-20% cases.• Ovarian counterpart of testicular seminoma.• Elevated serum LDH at presentation

RISK FACTORS• 5% of dysgerminomas are discovered in phenotypic females with

karyotypically abnormal gonads, specifically, with the presence of a normal or abnormal Y chromosome

Turner syndrome mosaicism (45,X/46,XY), Klinefelter syndrome (46,XY, male pseudohermaphroditismSwyer syndrome (46,XY, puregonadal dysgenesis)

• The dysgenetic gonads of these individuals often contain gonadoblastomas, which are benign germ cell neoplasms.• These tumors may regress or alternatively may undergo malignant

transformation, most commonly to dysgerminoma. • Because approximately 40% of gonadoblastomas in these individuals

undergo malignant transformation, both ovaries should be removed.

• Radiosensitive • Composed entirely of germ cells that show morphologic,

ultrastructural, and histochemical similarity to primordial germ cells

CLINICAL FEATURES.• The signs and symptoms associated with these tumours are varied, but in

general, most arise from tumour growth and hormones the tumour produces.• Presentation over half the patients is non specific, • Most common presentation is abdominal enlargement and presence of a

mass in the lower abdomen, sometimes with abdominal pain and weight loss.• Duration of symptoms : 1month- 2 years,• Less than 4 months In half of the patients.• If discovered during pregnancy, the tumour is usually an incidental finding, or

it may obstruct labour.

• Menstrual abnormalities are uncommon in younger women with dysgerminoma.• About 10 % of the patients are asymptomatic,• Children may have isosexual precocious puberty or virilization,• The former is associated with positive pregnancy test.• About 2% of non pregnant women have positive pregnancy test from

hCG production by isolated syncitiotrophoblastic cells with in the tumour.

•FIGO STAGING

•STAGE 1 : Tumour confined to the ovaries

• 1A – Tumour limited to one ovary, capsule intact, no tumour on surface, negative washings• 1B – Tumour involves both ovaries otherwise like 1A• 1C – Tumour limited to one or both ovaries• 1C1 - Surgical spill• 1C2 - Capsule rupture before surgery or the tumour is on the

ovarian surface• 1C3 – Malignant cells in the ascites or peritoneal washings

•STAGE II : Tumour involves one or both ovaries with pelvic extension [below pelvic brim] or primary peritoneal cancer

• IIA – Extension and/or implant on uterus and/or fallopian tubes

• IIB – Extension to other pelvic intraperitoneal tissues

• STAGE III : Tumour involves one or both ovaries with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes

• IIIA [Positive retroperitoneal lymph nodes and/or microscopic metastasis beyond the pelvis]

• IIIA1 - Positive retroperitoneal lymph nodes only• IIIA1(i) – Metastasis ≤ 10mm• IIIA1(ii) – Metastasis > 10mm

• IIIA2 - Microscopic, extrapelvic [above the brim] and peritoneal involvement +/-

positive retroperitoneal lymph nodes

• IIIB - Macroscopic, extrapelvic, peritoneal metastasis ≤ 2cm +/- positive retro peritoneal lymph nodes.

Includes extension to capsule of liver or spleen.

• IIIC - Macroscopic, extrapelvic, peritoneal metastasis > 2cm +/- positive retro peritoneal lymph nodes. Includes extension to capsule of liver and spleen.

•STAGE IV : Distant metastasis excluding peritoneal metastasis

• IVA - Pleural effusion with positive cytology• IVB - Hepatic and/or splenic parenchymal metastasis,

metastasis to extra abdominal organs [including inguinal lymph nodes and lymph nodes outside the abdominal cavity.]

Dysgerminoma gross features

• Variable size• Solid, fleshy tumour with a smooth

lobulated exterior.• Capsulated.• Firm consistency.• Uniform, pale tan to gray-pink cut surface.• Areas of cystic degeneration, necrosis, and

hemorrhage are occasionally present.• Focal calcification at the periphery

suggests gonadoblastoma.• Dysgerminoma contains other malignant

germ cell elements upto 1/5th of cases.

Dysgerminoma microscopy• Identical to • Seminoma of the testis, mediastinum, sacrococcygeal area, pineal region.

• Pattern- • Composed of aggregates, islands, or strands of large uniform cells

surrounded by varying amounts of connective tissue stroma containing lymphocytes (T).• Composed of cells that resemble primordial germ cells, morphologically,

histochemically and ultrastructurally, but tend to be smaller.• Cells are round or polygonal and are about 20µ in diameter.• When the cells are well fixed, they prominent vesicular nucleus

containing one or more large eosinophilic nucleoli.

• Cytoplasm is clear or slightly granular, contains glycogen and gives positive periodic acid Schiff stain and positive alkaline phosphatase reactions.• A vague glandular trend may be evident in some tumours, reflecting

differentiation towards embryonal carcinoma.• Immunokeratin stains are usually negative.• Negative for AFP and hCG , but positive for placental alkaline

phosphatase.

• In 2-3 % of dysgerminomas , rare giant cells resembling syncitiotrophoblasts are present.• Hcg has been demonstrated by immunoperoxidase reaction .• About 20 % dysgerminomas contain foreign body type giant cells

which like the presence of a diffuse lymphocytic infiltrate, correlate with a better prognosis.

• A rare subtype, anaplastic dysgerminoma, is analogous with anaplastic seminoma of the testis.• It has a overall pattern of a dysgerminoma but with more cellular

pleomorphism , multinucleated cells and increase numbers of mitoses.

• LDH, PLAP, Ca 125 may be elevated and in some instances , can serve as tumour markers.• LDH in particular has been successful in predicting recurrence in

dysgerminomas.

• Tumor is composed of large aggregates of uniform cells

• Tumor is composed of trabeculae of tumor cells surrounded by connective tissue stroma containing lymphocytes

• Tumor cells show centrally placed nuclei with delicate cytoplasmic membranes.• Prominent nucleoli seen

• Special stain• glycogen in cytoplasm of the tumor cells is PAS+ and removed by

diastase digestion

• IHC stains• PLAP (cytoplasmic and membrane staining)• OCT4 i.e. Octamer-binding transcription factor (nuclear staining),• D2-40 (podoplanin), SALL4, CD117 (c-kit) (membranous staining)

• 1-OCT4• 2-CD 117• 3- PLAP (placental alk

phos)

1, 2

• Malignant, slow growing neoplasm, less aggressive• Lymph node metastasis common to iliac artery and para

aortic lymph nodes• Direct extension by rupture of capsule, leading to adhesions

to nearby structures• Hematogenous spread occurs late, to liver, lungs, bones.• It is highly chemosensitive and radiosensitive.

DIAGNOSIS• Adnexal masses measuring ≥ 2cm in premenarcheal girls or ≥ 8cm in

other premenopausal patients will usually require surgical exploration• For young patients, blood tests should include serum hCG and AFP

and LDH.• A CT scan of chest is important because germ cell tumours can

metastasize to mediastinum or lungs.• Karyotype to be obtained pre-operatively for all pre-menarcheal girls

because of the propensity of these tumours to arise in dysgenetic gonads.

• A Pre-operative CT or MRI may document the presence and extent of retro-peritoneal lymphadenopathy or liver metastasis.

MANAGEMENT• The treatment of patients with early dysgerminoma is primarily

surgical including the resection of the primary lesion and proper surgical staging.• Chemotherapy is administered to metastatic disease.• Because the disease principally affects girls and young women ,

special consideration must be given to the preservation of fertility and use of chemotherapy whenever possible.

• Minimal surgical operation for ovarian dysgerminoma is a unilateral oophorectomy.• If there is a desire to preserve fertility , as there almost always is the

contralateral ovary, fallopian tube and the uterus should be left insitu even in the presence of metastatic disease4 because of the sensitivity of the tumour to chemotherapy.• If fertility need not be preserved it may be appropriate to perform a

total abdominal hysterectomy and bilateral salpingo oophorectomy for patients with advanced disease.

• For patients whose karyotype analysis reveals Y chromosome, both ovaries should be removed, although the uterus may be left insitu for possible future embryo transfer.• In patients, in whom neoplasms appears on inspection to be confined

to the ovary, a careful staging operation should be undertaken to determine the presence of any occult metastatic disease.• All peritoneal surfaces should be inspected and palpated and any

suspicious lesions should be sampled for biopsy.

• Unilateral pelvic lymphadenectomy and careful palpation and biopsy of enlarged paraaortic nodes are particularly important parts of staging.

• Dysgerminoma is the only germ cell tumour that tends to be bilateral, excisional biopsy of an suspicious masses is desirable.• If a small contralateral tumour is found, it may be possible to resect it

and preserve some normal ovary.

• The traditional approach for all patients with metastatic dysgerminoma has been abdominal hysterectomy and bilateral salpingo-oophorectomy followed by radiotherapy.• Standard RADIOTHERAPY programme consists of treatment of the

whole abdomen in a dose of approximately 20Gy either by the moving strip technique with a Cobalt-60 unit or • With open field technique employing a 25MeV photon beam .• Additional 15Gy is delivered to the pelvis .

• If paraaortic nodal disease is present as documented at surgery or by lymphangiography, a 10-15 Gy boost is administered to the para aortic field.• Following a gap of 4 weeks, the mediastinum and supraclavicular

areas receive 25Gy over 3 week period.

CHEMOTHERAPYPlatinum based chemotherapy is regarded as treatment of choice.The obvious advantage is the preservation of fertility.The most frequently used chemotherapeutic regimen is BEP.Bleomycin : 15 units/m2/week x 5 ; Etoposide : 100mg/m2/day x 5 days every 3 weeksCisplatin : 20mg/m2/day x 5 days or 100 mg/m2/day x 1day every 3weeks.Other regimens are EP or EC (etoposide and carboplatin)

RECURRENT DISEASE• About 75% of recurrences occur within the first year after initial

treatment.• Most common sites; Peritoneal cavity, Retroperitoneal Lymph Nodes.• Treatment: Chemotherapy.• Patients with recurrent disease who had no therapy other than

surgery should be treated with chemotherapy.

• If prior chemotherapy with BEP regimen was given, there are number of second line options including • TIP [Paclitaxel, Iphosphamide, Cisplatin] or• VIP [Vinblastine, Iphosphamide, Cisplatin]

• Radiation therapy is effective for this disease with a major disadvantage being loss of fertility if pelvic and abdominal irradiation is required.

DYSGERMINOMA IN PREGNANCY• Because dysgerminomas tend to occur in young patients, they may

coexist with pregnancy• When a stage 1A cancer is found, the tumour can be removed intact

and pregnancy continued.• For the patients with more advanced disease, continuation of

pregnancy depends on the gestational age of the foetus• Chemotherapy can be given in the second and third trimesters in the

same dosages, as given for the non-pregnant without apparent detriment to the foetus

Survival RatesDYSGERMINOMA

STAGE AT DIAGNOSIS

I 66%

II- IV 34%

FIVE – YEAR SURVIVAL

Stage I 99%

Stage II-IV >98%

WILLIAMS GYNECOLOGY 3RD EDITION

Endodermal sinus tumor

• Also termed Yolk sac tumor because they are derived from primitive yolk sac• Third most frequent Malignant germ cell tumour of ovary.• Represents about 1% of all ovarian malignancies. • Second most common malignant ovarian germ cell neoplasm• Common age-• Median age of 16 to 18 years.• About one-third of the patients are premenarcheal at the time of

diagnosis.

• Usual presentation is abdominal pain with a large abdominal or pelvic mass, commonly with extraovarian spread (peritoneum, retroperitoneal nodes) or pelvic pain.• Usually the presentation is acute.• Half of the patients have symptoms for 1 week or less.• Patients usually do not have endocrine or menstrual abnormalities.• Serum hCG is not elevated.• Tumor marker- elevated serum AFP is almost always present; a very high level is

suggestive of the diagnosis

Gross features• It is unilateral in 100% of cases therefore biopsy of opposite ovary is

contraindicated.• Usually large, oval shaped, encapsulated, firm, and gray-brown.• Majority being over 10cm in diameter.• Cut surface- solid and cystic(containing gelatinous fluid) with necrosis and

hemorrhage. [These often lead to rupture and spillage at the time of surgery]• Tumor may form adhesions to the surrounding structures and invade them

YST microscopy patternsPattern Features

Microscystic or reticular

Composed of a loose network of small cystic spaces forming a honeycomb pattern. The microcysts are lined by flat cells with pleomorphic,hyperchromatic nuclei

Macrocystic

Myxomatous Small collections of epithelial-like cells forming strands or gland like structures are seen within abundant myxomatous tissue

Solid

Endodermal sinus Composed of perivascular formations, consisting of a narrow band of connective tissue with a capillary in the center and lined by a layer of cuboidal or low columnar epithelial-like cells. The cells have large,vesicular nuclei and prominent nucleoli. These structures are known as sinuses of Duval or Schiller– Duval bodies. The presence of these structures can be considered diagnostic of yolk sac tumor, but their absence does not exclude the diagnosis.

YST microscopy patternsPattern Features Alveolar-glandularPolyvesicular composed of numerous small vesicles surrounded by connective tissuePapillary

Hepatoid Composed of solid aggregates or cords of polygonal cells with even orgranular eosinophilic cytoplasm resembling hepatocytes. Hyaline bodies may be present.

Glandular or primitive endodermal

YST microscopy

• Cell features• Cytoplasm-moderate amount, pale to clear• Nucleus- hyperchromatic, irregular• Nucleoli- prominent• Mitoses common.

• The cells lining microcystic spaces may be flattened and less obviously malignant in appearance.

• Schiller–Duval bodies (SDBs)• in only 20% of tumors• rounded to elongated papillae with a fibrovascular core ensheathed by primitive columnar

cells. • The papilla may occupy a space lined by cuboidal, flat, or hobnail cells. • SDBs are usually sparse, but when numerous, create a distinctive ‘endodermal sinus’ pattern.

• Eosinophilic, PAS-positive, diastase-resistant hyaline bodies of different sizes are present in most YSTs, being most numerous in areas with a reticular or hepatoid pattern.

• Microcystic pattern

• Schiller-Duvall bodies

• Special stains• PAS-positive, diastase-resistant hyaline bodies

• IHC stains• AFP-cytoplasmic,patchy• Alpha antitrypsin1• SALL4• Glypican 3-cytoplasmic• AE1/AE3-cytoplasmic• LIN28

Clinical behavior• Highly malignant neoplasm, with early metastasis and invasion

of surrounding structures.• Lymphatic spread -paraaortic and common iliac lymph nodes

and later supraclavicular nodes.• Hematogenous spread- late to lungs, liver etc.• Early recurrences common even after complete excision.• Serial serum AFP measurements are used for monitoring

therapy and for early detection of metastasis and recurrences.

• Adverse prognostic factors -stage II or greater, gross residual tumor after cytoreductive surgery, and liver involvement.

• Stage I – 71%• Stage II – 6%• Stage III – 23%

TREATMENTSURGERY :-• Consists of surgical exploration, Unilateral Salpingo-oophorectomy and a frozen

section for diagnosis.

• About a quarter of tumours are ruptured before of during surgery.

• Any gross metastasis should be removed, if possible but thorough surgical staging is not indicated because all patients need chemotherapy.

• Involvement of the contralateral Ovary does not occur in the absence of peritoneal spread

CHEMOTHERAPY• All patients with endodermal sinus tumour are treated with either

adjuvant chemotherapy or therapeutic chemotherapy.• Cisplatin containing combination chemotherapy with 3-4 cycles of BEP

should be used as primary chemotherapy

• The regimen which can be used is • VAC –• Vincristine 1-1.5mg/m2 on Day 1 every 4 weeks• Actinomycin D 0.5mg/day X 5days every 4 weeks• Cyclophosphamide 150mg/m2/day X 5days every 4 week

Survival RatesYOLK SAC TUMOUR

STAGE AT DIAGNOSIS

I 61%

II- IV 39%

FIVE – YEAR SURVIVAL

Stage I 93%

Stage II-IV 64-91 %

WILLIAMS GYNECOLOGY 3RD EDITION