The 3 major types of ovarian tumors are epithelial, sex cord, and germ cell.

Epithelial cell tumors

represent the majority of all ovarian neoplasms (82%). Conversely, germ cell tumors (GCTs) are
rare, comprising approximately 20% of all ovarian tumors, both benign and malignant.
Approximately 3-5% of ovarian GCTs are malignant. The most commonly occurring GCT is the
dysgerminoma, which accounts for approximately 2% of all ovarian cancers.

Although rare, dysgerminomas are important irrespective of incidence because they most
commonly affect women of reproductive age (ie, < 30 y). In fact, dysgerminomas make up two
thirds of all malignant ovarian neoplasms in women younger than 20 years. Moreover, once
diagnosed, dysgerminomas respond well to therapy, potentially sparing patients from infertility
and early mortality.

Typically, germ cells are encapsulated at birth within the primordial follicle. If they somehow
escape encapsulation, cell death usually occurs. If the germ cells survive, rapid growth ensues,
owing to the lack of normal contact inhibition, hence germ cell tumor (GCT) formation. All
dysgerminomas are considered malignant, but only one third of dysgerminomas behave
aggressively. The exact etiology of dysgerminomas has not been determined, although recent
molecular studies have implicated loss of function with potential tumor suppressor gene
TRC8/RNF139 as a possible etiology.[1]

Additionally, 5% of all dysgerminomas occur in dysgenetic gonads and may be associated with
gonadoblastomas. Genetic disorders of the ovary are associated with karyotypic abnormalities
and are discussed in Dysgerminomas in patients with karyotypic abnormalities in Complications.
Epidemiology
Frequency

United States

The incidence of dysgerminomas has remained unchanged over the last 30 years. The
frequencies of the most common malignant ovarian neoplasms in women of reproductive age are
as follows: epithelial tumors (42%); dysgerminoma and other germ cell tumors (GCTs) (30%);
metastatic Krukenberg tumors (14%); and sex cord stromal tumors (ie, Sertoli-Leydig cell
tumors) (13%).

International

No data are available.

Mortality/Morbidity

The 5-year survival rate is 96% if the tumor is confined to the ovary and 63% if extension occurs
beyond the ovaries. Pregnancy does not alter the prognosis of most ovarian malignancies, but
complications such as torsion and rupture may increase the incidence of spontaneous abortion or
preterm delivery.

Race

To date, no racial predilection exists for ovarian germ cell tumors (GCTs).

Sex

These tumors mostly occur in women, although the disease also occurs in pseudohermaphrodites
and patients with gonadal dysgenesis (see Complications). Testicular seminomas are the male
histologic counterparts to dysgerminomas.

Age

Although most ovarian cancers occur during the menopausal and perimenopausal years (ie, 50-
59 y), dysgerminomas tend to occur frequently in the pediatric population. Dysgerminomas are
most commonly observed in younger women. Seventy-five percent of dysgerminomas occur in
patients in the third and fourth decades of life, with the mean age being 22 years.

History

No specific symptoms are diagnostic of dysgerminoma tumors. Many of the presenting

symptoms are universal for any adnexal/ovarian mass.
Most patients with dysgerminomas present with abdominal pain and a palpable abdominopelvic
mass.

Frequently associated symptoms include the following:

Pelvic fullness

Pain

Early satiety

Urinary frequency

Dysuria

Vague abdominal symptoms (eg, dyspepsia, digestive disturbances) are less common.

These tumors usually present as a unilateral mass and can occur during pregnancy.

These tumors can have rapid growth and predispose to rupture and torsion with associated acute
change in symptoms in approximately 5-10% of patients

Physical

The physical examination should be complete in order to look for signs of metastatic disease
outside the abdominal cavity, including lymphadenopathy, pleural effusions, and other focal
findings. Although not commonly seen with dysgerminomas, it may help in narrowing the
differential.

A thorough abdominal and pelvic examination on a gynecology table with stirrups should
include a careful rectovaginal examination because some enlarged adnexal masses can be
detected from this approach. Moreover, it may identify patients with irregularities of the sidewall
and cul-de-sac peritoneum

Causes

The exact etiology for this tumor type has not been elucidated.

Diagnostic Considerations
Gastrointestinal considerations are as follows:

Colorectal cancer
 Bowel/omental adhesions

Diverticula

Fecal impaction

Low-lying cecum

Genitourinary considerations are as follows:

Pelvic abscess

Uterine fibroids

Ovarian torsion

Benign ovarian cyst

Hydrosalpinx (salpingitis isthmic nodosum)

Retroperitoneal tumor

Bladder distention

Pelvic kidney

Urachal cyst

Differential Diagnoses
Ectopic Pregnancy

Laboratory Studies
Tests for pregnancy and sexually transmitted diseases

One should always initially obtain a pregnancy test. This test should be mandatory in any woman
of reproductive age, even at the extremes of reproductive age, who presents with abdominopelvic
symptoms.

Because dysgerminoma tumors affect women of a reproductive and sexually active age, cultures
for gonorrhea and chlamydia and a wet mount are recommended at the time of speculum
examination, especially if patients experience abdominopelvic pain and/or fevers. In this way,
sexually transmissible diseases may be detected and treated before surgery.

Once a pelvic mass is detected, especially in younger female patients, the standard workup for
suspected germ cell tumors (GCTs) requires lactate dehydrogenase (LDH), alpha-fetoprotein
(AFP), and beta-human chorionic gonadotropin (beta-hCG) levels. If any levels are elevated,
they may assist in diagnosis and/ or follow-up of women diagnosed with malignant ovarian
GCTs.

Other laboratory studies

Dysgerminomas have most commonly been associated with elevations in LDH, although it is not
elevated in all cases. Occasionally, dysgerminomas may become infiltrated with
syncytiotrophoblastic giant cells, which produce beta-hCG. Elevations in AFP are even less
common. However, preoperative evaluation of all of these markers is suggested in patients with
suspected ovarian GCTs/dysgerminomas. Additionally, serum inhibin levels can be useful in this
age group. Although inhibin B seems to be more sensitive and has a greater elevation in GCTs,
inhibin A can also be elevated with inhibin B or, more rarely, without elevation of inhibin B, as
sex cord stromal tumors are also in the differential for women in this age group who present with
pelvic masses.

Therefore, useful tumor markers for the workup of dysgerminomas include the following:

Beta-hCG

AFP

LDH

Inhibin A and B

Cancer antigen 125 (CA-125) - For epithelial tumors

Nuclear protein in the testis

A potentially useful test for ovarian germ cell tumors, including dysgerminomas, is
immunoreactivity of nuclear protein in the testis (NUT).[2] In situ and invasive germ elements of
dysgerminoma associated with gonadoblastoma were positive for NUT in a study that evaluated
NUT immunostaining in mature cystic teratomas and malignant ovarian germ cell tumors.[2]

Imaging Studies
Imaging should never replace a careful history and physical examination in evaluating a patient
with an ovarian mass. The initial approach should be an attempt to determine the nature and
extent of the mass.
Transvaginal ultrasound is a good preliminary imaging modality to determine if the mass is
ovarian and, more importantly, if it has any malignant features (eg, thickened septations, solid
and cystic components). Free abdominal fluid and bilateral masses heighten the suspicion of
malignancy. Occasionally, pelvic MRI may be necessary to better assess anatomy if a nonovarian
origin for the mass is suspected. CT scanning of the chest, abdomen, and pelvis are frequently
used to evaluate for metastasis.

Occasionally, patients may present with signs or symptoms of gastrointestinal or genitourinary

obstruction. In these cases, additional studies to consider in the workup include the following:

Barium enema

Upper gastrointestinal series

Colonoscopy

Intravenous pyelography (IVP) - No longer used if CT scanning is used

Procedures

Diagnosis of malignant ovarian tumors must be made surgically through either laparoscopy or
laparotomy. The appropriate surgical approach depends on findings from the clinical
examination, imaging, and laboratory workup, as well as index of suspicion for a malignancy.
Care should be taken not to rupture ovarian masses that are suggestive of malignancy. If
laparoscopy is undertaken and cyst drainage or morcellation is to be performed, the mass should
be placed into a laparoscopic bag to avoid tumor spillage or dissemination. Dysgerminomas, like
all ovarian cancers, are staged surgically.

Histologic Findings

Grossly, dysgerminomas have a solid texture, with a tan, fleshlike appearance. Microscopically,
dysgerminoma cells are round and ovoid and contain an abundance of clear cytoplasm secondary
to glycogen buildup. The nuclei are irregularly shaped and contain more than one prominent
nucleolus. These cells tend to coalesce, forming cords and sheets that are identified easily
through low-power magnification. Granulocytic and lymphocytic infiltration within the
intervening fibrous stroma and granulomatous changes also can be observed. Interestingly, cystic
teratomas occasionally have small nests of dysgerminomatous tissue and vice versa. Additional
assays detecting transcription factors GATA-4, Ihh, and BMP-2 may also prove useful in
differentiating between dysgerminoma and other germ cell tumors.

Note the image below.

 Ovarian dysgerminomas.
Microscopic image at 20 X.

Staging
International Federation of Gynecology and Obstetrics (FIGO) staging

Stage I (as follows) - Limited to ovaries:

Ia - Limited to one ovary

Ib - Limited to both ovaries

Ic - Ascites with malignant cells on peritoneal washings or extension beyond the capsule
in either Ia or Ib

Stage II (as follows) - Pelvic extension:

IIa - Involvement of uterus or fallopian tubes

IIb - Extension to the bladder or rectum

IIc - Stage IIa or IIb but with positive peritoneal washings

Stage III (as follows) - Peritoneal implants outside of pelvis:

IIIa - Microscopic seeding of abdominal surfaces, implants < 2 mm

IIIb - Abdominal peritoneal implants >2 mm and < 2 cm

IIIc - Abdominal implants >2 cm or positive lymph nodes (pelvic, paraaortic, or inguinal)
Stage IV (as follows) - Distant metastases:

Pleural effusions - Must confirm with positive cytology to be deemed stage IV

Any involvement of the liver parenchyma

Medical Care
A preponderance (75-80%) of dysgerminomas present as stage I cancers and, therefore, can be
treated by surgical resection alone with a unilateral salpingo-oophorectomy and staging. This is
preferred when attempting to preserve fertility; however, diligent follow-up care, with serial
pelvic examinations and tumor markers (ie, beta-human chorionic gonadotropin [beta-hCG],
alpha-fetoprotein [AFP], lactate dehydrogenase [LDH]) is mandatory if resection is the only
treatment modality.

Adjuvant therapy should be reserved for women with stage Ib-IV ovarian dysgerminomas.
Platinum-based chemotherapy has become the standard of care for these patients and is generally
well tolerated. Radiation therapy has also been administered to patients with stage I-III tumors,
with excellent response rates overall. However, this has been mostly abandoned due to high
success rates with platinum-based chemotherapy, as well as avoiding long-term complications
from radiation, including sterility and early menopause.

Stage Ia dysgerminomas

Typically, the authors do not recommend any adjuvant chemotherapy for stage Ia
dysgerminomas. Although 10-15% of stage Ia tumors may recur, essentially all of them are
salvaged with chemotherapy. Patients with completely resected stage Ib and Ic tumors should
receive 3 cycles of BEP (bleomycin, etoposide, platinum), and those with completely resected
stage II-IV tumors should receive 4 cycles of BEP. Patients with bulky residual disease may
require additional cycles. However, care should be taken to watch for pulmonary toxicity with
bleomycin and the potential for secondary leukemias with high cumulative doses of etoposide;
these precautions should be discussed with the patient.

Fertility after chemotherapy

In studies of young women who received platinum-based chemotherapy for ovarian germ cell
tumors (GCTs), 62 (87%) of 71 resumed regular menstrual function and 24 of these women
delivered 37 children after chemotherapy.[3] In a study by Weinberg et al,[4] 40 women with
malignant ovarian GCTs were followed for reproductive outcomes. Twenty-two women
underwent fertility-sparing surgery and 16 of these received chemotherapy. The majority of
patients (14 of 16) received BEP. Follow-up was available for 14 of the 16 patients. All 14
returned to normal menstrual function. Eight of the 10 women who attempted pregnancy had 11
pregnancies with 14 live births.

Adjuvant chemotherapy regimens

The 4 regimens for chemotherapy are as follows: (1) BEP, which is the preferred regimen; (2)
methotrexate, actinomycin D, and chlorambucil (MAC); (3) cisplatin, vincristine, and bleomycin
(PVB); and (4) vincristine, actinomycin D, and cyclophosphamide (VAC). Although the efficacy
has been analyzed for each protocol, the BEP protocol has been favored in recent years owing to
high cure rates with a favorable toxicity profile.

Important to note is that the authors attempt to keep patients on schedule despite bone marrow
toxicity that may develop. Given the high cure rates and relatively low rates of neutropenic fever,
it is best to continue treatment as scheduled even if blood counts are lower than what is typically
considered acceptable to begin a new cycle. Consideration for dose reduction and addition of
growth factors should be made on a case-by-case basis and should be used after neutropenic
fever.

BEP protocol (generally preferred)

The protocol is as follows[5] :

Bleomycin - Maximum 30 U IV per week for 9 weeks; dose at 20 U/m 2

Etoposide (ie, VP-16) - 100 mg/m 2 on days 1-5 q3wk for 3 courses; reduced 20% for
granulocytic fever or previous radiotherapy

Cisplatin - 20 mg/m 2 on days 1-5 q3wk for 3 courses

In 2004, the Gynecologic Oncology Group (GOG) published their experience using carboplatin
and etoposide in ovarian dysgerminomas.[6] They followed 39 eligible patients with completely
resected stage Ib-III disease for a median follow-up of 7.8 years. There were no disease
recurrences, although one patient had an intercurrent death from lung cancer. Although not
considered the standard, this regimen may be considered in patients with preexisting renal or
neurologic disease.

This regimen is carboplatin t 400 mg/m2 on day 1 and etoposide at 120 mg/m2 on days 1-3 q4wk
for 3 cycles.

Antiemetics

Antiemetics that may be used in chemotherapy are as follows:

Chlorpromazine - 25-50 mg PO/IM/PR q4h

Odansetron 4-8 mg IV/PO prior to chemotherapy

Lorazepam 1-2 mg PO/IV q6h

Dexamethasone 8 mg IV prior to cisplatin and 4 mg q4h for 2 doses

Radiation therapy

Primary therapy with radiation is reserved for patients who cannot tolerate chemotherapy or
surgical resection.

Radiation is used to treat periaortic and pelvic lymph node metastases. Shielding the remaining
ovary in an attempt to preserve fertility is not uncommon. Oophoropexy may be used to
mechanically hold the remaining ovary away from the radiation field.

Radiation therapy may be used for any dysgerminomas staged Ib-III. The field of exposure
extends from T11 to L5, with shielding of the contralateral ovary and the femur head.

The use of radiation in stage Ia cancers is considered precautionary. Most patients present with
stage I disease and usually can be treated with simple resection (eg, unilateral salpingo-
oophorectomy). Some authors have advocated radiation therapy for stage IA tumors larger than
10 cm. However, owing to the high sensitivity for radiation and platinum-based chemotherapy,
the authors do not recommend treating stage Ia tumors with any adjuvant therapy.

De Palo,[7] Freed, and Lawson developed the 3 major radiation therapy protocols. These protocols
differ mainly in their treatment of the abdomen for node-positive disease and in prophylactic
treatment of the mediastinum.

Surgical Care

Full surgical staging is recommended for ovarian germ cell tumors (GCTs) to identify women
with greater than stage Ia disease. Pattern of spread for ovarian dysgerminomas often follows a
lymphatic rather than peritoneal route, with up to 25% of patients having lymphatic involvement.
Therefore, complete lymphadenectomy should be performed.

Fertility preservation

Since many women with ovarian dysgerminomas are be in their 20s and 30s, any woman who
wishes to maintain fertility should undergo exploratory laparotomy, pelvic washings, unilateral
salpingo-oophorectomy, ipsilateral pelvic and bilateral para-aortic lymphadenectomy,
omentectomy, and peritoneal biopsies. It is not recommended to leave the ipsilateral tube, owing
to the rich lymphovascular connection between the tube and the ovary.

It should be noted that contralateral positive pelvic nodes may be seen in 10-50% of women with
positive pelvic lymph nodes at surgery for epithelial ovarian cancers. Although no data exist for
dysgerminomas, bilateral pelvic lymphadenectomy should be performed if there is extraovarian
pelvic involvement and should be considered in patients in whom disease appears to be confined
to the ovary.
Additionally, note that the contralateral ovary may be involved in 5-10% of patients who appear
to have stage Ia disease. Historically, a wedge biopsy of the contralateral ovary was
recommended to rule out microscopic spread in the contralateral ovary. However, the authors of
this article advocate leaving the opposite ovary undisturbed if it is of normal size and
appearance. This is suggested for 2 reasons. First, dysgerminomas are highly responsive to both
radiation and platinum-based chemotherapy, so adjuvant therapy for advanced-stage disease and
treatment of recurrence are typically very successful. Second, performing a biopsy of a normal
contralateral ovary may diminish fertility as a result of adhesion formation following the biopsy.

Women who have completed childbearing

These women should undergo exploratory laparotomy, pelvic washings, total abdominal
hysterectomy, bilateral salpingo-oophorectomy, ipsilateral pelvic and bilateral para-aortic
lymphadenectomy, omentectomy, and peritoneal biopsies.

Women with metastatic disease

Identification of disease extending beyond the ovary at laparotomy should lead to an attempt at
complete surgical cytoreduction. Although no prospective data comparing outcomes of surgical
debulking in advanced-stage ovarian GCTs are available, evidence suggests that women treated
with chemotherapy after optimal surgical cytoreduction have a better prognosis than those with
bulky residual or unresectable disease. However, one should bear in mind that these tumors do
have an excellent response to platinum-based chemotherapy, so the risk-to-benefit ratio of radical
surgical procedures should be considered in this context.

Incompletely staged patients with presumed stage Ia disease

National Comprehensive Cancer Network (NCCN) guidelines suggest checking tumor markers
and CT scanning of the chest, abdomen, and pelvis. If results are normal, patients may be
observed. If any abnormalities are noted on these tests, laparotomy and complete surgical staging
should be performed.

An Italian study of 26 women with ovarian dysgerminomas showed only 19.2% had complete
surgical staging. Three of these women (11.5%) suffered recurrence, with 2 having lymph nodes
as part of their recurrent disease.[8] All of them were salvaged with chemotherapy with or without
surgery. The overall recurrence risk in unstaged women was 20% in this study, which may help
in counseling women in this situation.

Laparoscopy

Case reports describe laparoscopic management and staging of ovarian GCTs. However, data on
outcome are lacking and should still be considered investigational, as the standard is still
laparotomy.
Surgical preparation

Traditionally, patients undergoing surgery for ovarian cancer often undergo a mechanical and/or
antibiotic bowel preparation before surgery. This was once felt to be critical in the case of
unsuspected gastrointestinal spread requiring bowel resection. However, current data in the
colorectal literature suggests that bowel preparation can be safely abandoned.

Second-look surgery

According to current American College of Obstetricians and Gynecologists (ACOG)

recommendations, second-look laparotomies are not considered the standard of care for
dysgerminomas.[9] . However, second-look surgery should be considered for patients with
persistent elevation in tumor markers, especially if associated with abnormal findings on
posttreatment imaging.

Management in pregnancy

Most adnexal masses found in pregnancy resolve spontaneously within the first trimester. Two
percent of all adnexal masses persisting during pregnancy are malignant (dysgerminomas
included). For this reason, a more cautious observational approach is advocated up to 16 weeks'
gestation. Moreover, the risk of aborting a viable fetus with surgery in the first trimester
approaches 30%.

If surgery is indicated, the ideal intervention time is 16-18 weeks' gestation. General anesthesia
should be used. Placement of a higher-than-usual vertical incision is necessary because the ovary
becomes an abdominal structure after 16 weeks' gestation.

Frozen sections should be taken at the time of surgery. If the pathology is hyperreactio luteinalis
or luteoma, no intervention is indicated and the abdomen should be closed. Since the majority
(90%) of dysgerminomas found in pregnancy are unilateral, one should avoid biopsy of the
contralateral ovary if this ovary appears normal. Lymphadenectomy may also be limited if the
uterus is obstructive to the pelvic sidewalls or paraaortic regions.

Benign or low-grade tumors generally require unilateral salpingo-oophorectomy, whereas

bilateral involvement of malignant or widely metastatic tumors requires bilateral salpingo-
oophorectomy with or without total abdominal hysterectomy. If patients are at or near term,
delivery of the fetus is performed and hysterectomy may be performed.

Postoperative progesterone and uterotonic agents (eg, nifedipine, magnesium sulfate, terbutaline)
have unproven efficacy postoperatively for the prevention of preterm labor, so treatment should
be individualized and plans made in conjunction with consultation from obstetrical or maternal-
fetal medicine specialists.
The 5-year patient survival rate for dysgerminoma in pregnancy is 90%. The fetal mortality rate
approaches 25%, especially if surgery is performed in the first trimester.

Antineoplastic Agents

Class Summary

Treatment entails chemotherapy and radiation therapy. Lesions staged higher than stage Ia
require a combination of BEP (bleomycin, etoposide, platinum). Alternate combinations are VAC
(vincristine, actinomycin D, cyclophosphamide) or PVB (cisplatin, vincristine, bleomycin), but
these combinations have higher toxicity and/or lower response rates. Etoposide and carboplatin
should be considered if the patient has significant renal, pulmonary, or neurologic impairment.

View full drug information

Bleomycin (Blenoxane)

Bleomycin is a copper-chelating glycoprotein capable of inducing DNA strand scission breaks

via oxidative processes. This drug is eliminated by the kidneys.

View full drug information

Carboplatin (Paraplatin)

Carboplatin is an analog of cisplatin. This is a heavy metal coordination complex that exerts its
cytotoxic effect by plastination of DNA, a mechanism analogous to alkylation, leading to
interstrand and intrastrand DNA cross-links and inhibition of DNA replication. Carboplatin binds
to protein and other compounds containing the SH group. Cytotoxicity can occur at any stage of
the cell cycle, but the cell is most vulnerable to action of these drugs in G1 and S phase.

Carboplatin has the same efficacy as cisplatin but with a better toxicity profile. Its main
advantages over cisplatin include less nephrotoxicity and ototoxicity not requiring extensive
prehydration and less likelihood of inducing nausea and vomiting, but it is more likely to induce
myelotoxicity.

The dose is based on the following formula: total dose (mg) = (target AUC) x (GFR+25), where
AUC (area under plasma concentration-time curve) is expressed in mg/mL/min and GFR
(glomerular filtration rate) is expressed in mL/min.

View full drug information

Etoposide (Toposar)

Etoposide inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation
to arrest in the late S or early G2 portion of the cell cycle.
Therapy should be withheld or suspended if platelet counts are less than 50,000 or absolute
neutrophil counts are less than 500/L.

Reduce the dose by 20% for granulocytic fever or previous radiotherapy.

View full drug information

Cisplatin (Platinol)

Cisplatin inhibits DNA synthesis and, thus, cell proliferation, by causing DNA cross-links and
denaturation of the double helix.

In general, the drug should not be administered if the leukocyte count is less than 4000/L and
platelet count is less than 100,000/L. Cisplatin is renally excreted; those with impaired renal
function should postpone therapy. Do not administer to patients with serum creatinine greater
than 1.5 mg/dL and BUN greater than 25 mg/dL.

It is administered intravenously in saline solution.

Further Outpatient Care

No precise recommendations are known based on any randomized controlled trials. However,
follow-up should maximize the ability to identify recurrences while minimizing risks (ie, from
repetitive imaging). Follow-up care depends on the stage of disease, which is typically predictive
of recurrence risk. Ovarian dysgerminomas tend to recur most often in the first 2-3 years after
treatment. Therefore, most authors suggest follow-up observation and a physical examination
every 3-4 months for the first 3 years, every 6 months during the fourth and fifth year, and
annual surveillance thereafter.

CT imaging should be considered during months 6 and 12, especially if tumor markers were
negative at the time of diagnosis. However, the risks of repetitive imaging in women with no
symptoms and a normal examination should be considered in this young population of women.

Tumor markers should be drawn (see Lab Studies), especially if known to be elevated
preoperatively. The authors recommend following lactate dehydrogenase, but if marker status is
unknown, they add serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin
(beta-hCG). An increasing trend in tumor markers warrants repeat body imaging and possible
surgical exploration. Tumor marker levels may begin to rise several months before a clinical
recurrence can be identified. Moreover, pregnancy should be ruled out in patients who underwent
fertility-sparing surgery and have elevations in AFP and beta-hCG.

Given the potential for late recurrences, patients should be observed for up to 10 years, although
they are rare.