Clinical Features

Dysgerminoma is one of the most common MGCTs of the ovary, but it accounts for only 1–2% of all ovarian cancers. They occur almost exclusively in children and young women. The average patient age is 22 years. Most patients present with a rapidly growing abdominal mass that often causes lower abdominal pain or pressure and may simulate pregnancy. Premenarchal patients with a pelvic mass should have their karyotype determined, as approximately 5% of dysgerminomas arise from gonadoblastomas in phenotypic females with abnormal gonads. These patients have pure gonadal dysgenesis (46,XY, bilateral streak gonads) or mixed gonadal dysgenesis (45,X/46,XY, unilateral streak gonad, contralateral testis). The estimated risk of malignancy is 28% by the age of 20 years for the former patients and 19% risk by the same age for the latter. Therefore, prophylactic removal of the gonads is recommended in both groups of patients at an early age. Almost all patients with dysgerminoma have elevated serum levels of lactic dehydrogenase (1 and 2 fractions) at presentation. In rare cases (3–5%), dysgerminomas may produce hCG and these patients may present with endocrine symptoms that are characteristically estrogenic (menstrual irregularities, isosexual pseudoprecocity, pseudopregnancy), but rarely androgenic. Serum levels of CA125, placental-like alkaline phosphatase (PLAP), and neuron-specific enolase (NSE) have been elevated in some cases. Paraneoplastic hypercalcemia has been described in some patients. One tumor occurred in a patient with a germline BRCA1 mutation. About two-thirds of dysgerminomas are stage IA at diagnosis; higher stage tumors involve the contralateral ovary (20%), pelvic and para-aortic lymph nodes, and/or the pelvic and abdominal peritoneum.

Macroscopic Features

Dysgerminomas are characteristically solid, and are well-encapsulated tumors with an average diameter of 15 cm. On section, they are lobulated, soft, and fleshy, and may appear gray-white or light tan ( Figure 29.3 ). Areas of coagulative necrosis and hemorrhage typically associated with cystic change may be seen. Such areas should be sampled to rule out the presence of other types of MGCT. The presence of calcification suggests an underlying gonadoblastoma. Dysgerminoma is the only MGCT that has a significant rate of bilaterality. Gross involvement of the contralateral ovary is seen in 10% of cases, and in another 10% microscopic foci of tumor are found.

Dysgerminoma. The sectioned surface appears solid, yellowish white, and lobulated. Note the absence of significant hemorrhage and necrosis.

Microscopic Features

The microscopic appearance of dysgerminoma is identical to that of testicular seminoma and extragonadal germinoma. It is composed of a monotonous population of rounded cells resembling primordial germ cells in a predominantly diffuse or insular arrangement. The cells may also grow as trabeculae, cords, or small nests ( Figure 29.4 ). Lack of intercellular cohesion may result in the formation of pseudoglandular spaces. The tumor cells are polygonal, with discrete cell membranes and abundant eosinophilic to clear, glycogen-rich, cytoplasm. The nuclei are large, central, and rounded, and they contain one or a few prominent nucleoli. Mitotic figures are often numerous. Aggregates of tumor cells are usually separated by thin fibrous septa almost always infiltrated by T-lymphocytes. In some tumors, lymphocytes are abundant and may form follicles with germinal centers. In approximately 20% of the cases, epithelioid sarcoid-like granulomas with multinucleated giant cells are present ( Figure 29.5 ). About 5% of dysgerminomas contain syncytiotrophoblastic giant cells (SGCs) in the absence of any other non-germinomatous differentiation. Such tumors, which have the same prognosis as dysgerminomas in which SGCs are absent, should be sampled extensively to rule out foci of choriocarcinoma or EC. The SGCs have a perivascular location, are immunoreactive for human chorionic gonadotropin (hCG)( Figure 29.6 ), and are often associated with stromal luteinization. The luteinized stromal cells, which may be admixed with the tumor cells or located at the periphery of the neoplasm, are probably responsible for the estrogenic or androgenic symptoms that are found in some patients.

Dysgerminoma. The tumor cells are distributed in nests separated by delicate fibrous septa. The stroma contains numerous lymphocytes.

Dysgerminoma. A sarcoid-like granuloma is present.

Dysgerminoma with syncytiotrophoblastic giant cells. Positive immunostain for hCG.

Immunohistochemistry

Dysgerminoma cells show cytoplasmic and membranous immunoreaction for vimentin, PLAP, CD117 ( c-kit ), and D2-40 (podoplanin); the membranous reaction is characteristic of dysgerminoma. There is nuclear immunoreaction for the stem cell/primitive germ cell nuclear transcription factors OCT3/4, NANOG, and SALL4 ( Table 29.3 ). OCT3/4 is expressed very early during embryogenesis and has an essential role in blastocyst differentiation. However, when the female germ cells enter meiosis the expression of OCT3/4 is downregulated. OCT3/4 regularly shows positivity in dysgerminoma ( Figure 29.7 ) but can also be expressed in EC and in some immature neural elements of ovarian teratoma.

Dysgerminoma. OCT3/4-positive nuclear immunoreaction recognizes germ cells in poorly fixed specimen.

(Courtesy of Dr. Francisco Nogales.)

SALL4 can also show positivity in EC, YST, and primitive areas of immature teratoma (IT). Dysgerminomas may exhibit limited cytoplasmic dot- or rim-like staining for cytokeratin ( Figure 29.8 ) but epithelial membrane antigen (EMA) is negative. The SGCs that are found in a small percentage of dysgerminomas exhibit positive cytoplasmic staining for hCG ( Figure 29.6 ).

Dysgerminoma. Positive ‘dot-like’ immunostain for cytokeratin.

Somatic Genetics

Dysgerminomas, like seminomas, show by comparative genomic hybridization frequent (75%) chromosome 12p gain, usually in the form of an isochromosome 12p. The c-kit gene encodes a tyrosine kinase receptor (KIT), which is required in normal spermatogenesis and is expressed in seminomas and dysgerminomas. c-kit point mutations localized to exon 17, codon 816 (Asp>Val), involving the phosphotransferase domain, have been identified in 25–50% of ovarian dysgerminomas. The mutations are in exon 17, not in the exon 11 location, which confers susceptibility to imatinib therapy.

Genetic Susceptibility

Dysgerminoma is the most common malignant gonadal tumor in patients with gonadal dysgenesis and a Y chromosome. In these cases, the dysgerminoma typically arises in a gonadoblastoma.

Differential Diagnosis

Dysgerminoma should be distinguished from the solid type of YST, EC, clear cell carcinoma, and large cell lymphoma. The solid YST is almost always associated with other more typical patterns that are not seen in dysgerminomas. YSTs exhibit greater nuclear variation, contain hyaline bodies, immunoreact for AFP and glypican-3, and lack the lymphocytic infiltrate of dysgerminomas. Moreover, in contrast to dysgerminoma, YSTs fail to react for D2-40 and OCT3/4. The extremely rare EC shows larger cells with more ample nuclei that are more hyperchromatic and irregular than those of dysgerminoma. ECs are CD30 and cytokeratin positive, almost always contain SGCs, and lack the stromal infiltrate of lymphocytes. The distinction of dysgerminoma from clear cell carcinoma is discussed in Chapter 27 . Large cell lymphomas may resemble dysgerminomas both grossly and microscopically. Lymphomas, however, are bilateral in approximately one-half of the cases, and simultaneous involvement of the ipsilateral tube occurs in 25% of them (see Chapter 30 ). Careful attention to the nuclear features and immunostains for PLAP, D2-40, SALL4, and lymphoid markers facilitate the correct diagnosis. Poorly fixed dysgerminomas may occasionally be misdiagnosed as poorly differentiated carcinomas, as the cellular features of the former tumors are lost.

Treatment and Prognosis

The treatment of patients with dysgerminoma is primarily surgical, including the resection of the ovarian tumor and complete surgical staging. Given that the tumor mainly affects young females, for whom preservation of fertility is important, unilateral adnexectomy with frequent patient follow-up (every 2–3 months for the first 2–3 years) is the treatment of choice. This conservative approach is currently used in young patients even in the presence of metastasis. Therefore, biopsy of an apparently normal contralateral ovary is not recommended as it increases the risk of infertility. Dysgerminoma is highly sensitive to chemotherapy, which is usually reserved for the treatment of recurrent disease. Although these tumors are equally sensitive to radiotherapy, its use has been discontinued in an effort to preserve patient fertility, and cisplatin-based chemotherapy is currently preferred. In young patients whose karyotype analysis reveals a Y chromosome, both ovaries should be removed. When the patient’s fertility is not a factor, hysterectomy with bilateral salpingo-oophorectomy is recommended; chemotherapy is subsequently administered in the case of higher stage tumors. Postoperative work-up includes the serum markers AFP and hCG, chest X-ray, and abdominopelvic CT or MRI. Recurrence in the retained contralateral ovary can occur in 5–15% of cases over the next 2 years. About 75% of the recurrences occur within the first postoperative year, and the most common sites are the peritoneal cavity and the retroperitoneal lymph nodes.

Patients with dysgerminoma have an excellent prognosis. The 5 year survival rate is greater than 95% for patients with stage IA tumor, and 85% for those with advanced stage or recurrent tumor. Features associated with recurrence include a tumor diameter greater than 10 cm, and age younger than 20 years. Although the designation ‘anaplastic dysgerminoma’ has been applied to tumors with numerous mitoses, there is no evidence that such tumors are associated with a worse prognosis, and therefore this term is not recommended. Most dysgerminomas are nondiploid and ploidy is not a useful prognostic factor.

Clinical Features

Yolk sac tumors (YSTs) (also referred to as primitive endodermal tumors ) account for approximately 10% of MGCTs and are almost as common as dysgerminoma in patients under the age of 20 years. They occur at a median age of 18 years and are rare over the age of 40 years. Patients most frequently present with abdominal pain and a large, rapidly growing, pelvic mass. Rupture or torsion of the tumor occurs in about 10% of patients. YSTs consistently produce AFP, which can be demonstrated in the patient’s serum, usually at a level greater than 1000 ng/ml. This substance, which is normally produced in the yolk sac of the developing embryo, may serve as a tumor marker in monitoring the patient during and after therapy. Lower serum levels of AFP may be encountered in other tumors that also occur in young females such as IT and Sertoli–Leydig cell tumors (SLCTs). CA125 and carcinoembryonic antigen (CEA) are also elevated in 100% and 10% of YSTs, respectively. Rare examples of YST have occurred in older patients in association with mucinous or endometrioid tumors; in such cases, a somatic cell rather than a germ cell origin is almost certain.

Yolk sac tumor is a highly malignant neoplasm. At laparotomy, evidence of extraovarian spread has been reported in 30–70% of cases. In an older study, subclinical metastases were present in 84% of cases regarded as ‘stage I’ tumors, which most likely reflects incomplete staging. When the tumor spreads beyond the ovary, it involves the omentum and peritoneum, the para-aortic lymph nodes, and the liver.

Macroscopic Features

Yolk sac tumors are large, well-encapsulated masses, with an average diameter of 15 cm. The external surface is usually smooth and glistening. The sectioned surface is characteristically solid and cystic and shows soft, gray to yellow tissue with extensive areas of hemorrhage and necrosis ( Figure 29.9 ). When a polyvesicular vitelline component is present, the tumor shows a microcystic appearance. Although YSTs are bilateral in less than 5% of patients, the contralateral ovary may contain a dermoid cyst in about 10% of cases.

Yolk sac tumor. Solid and cystic tumor with extensive hemorrhage, necrosis, and gelatinous degeneration.

Microscopic Features

Although YSTs often exhibit a wide variety of microscopic patterns, most tumors have a reticular architecture reflecting extraembryonic differentiation. They are composed of a network of irregular spaces lined by primitive epithelial cells with glycogen-rich, clear cytoplasm, and large, hyperchromatic nuclei with prominent nucleoli; mitotic figures are numerous ( Figure 29.10 ). The most characteristic feature is the presence of isolated papillary projections with a central blood vessel and peripheral sleeve of embryonic epithelial cells (Schiller–Duval bodies; Figure 29.11 ). Cross sections of this structure once were erroneously compared with immature glomeruli (Schiller’s mesonephroma). In fact, they closely resemble invaginations of yolk sac endoderm, as seen best in the rat placenta, forming the endodermal sinuses of Duval. Nevertheless, Schiller–Duval bodies are present in only 20% of cases. The term ‘endodermal sinus tumor’ is misleading, since the endodermal sinus is neither a structure present in human embryogenesis nor a constant feature of these neoplasms. Accordingly, the designation primitive endodermal tumor has recently been proposed. Another distinctive feature is the presence of brightly eosinophilic, periodic acid–Schiff (PAS)-positive, diastase-resistant hyaline globules ( Figure 29.10 ). Occasionally, multiple small vesicles with eccentric constrictions resembling the yolk sac vesicle of the normal embryo are present, and the tumor is designated a polyvesicular vitelline tumor ( Figure 29.12 ). This pattern recapitulates the subdivision of the primary yolk sac vesicle into a large component lined by flat cells (vestigial primary yolk sac) and a smaller component lined by taller epithelium that simulates the forerunner of the primitive gut and its appendages (secondary yolk sac vesicle) in normal embryogenesis ( Figure 29.13 ). Like the normal yolk sac vesicle, the neoplastic yolk sac may give rise to tumors of embryonal type. These tumors recapitulate primitive gut (glandular YST) and primitive liver (hepatoid YST).

Yolk sac tumor. Reticular pattern. Irregular spaces lined by primitive epithelial cells with glycogen-rich, clear cytoplasm, and large, hyperchromatic nuclei with prominent nucleoli. A hyaline body is present (upper center). Mitotic figures are seen.

Yolk sac tumor. Schiller–Duval (glomeruloid) body. Central blood vessel and peripheral sleeve of embryonic epithelial cells.

Yolk sac tumor, polyvesicular vitelline variant. The vesicles are lined by flattened epithelial cells and some of them exhibit eccentric constrictions.

Diagram of a median longitudinal section through a 10 mm human embryo (about 6 weeks old). The primitive yolk sac (blue) is in continuity with the midgut. The rudiment of the liver and biliary tract appears attached to the ventral wall of the foregut.

(Modified from Prat J, Pathology of the ovary. Saunders, Philadelphia, 2004. With permission.)

Endodermal-type glands may be found in approximately 50% of YSTs, often admixed with reticular and polyvesicular vitelline components. In some tumors, a glandular pattern predominates, and may appear as rounded cribriform aggregates of primitive epithelial cells (‘intestinal’ variant; Figure 29.14 ), or glands of ‘endometrioid’ type, which can be mistaken for typical or secretory endometrioid adenocarcinoma (endometrioid-like variant; Figure 29.15 ); foci of carcinoid tumor have been described in one of the latter tumors. Occasionally, the mature intestinal component may give rise to a mucinous carcinoid.

Yolk sac tumor, glandular variant, intestinal type. The tumor shows a cribriform pattern.

Yolk sac tumor, endometrioid-like glandular variant. The tumor glands resemble those of the secretory endometrium.

Although small foci of hepatoid differentiation are found in 16–48% of YSTs, neoplasms with a predominant hepatoid component are infrequent. These tumors are characterized by compact masses of large polyhedral cells with abundant eosinophilic cytoplasm, and round central nuclei with prominent single nucleoli, separated by thin fibrous bands, resembling hepatocellular carcinoma ( Figure 29.16 ). Hyaline bodies are usually numerous. In some cases, glandular spaces containing mucin are present. Ultrastructural examination of hepatoid YSTs reveals features similar to hepatocellular carcinoma. A ‘parietal’ differentiation characterized by small extracellular accumulations of basement membrane material has been described in over 90% of YSTs. Rarely, YSTs may contain SGCs.

Yolk sac tumor, hepatoid variant. The tumor is composed of compact masses and nests of large polyhedral cells with abundant eosinophilic cytoplasm separated by a fibrous stroma. Note the striking resemblance to a hepatocellular carcinoma.

The loose stromal component of YST recapitulates the extraembryonic mesenchyme (magma reticulare), and may be the site of origin of the sarcomas that develop in some patients after chemotherapy.

Immunohistochemistry

Similar to the primitive gut (secondary yolk sac) and its appendages, YSTs are immunoreactive for AFP ( Figure 29.17 ), glypican-3 ( Figure 29.18 ), SALL4 ( Figure 29.19 ), villin, CDX2. and hepatocyte paraffin antigen 1. AFP is expressed often focally either as granular cytoplasmic deposits or delineating intracellular canaliculi. Glypican-3 immuno­reaction is usually stronger than that of AFP; however, it is not as specific since it is expressed by other germ cell tumors and clear cell carcinoma. Nuclear transcription factor SALL4 is regularly expressed in both epithelium and mesenchyme and there is cytoplasmic reactivity of RNA-binding protein LIN28. Villin is also constantly expressed in membranes and cytoplasms of epithelial cells. The different endodermal elements may be immunoreactive for their corresponding tissue markers, i.e., hepatic components for hepatocyte paraffin antigen 1, intestinal elements for CDX2, and foregut-derived epithelia for thyroid transcription factor 1. However, YSTs are negative for OCT4, SOX2, D2-40, and CD30 ( Table 29.3 ). Combined expression of AFP, glypican-3, villin, SALL4, or LIN28 makes an ideal panel for confirming the diagnosis.

Yolk sac tumor. Schiller–Duval body exhibiting a strong immunoreaction for AFP.

Yolk sac tumor. Glypican-3 immunoreaction delineates a clean microcystic pattern.

(Courtesy of Dr. Francisco Nogales.)

Yolk sac tumor. SALL4 nuclear immunoreaction in epithelial and in some mesenchymal cells.

(Courtesy of Dr. Francisco Nogales.)

Differential Diagnosis

Because of their various microscopic patterns, YSTs can be confused with many other ovarian tumors, both primary and metastatic. The most common problems in differential diagnosis include clear cell carcinoma and endometrioid adenocarcinoma (see Chapter 27 ), the retiform variant of SLCT (see Chapter 28 ), and hepatoid carcinoma (see Chapter 27 ). YSTs should also be distinguished from other germ cell tumors such as dysgerminoma and the very rare EC. These differential diagnoses are discussed under those headings.

Treatment and Prognosis

The treatment of YST includes surgical exploration, unilateral salpingo-oophorectomy, and frozen section for diagnosis. Although gross metastases should be removed, a thorough surgical staging is not necessary because all patients need chemotherapy. Prior to combination chemotherapy, the prognosis for patients with YSTs was dismal despite apparently adequate surgery. In one large study of patients treated prior to 1975 the 3 year survival was only 13%. The development of the vincristine, dactinomycin, and cyclophosphamide (VAC) combination chemotherapy dramatically changed the outlook for patients with YSTs. Currently, cisplatin-based chemotherapy provides still better results. Survival rates have approached 100% for patients with stage I tumors, and 75% for patients with higher stage tumors. Serum AFP can be used to monitor the response to treatment and to detect tumor recurrence. Adverse prognostic factors include tumor stage II or higher, gross residual tumor after surgery, and ascitic fluid of more than 100 ml. The good long-term outcome in two polyvesicular-vitelline tumor (PVVT) cases supports prior evidence that this form of YST may be more indolent than the conventional forms of the tumor.

Clinical Features

Mature teratomas, usually dermoid cysts, represent the most common ovarian neoplasms, accounting for 27–44% of all primary ovarian tumors and over two-thirds of all ovarian tumors in patients under 15 years of age. Most patients are between 20 and 40 years, but the tumors occur at all ages. Although they usually occur in pure form, dermoid cysts are found grossly within 26% of ITs and in the ovary contralateral to a MGCT in about 5–10% of cases. Most patients with mature teratomas present the typical signs and symptoms of benign ovarian tumors, but approximately 25% are asymptomatic and the tumors are discovered on routine examination. Radiologically, dermoid cysts are characterized by central areas of very low density enclosed by a ring of increased capsular density. Calcified tissues including bone and teeth may be present and facilitate the radiologic diagnosis. Dermoid cysts may undergo torsion or rupture, with acute abdominal symptoms, or hemoperitoneum. Leakage of the cyst contents into the abdominal cavity results in granulomatous peritonitis, which may mimic tuberculosis or metastatic carcinoma. Peritoneal melanosis may also occur. Autoimmune hemolytic anemia has been reported in some cases. Mature solid teratomas may occasionally produce mature peritoneal glial implants (grade 0), which have an excellent prognosis.

Although mature teratomas are benign tumors, malignant transformation may occur in approximately 1–2% of cases, usually in postmenopausal women (mean age, 51–62 years). Almost any component may become malignant, but squamous cell carcinoma accounts for 80% of the cases.

Macroscopic Features

Mature teratomas are almost always cystic tumors and are bilateral in approximately 15% of cases. They range in size from 0.5 to 40 cm (average 15 cm) and have a smooth grayish white external surface. On section, a unilocular or, less frequently, a multilocular cyst lined by skin appears filled with sebaceous material and hair ( Figure 29.23 ). The cyst contents are liquid at body temperature but they solidify at room temperature. A solid nodule composed of fat tissue with teeth or bone usually protrudes into the cyst lumen (Rokitansky’s protuberance). Dermoid cysts may contain a great variety of mature somatic tissues that may be seen grossly, such as brain tissue, bone, cartilage, adipose tissue, mucinous cysts, and thyroid. In rare cases, partially developed organs may be identified. Rarely, mature teratomas are completely solid and differ grossly from ITs by the absence of hemorrhagic and necrotic areas. Twenty-two cases of a rare type of mature solid teratoma resembling a malformed human fetus have been reported. This form of teratoma has been designated homunculus or fetiform teratoma. Dermoid cysts that are unusually large and adherent to surrounding structures or that contain mural nodules, or extensive necrosis and hemorrhage, are suspicious of harboring a secondary malignant tumor.

Dermoid cyst (mature cystic teratoma). The cyst contains sebaceous material and hairs.

Microscopic Features

Mature teratomas are composed of adult and sometimes fetal-type tissue derived from two or three embryonic layers. Ectodermal elements predominate in almost all cases, particularly epidermis ( Figure 29.24 ), pilosebaceous structures, teeth, sweat glands, and neural tissue (usually glia). In mature solid teratomas, well-differentiated glia may constitute the predominant component. Other ectodermal derivatives, such as cerebrum, cerebellum, choroid plexus, and retina, may also be found. The common presence of cranially derived tissues in one study suggests that the type of differentiation in mature cystic teratomas parallels anterior embryonic plate development. Frequent endodermal elements include respiratory and gastrointestinal structures and thyroid tissue. The most common mesodermal derivatives are smooth or striated muscle, adipose tissue, bone, teeth, and cartilage. Less frequently, adrenal, pituitary, pancreatic, renal, thymic, mammary, or prostatic tissue are encountered. Although mitotic figures are rare, they may be seen in recognizable fetal tissues. The various tissues exhibit an organoid arrangement; for instance, cartilage, mucinous glands, and respiratory epithelium may appear together as in normal bronchus. Rarely, a florid benign vascular proliferation may be found in association with glial tissue and can be misinterpreted as an immature component.

Dermoid cyst (mature cystic teratoma). Squamous epithelium and sebaceous glands.

Benign tumors, such as carcinoid, struma, adrenal adenoma, prolactinoma, glomus tumor, sebaceous adenomas, and nevus, may develop within a dermoid cyst. Six mucinous–intestinal tumors associated with pseudomyxoma peritonei arose in ovarian dermoid cysts. The great majority of secondary cancers are invasive or, rarely, in situ squamous cell carcinomas (see later). Sebaceous carcinomas, sarcomas, and melanomas are occasionally seen.

Treatment and Prognosis

Dermoid cysts are treated conservatively, particularly in children and young women. Ovarian cystectomy is adequate treatment. With the exception of rare cases in which a secondary malignant tumor develops, dermoid cysts are benign tumors even if they contain microscopic foci of immature neural tissue. Similarly, mature solid teratomas, including those associated with mature implants, have a favorable clinical course. Patients with squamous cell carcinoma that has disseminated beyond the ovary typically have a poor prognosis.

Clinical Features

Immature teratomas (ITs) are probably the most common MGCTs of the ovary, representing about 36% of such tumors and 1% of ovarian cancers in general. Only 3% of ovarian teratomas are immature. They occur predominantly in children and young women, at a median age of 18 years, who have a palpable abdominal mass and complain of pelvic or abdominal pain. In rare cases, ITs are preceded by ipsilateral dermoid cysts that have been removed some years previously. Serum AFP can be elevated in patients with pure IT but levels only rarely exceed 1000 ng/ml. Higher levels almost always indicate the presence of a YST component. Other tumor markers include hCG, NSE, CEA, and CA125. Extraovarian spread, usually in the form of peritoneal implants and less frequently as lymph node metastases, is found in one-third of patients at the time of surgery. Ruptured or adherent tumors are most commonly associated with peritoneal implants.

Macroscopic Features

Immature teratomas are typically large (mean size, 18 cm), encapsulated tumors that are ruptured in nearly 50% of cases. On section, they are predominantly solid, but small cysts containing mucin or blood are often seen ( Figure 29.25 ). The solid areas, which usually correspond to neural tissue, are soft, fleshy, and gray to pink and frequently show hemorrhage and necrosis. Foci of bone and cartilage may be present. Grossly visible dermoid cysts are found in 26% of cases. The tumor is almost always unilateral, but the contralateral ovary contains a dermoid cyst in about 10% of patients.

Immature teratoma. The sectioned surface is predominantly solid but also shows numerous small cysts containing bloody fluid.

Microscopic Features

Most tumors contain a mixture of mature and immature embryonal elements. The embryonic-type tissue varies from microscopic foci to large amounts and is composed predominantly of neuroepithelial rosettes ( Figure 29.26 ) and tubules admixed with areas of hypercellular glia with numerous mitoses. The neuroepithelial rosettes are lined by crowded cells ( Figure 29.27 ) and may be pigmented. Islands of immature cartilage, bone, skeletal muscle, and glandular structures are distributed through a myxoid stroma. Embryonal endodermal elements, such as hepatic tissue and intestinal-type epithelium, may also be found. The presence of these elements in grade 3 ITs (see later) with markedly elevated serum AFP levels should alert the pathologist to perform a diligent search for a YST component. In childhood ITs, such a component may develop as well-differentiated glandular or hepatoid YST. Two cases of ITs composed predominantly of endodermal elements without neural component have been described ( Figure 29.28 ). Rarely, immature renal tissue, SGCs, and yolk sac-like tissue may be found. Vascular proliferation occurs in relationship with neural tissues.

Immature teratoma. The tumor shows both immature neuroepithelial and mesenchymal elements.

Immature teratoma. Glial tissue with neuroepithelial tubules.

Immature endodermal teratoma. The tumor is exclusively composed of endodermal elements without neural component. The intestinal-like glands show positive AFP immunoreaction.

The relative amount of primitive neuroepithelial tissue is an important factor in grading and determining the prognosis of ITs. Grading is performed by a subjective, semiquantitative analysis of the relative amount and atypicality of the immature neural tissue (neuroepithelial tubules and neural blastema) present in the tumor. Grade 1 has been applied to tumors with rare foci of immature neural tissue that occupy less than one low-power field (LPF) (40×) in any slide, grade 2 to tumors with moderate amounts of immature neural tissue occupying more than 1 but less than 4 LPF in any slide, and grade 3 to tumors with immature neural tissue occupying 4 or more LPFs in any slide ( Table 29.4 ). The grading system is also applied to peritoneal implants ( Figure 29.29 ) and lymph node metastases. A two-grade system (low grade and high grade), which combines grades 2 and 3, has been proposed but has not been formally adopted. ITs as well as mature solid teratomas may be associated with mature (grade 0) peritoneal implants (so-called peritoneal gliomatosis). The pathogenesis of this phenomenon is unclear and both, direct seeding of immature cells from the primary tumor with subsequent differentiation in the peritoneum and peritoneal metaplasia from stem cells have been proposed. In some cases, the glial implants appear admixed with endometriosis. As mature and immature implants may coexist, generous sampling of the peritoneal lesions is recommended. The pelvic and para-aortic lymph nodes may also contain similar glial tissue.

Peritoneal implant of immature teratoma. The implant is partly composed of immature glial tissue (left).

Immunohistochemistry

SALL4 is positive in both intestinal and neural immature tissues. SOX2, however, identifies more specifically immature neural areas, highlighting them, and is helpful for grading of immature teratoma. Glypican-3 may also exhibit a patchy neuroepithelium immunoreaction. The neuro­ectodermal tissues are also immunoreactive for several neural markers, including glial fibrillary acidic protein (GFAP), NSE, S-100 protein, neurofilament protein, synaptophysin, and nerve growth factor receptor. The intestinal-type glands and hepatic tissue stain strongly for AFP. SGCs stain positively for hCG.

Somatic Genetics

Immature teratomas seem to originate from premeiotic germ cells. By comparative genomic hybridization, ITs exhibit fewer DNA changes than other ovarian germ cell tumors. No gain of 12p or i(12p) has been identified. Grades 1–2 ITs are diploid in 90% of cases, whereas most grade 3 tumors are aneuploid.

Differential Diagnosis

Immature teratoma is distinguished from mature solid teratoma by the presence of immature embryonal tissue. The finding of fetal cartilage and mitotically active cerebrum or cerebellum does not justify the diagnosis of immature teratoma. Typical dermoid cysts may contain minor foci of immature neural tissue. Malignancy arising in a dermoid cyst occurs most commonly in postmenopausal patients. In contrast to IT, only one element, usually squamous epithelium, is malignant (see later). IT is a frequent component of mixed MGCTs; therefore, the presence of other primitive elements such as dysgerminoma or YST should be excluded by generous sampling. In primitive mixed tumors occurring in children and adolescents, the YST components may be of the glandular (enteric) or hepatoid type and, thus, difficult to distinguish from the embryonal or fetal gastrointestinal glands or hepatocytes that can be found in pure ITs. The additional presence of extraembryonal patterns (reticular or polyvesicular vitelline patterns) of YST, as well as the typically elevated serum levels of AFP, facilitate the differential diagnosis. The differential diagnosis between immature teratomas and malignant mixed müllerian tumor with heterologous elements and primitive neuroectodermal tumors is discussed in Chapter 27 and in the following sections, respectively.

Treatment and Prognosis

In a young patient whose tumor appears localized to a single ovary (stage IA), a unilateral salpingo-oophorectomy and surgical staging should be done. If preservation of fertility is not an issue, or the contralateral ovary or uterus is involved, a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be carried out. Any peritoneal lesions should be sampled carefully and submitted for histologic evaluation. The primary prognostic factor in patients with immature teratoma is the tumor grade. Patients with stage IA, grade 1 tumors or those with exclusively mature (grade 0) glial implants have an excellent prognosis and are treated by surgery alone. Patients with grade 2 or 3, stage IA, or those with immature implants should receive combination chemotherapy. The VAC regimen has been replaced by platinum-containing regimens such as cisplatin, etoposide, and bleomycin (BEP). In patients with no residual tumor after surgery, the survival rate is 90–100%. Prognosis is less favorable for patients with residual gross tumor or recurrent IT. Following chemotherapy, high-grade implants typically disappear, or are replaced by mature, necrotic, or fibrotic tissue. Mature implants may continue to grow (‘growing teratoma syndrome’) and may require reoperation. However, on rare occasions, gliomatosis peritonei can induce a florid vascular proliferation that may result in peritoneal hemorrhage and shock. Rare cases of glioblastoma multiforme arising from peritoneal gliomatosis have been described. Cytogenetically abnormal or aneuploid ITs may be associated with a worse prognosis than karyotypically normal or diploid tumors.

According to a report from the Pediatric Oncology Group, surgery alone is curative in children and adolescents with IT of any grade, and chemotherapy should only be used for cases with tumor recurrence. In such cases, the presence of a YST component rather than the grade of the IT component is the only valid predictor of recurrence.

Clinical Features

Over 20% of dermoid cysts may contain thyroid tissue on microscopic examination, but the term struma ovarii is only applied to teratomas composed either exclusively or predominantly of such tissue. Struma ovarii is the most common form of monodermal teratoma accounting for 3% of all ovarian teratomas. Most patients are in their fifth decade. Along with a palpable abdominal mass, patients may present with ascites and hydrothorax (‘pseudo-Meigs’ syndrome’), cervical thyroid enlargement, and hyperthyroidism with high pelvic iodine uptake.

Macroscopic Features

Most tumors are unilateral and range from 0.5 to 10 cm in diameter. On section, the thyroid tissue appears solid, gelatinous, and typically brown or green-brown ( Figure 29.30 ). Usually, struma occurs in a pure form; less frequently, it is associated with a dermoid cyst or is a component of strumal carcinoid. Occasionally, strumas are found in the wall of mucinous cystadenomas or are admixed with Brenner tumor. Some cases of struma ovarii appear as unilocular or multilocular cysts containing brown to green gelatinous fluid. Rarely, the contralateral ovary contains a dermoid cyst or even another struma.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Vagina
2. Ovarian Mucinous Tumors
3. Ovarian Epithelial-Stromal Tumors. Serous Tumors
4. Endometrial Stromal Tumors, Mixed Müllerian Tumors, Adenomyosis, Adenomyomas and Rare Sarcomas

Stay updated, free articles. Join our Telegram channel

Join