Clinical case
A 22-year-old G0 presents to an emergency department with pain and vomiting. CT scan of the abdomen/pelvis reveals a complex mass with cystic and solid components, including scattered calcifications, which occupies a large portion of the abdomen and pelvis and measuring up to 24 cm ( Fig. 1.1 ). There is also a small amount of pelvic fluid and an enlarged paraaortic lymph node in the aortocaval region measuring 1.5 × 0.8 cm. Tumor markers were drawn and are as follows: CA-125 127; Inhibin A 9.8; Inhibin B 27; Beta-hCG 3.4; AFP 3506; LDH 200. The patient undergoes an exploratory laparotomy, right salpingo-oophorectomy (RSO) with omentectomy, right paraaortic lymphadenectomy, and pelvic peritonectomy with no gross residual disease. Final pathology reveals a mixed ovarian germ cell tumor [20% high-grade immature teratoma (IT); 20% yolk sac tumor (YST); 60% mature teratoma] with metastatic YST in 1 paraaortic node and in a cul-de-sac nodule. How would you now manage this patient?
Epidemiology
Malignant ovarian germ cell tumors (MOGTs) are overall rare, accounting for only 3%–5% of ovarian cancers. Additionally, the incidence of germ cell tumors varies greatly depending on age. The incidence of MOGTs rises steadily in young girls from age 9 to peak in the late teens between the ages of 15 and 19. This incidence then steadily declines after that, and malignant germ cell tumors are extremely rare after age 40. A SEER database study identified 2451 women with MOGTs between 1978 and 2010. The median age at diagnosis was 22 years old, and 93% of the women were under age 40 at diagnosis. Germ cell tumors make up 75% of ovarian cancers in women less than 20 years old but less than 5% of ovarian cancers in adult women. The most common germ cell tumors are benign mature cystic teratomas which can account for 20% of all ovarian tumors. When looking specifically at malignant germ cell tumors, the most common histologies are dysgerminoma, IT, and YST ( Table 1.1 ). Rarer histologies are mixed tumors, embryonal carcinomas, and nongestational choriocarcinomas.
| Histology | Percent of malignant ovarian germ cell tumors |
|---|---|
| Dysgerminoma | 33% |
| Immature teratoma | 36% |
| Yolk sac tumor | 15% |
| Mixed germ cell tumor | 5% |
| Embryonal carcinoma | 4% |
| Choriocarcinoma | 2% |
A major risk factor for development of germ cell tumors is gonadal dysgenesis. Swyer syndrome is a condition in which a woman or girl is phenotypically female but has a 46XY karyotype. These patients generally have intraabdominal streak gonads. There can be an up to a 30% risk of development of germ cell tumors such as gonadoblastoma and dysgerminoma with a much smaller risk of a mixed germ cell tumor. More rarely, germ cell tumors have been described in women with Turner syndrome (45X) and mosaicism which can lead to gonadal dysgenesis. These women appear to be at risk of gonadoblastomas and dysgerminomas, but dysgerminomas are very rare compared to gonadoblastomas, which have a generally benign course. MOGTs have no relation to hereditary cancer syndromes, such as BRCA or Lynch syndrome. The only other risk factor may be geographic location. There seems to be an increased risk for development of MOGTs in southeast Asian countries, especially in adolescent girls. The exact mechanism for this, genetic or environmental, is not clear.
Pathology
Dysgerminoma
Gross appearance
Dysgerminomas are usually large (~ 15 cm) and have a fleshy, yellow, solid and lobulated appearance. Areas of cystic degeneration, hemorrhage, and necrosis may also be seen. Calcification may indicate the presence of a gonadoblastoma. Bilateral ovarian involvement occurs in relatively small proportion of cases.
Histopathologic features
Dysgerminomas are histologically characterized by sheets, nests, and cords/trabeculae of tumor cells with intervening lymphocyte-rich fibrous septae ( Fig. 1.2 A and B). Poorly formed granulomas may be present in the surrounding stroma. The tumor cells are monotonous with clear or eosinophilic cytoplasm, well-defined cell borders, and a central nucleus with one or two macronucleoli. Mitotic figures are often conspicuous. Scattered syncytiotrophoblastic cells may be found in a minority of tumors. When seen in cytologic preparations, dysgerminomas classically show a “tigroid” background.
Immunohistochemistry
Immunohistochemical markers of dysgerminoma include SALL4, OCT4, c-kit (CD117), D2-40, and PLAP. They may exhibit focal staining for cytokeratins, and hCG could be used to highlight syncytiotrophoblastic cells, if present. Dysgerminomas are negative for EMA, AFP, Glypican-3, and CD30.
Differential diagnosis
The morphological differential diagnosis for dysgerminoma includes other germ cell tumors (YST, embryonal carcinoma, and mixed germ cell tumor), epithelial primary ovarian tumors (clear cell carcinoma, undifferentiated carcinoma), and metastatic/secondary tumors involving the ovary (melanoma, lymphoma). Dysgerminomas, especially when large, must be well sampled to exclude other mixed germ cell components such as YST or embryonal carcinoma. YSTs have variable architecture with papillary, glandular, reticular, and solid patterns, unlike dysgerminomas that are usually solid and monotonous. Immunostains such as AFP and glypican-3 are positive in the former, and OCT4 and CD117 will be positive in the latter. Embryonal carcinoma has higher-grade nuclei and is positive for CD30. Clear cell carcinoma can be particularly challenging on morphology, but markers such as PAX8 and napsin-A (positive in CCC), and SALL4 (positive in dysgerminoma) will help in the differential. Lymphomas and melanomas are distinguished from dysgerminoma using characteristic immunostains of these entities. Distinction between the above entities at the time of intraoperative consultation can be particularly challenging.
Molecular features
Chromosome 12 amplification or isochromosome 12p is present in 80% of dysgerminomas, and KIT mutation or amplification is present in 30%–50% of cases.
Yolk sac tumor
Gross examination
YSTs are usually unilateral, large (> 10 cm), solid and cystic. The external surface is usually smooth. The solid cut surface has a tan yellow appearance, frequently with areas of hemorrhage and necrosis. The polyvesicular vitelline areas may grossly have a spongy/honeycomb-like appearance.
Histopathologic features
There is considerable heterogeneity in the histologic appearance of YST and a number of architectural patterns have been described including microcystic/reticular (most common), ( Fig. 1.3 A) endodermal sinus (with Schiller–Duval bodies), polyvesicular-vitelline, glandular, papillary, solid, and others. Schiller–Duval bodies ( Fig. 1.3 B) are characterized by the presence of a cystic space that envelops a central papillary structure with a fibrovascular core that is lined by a layer of tumor cells. The tumor cells usually exhibit clear cytoplasm and large nuclei with prominent nucleoli. Hyaline globules are often present ( Fig. 1.3 C).
Immunohistochemistry
Immunohistochemical markers of YST include SALL4, AFP, Glypican-3, CDX2 (in tumors with intestinal differentiation), HepPar-1 (in tumors with hepatoid differentiation) and TTF1 (in tumors with foregut/respiratory differentiation). YSTs are negative for EMA, CK7, ER, PR, OCT4, D2-40, and CD30.
Differential diagnosis
Given the extraordinary morphologic variability that YSTs may exhibit, depending on the morphologic appearance of the tumor, the differential diagnosis is quite broad. In addition to other germ cell tumors (dysgerminoma and embryonal carcinoma, in particular), clear cell carcinoma and endometrioid carcinoma can also share significant morphologic overlap with YST. Clear cell carcinomas and YSTs can have papillary, glandular and solid patterns with cytoplasmic clearing. Immunostains such as CK7, napsin-A and above described markers of YST will allow the distinction. YST can have a prominent glandular pattern mimicking endometrioid carcinoma. The presence of squamous morules and lower grade cytology in conjunction with positive staining for PAX8 and hormone receptors (ER and PR) will confirm endometrioid carcinoma. Other tumors that may enter into the differential diagnosis include Sertoli–Leydig cell tumor (intermediate or poor differentiation) or the rare hepatoid carcinoma (which resembles hepatocellular carcinoma). Somatically derived YSTs are admixed with an epithelial tumor and can be difficult to diagnose. Subtle histologic features typical of YST must be looked for to make the correct diagnosis.
Embryonal carcinoma
Gross examination
Ovarian embryonal carcinomas are exceedingly rare and they are usually seen as a component of a mixed germ cell tumor. These tumors are unilateral, large, solid, hemorrhagic and necrotic.
Histopathologic features
Ovarian embryonal carcinoma is morphologically identical to its testicular counterpart and these tumors are characterized by polygonal tumor cells arranged in solid, nested, glandular and papillary arrangements. Primitive nuclei with marked cytologic atypia is the norm, and mitotic activity is usually conspicuous. Scattered syncytiotrophoblastic cells may be seen.
Immunohistochemistry
Immunohistochemical markers of embryonal carcinoma include cytokeratins, SALL4, OCT4, PLAP, and CD30. These tumors are negative for c-kit (CD117), D2-40, AFP, and Glypican-3.
Differential diagnosis
The main differential diagnoses for embryonal carcinoma are dysgerminoma and YSTs, as previously discussed. High-grade ovarian carcinomas may also enter into the differential diagnosis, although these typically occur in older patients. The presence of syncytiotrophoblasts may raise the possibility of choriocarcinoma, but a second population of cytotrophoblasts is not identified.
Molecular features
Like dysgerminoma and YSTs, chromosome 12 abnormalities including 12p amplification or isochromosome formation are common.
Immature teratoma
Gross examination
These tumors are usually unilateral, large (average of 16 cm), fleshy, solid, and cystic with areas of hemorrhage and necrosis. Mature teratomatous elements such as hair, teeth, cartilage, or bone may be present. Adequate sampling of these tumors (at least 1 section/centimeter) is imperative to exclude the presence of other germ cell components.
Histopathologic features
IT is a teratoma containing variable amounts of mature tissues of various lineages and an immature primitive component. The immature component is specific to the presence of neuroepithelial tissue, which commonly takes the form of tubules and rosettes that are composed of mitotically active cells with high nuclear-cytoplasmic ratios and hyperchromatic nuclei. Immature mesenchyme usually is present in association with the neuroectodermal rosettes ( Fig. 1.4 A–D). The grading scheme for these tumors is shown in Table 1.2 . The two-tier grading system is recommended.
| Grading criteria | Three-tier grading scheme | Two-tier grading scheme |
|---|---|---|
| Immature neural tissue occupying less than one low-power field (40 ×) in any slide | 1 | Low |
| Immature neural tissue occupying > 1 but ≤ 3 low-power fields (40 ×) in any slide | 2 | High |
| Immature neural tissue exceeding three low-power fields (40 ×) in any slide | 3 |
Metastases/implants are considered Grade 0 when no immature tissue is present, regardless of the grade of the ovarian tumor. Gliomatosis peritonei is a specific type of Grade 0 implant comprised of mature glial tissue and is associated with good prognosis.
Immunohistochemistry
Immunohistochemical workup is not typically used in the evaluation of ITs, although it may be necessary to definitively identify and characterize immature neuroepithelium which would be expected to express SALL4 and OCT4, in addition to markers of neural differentiation (S100, GFAP, NSE). The Ki-67 proliferation index in the immature component is high.
Differential diagnosis
The diagnosis of a teratomatous neoplasm is usually straightforward, given the distinctive presence of different tissue types not normally found in the ovary. Care should be taken not to confuse normal tissue types in a teratoma including cerebellum and lymphoid aggregates with immature neuroepithelial elements. When the immature component is widespread, distinction should be made with primitive neuroectodermal tumor (PNET), which consists of massive, confluent growth of neuroectodermal tissue, while IT shows a spectrum of neuroepithelial differentiation and an admixture of other tissue types. Carcinosarcoma may also enter into the differential diagnosis but this tumor occurs in older patients and consists of high-grade epithelial and mesenchymal components.
Nongestational choriocarcinoma
General review
Nongestational choriocarcinomas are exceedingly rare and may occur in pure form or as a component of a mixed germ cell tumor. These tumors are large with a friable and hemorrhagic cut surface.
Histopathologic features
Choriocarcinoma is a malignant biphasic germ cell tumor composed of an admixture of cytotrophoblast and syncytiotrophoblast cells ( Fig. 1.5 ) and, less frequently, intermediate trophoblast cells. Syncytiotrophoblast cells have abundant eosinophilic cytoplasm and multinucleated smudgy nuclei, while cytotrophoblast cells are smaller with pale cytoplasm and a single nucleus with evident brisk mitotic activity and prominent nucleoli. Intermediate trophoblast cells are also mononuclear, and if present are usually seen clustering around blood vessels. The syncytiotrophoblast component is usually the most prominent, but in some cases, the cytotrophoblast component predominates and shows solid sheet-like growth. Extensive hemorrhage and necrosis are common.
Immunohistochemistry
Choriocarcinomas are positive for hCG, keratin, and inhibin, while negative for OCT4, c-kit (CD117), and CD30.
Differential diagnosis
In its classic form, choriocarcinoma has a characteristic appearance although other germ cell tumors with a syncytiotrophoblastic component, in addition to high-grade ovarian carcinomas may enter into the differential diagnosis. Nongestational and gestational choriocarcinoma cannot be definitively distinguished on histologic grounds alone and correlation with clinical history is necessary, and in addition, genotype analysis may also be necessary depending on the clinical scenario.
Diagnosis and workup
Differential diagnosis
Ovarian germ cell tumors should be suspected in any adolescent or preadolescent girl who presents with a pelvic mass. While the risk of MOGTs decreases dramatically after age 20, the possibility of an ovarian germ cell tumor should be considered in women under the age of 40 with complex adnexal masses.
Signs and symptoms
Evaluation should start with a thorough history and physical exam. Specific questions to ask on history taking are: (1) Any changes to menstrual patterns if the woman is or was having regular menses; (2) Whether the patient has experienced any recent weight change or change in the fit of their clothes; also, (3) Whether she has noticed any new bloating or abdominal discomfort or even whether or not she can palpate an abdominal-pelvic mass. Pain can also be a presenting complaint as these tumors can grow rapidly and also can be associated with internal hemorrhage and rupture. YSTs, in particular, are known to be hemorrhagic, friable, can bleed easily, and often present with pain. Patients may complain of abnormal vaginal bleeding.
Physical exam findings
On physical exam, there is often a palpable, tender pelvic mass on bimanual exam up to 85% of the time. Sometimes, MOGTs can be quite large and can be palpated on abdominal exam as well. Rarely, there are no specific findings or palpable mass on exam. Precocious puberty has been described as a presenting sign, but this is extremely rare and more common with mixed germ cell tumors.
Tumor markers
Tumor markers should be drawn when evaluating a young woman with a complex pelvic mass and a suspicion for MOGTs. In addition to CA-125, young women with any pelvic mass should have alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and beta-human chorionic gonadotropin (β-hCG) drawn. Often, in malignant germ cell tumors, one or more of these will be elevated, though it is also possible that they can all be within the normal range as well ( Table 1.3 ). CA-125 will often be elevated but not usually to the levels seen in epithelial ovarian cancers, and it is also not as discriminating in premenopausal women. AFP is almost always elevated in YSTs and is a useful marker not only to aid in diagnosis but also for monitoring response to treatment and in surveillance. AFP may also be elevated in patients with mixed germ cell tumors and about one-third to one-half of those with pure ITs, though usually to a lower level than those seen in YSTs. AFP elevation may be more prevalent in pediatric and adolescent patients with ovarian ITs, and in some centers, AFP level helps in the decision on postsurgical observation vs. chemotherapy in these patients. Dysgerminomas will classically have an increase in LDH, but LDH can be nonspecific and milder elevations can be seen in other germ cell tumors. Nongestational choriocarcinomas will have elevated levels of beta-hCG, but again, mixed germ cell tumors can also show a variety of tumor marker elevations including beta-hCG as seen in Table 1.3 .
| Tumor | Beta-hCG | AFP | LDH |
|---|---|---|---|
| Dysgerminoma | +/− | − | + |
| Yolk sac tumor | − | + | +/− |
| Choriocarcinoma | + | − | − |
| Immature teratoma | − | +/− | +/− |
| Embryonal carcinoma | + | + | +/− |
| Polyembryoma | +/− | +/− | +/− |
| Mixed tumor | +/− | +/− | +/− |
Imaging
Imaging workup is similar to that for any pelvic mass in a young woman. Pelvic ultrasound or MRI are appropriate to characterize the pelvic mass. Whatever modality of imaging one chooses, characteristics to pay particular attention to for any signs of malignancy are architectural complexity (presence of both solid and cystic components), increased blood flow, or invasion into adjacent structures. Benign, mature teratomas are the most common ovarian germ cell tumors and will usually have a significant, and even predominantly, cystic component in addition to a solid or fat component. On CT scan, mature teratomas characteristically have significant fat signal in the solid component and calcifications, if present, are usually not described as “course”. ITs, on the other hand, will have a more solid rather than cystic appearance, will have “course calcifications” on CT scan and increased vascularity in the solid components on Doppler ultrasound. Dysgerminomas are predominantly solid, multilobulated, masses with “fibrovascular septa” that show postcontrast enhancement. YSTs are usually mixed solid and cystic masses that will often have areas of hemorrhage and a smooth external surface. There may also be a “bright dot sign” on contrast enhanced CT due to the increased vascularity. If suspicion for malignancy is high, CT of the chest, abdomen, and pelvis is warranted to help assess for extra-pelvic disease, lymphadenopathy, as well as to assess for surgical resectability and approach.
Definitive preoperative diagnosis of MOGTs is difficult as this is a pathologic diagnosis. As with adnexal masses in postmenopausal women, preoperative biopsy of an ovarian mass is not recommended. Surgery, for both diagnosis and treatment, is almost always warranted—especially in those women with a large or solitary mass on imaging.
Staging
MOGTs are staged by either the Children’s Oncology Group (COG) or FIGO staging, depending on the woman’s age and who has operated on the patient. Generally, adolescents younger than 18 or 20 years of age are staged by the pediatric staging system ( Table 1.4 ), while women in their 20s and older are managed by gynecologic oncologists ( Table 1.5 ).
| Ovarian malignant germ cell tumors | |
|---|---|
| Stage | Extent of disease |
| I |
|
| II |
|
| III |
|
| III-X | Patients otherwise Stage I or II by COG criteria but with the following:
|
| IV | Metastatic disease to the parenchyma of the liver (surface implants are Stage III) or metastases outside the peritoneal cavity to any other viscera (bone, lung, brain) and pleural fluid with positive cytology |
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