Germ Cell Tumors of the Ovary
Germ cell tumors are composed of a number of histologically different tumor types derived from the primitive germ cells of the embryonic gonad. The concept of germ cell tumors as a specific group of gonadal neoplasms has evolved over the last several decades. It is based on (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 (Witschi, Contrib Embryol 32:67, 1948), and (4) the remarkable homology between the various tumors in males and females. In no other group of gonadal neoplasms is this homology better illustrated. Although the strong morphologic resemblance between the testicular seminoma and its ovarian counterpart, the dysgerminoma, was noted soon after these neoplasms were first described, for a long time there was no agreement as to their histogenesis. Nevertheless, these were the first neoplasms to become accepted as originating from germ cells. It was not until the studies by Teilum (Acta Obstet Gynecol Scand 24:480, 1944; Acta Pathol Microbiol Scand 23:242, 1946) on the homology of ovarian and testicular neoplasms, the studies by Friedman and Moore (Mil Surg 99:573–593, 1946) and Dixon and Moore (Tumors of the male sex organs. Atlas of tumor pathology, sect VIII, fasc 31b, 32. Armed Forces Institute of Pathology, Washington, DC, 1952) on testicular tumors, and those by Friedman (Cancer (Phila) 4:265–276, 1951) on related extragonadal neoplasms that the germ cell origin of other neoplasms belonging to this group was proposed. These views were supported by the embryologic studies of Witschi (Contrib Embryol 32:67, 1948) and Gillman (Contrib Embryol 32:83, 1948) and later by the experimental work of Stevens (J Natl Cancer Inst 23:1249–1295, 1959; Dev Biol 2:285–297, 1960; Annee Biol 1:585–610, 1962) and Pierce et al. (Am J Pathol 41:549–566, 1962; Pierce and Verney, Cancer (Phila) 14:1017–1029, 1961) on germ cell tumors in rodents.
Although occasional unusual neoplasms composed of germ cells and sex cord derivatives had been noted previously, it was not until Scully’s detailed description of gonadoblastoma (Scully, Cancer (Phila) 6:455–463, 1953) that these neoplasms were established as a distinct entity. More recently, another neoplasm composed of germ cells and sex cord derivatives, the mixed germ cell–sex cord–stromal tumor, has been described in detail (Talerman, Cancer (Phila) 30:1219–1224, 1972a; Talerman, Obstet Gynecol 40:473–478, 1972b). This chapter, therefore, is devoted not only to neoplasms of germ cell origin but also to those composed of germ cells and sex cord derivatives.
WHO classification of germ cell tumors of the ovary
Germ cell tumors
Yolk sac tumor (endodermal sinus tumor)
Mixed germ cell tumor
Monodermal teratoma and somatic-type tumors arising from a dermoid cyst
Struma ovarii, benign
Struma ovarii, malignant
Other rare monodermal teratomas
Squamous cell carcinoma
Germ cell–sex cord–stromal tumors
Mixed germ cell–sex cord–stromal tumor, unclassified
Clinical and Pathologic Features of Germ Cell Tumors
Germ cell tumors constitute the second largest group of ovarian neoplasms (after epithelial tumors) and comprise approximately 20% of all ovarian neoplasms observed in Europe and North America. In countries like in Asia and Africa, where the prevalence of epithelial tumors is much lower, germ cell tumors constitute a much larger proportion of ovarian neoplasms. Germ cell tumors are encountered at all ages from infancy to old age but are seen most frequently from the first to the sixth decades. They also have been observed during fetal life. In children and adolescents, more than 60% of ovarian neoplasms are of germ cell origin, and one third are malignant (Norris and Jensen 1972). In adults, the great majority of germ cell tumors (95%) are benign and consist of mature cystic teratomas (dermoid cysts). Malignant ovarian germ cell tumors occur in the first four decades and are rare thereafter.
Dysgerminoma is composed entirely of germ cells that show morphologic, ultrastructural (Lynn et al. 1967), and histochemical (McKay et al. 1953) similarity to primordial germ cells. The cells of dysgerminoma are considered to be in an early and sexually indifferent stage of differentiation; they are generally believed to be arrested at a developmental stage at which they have not yet gained the ability for further differentiation (Teilum 1946). However, there is evidence that occasional cells may acquire this ability and differentiate to embryonal carcinoma and further (Miettinen et al. 1985a; Parkash and Carcangiu 1995). An origin from the primordial germ cells that migrate to the ovary during early embryogenesis from their site of origin in the wall of the yolk sac (Witschi 1948) is the most widely accepted view of the histogenesis of dysgerminoma. It is supported by the occurrence of homologous neoplasms in the testis (seminoma) and along the route of migration of the primordial germ cells from the wall of the yolk sac to the primitive gonad, including the mediastinum, retroperitoneum, posterior abdominal wall, and parapineal and sacrococcygeal regions.
Cytogenetic and Molecular Features
The majority of dysgerminomas demonstrate an increased amount of nuclear DNA (tetraploid, polyploid, or aneuploid) (Asadourian and Taylor 1969; Kommoss et al. 1990; Kraggerud et al. 2013). Isochromosome 12p (i(12p)), which is present as a specific abnormality in testicular germ cell tumors, especially seminoma (Atkin and Baker 1983), has also been demonstrated in dysgerminomas (Atkin and Baker 1987; Cossu-Rocca et al. 2006b). However, i(12p) has also been identified in non-dysgerminatous components of ovarian germ cell tumors and therefore is not specific for dysgerminoma (Poulos et al. 2006).
Comparative genomic hybridization has revealed multiple DNA copy number changes in dysgerminoma (Kraggerud et al. 2000; Riopel et al. 1998). Common alterations include gains on chromosome arms 12p, 12q, 21q, and 22q and losses from 13q. A subset of tumors exhibit mutation or amplification of the KIT oncogene (Cheng et al. 2011; Hoei-Hansen et al. 2007). KIT mutations may be associated with advanced-stage disease (Cheng et al. 2011) and occur more commonly in dysgerminomas unassociated with dysgenetic gonads (Hersmus et al. 2012).
Dysgerminoma is an uncommon tumor, accounting for 1–2% of primary ovarian neoplasms and 3–5% of ovarian malignancies (Mueller et al. 1950; Santesson 1947). It is the most common malignant ovarian germ cell neoplasm occurring in pure form. The exact prevalence of dysgerminoma in different parts of the world is not known because most cancer registry reports do not differentiate between the various types of ovarian neoplasms. Although most reports emanate from Europe and North America, dysgerminoma has been encountered in all parts of the world and in all races. In some countries, there are considerable regional variations.
Dysgerminoma has been reported in infants from 7 months to women aged 70 years (Mueller et al. 1950), but most cases occur in the second and third decades; nearly half the patients are under 20 years of age, and 80% are under 30 years (Asadourian and Taylor 1969; Björkholm et al. 1990; Gordon et al. 1981; Mueller et al. 1950). Dysgerminoma occurs not infrequently before puberty but is very rare after menopause. Therefore, dysgerminoma is one of the most common malignant ovarian neoplasms of childhood, adolescence, and early adult life (Asadourian and Taylor 1969; Björkholm et al. 1990; Gordon et al. 1981; Mueller et al. 1950; Norris and Jensen 1972).
Pure dysgerminoma has been reported in siblings (Talerman et al. 1973) as well as in a mother and daughter. The symptomatology of dysgerminoma is not distinctive and is similar to that observed in patients with other solid ovarian neoplasms (Asadourian and Taylor 1969; Björkholm et al. 1990; Gordon et al. 1981; Mueller et al. 1950). The duration of symptoms is usually short; despite this, the tumor is often large, indicating rapid growth (Björkholm et al. 1990). The most common presentation is abdominal enlargement and presence of a mass in the lower abdomen, which is sometimes associated with abdominal pain due to torsion. Weight loss may also occur. In a number of cases, the tumor has been found incidentally; in these, the tumor is usually small. In pregnancy, the tumor may be discovered as an incidental finding or may present with abdominopelvic pain and/or obstruct labor.
The common association of dysgerminoma with gonadoblastoma, a tumor that nearly always occurs in patients with dysgenetic gonads (Schellhas 1974a, b; Scully 1970a), indicates that there is a relationship between dysgerminoma and genetic and somatosexual abnormalities. Several reports emphasize the occurrence of dysgerminoma in normal female patients (Asadourian and Taylor 1969; Björkholm et al. 1990), and it has been proposed that two different mechanisms are involved in the tumorigenesis of dysgerminoma in these patients versus those with disorders of sex development, with the former related to KIT mutations and the latter related to the TSPY gene on the Y chromosome (Hersmus et al. 2012).
Dysgerminoma may also be discovered incidentally in patients investigated for primary amenorrhea; in these cases, it is usually associated with gonadoblastoma (Schellhas 1974a, b; Scully 1970a; Williamson et al. 1976). Occasionally, menstrual and endocrine abnormalities may be the presenting symptoms, but this finding tends to be more common in patients with dysgerminoma containing syncytiotrophoblastic giant cells or when combined with other neoplastic germ cell elements, especially choriocarcinoma. The latter qualifies as a mixed germ cell tumor. In children, precocious sexual development may occur (Rutgers and Scully 1986). Dysgerminoma associated with evidence of virilization is found mostly in association with gonadoblastoma in patients with pure or mixed gonadal dysgenesis. A few cases of dysgerminoma associated with hypercalcemia have been reported and were found to be due to increased circulating levels of the active form of vitamin D, 1,25-dihydroxyvitamin D3, rather than increased synthesis of parathyroid hormone-related peptide, as seen in other ovarian tumors with hypercalcemia (Evans et al. 2004). A few other unusual paraneoplastic syndromes have also been described in association with dysgerminoma, including anti-Ma-associated encephalitis (Abdulkader et al. 2013; Al-Thubaiti et al. 2013).
Dysgerminoma affects the right ovary in approximately 50% of cases and the left in 35%, and it is bilateral in 15% (Asadourian and Taylor 1969; Gordon et al. 1981; Mueller et al. 1950). A much higher frequency of bilateral tumors is observed in patients with dysgerminoma associated with gonadoblastoma, the dysgerminoma arising from and overgrowing the gonadoblastoma (Schellhas 1974a, b; Scully 1970a). Thus, inclusion of such cases tends to increase the prevalence of bilaterality.
The centrally located vesicular nucleus is large, occupying nearly half the cell. The nucleus is oval or round, has a sharp nuclear membrane with unevenly dispersed finely granular chromatin, and contains usually one but sometimes two prominent eosinophilic nucleoli. Some variation in the size of the cells and nuclei and in the amount of nuclear chromatin is usually seen. Large or giant mononucleate tumor cells, which in all other respects resemble typical dysgerminoma cells, may be seen. Mitotic activity is almost always detectable and may vary from slight to brisk. This difference in mitotic activity may be observed not only in different tumors but also in different parts of the same tumor.
The cytoplasm of the tumor cells contains glycogen, which can be demonstrated with the periodic acid–Schiff (PAS) reaction and is removed by diastase digestion. The amount of glycogen in tumor cells is variable, and glycogen is lost from the cytoplasm on prolonged fixation in formalin. In view of this, the PAS reaction may vary from strong to very weak. Lipid can be demonstrated in the cytoplasm of the tumor cells in frozen tissue.
The stroma that surrounds the tumor cells almost always displays lymphocytic infiltration, which can vary from slight to marked (Fig. 5). Occasionally, lymphoid follicles containing germinal centers may be seen. Plasma cells, eosinophils, and sometimes a granulomatous reaction are present in the connective tissue stroma. The lymphoreticular cell infiltrate has previously been studied immunohistochemically, and most of the cells are T cells and macrophages. There are relatively few B cells, natural killer cells, and other types of lymphoreticular cells (Dietl et al. 1993).
The connective tissue stroma shows considerable variation, ranging from a fine, delicate fibrovascular network that can be loose and edematous to densely hyalinized. Depending on the amount of stroma, the tumor cells form large aggregates, smaller nests, islands, cords, or strands. Occasionally, the amount of stroma may be very abundant leading to wide separation of the nests of tumor cells. In some cases hyalinization may be so marked that tumor cells are detected with difficulty. At the opposite end of the spectrum, there are tumors that are cellular and contain only an imperceptible amount of stroma. There may be considerable variation in the amount of stroma in various parts of the same tumor.
In 6–8% of dysgerminomas, there are individual or collections of syncytiotrophoblastic giant cells that produce human chorionic gonadotropin (hCG). The presence of these cells is associated with elevation of serum hCG levels; hCG can also be demonstrated in tissue sections by immunohistochemistry. This evidence provides another possible explanation, apart from the presence of true choriocarcinomatous elements, for the occasional presence of endocrine activity in cases of dysgerminoma. However, there remains a small group of cases in which, despite a careful search, trophoblastic elements have not been found. In some of these cases, the dysgerminoma has been associated with an increase in luteinized stromal cells, which are likely responsible for the feminizing side effects and occasionally virilization (Rutgers and Scully 1986).
Pure dysgerminoma is not associated with elevated levels of serum alpha-fetoprotein (AFP) (Talerman et al. 1980). The presence of elevated levels of AFP is an indication of the presence of other neoplastic germ cell elements, virtually always yolk sac tumor, either within the primary tumor or its metastases.
Immunohistochemical Features and Differential Diagnosis
The main tumors in the differential diagnosis of dysgerminoma include embryonal carcinoma, yolk sac tumor, clear cell carcinoma, and steroid cell tumor. Solid patterns of embryonal carcinoma, yolk sac tumor, and clear cell carcinoma can overlap with the histologic appearance of dysgerminoma, but (a) the admixture of glandular and papillary growth patterns in embryonal carcinoma, yolk sac tumor, and clear cell carcinoma; (b) lobulated architecture with lymphocytes in the interlobular fibrous septa seen in some dysgerminomas; and (c) immunohistochemical differences mentioned above usually allow for distinction. In addition, embryonal carcinoma typically shows a greater degree of nuclear pleomorphism than dysgerminoma. Histologically, dysgerminoma and steroid cell tumor can occasionally resemble one another, as both contain sheets of clear or eosinophilic cells. The younger age of patients with dysgerminoma, lobulated architecture with lymphocytes in the interlobular fibrous septa seen in some dysgerminomas, finely vacuolated cytoplasm of steroid cell tumor, and immunohistochemical expression of inhibin, SF-1, and calretinin in steroid cell tumor and CD117 and OCT-4 in dysgerminoma should facilitate the distinction.
Clinical Behavior and Treatment
Dysgerminoma is a malignant neoplasm capable of metastatic and local spread. Despite its less aggressive behavior compared with other malignant germ cell neoplasms, the malignant potential of dysgerminoma should not be underestimated. Dysgerminoma is a rapidly growing neoplasm, but metastatic spread does not usually occur early in the course of the disease (although it is not possible to predict this in individual cases). When the tumor is small and freely mobile, its capsule is usually intact, but large tumors may be adherent to surrounding structures or may rupture. Rupture may occur either spontaneously or at surgery; this leads to spillage of the tumor contents and peritoneal implantation, which may have serious sequelae. Penetration of the ovarian surface by the tumor and formation of adhesions to surrounding structures may lead to direct extension by the tumor into adjacent structures.
Metastatic spread occurs via the lymphatic system; the lymph nodes in the vicinity of the common iliac arteries and the terminal part of the abdominal aorta are first affected. Occasionally, there may be marked enlargement of these lymph nodes, with formation of large masses. Usually the enlargement is slight to moderate and can be detected by computerized tomography (CT) scanning or magnetic resonance imaging (MRI). From the abdominal lymph nodes, the tumor spreads to the mediastinal and supraclavicular lymph nodes. Hematogenous spread to distant organs occurs later, and any organ may be affected, although involvement of the liver, lungs, and bones tends to be most common (Asadourian and Taylor 1969; Björkholm et al. 1990; Mueller et al. 1950). In cases of pure dysgerminoma, the metastases usually appear histologically similar to the primary tumor, but occasionally tumors composed of pure dysgerminoma may be associated with metastases composed of other neoplastic germ cell elements. This metastatic pattern is observed much more commonly in combined tumors. It has been suggested that cellular tumors with marked atypia and high mitotic activity and small amounts of stroma with only slight lymphocytic infiltration tend to be more aggressive (Asadourian and Taylor 1969). However, there is at present no good evidence that the behavior of an individual tumor can be predicted by its histologic appearance (Björkholm et al. 1990). The presence of other malignant germ cell elements, however, has an adverse effect on prognosis (Asadourian and Taylor 1969; Björkholm et al. 1990; Kurman and Norris 1976c; Pedowitz et al. 1955).
Dysgerminoma, similar to its testicular counterpart seminoma, is associated with elevated levels of serum lactate dehydrogenase (LDH) and its isoenzyme-1 (LDH-1). These substances can be used as tumor markers (Fujii et al. 1985; Schwartz and Morris 1988). There is a good correlation between the volume of tumor tissue present and the serum levels of the enzymes.
The prognosis of patients with pure dysgerminoma is very favorable, with a 5-year survival of >90% using current treatment modalities (A. L. Husaini et al. 2012; Vicus et al. 2010). Unfavorable prognostic features include higher stage at diagnosis (in particular lymph node metastasis) and large tumor size (Gordon et al. 1981; Kumar et al. 2008; Pedowitz et al. 1955). It should be noted that even when these features are present, most patients have been cured with chemotherapy. Age does not appear to be an important prognostic factor (Asadourian and Taylor 1969; Björkholm et al. 1990; Gershenson 1993; Peccatori et al. 1995).
Like other malignant germ cell tumors, dysgerminoma responds very well to platinum-based combination chemotherapy, and the most commonly used regimen is cisplatin, etoposide (VP-16), and bleomycin (BEP). Almost all recurrences occur in the first 2 years after diagnosis (A. L. Husaini et al. 2012; Vicus et al. 2010).
For young women with unilateral encapsulated pure dysgerminoma, two different therapeutic approaches have been advocated. One consists of unilateral oophorectomy or salpingo-oophorectomy and careful follow-up. The second approach advocates similar surgical therapy, but to decrease and prevent metastases and recurrences, adjuvant chemotherapy is administered. The advantages of the first approach are that fertility is preserved and the long-term effects of chemotherapy are avoided. Although the second approach decreases the risk of recurrence (A. L. Husaini et al. 2012; Björkholm et al. 1990; Talerman et al. 1973; Vicus et al. 2010), this risk does not preclude the conservative approach, as recurrences can be treated successfully by adjuvant therapy (A. L. Husaini et al. 2012; Asadourian and Taylor 1969; Björkholm et al. 1990; Bonazzi et al. 1994; Gershenson 1993; Peccatori et al. 1995; Vicus et al. 2010). The success of salvage therapy in the majority of patients with recurrences has also called into question the utility of complete surgical staging at the time of initial surgery (A. L. Husaini et al. 2012; Mangili et al. 2011; Vicus et al. 2010). The conservative approach to the therapy of unilateral encapsulated dysgerminoma is therefore recommended (National Comprehensive Cancer Network 2017), but each case should be considered individually. It should be noted that before this mode of treatment can be considered, a normal female 46,XX karyotype should be confirmed.
In patients with widely disseminated metastases, administration of three to four cycles of platinum-based combination chemotherapy has been successful in eradicating the disease (A. L. Husaini et al. 2012; Gershenson 1993; Peccatori et al. 1995; Vicus et al. 2010). Recently, fertility-sparing surgery with adjuvant chemotherapy has been demonstrated to be successful even for patients with bilateral disease and residual tumor remaining after surgery (Sigismondi et al. 2015). Neoadjuvant chemotherapy may also be useful for patients with advanced disease or who are not surgical candidates (Talukdar et al. 2014).
The treatment of patients with dysgerminoma occurring in dysgenetic gonads must be hysterectomy and bilateral salpingo-gonadectomy due to the high risk of developing bilateral neoplasms in these patients (Gallager and Lewis 1973). Furthermore, their gonads are hormonally and functionally inactive. Therefore, determination of the karyotype of all patients with dysgerminoma, especially those with evidence of virilization or developmental and menstrual abnormalities, is recommended. This is especially important in prepubertal patients, because these patients lack other signs of abnormal function, such as primary amenorrhea, virilization, and absence of normal sexual development. Following adnexectomy, patients are given hormone replacement therapy. Adequate treatment in these cases prevents development of a tumor in the opposite gonad (Gallager and Lewis 1973). Follow-up is advisable to prevent any deleterious effects of hormone replacement therapy.
Yolk Sac Tumor
Yolk sac tumor is a malignant germ cell neoplasm that is thought to originate from the undifferentiated and multipotential embryonal carcinoma by selective differentiation toward yolk sac or vitelline structures, in the same way that non-gestational choriocarcinoma differentiates toward trophoblastic structures. Although the vast majority of yolk sac tumors are of germ cell derivation, a subset of cases are thought to evolve from an underlying carcinoma (Roth et al. 2011). Thus, some yolk sac tumors uncommonly may be of epithelial rather than germ cell origin.
The recognition and classification of yolk sac (endodermal sinus) tumor as a specific entity stems from the studies of Teilum (1946, 1950, 1959). The concepts regarding the histogenesis of this neoplasm that Teilum proposed have been supported by the experimental studies of the neoplastic rodent yolk sac by Pierce et al. (1962). The hyaline, PAS-positive material in yolk sac tumor has been found to be similar to the hyaline material produced by mouse teratocarcinoma during its conversion to the ascitic form, and this is considered to be a strong argument in favor of the yolk sac origin of the tumor (Pierce and Dixon 1959a, b, 1962, 1964). When examined with the electron microscope, the cells of yolk sac tumor resemble those of the normal human yolk sac (Gonzalez-Crussi and Roth 1976; Jacobsen and Talerman 1989; Nogales-Fernandez et al. 1977).
In 1939, Schiller (1939) described an ovarian neoplasm composed of clear and hobnail cells with a pattern that he designated as mesonephroma because of the presence of structures resembling immature glomeruli. Other investigators (Kazancigil et al. 1940) were unable to demonstrate the mesonephric origin of this tumor and considered it an endothelioma of the ovary (Schmitz 1925). In 1946, Teilum (1946) demonstrated that the tumor described as mesonephroma (Schiller 1939) included two distinct neoplasms with different histogeneses, histologic patterns, age distributions, and clinical behaviors. One of these tumors was highly malignant, occurred in young patients, was homologous with certain testicular neoplasms, and was of germ cell origin (Teilum 1946). The other tumor was less aggressive, occurred in older women, and ultimately was shown by Scully to be of müllerian-type origin. He designated this neoplasm “clear cell carcinoma.”
In addition to the terms mesonephroma and endothelioma, yolk sac tumors have been designated as embryonal carcinoma because of certain similarities to embryonal carcinoma of the testis (Dixon and Moore 1952). Although a histologic pattern resembling typical embryonal carcinoma of the testis (Dixon and Moore 1952) is seen occasionally in ovarian germ cell tumors (Kurman and Norris 1976a), tumors with a distinctive pattern of differentiation toward yolk sac or vitelline structures should be termed yolk sac tumor (Teilum 1959, 1965).
The term yolk sac tumor is more inclusive than the original term endodermal sinus tumor. Ovarian yolk sac tumor differs from the undifferentiated embryonal carcinoma (Dixon and Moore 1952) and resembles closely the yolk sac tumor of both infantile and adult testes (Talerman 1975; Teilum 1959, 1965). It is now generally accepted that the term embryonal carcinoma should be used only to designate ovarian neoplasms showing the typical histologic pattern of embryonal carcinoma as described in testicular tumors (Dixon and Moore 1952; Kurman and Norris 1976a). It is notable that most true ovarian embryonal carcinomas are combined with yolk sac tumor. The not infrequent combination of yolk sac tumor elements with other neoplastic germ cell elements in ovarian tumors (Jacobsen and Talerman 1989; Kurman and Norris 1976c) is one of the arguments in favor of the germ cell origin of this neoplasm. Yolk sac tumor, either pure or combined with other neoplastic germ cell elements, has been encountered in extragonadal locations where germ cell tumors are known to occur, including the mediastinum, sacrococcygeal region, pineal gland, and vagina. Recently, the name “primitive endodermal tumor” has been proposed to encompass the diverse patterns and types of differentiation encountered in yolk sac tumors, as well as tumors with similar features in other sites (Nogales et al. 2012).
Alpha-fetoprotein (AFP) was first identified as a specific constituent of normal human fetal serum by Bergstrand and Czar in 1956 (Bergstrand and Czar 1956). In the human embryo, serum AFP peaks at approximately 3000 mg/L at about 12–13 weeks of gestation. The level decreases slowly until birth, when it is approximately 55 mg/L. After birth, AFP disappears rapidly from the serum, and 3 weeks after full-term delivery, it can be detected only in very small amounts (0–15 ng/mL) by radioimmunoassay or sensitive enzyme immunoassays. In fetal development, AFP is produced by the yolk sac, liver, and upper gastrointestinal tract. Certain histologic components of germ cell neoplasms correlate with elevated serum AFP. It has been demonstrated that germ cell tumors in patients with elevated serum AFP are either composed entirely of, or contain, yolk sac tumor elements (Norgaard-Pedersen et al. 1975; Talerman et al. 1980). Elevation of serum AFP has not been observed in patients with pure dysgerminoma, mature cystic teratoma of the ovary, or pure gonadoblastoma (Talerman et al. 1980). Slight elevations of serum AFP have been noted in occasional cases of immature teratoma of the ovary; this is most likely related to the presence of neuroepithelium.
Apart from yolk sac tumor, elevated levels of serum AFP are seen in patients with hepatoid carcinoma of the ovary and occasional Sertoli–Leydig cell tumors, especially those showing a retiform pattern (Talerman 1987; Talerman and Haije 1985; Young and Scully 1983). Slightly elevated levels of serum AFP up to 60 ng/mL (upper limit of normal serum AFP, 20 ng/mL) have been observed in some cases of embryonal carcinoma of the testis (Talerman et al. 1980). Using immunohistochemical techniques, AFP has been identified in the cells of yolk sac tumor and embryonal carcinoma of the ovary (Jacobsen and Talerman 1989; Kurman and Norris 1976a), and in the eosinophilic, PAS-positive, diastase-resistant globules present both inside and outside the tumor cells. Large amounts of AFP have been extracted from tumor tissue in yolk sac tumors of the ovary and testis (Talerman et al. 1978).
In view of the fact that normal yolk sac in humans and other mammalian species has been shown to be associated with AFP synthesis (Gitlin et al. 1972), it is reasonable to assume that the selective synthesis of AFP by yolk sac tumors provides further support to the view that yolk sac tumor develops as a result of differentiation of primitive malignant germ cell elements in the direction of yolk sac or vitelline structures (Jacobsen and Talerman 1989; Kurman and Norris 1976b; Talerman and Haije 1974; Talerman et al. 1980). The immunohistochemical localization of AFP in embryonal carcinoma and in areas of yolk sac tumor showing no morphologic evidence of yolk sac differentiation suggests that the biochemical manifestations of yolk sac differentiation, such as AFP synthesis, precede morphologic differentiation (Jacobsen and Talerman 1989; Kurman and Norris 1976a).
Yolk sac tumor is the second most common malignant ovarian germ cell neoplasm after dysgerminoma. It is one of the most common malignant ovarian neoplasms of childhood, adolescence, and early adult life (Jacobsen and Talerman 1989).
Yolk sac tumor has been encountered in all races (Gershenson et al. 1983; Jacobsen and Talerman 1989; Kurman and Norris 1976b). The reported age distribution of patients with yolk sac tumor ranges from 16 months to 46 years, but most patients have been under 30 years of age (Gershenson et al. 1983; Jacobsen and Talerman 1989; Kurman and Norris 1976b). Yolk sac tumor is encountered most frequently in the second and third decades, followed by first and fourth, and is rare in women in the fifth decade. It has also been encountered in occasional peri- and postmenopausal patients, most often in association with a somatic-type malignancy. The most commonly associated somatic neoplasm is endometrioid carcinoma, but other reported associated tumors include high-grade serous carcinoma, clear cell carcinoma, and mucinous tumors (Mazur et al. 1988; McNamee et al. 2016; Nogales et al. 1996; Roth et al. 2011; Rutgers et al. 1987). Although the histogenesis of these yolk sac tumors is uncertain, they are believed to arise from the somatic component by a process of “neometaplasia” or “retrodifferentiation” (Mazur et al. 1988; McNamee et al. 2016; Rutgers et al. 1987). Rare cases of yolk sac tumor in postmenopausal women without an accompanying somatic neoplasm have also been described and are believed to represent overgrowth of the yolk sac component (McNamee et al. 2016; Nogales et al. 1996; Roth et al. 2011). The term “somatically derived yolk sac tumors” has been proposed to encompass these tumors (McNamee et al. 2016; Roth et al. 2011). Of note, the serum AFP levels approximately correlate with the quantity of the yolk sac component (Roth et al. 2011).
Most patients with yolk sac tumor present with abdominal enlargement, pain, and a lower abdominal or pelvic mass (Gershenson et al. 1983; Jacobsen and Talerman 1989; Kurman and Norris 1976b). Occasionally, symptoms are acute and severe and may lead to the diagnosis of acute appendicitis or a ruptured ectopic pregnancy; this is usually caused by torsion of the tumor. A number of cases have been encountered during pregnancy (Jacobsen and Talerman 1989; Kurman and Norris 1976b). The presence of yolk sac tumor is not associated with endocrine manifestations. On clinical examination, a tumor mass is usually palpable and is frequently of considerable size (Gershenson et al. 1983; Jacobsen and Talerman 1989; Kurman and Norris 1976b). Increased levels of AFP are found in the serum (Gershenson et al. 1983; Norgaard-Pedersen et al. 1975; Talerman et al. 1978), and this is a useful diagnostic test for the presence of yolk sac tumor elements in the primary tumor, its metastases, and recurrences (Talerman et al. 1978, 1980).
Yolk sac tumors are almost always unilateral (Gershenson et al. 1983; Jacobsen and Talerman 1989; Kurman and Norris 1976b; Talerman et al. 1978). Bilaterality is typically a manifestation of metastatic spread. Yolk sac tumor shows a certain predilection for the right ovary (Jacobsen and Talerman 1989; Kurman and Norris 1976b). The tumor is usually large, varying from 3 to 30 cm in diameter, with most tumors measuring more than 10 cm (Jacobsen and Talerman 1989; Kurman and Norris 1976b; Talerman et al. 1978). It frequently weighs more than 500 g; tumors weighing 5 kg have been recorded. The tumor is usually encapsulated, round, ovoid, or globular; firm, smooth, or somewhat lobulated; and gray–yellow, with areas of hemorrhage and cystic or gelatinous changes. The tumor may form adhesions to the surrounding structures and invade them. On sectioning, yolk sac tumors are mainly solid, but cystic spaces containing gelatinous fluid are frequently present. Necrosis and hemorrhage and the presence of other neoplastic germ cell elements, especially teratoma, may alter the appearance of the tumor.
The endodermal sinus pattern (Fig. 9) is composed of perivascular formations, consisting of a narrow band of connective tissue with a capillary blood vessel in the center and lined by a layer of cuboidal or low columnar embryonal epithelial-like cells. The cells have large, slightly vesicular nuclei and prominent nucleoli and show mitotic activity. The surrounding capsular sinusoid space is lined by a single layer of flat cells with prominent hyperchromatic nuclei. These characteristic perivascular formations are said to recapitulate the so-called endodermal sinuses (Teilum 1959, 1965) that, although not conspicuous in the human placenta, are well-defined embryologic structures in the rat placenta. These structures are also known as sinuses of Duval, Schiller–Duval bodies, or glomerulus-like structures and resemble superficially immature renal glomeruli. When sectioned longitudinally, the perivascular structures consist of a central connective tissue core containing a longitudinal vessel surrounded by epithelial-like cells that often form small papillary formations projecting into the surrounding capsular sinusoid space.
The presence of these perivascular formations or Schiller–Duval bodies can be considered diagnostic of yolk sac tumor, but in some tumors they may be poorly represented, somewhat atypical or absent. Although the tumor should always be examined carefully and searched to identify these structures, their absence does not preclude the diagnosis if the appearance of the tumor is typical in all other respects. Apart from the presence of the perivascular structures, the endodermal sinus pattern consists of a complicated labyrinth of communicating cavities and channels. In addition, there are papillary processes and blood vessels surrounded by narrow connective tissue cores and epithelial-like cells radiating into the surrounding stroma, resembling the typical perivascular formations but differing from them by the absence of the sinusoid space.
The eosinophilic, hyaline droplets may be present either within the tumor cells or outside them; they may be numerous and prominent in some tumors (Fig. 12). The droplets may be observed in tumors with any of the histologic patterns described, and their identification is a helpful diagnostic feature. However, their presence is not diagnostic of yolk sac tumor because they are observed in many malignant, often poorly differentiated neoplasms, particularly clear cell carcinoma. The droplets are considered to be secreted by the tumor cells and accumulate within the cytoplasm. As the amount of secretion increases, the cell becomes distended and ruptures, discharging its contents into the surrounding tissue. These globules have been previously shown by immunohistochemical techniques to contain AFP (Jacobsen and Talerman 1989; Kurman and Norris 1976b; Shirai et al. 1976). Other globules may contain alpha1-antitrypsin and other plasma proteins such as transferrin (Jacobsen and Talerman 1989; Shirai et al. 1976; Tsuchida et al. 1978).
Occasionally, yolk sac tumor may exhibit a greater degree of cellular and nuclear pleomorphism with some giant cells, usually mononucleated, but sometimes multinucleated. This picture may be seen in association with the solid, papillary, and glandular–alveolar patterns. The pleomorphic cells show variable immunohistochemical staining for AFP, and the absence of hCG confirms that the giant cells are not trophoblastic in origin but are part of the yolk sac tumor.
Another rarely reported occurrence in yolk sac tumor is sarcomatous transformation of a mesenchyme-like component which is either stimulated by or arises from the epithelial tumor cells (Futagami et al. 2010; Nogales et al. 2012). The mesenchymal component can undergo various forms of differentiation and may be the only component remaining following platinum-based chemotherapy, resulting in a diagnostic challenge (Ali et al. 2010; Futagami et al. 2010; Nogales et al. 2012). Similar post-chemotherapy sarcomatoid yolk sac tumors have also been described in the testis (Howitt et al. 2015).
Immunohistochemical Features and Differential Diagnosis
Yolk sac tumor may be confused with clear cell and endometrioid carcinomas, embryonal carcinoma, and dysgerminoma. Clear cell carcinoma shows a more regular tubular pattern, lacks the honeycomb network composed of microcysts, and has papillary frond-like projections that are often lined by clear or hobnail cells. The typical perivascular formations or Schiller–Duval bodies present in yolk sac tumor are absent. The epithelial cells lining the tubules are cuboidal with clear cytoplasm or are hobnail with nuclei bulging into the lumen. Areas composed of large polygonal cells with clear cytoplasm and small, dark, uniform, centrally situated nuclei resembling those of renal cell carcinoma are present. When clear cell carcinoma is composed entirely of tubules or spaces, confusion may arise with the polyvesicular vitelline pattern of yolk sac tumor. However, the epithelial lining in clear cell carcinoma is usually composed of hobnail cells and not of the two types of epithelia in the vesicles comprising the polyvesicular vitelline pattern. The cystic spaces are more tubular and less vesicle-like. Clear cell carcinoma shows diffuse immunohistochemical expression of CK7 and EMA and is usually negative for AFP, while yolk sac tumor typically shows the opposite immunoprofile (Esheba et al. 2008; Ramalingam et al. 2004). Glypican-3 is more sensitive than AFP and is usually diffusely expressed in yolk sac tumor (Zynger et al. 2010), whereas clear cell carcinoma is either negative or focally positive (Esheba et al. 2008); however, the extent of expression of this marker can overlap between both tumors (Maeda et al. 2009). Clear cell carcinomas also typically express HNF1-beta, napsin A, and AMACR; of these, HNF1-beta is expressed yolk sac tumor but napsin A and AMACR are not (Fadare et al. 2015). SALL4 is highly sensitive and relatively specific for primitive germ cell tumors, including yolk sac tumor (Cao et al. 2009), but can be occasionally expressed in non-germ cell tumors (Miettinen et al. 2014b).
The endometrioid-like glandular variant of yolk sac tumor can simulate endometrioid carcinomas with secretory differentiation. However, women with yolk sac tumor are typically younger and have an elevated serum AFP level, while a subset of patients with endometrioid carcinoma has endometriosis in the ipsilateral ovary or elsewhere in the pelvic cavity. Other admixed classic patterns of yolk sac tumor or endometrioid carcinoma, as well as hyaline globules in the former and squamous differentiation in the latter, help support either diagnosis. Demonstrating immunohistochemical expression of AFP, glypican-3, or SALL4 in yolk sac tumor and CK7 and EMA in endometrioid carcinoma is also useful (Ramalingam et al. 2004). Estrogen and progesterone receptors are not detected in yolk sac tumors (Kommoss et al. 1989), but diffuse expression of these markers is common in endometrioid carcinomas (Zhao et al. 2007). It should be noted, however, that somatically derived yolk sac tumors may be admixed with clear cell carcinoma and/or endometrioid carcinoma and that these yolk sac tumors may also express CK7 and EMA diffusely (McNamee et al. 2016; Roth et al. 2011).
Embryonal carcinoma, which is uncommon in the ovary (Jacobsen and Talerman 1989; Kurman and Norris 1976a; Teilum 1959), lacks the specific patterns observed in yolk sac tumor. In its undifferentiated form, it is composed of aggregates of primitive embryonal cells. The tumor cells are frequently larger than those seen in the solid cellular aggregates in yolk sac tumor. The cytoplasm is more granular, there is more marked cellular and nuclear pleomorphism, and the nucleoli are more prominent. Even when the tumor is better differentiated, with the embryonal cells forming cords, tubules, or papillae and lining clefts or spaces, it still lacks the typical patterns associated with yolk sac tumor. Immunohistochemistry can be useful, as embryonal carcinoma is usually positive for OCT-4 and CD30 and negative for glypican-3, while yolk sac tumor typically displays the opposite pattern (Cheng et al. 2010).
Yolk sac tumor with a solid pattern may be confused with dysgerminoma. The cells of dysgerminoma are usually more uniform, lack microcysts, and are usually associated with lymphocytic and granulomatous reactions. The cells of yolk sac tumor are uniformly low molecular weight cytokeratin positive (Miettinen et al. 1985a, b). The presence of this feature as well as positive staining for AFP and lack of expression of CD117 and OCT-4 differentiate between yolk sac tumor and dysgerminoma, the latter of which shows only occasional cytokeratin-positive cells.
Yolk sac tumor, because of its cystic pattern and the presence of numerous small blood vessels, has been confused with vascular tumors, but careful examination reveals that the pattern is more cystic and a vascular tumor can be excluded with the use of appropriate immunohistochemical stains. It should be pointed out that yolk sac tumor elements may show hematopoiesis and are sometimes intimately associated with immature vascular tissue in some mixed germ cell tumors; this may also contribute to diagnostic problems. Confusion may arise occasionally with some Sertoli–Leydig cell tumors showing a retiform pattern, especially when the latter are associated with elevated serum levels of AFP (Talerman 1987; Young and Scully 1983). The presence of more marked cellular and nuclear pleomorphism, brisk mitotic activity, and other histologic patterns observed in yolk sac tumor (as well as their absence in Sertoli–Leydig cell tumors) aid in the differential diagnosis. Immunohistochemical expression of inhibin and steroidogenic factor-1 (SF-1) further confirms the diagnosis of Sertoli–Leydig cell tumor.
Occasionally, confusion may arise with adult or juvenile granulosa cell tumors when they present with a reticular pattern or with small vesicle-like collections of cells surrounded by connective tissue stroma that simulate the vesicles seen in polyvesicular vitelline yolk sac tumor. The presence of features typical of adult or juvenile granulosa cell tumor, absence of the various patterns of yolk sac tumor, absence of immunohistochemical staining for AFP and SALL4, immunohistochemical expression of SF-1 and inhibin, and a lack of elevated serum levels of AFP indicate that the tumor is a granulosa cell tumor (Bai et al. 2013).
The rare hepatoid variant of yolk sac tumor can cause a diagnostic dilemma with hepatocellular carcinoma and with primary hepatoid carcinoma of the ovary. Hepatocellular carcinoma can express SALL-4, although to a lesser extent than hepatoid yolk sac tumor, and a cutoff of 25% expression has been demonstrated to improve specificity for the latter (Gonzalez-Roibon et al. 2013). The addition of hepatocyte paraffin 1 (HepPar1) immunohistochemistry can also be useful. Although hepatoid yolk sac tumor does express this marker (Pitman et al. 2004), the extent of expression is typically greater in both hepatocellular carcinoma and primary hepatoid carcinoma of the ovary (Gonzalez-Roibon et al. 2013; Rittiluechai et al. 2014). The presence of bile production and the expression of polyclonal CEA in a canalicular pattern also favor a diagnosis of hepatocellular carcinoma (Rittiluechai et al. 2014).
It should be cautioned that, depending on the type of differentiation, yolk sac tumor can express differentiation markers of various endodermal lineages, including TTF-1, CDX2, and HepPar1 (Shojaei et al. 2016). Additionally, the less differentiated patterns of yolk sac tumor (reticular-microcystic, endodermal sinus, polyvesicular) also express GATA-3 (Miettinen et al. 2014a; Schuldt et al. 2016).
Clinical Behavior and Treatment
Yolk sac tumor is highly malignant, metastasizing early and invading surrounding structures and organs. Local invasion and intra-coelomic spread frequently lead to extensive involvement of the abdominal cavity. Yolk sac tumor metastasizes first via the lymphatic system to the para-aortic and common iliac lymph nodes and then to the mediastinal and supraclavicular lymph nodes. Hematogenous spread occurs later, with metastases found in the lungs, liver, and other organs. The tumor is locally aggressive, and spread beyond the ovary is observed in a number of patients at diagnosis (Gershenson et al. 1983; Jacobsen and Talerman 1989; Kurman and Norris 1976b). Recurrences in the pelvis are frequent, even when the tumor and the affected adnexa have been excised completely (Jacobsen and Talerman 1989; Kurman and Norris 1976b). Such recurrences usually appear within a few weeks or months after excision of the primary tumor.
Until the advent of efficacious combination chemotherapy, the treatment of patients with yolk sac tumor was very disappointing. The treatment was primarily surgical; however, extensive surgery did not improve prognosis (Kurman and Norris 1976b; Teilum 1959). The few long-term survivors in the past had tumors confined to the ovary, and most were treated by unilateral adnexectomy (Kurman and Norris 1976b; Teilum 1959). Since then, there has been marked improvement in prognosis with conservative surgery (unilateral salpingo-oophorectomy) and adjuvant multiagent combination chemotherapy (Gershenson 1993; Peccatori et al. 1995; Teilum 1959). The combination chemotherapy originally used was dactinomycin, vincristine, and cyclophosphamide or dactinomycin, 5-fluorouracil, and cyclophosphamide. Although this therapy proved to be effective in many cases, recurrences were still frequent.
The introduction of a combination of cisplatin, bleomycin, and vinblastine, which has been superseded by the less toxic cisplatin, etoposide (VP-16), and bleomycin (BEP) combination, has been found to be much more effective and has produced remissions in patients with advanced-stage disease and in patients in whom other combinations of multiagent chemotherapy have failed (Gershenson 1993; Peccatori et al. 1995). This combination chemotherapy has revolutionized the treatment of patients with yolk sac tumor. Complete cure for all stages is more than 80%, even with fertility-sparing surgery (Gershenson 1993; Peccatori et al. 1995; Weinberg et al. 2011). Neoadjuvant chemotherapy has also been used effectively in a subset of patients with advanced-stage disease (Lu et al. 2014; Talukdar et al. 2014). The occasional cases of pure hepatoid and glandular (primitive intestinal) yolk sac tumor were previously shown to have a less satisfactory response to combination chemotherapy and therefore a poorer prognosis (Clement et al. 1987; Cohen et al. 1987; Prat et al. 1982), but it has been recently demonstrated that hepatoid yolk sac tumor treated with platinum-based combination chemotherapy may have a prognosis similar to other yolk sac tumor types (Rittiluechai et al. 2014). Somatically derived yolk sac tumors have been reported to have a worse prognosis than their germ cell-derived counterparts, even with low-stage disease; however, it is suggested that the use of adjuvant chemotherapy aimed at both components results in a better survival for low-stage disease (Roth et al. 2011).
Serum AFP determination is useful diagnostically and in monitoring therapy. It should be noted, however, that a normal result may not always indicate the absence of active disease but only the absence of the tumor element associated with AFP synthesis. Preoperatively, if the tumor contains yolk sac tumor elements, considerable amounts of AFP can be detected in the serum. AFP levels fall postoperatively and, if there are no metastases, reach normal levels within 4–6 weeks, depending on the preoperative serum AFP level. Serum alpha1-antitrypsin levels can also be used to monitor disease activity, but are inferior to AFP (Talerman et al. 1977a). A favorable serum AFP decline rate is associated with a better overall survival, as is the absence of ascites at diagnosis (de la Motte Rouge et al. 2016; Guo et al. 2015).
Beta-hCG is normal in patients with yolk sac tumor. Carcinoembryonic antigen (CEA) has also been studied in patients with germ cell neoplasms and has been found to be of no value as a tumor marker in this group of patients (Talerman et al. 1977b).
The term embryonal carcinoma in this text includes only ovarian neoplasms showing a histologic appearance resembling that observed in embryonal carcinomas of the adult testis. Dixon and Moore (1952) consider embryonal carcinoma as both a morphologic and a conceptual entity, and this interpretation is being followed. Embryonal carcinoma is considered to be the least differentiated form of germ cell tumor and may differentiate toward either somatic (teratomatous tumors) or extraembryonal structures, including yolk sac/vitelline structures (yolk sac tumor) or trophoblast (choriocarcinoma) (Fig. 1). Although ovarian embryonal carcinoma (Jacobsen and Talerman 1989; Kurman and Norris 1976a) shows similar appearances and is considered to be homologous to its testicular counterpart, it is uncommon as a component of mixed germ cell tumors and rare as a pure entity. However, tumors showing this histologic pattern are relatively frequent in the testis. The reason for this difference is unknown. Ovarian embryonal carcinoma is usually combined with other neoplastic germ cell elements, most frequently yolk sac tumor, and forms a part of a mixed germ cell tumor (Jacobsen and Talerman 1989; Kurman and Norris 1976c; Talerman et al. 1978). Embryonal carcinoma occasionally has been observed in association with gonadoblastoma (Scully 1970a; Talerman 1974; Talerman and Dlemarre 1975).
The age and clinical presentation of embryonal carcinoma are similar to those observed in patients with other malignant germ cell neoplasms, with the tumor almost always occurring in children and young adults (Jacobsen and Talerman 1989; Kurman and Norris 1976a; Talerman et al. 1978).
Embryonal carcinoma may produce AFP, even when it is not combined with yolk sac tumor, but the serum AFP levels in such cases are only slightly elevated. When embryonal carcinoma contains syncytiotrophoblastic giant cells, as is often the case, or is combined with choriocarcinoma, it produces hCG and is associated with endocrine manifestations, such as isosexual precocious puberty in children and abnormal vaginal bleeding in adults (Kurman and Norris 1976a). A positive pregnancy test is found in almost all such patients.
Because embryonal carcinoma usually is a component of mixed germ cell tumors, the appearance of the tumor varies according to the type and amount of the different components present. On sectioning, the embryonal carcinomatous component is solid, gray–white, and slightly granular, with foci of necrosis and hemorrhage in the larger tumors.
In the better differentiated tumors, the cells, apart from forming solid areas, also tend to line clefts and spaces and form papillae. The cells appear more epithelioid than those of the more undifferentiated type, being more cuboidal or columnar in shape. Although there is a suggestion of glandular differentiation, true gland formation is absent. The papillae are composed of solid collections of cells or may contain a cystic space or a small vessel surrounded by tumor cells. They must be differentiated from perivascular formations observed in yolk sac tumor. Very primitive mesenchymal tissue may be present in conjunction with the epithelioid component. Syncytiotrophoblastic giant cells immediately adjacent to aggregates of embryonal carcinoma cells or lying isolated in the stroma are frequently found. Foci of necrosis and hemorrhage are also frequent.
Immunohistochemical Features and Differential Diagnosis
Additional considerations in the differential diagnosis of embryonal carcinoma include the solid variant of yolk sac tumor as well as immature teratoma with extensive primitive neuroectodermal tissue (Cheng et al. 2010). Positivity for OCT-4 and CD30 and negativity for glypican-3 assist with distinction from yolk sac tumor. The primitive neuroectodermal tissue of an immature teratoma is also negative for CD30, but can demonstrate immunohistochemical overlap with embryonal carcinoma in the expression of OCT-4 and SOX2 (Cheng et al. 2010). The latter marker is expressed in many (though not all) cases of embryonal carcinoma, but is not entirely specific due to its expression in immature teratomas and in a minority of epithelial ovarian tumors (Chang et al. 2009). Morphologic features favoring a diagnosis of immature neuroectodermal tissue include the presence of surrounding cellular glial elements and the identification of rosettes with karyorrhectic cells; in difficult cases, employing GFAP or other neural immunohistochemical markers can be of use (Cheng et al. 2010).
Embryonal carcinoma can also occasionally mimic non-germ cell tumors, including epithelial tumors and sex cord–stromal tumors. Negativity for EMA is useful in the distinction from epithelial tumors (Iczkowski et al. 2008). While a minority of sex cord–stromal tumors can express OCT-4, they are typically negative for SOX2 and NANOG (Chang et al. 2009). Additionally, SALL4 is highly sensitive and relatively specific for primitive germ cell tumors, including embryonal carcinoma (Cao et al. 2009), although it can be occasionally expressed in non-germ cell tumors (Miettinen et al. 2014b). The presence of abnormalities of chromosome 12p also helps exclude non-germ cell tumors (Cheng et al. 2010).
Clinical Behavior and Treatment
Embryonal carcinoma of the ovary is a highly malignant neoplasm. It is aggressive locally, spreads extensively in the abdominal cavity, and metastasizes early. The pattern of metastatic spread is similar to that of other malignant germ cell neoplasms, taking place first via the lymphatics and later by the hematogenous route. Specific treatment and prognostic data for embryonal carcinoma are mostly lacking in the literature due to its rarity, but overall survival has been reported as 39% (Kurman and Norris 1976a). Management is similar to that for other malignant ovarian germ cell tumors, consisting of unilateral salpingo-oophorectomy and chemotherapy using cisplatin, etoposide (VP-16), and bleomycin (BEP) (Gershenson 1993; Peccatori et al. 1995). Due to its aggressive nature, conservative treatment of higher stage disease, which may be effective in other germ cell tumors, is likely not appropriate in most cases of embryonal carcinoma (Kurman and Norris 1976a; Sigismondi et al. 2015).
Polyembryoma is a rare ovarian germ cell neoplasm composed of numerous embryoid bodies resembling morphologically normal presomite embryos (Beck et al. 1969; King et al. 1991; Takeda et al. 1982). Similar homologous neoplasms occur more frequently in the human testis (Beck et al. 1969; Evans 1957), although pure polyembryoma is very rare. In all ovarian cases, the polyembryoma was associated with other neoplastic germ cell elements, mainly immature or mature teratoma (Beck et al. 1969; King et al. 1991; Simard 1957; Takeda et al. 1982). All these tumors occurred in young patients or in patients in the reproductive age group (Beck et al. 1969; King et al. 1991; Simard 1957; Takeda et al. 1982); the oldest patient was 38 years old (Simard 1957). The clinical findings are similar to those observed in patients with other malignant germ cell neoplasms of the ovary. It should be noted that polyembryoma is not the same entity as “diffuse embryoma,” which is a form of mixed germ cell tumor composed of yolk sac tumor and embryonal carcinoma with a unique admixture of both components (Scully et al. 1998).
There are conflicting views of the origin of embryoid bodies. It has been suggested that they arise by parthenogenic development from primitive germ cells present in an immature (malignant) teratoma (Marin-Padilla 1965; Peyron 1939; Simard 1957). Other investigators question this view as well as the entire concept that embryoid bodies bear a close similarity to early human embryos because embryoid bodies never appear to develop beyond the 18-day stage (Beck et al. 1969). They suggest instead that embryoid bodies probably develop transiently by bizarre differentiation, possibly in response to local release of factors in malignant teratomas of the gonads.
Another view that has been advanced accepts the morphologic similarities between the early embryo and the embryoid bodies but disputes their parthenogenic origin (Evans 1957; Pierce and Dixon 1959b; Stevens 1960). It maintains that embryoid bodies are formed after initiation of teratogenesis, most likely from multipotential malignant embryonal cells present in a tumor and not directly from germ cells (Stevens 1962). This concept is supported by the observations of the development of embryoid bodies from undifferentiated embryonal cells in strain 129 mice. The tumor, a teratoma that had been serially transplanted for many years, was considered to be devoid of germ cells (Pierce and Dixon 1959b; Stevens 1960). These findings are in accordance with the view that embryoid bodies probably persist only transiently within the tumor, and while new embryoid bodies are being formed, others lose their identity and their multipotential cells undergo further differentiation (Evans 1957). Although the origin and development of embryoid bodies are still a matter of dispute, the view that they originate from multipotential malignant embryonal cells, which is supported by experimental observations (Pierce and Dixon 1959b; Stevens 1960), is most favored at present.
The place of polyembryoma in the classification of germ cell tumors has also been a matter of some debate. It was proposed by Dr. Scully that polyembryoma represents the most primitive form of an immature teratoma, while others have endorsed the view that it is a distinct type of mixed germ cell tumor, with an embryonal carcinoma-like component and a yolk sac component (Young et al. 2016). In the current WHO classification, polyembryoma is not classified as an independent germ cell tumor but rather described under the heading of immature teratoma (Kurman et al. 2014). A recent review suggests that a tumor with numerous embryoid bodies may be classified as polyembryoma when pure (an essentially nonexistent entity), polyembryoma with teratoma when the latter component is present, or mixed germ cell tumor containing polyembryoma when admixed with other components (most commonly yolk sac tumor, embryonal carcinoma, and teratoma) (Young et al. 2016).
Polyembryoma is usually unilateral. Macroscopically, the tumor resembles other malignant germ cell tumors, varying from 9.5 cm (Beck et al. 1969) to tumors filling almost the whole abdominal cavity and invading the surrounding structures (Simard 1957). The tumor is usually solid and contains hemorrhagic and necrotic areas.
Microscopic and Immunohistochemical Features
Some embryoid bodies may be malformed and show bizarre appearances. None of the embryoid bodies appear to have developed beyond the 18-day stage. The embryonic disk of a typical embryoid body is lined on one side by cuboidal epithelial cells of uniform size, resembling endoderm, and on the other by tall columnar epithelium, resembling ectoderm. The latter merges with low cuboidal epithelium lining the rest of the cavity, which resembles the amnion. The cavity resembling the yolk sac is on the opposite side of the embryonic disk from the amnion (Fig. 26). The embryoid bodies are surrounded by extraembryonic mesenchyme, which is composed of either closely or more loosely packed spindle cells of regular appearance and showing occasional mitotic figures. Loose myxomatous areas may be present.
Occasionally, embryoid bodies resemble earlier developmental stages, mainly the blastocyst and morula stage, and form numerous round or oval structures. In some tumors this pattern may predominate, although occasional fully developed embryoid bodies may be seen (King et al. 1991). Teratomatous structures in various stages of differentiation are frequently seen interspersed with the embryoid bodies. In one reported case (Beck et al. 1969), hCG and human placental lactogen were demonstrated within syncytiotrophoblastic cells that were present in the vicinity of the embryoid bodies. Cytotrophoblastic cells were not identified in this tumor. In another reported case, there was elevation of serum AFP and hCG. AFP was demonstrated by immunohistochemistry within the cells lining the yolk sac cavities and hCG within the syncytiotrophoblastic giant cells that were present in the vicinity of the embryoid bodies (Takeda et al. 1982). Of interest, OCT-4 and CD30 positivity have also been described in the embryonic disk of the embryoid body (Cheng et al. 2010).
Clinical Behavior and Treatment
Polyembryoma is a highly malignant germ cell neoplasm. In most cases, it has been associated with invasion of adjacent structures and extensive metastases, which were mainly confined to the abdominal cavity (Simard 1957).
The primary treatment of polyembryoma is surgical, and because the tumor is usually unilateral unless there is spread beyond the ovary, excision of the tumor and the adjoining adnexa is the treatment of choice. Polyembryoma responds to the combination chemotherapy used in treatment of malignant germ cell tumors (Gershenson 1993; Takeda et al. 1982).
One patient with a relatively small mobile tumor, absence of capsular penetration, and no evidence of metastases survived more than 5 years (Beck et al. 1969). Another patient was alive and free of disease for more than 12 years after excision of the affected adnexa and excision of intra-abdominal metastases composed of grade 1 immature teratoma (King et al. 1991). A third patient was well and disease-free 6 months after diagnosis (Takeda et al. 1982). Before the introduction of effective combination chemotherapy, most patients with polyembryoma died of their disease.
Pure ovarian choriocarcinoma of germ cell origin is a rare neoplasm (Jacobs et al. 1982; Jacobsen and Talerman 1989; Scully et al. 1998; Vance and Geisinger 1985), and even the presence of choriocarcinomatous elements admixed with other neoplastic germ cell elements is uncommon. In most cases, the tumor is admixed with other neoplastic germ cell elements, and their presence is generally diagnostic of non-gestational choriocarcinoma, except for the remote possibility of the tumor being a gestational choriocarcinoma metastatic to an ovarian germ cell tumor. The presence of other neoplastic germ cell elements is a particularly helpful diagnostic feature in postmenarchal patients in whom exclusion of gestational origin of the tumor may be difficult. In view of this, non-gestational choriocarcinoma may be diagnosed with confidence in postmenarchal patients and not only in young children, as had been considered earlier. The tumor most often occurs in children and young adults. In some series, 50% of cases occurred in children who had not reached puberty (Marrubini 1949). This high frequency in children may stem from the reluctance of making the diagnosis in adults. A small number of cases have been reported in association with adenocarcinoma, predominantly in postmenopausal patients, a phenomenon thought to be similar to somatic-type yolk sac tumor (Hirabayashi et al. 2006; Hu et al. 2010; Oliva et al. 1993). Detection of paternal DNA has been successful in differentiating gestational and non-gestational choriocarcinoma. In a few reported cases, DNA polymorphism analysis confirmed the non-gestational origin of the tumor (Exman et al. 2013; Hirata et al. 2012; Shigematsu et al. 2000; Tsujioka et al. 2003).
Choriocarcinoma of the ovary may originate in three different ways: (1) as a primary gestational choriocarcinoma associated with ovarian pregnancy, (2) as metastatic choriocarcinoma from a primary gestational choriocarcinoma arising in other parts of the genital tract, mainly the uterus, and (3) as a germ cell tumor differentiating in the direction of trophoblastic structures, usually admixed with other neoplastic germ cell elements. In each case, it is important to ascertain the mode of origin of the tumor because this has important therapeutic and prognostic implications. Alternatively, choriocarcinoma of the ovary may be divided into two broad groups: (1) gestational choriocarcinoma encompassing the first two groups mentioned and (2) non-gestational choriocarcinoma, a germ cell tumor with differentiation toward trophoblastic structures. As this chapter is concerned solely with germ cell tumors, only the non-gestational choriocarcinoma is discussed here.
The clinical findings in patients with ovarian non-gestational choriocarcinoma are similar to those observed in patients with other malignant ovarian germ cell neoplasms, except that they may be modified by the endocrine activity of the tumor, which secretes hCG. This effect is particularly noticeable in prepubertal children, who show evidence of isosexual precocious puberty, with mammary development, growth of pubic and axillary hair, and uterine bleeding. Adult patients may have signs of ectopic pregnancy. Very occasionally, the tumor may cause symptoms of thyrotoxicosis, including a severe acute form. Determination of urinary or plasma hCG is a useful diagnostic test. Serum hCG levels are also useful in monitoring response to therapy. It should be noted that normal levels of hCG do not exclude the presence of metastases or recurrences composed of other neoplastic germ cell elements.
The tumor is typically large, unilateral, solid, gray–white, and hemorrhagic. Necrosis may be evident. Because most of these tumors are composed of a combination of neoplastic germ cell elements, the appearances tend to vary according to the specific elements present.
Microscopic and Immunohistochemical Features
There is considerable variation in the pattern and ratio of the two components in different parts of the same tumor and in different tumors. The tumor cells form solid aggregates, nearly always associated with hemorrhage and necrosis. At times the tumor is limited to the periphery of the hemorrhagic mass. The presence of other germ cell elements within the tumor is a frequent finding. When the tumor is combined with other germ cell elements, the choriocarcinoma may form small nodules associated with hemorrhage and surrounded by other germ cell elements. As choriocarcinoma is often hemorrhagic, a careful search may be necessary to demonstrate the presence of choriocarcinomatous elements.
The cytotrophoblast is the more primitive element, and the syncytiotrophoblast is formed from it either directly or indirectly. The syncytiotrophoblast is the differentiated, nondividing, hormone-secreting component. These findings are supported by electron microscopic and immunohistochemical studies (Pierce and Midgley 1963; Pierce et al. 1962, 1964). Immunohistochemical staining for beta-hCG provides a useful confirmatory diagnostic method. Although intermediate trophoblastic cells may be seen occasionally in non-gestational choriocarcinomas, diagnostic confusion with other tumors of intermediate trophoblast is typically not an issue given the extreme rarity of ovarian placental site trophoblastic tumors and ovarian epithelioid trophoblastic tumors (Arafah et al. 2015; Arroyo et al. 2009; Baergen et al. 2003; Condous et al. 2003).
Clinical Behavior and Treatment
Non-gestational choriocarcinoma of the ovary is a highly malignant germ cell neoplasm. It invades adjacent structures, spreads widely throughout the abdominal cavity, and metastasizes via the lymphatics and the blood vessels. Although gestational choriocarcinoma tends to spread primarily via the bloodstream, non-gestational choriocarcinoma shows lymphatic and intra-abdominal spread as well as hematogenous spread. Sometimes the hematogenous spread may be less marked.
Until the introduction of effective combination chemotherapy, the prognosis of patients with choriocarcinoma was distinctly unfavorable, though somewhat better than that of patients with yolk sac tumor. Treatment has been revolutionized by the introduction of combination chemotherapy containing cisplatin or methotrexate, with marked improvement in prognosis and survival. The most frequently used chemotherapy regimens are cisplatin, etoposide (VP-16), and bleomycin (BEP), as in other ovarian germ cell tumors, and etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA/CO), as in gestational choriocarcinoma (Gershenson 1993; Kong et al. 2009; Ozturk et al. 2010; Peccatori et al. 1995). Fertility-sparing surgery with adjuvant combination chemotherapy has been successfully employed in a number of cases (Jiao et al. 2010).
The origin of teratomas has been a matter of interest, speculation, and dispute for centuries. The parthenogenic theory, which suggests an origin from the primordial germ cell, is now the most widely accepted. Two other theories, one suggesting an origin from blastomeres segregated at an early stage of embryonic development and the second suggesting an origin from embryonal rests, have few adherents currently. Support for the germ cell theory has come from the anatomic distribution of the tumors, which occur along the line of migration of the primordial germ cells from the yolk sac to the primitive gonad, and from the fact that the tumors occur most commonly during the years of reproductive activity. Support also comes from animal experiments in which cystic teratomas can be produced only during the period of reproductive activity of the gonad, as in roosters injected with zinc and copper salts (Bagg 1936; Carleton et al. 1953), and from the 46,XX karyotype of mature ovarian teratomas (Linder et al. 1975; Rashad et al. 1966).
The histogenesis of teratoma of the ovary has been studied using both cytogenetic techniques and the electrophoretic patterns of four enzymes in normal as well as in tumor cells. These studies demonstrated that teratomas are of germ cell origin and arise from a single germ cell after the first meiotic division (Linder et al. 1975; Linder and Power 1970). Subsequent studies using more advanced genotyping techniques further confirmed these observations (Snir et al. 2017). Although most mature cystic teratomas arise in this manner, some have been demonstrated to arise before the first meiotic division (Nomura et al. 1983; Parrington et al. 1984; Snir et al. 2017; Wang and Lai 2016). It has been hypothesized that teratomas preferentially differentiate toward tissues normally derived from the anterior embryonic plate (Chen et al. 2010). The basis for this theory is the frequent presence of tissues which may be localized to the head and neck region (e.g., hair-bearing skin in close proximity to glial tissue, recapitulating hair-bearing scalp), combined with the much less frequent presence of tissue types normally localized to more caudal parts of the body (e.g., intestine).
The classification of ovarian teratomas is shown in Table 1. Briefly, they are divided into three main groups: (1) immature teratomas, (2) mature teratomas, and (3) monodermal and highly specialized teratomas. Most cases (99%) are mature cystic teratomas, also known as dermoids or dermoid cysts.
Immature teratomas are composed of tissues derived from any or all of the three germ layers – ectoderm, mesoderm, and endoderm – and, in contrast to the much more common mature teratoma, they contain immature or embryonal neuroectodermal tissue. Other immature tissues may also be present. Mature tissues are frequently present and sometimes may predominate. In these cases, the tumor should be differentiated from a mature teratoma with malignant transformation. The presence of immature neuroectoderm as opposed to the neoplastic transformation of mature tissues differentiates between these two types of neoplasm.
The immature teratoma of the ovary is an uncommon tumor, comprising less than 1% of teratomas of the ovary (Bonazzi et al. 1994; Caruso et al. 1971; Malkasian et al. 1965; Roth and Talerman 2006; Scully et al. 1998; Woodruff et al. 1968). In contrast to the mature cystic teratoma, which is encountered most frequently during the reproductive years but occurs at all ages, the immature teratoma has a specific age incidence, occurring most commonly in the first two decades of life and being almost unknown after menopause (Bonazzi et al. 1994; Breen and Neubecker 1967; Malkasian et al. 1965; Scully et al. 1998; Woodruff et al. 1968). In view of this, teratomas occurring in childhood, adolescence, and early adult life should always be examined carefully and thoroughly sampled.
The tumor is usually asymptomatic until it reaches a considerable size. It tends to grow rapidly and may manifest as a pelvic or lower abdominal mass. It may cause pressure symptoms, abdominal heaviness, and dull pain, or it may undergo torsion, causing acute abdominal pain.
The tumor is usually unilateral (Bonazzi et al. 1994; Breen and Neubecker 1967; Caruso et al. 1971; Heifetz et al. 1998; Woodruff et al. 1968), but may coexist with a mature cystic teratoma in the opposite ovary (Wisniewski and Deppisch 1973), as is seen in at least 10–15% of cases. Immature teratomas are usually larger than their mature counterparts, with the reported range from 9 to 28 cm in the largest dimension (Breen and Neubecker 1967). They may form a round, ovoid, or lobulated, soft or firm solid mass, which frequently contains cystic structures with solid areas present in the cyst wall (Bonazzi et al. 1994; Breen and Neubecker 1967; Caruso et al. 1971; Heifetz et al. 1998; Malkasian et al. 1965; Wisniewski and Deppisch 1973). The tumor is often prone to perforate its capsule, which is not always well defined (Breen and Neubecker 1967; Wisniewski and Deppisch 1973). The cut surface is usually variegated, trabeculated, and lobulated, varying from gray to dark brown. Occasionally, foci of cartilage or bone may be recognizable and hair may be present. The cystic areas are usually filled with serous or mucinous fluid, colloid, or fatty material.
All these tissues, which may be in stages of maturity varying from embryonic to mature, are scattered haphazardly throughout the tumor and so differ from the orderly organoid arrangement seen in a mature teratoma. In cases in which the tumor is composed mainly of mature tissues, distinction from mature teratoma may be difficult, and patients have been diagnosed as having a benign lesion only to return within a short time with recurrence. In a number of such cases, review of the material taken from the original tumor has revealed immature elements. Therefore, careful examination and thorough sampling of the tumor are strongly recommended. Immature teratoma may be combined with other neoplastic germ cell elements, such as yolk sac tumor, dysgerminoma, embryonal carcinoma, choriocarcinoma, and polyembryoma. It can therefore form a part of a malignant mixed germ cell tumor. Immature teratoma has been reported to develop from the germ cell element of gonadoblastoma and mixed germ cell–sex cord–stromal tumor.
Immunohistochemical Features and Differential Diagnosis
Immature teratoma must be differentiated from malignant mesodermal mixed tumor (MMMT), which, although occurring most frequently in the uterus, also occurs in the ovary. MMMT is composed of tissue resembling derivatives of müllerian mesoderm, a primitive structure that gives rise to both the stroma and the epithelium of the endometrium. The characteristic histologic appearance of MMMT combined with the absence of other germ layer derivatives distinguishes MMMT from teratoma; neuroectodermal derivatives are seen only exceptionally in MMMT. MMMT occurs most frequently in postmenopausal women between the ages of 50 and 70 years and, unlike immature teratoma, occurs only occasionally in younger patients. MMMTs are composed of sarcomatoid and carcinomatous tissue. The carcinoma is invariably an adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma, and the sarcomatoid elements may be composed of a wide variety of tissues, including leiomyosarcoma, chondrosarcoma, rhabdomyosarcoma, fibrosarcoma, undifferentiated sarcoma, and myxomatous tissue. MMMT does not exhibit the great variety of tissues present in teratoma, and the tissues present in MMMT generally form more typical sarcomatous or carcinomatous patterns (see “Surface Epithelial Tumors of the Ovary”). Additionally, immature teratomas frequently express SALL4 within the immature elements, assisting in distinction from non-germ cell tumors (Cao et al. 2009). However, caution should be exercised in the distinction from MMMT, as a subset of these also demonstrate significant SALL4 expression (Bing et al. 2012).
Immunohistochemistry may also be of use in confirming the presence and extent of immature elements. SOX2 and SALL4 are both strongly expressed in immature neuroepithelium, but are weak or absent in well-differentiated neural elements (Nogales et al. 2014). Additionally, OCT-4 is expressed more frequently in higher-grade immature teratomas and may therefore be a good marker for highly malignant cases (Abiko et al. 2010).
Clinical Behavior and Treatment
Immature teratoma is a malignant neoplasm that usually grows rapidly, penetrates its capsule, and forms adhesions to the surrounding structures. It spreads throughout the peritoneal cavity by implantation and metastasizes first to the retroperitoneal, para-aortic, and more distant lymph nodes and later to the lungs, liver, and other organs. Peritoneal implants and metastases are not infrequently present at the time of primary tumor resection (Breen and Neubecker 1967; Wisniewski and Deppisch 1973). Excision of the tumor is often followed by a local recurrence within a few weeks or months. Recurrences usually occur within the first year after the primary treatment (Breen and Neubecker 1967). Rupture of the tumor with spillage of the contents during operation is not infrequent, but because of the satisfactory response of the tumor to combination chemotherapy, the favorable prognosis is not affected. The metastases and peritoneal implants may be composed of multiple different tissues, and thus their teratomatous nature is readily apparent, but they may also be composed of a single tissue. The histologic appearances of the metastases and of the peritoneal implants may or may not reflect the appearance of the primary tumor. Two related conditions may occur after treatment with chemotherapy for immature teratoma – the growing teratoma syndrome and chemotherapeutic retroconversion (Djordjevic et al. 2007; Merard et al. 2015). In both, the histologic appearance of the extra-ovarian tumor is that of pure mature teratoma. The following criteria have been proposed for growing teratoma syndrome: (a) clinical or radiologic enlargement of metastases during or after chemotherapy, (b) normalization of previously elevated serum tumor markers (AFP or HCG), and (c) metastases consisting of pure mature teratoma without malignant cells on histologic examination. Chemotherapeutic retroconversion is considered a chemotherapy-induced transformation of metastatic immature teratoma into mature teratoma. However, it is unclear whether these two conditions can be reliably distinguished in all cases.
It has been noted that there is good correlation between the histologic appearance of the tumor and prognosis (Bonazzi et al. 1994; Heifetz et al. 1998; Norris et al. 1976; O’Connor and Norris 1994). Very immature and poorly differentiated tumors have been found to be associated with worse prognosis, whereas a more favorable outcome has been observed in patients with more mature and better differentiated tumors (Heifetz et al. 1998; Norris et al. 1976; Wisniewski and Deppisch 1973). One study of immature teratoma in children showed that less mature tumors were more likely to be associated with yolk sac tumor (Heifetz et al. 1998).
O’Connor and Norris (1994) proposed that immature teratomas should be divided into two grades, those with a slight degree of immaturity (grade 1; low grade), which are not treated with combination chemotherapy, and those with a more marked degree of immaturity (grades 2 and 3; high grade), which are treated. It was demonstrated that although there was considerable inter- and intraobserver disagreement when a large series of immature teratomas were being graded using a three-tiered system, this was markedly decreased when a two-tiered system was used. The study further confirmed the good correlation between the grade of the tumor and behavior. Furthermore, it should be noted that rare and small microscopic foci of immature tissue within a mature cystic teratoma have been associated with an excellent outcome (Yanai-Inbar and Scully 1987).
Grading of immature teratomas
Amount of immature neuroectoderm occupies ≤1 low-power (4× objective) magnification field
Amount of immature neuroectoderm occupies >1 but ≤3 low-power (4× objective) magnification fields
Amount of immature neuroectoderm occupies >3 low-power (4× objective) magnification fields
Metastases/implants are considered grade 0 when no immature tissue is present, regardless of the grade of the ovarian tumor. In particular, a specific type of grade 0 implant composed entirely of mature glial tissue (“gliomatosis peritonei”) is associated with an excellent outcome (Liang et al. 2015).
The recommended treatment for patients with grade 1 (low-grade) immature teratoma confined to one ovary is unilateral salpingo-oophorectomy and careful follow-up (National Comprehensive Cancer Network 2017). This treatment is curative in nearly all cases (Bonazzi et al. 1994; Peccatori et al. 1995). For grade 2 and 3 (high-grade) tumors, adjuvant chemotherapy is administered following unilateral salpingo-oophorectomy, resulting in complete cure in the majority of patients (Bonazzi et al. 1994). More extensive surgery is necessary if the tumor extends beyond the ovary. The currently recommended combination therapy is the cisplatin, etoposide (VP-16), and bleomycin (BEP) regimen (National Comprehensive Cancer Network 2017). Therapy with vincristine, dactinomycin, and cyclophosphamide (VAC) had been the treatment of choice (Norris et al. 1976) because the results obtained were considered to be similar to those with vinblastine, bleomycin, and cisplatin (VBP) or BEP regimens and the latter are more toxic. However, there is evidence that the recurrence rate with BEP is less than with VAC regimen, and for patients with metastatic disease, the cisplatin-containing regimens are the treatment of choice, especially the BEP regimen as it is less toxic than the VBP regimen (Bonazzi et al. 1994; Gershenson 1993; Peccatori et al. 1995).
In a collaborative study of immature teratoma (ovarian, testicular, and extragonadal) in children (Heifetz et al. 1998), it was demonstrated that pure immature teratomas in this population have a very good prognosis. The authors concluded that the presence of microscopic foci of yolk sac tumor rather than the grade of immature teratoma was the only valid predictor of recurrence; however, it should be noted that ovarian cases were not separately analyzed for correlation between grade and outcome.
Mature Solid Teratoma
Mature solid teratoma is an uncommon ovarian teratoma. The age at presentation is similar to that of immature solid teratoma, the tumor occurring mainly in children and young adults (Peterson 1956; Woodruff et al. 1968). Most solid ovarian teratomas are composed at least partly of immature tissues and therefore are considered to be malignant. The occasional cases of solid ovarian teratoma composed entirely of mature tissues have usually been included in this group and thus misinterpreted as malignant. As the presence of immature neural elements immediately excludes the tumor from this group, it is very important to recognize the mature tissue as such, as by definition only tumors lacking immature neuroectoderm may be diagnosed as mature solid teratoma.
The tumors are usually large, do not exhibit any specific gross features, and show an appearance similar to immature solid teratomas. They grow slowly in comparison with immature solid teratoma, but because they are usually discovered after they have reached a considerable size, this feature is of little help in diagnosis. In all reported cases of mature solid teratoma, the tumor has been unilateral (Peterson 1956; Wisniewski and Deppisch 1973; Woodruff et al. 1968).
Clinical Behavior and Treatment
Mature Cystic Teratoma
Mature cystic teratoma of the ovary, or dermoid cyst, has been known since antiquity. The tumor is composed of well-differentiated derivatives of the three germ layers – ectoderm, mesoderm, and endoderm – with ectodermal elements predominating. In its pure form, mature cystic teratoma is always benign, but occasionally it may undergo malignant change in one of its elements. It may also form a part of a mixed germ cell tumor.
Mature cystic teratoma is the most common type of ovarian teratoma and the most common type of ovarian germ cell neoplasm. It occurs relatively frequently and comprises approximately 20% of all ovarian neoplasms (Peterson et al. 1955; Roth and Talerman 2006; Scully et al. 1998). Mature cystic teratoma occurs most commonly during the reproductive years, but, unlike other germ cell tumors of the ovary, it has a wider age distribution and may be encountered at any age from infancy to old age (Ayhan et al. 2000; Caruso et al. 1971; Peterson et al. 1955). In some series, more than 25% of cases have been observed in postmenopausal women (Malkasian et al. 1967). It has also been encountered in newborns. Mature cystic teratoma is often discovered as an incidental finding on physical examination, radiologic examination, or during abdominal surgery performed for other indications.
Patients present with abdominal pain (47.6%), abdominal mass or swelling (15.4%), and abnormal uterine bleeding (15.1%) (Peterson et al. 1955). The abdominal pain is usually constant, slight, or moderate but, in a number of cases, may be severe and acute because of torsion or rupture of the tumor. In children and young adults, the tumors tend to be more easily mobile and therefore are more frequently affected by torsion. Abnormal uterine bleeding and its cessation after excision of the tumor suggest hormone synthesis by the tumor, but histologic examination has failed to reveal any explanation for the endocrine function (Malkasian et al. 1967). Slightly decreased fertility has been observed in patients with mature cystic teratoma, but in most cases there is no satisfactory explanation. In 10% of cases, the tumor is diagnosed during pregnancy (Ayhan et al. 2000; Caruso et al. 1971). Mature cystic teratoma has been diagnosed radiologically because of the presence of teeth, bone, and cartilage (Malkasian et al. 1967; Peterson et al. 1955).
Mature cystic teratomas are diploid, have a normal 46,XX karyotype, and are believed to originate from germ cells after the first meiotic division; thus, they are in contrast to mature teratomas of the postpubertal testis, which are malignant, aneuploid with complex cytogenetic abnormalities including 12p amplification, and considered to originate from other forms of germ cell tumor (Atkin 1973; Linder and Power 1970; Ulbright 2005). Of note, ovarian mature cystic teratomas and prepubertal testicular mature teratomas are similar in that both are diploid, have normal karyotypes, and are benign (Ulbright 2005). Previous studies (Nomura et al. 1983; Parrington et al. 1984) using banding techniques demonstrated diverse modes of origin of mature cystic teratoma. Although most ovarian mature cystic teratomas originate from germ cells after the first meiotic division, some originate before this event (Nomura et al. 1983; Parrington et al. 1984). This distinction also applies to immature ovarian teratomas, which tend to be aneuploid, resembling their testicular counterparts.
The area around the dermoid protuberance may contain a large variety of tissues derived from the three germ layers. Ectodermal tissue, represented by squamous epithelium and other skin derivatives, is usually most abundant. Brain tissue, glia, neural tissue, retina, choroid plexus, and ganglia may also be encountered. In occasional cases, the glial tissue may be highly cellular, making the distinction between gliosis and a low-grade glial tumor, such as astrocytoma or oligodendroglioma, arising in a teratoma very difficult. Criteria have not been established for this distinction in the ovary. Furthermore, in view of the rarity of this problem in teratomas, the precise behavior of such lesions is not known.
Mesodermal tissue is represented by bone, cartilage, smooth muscle, and fibrous and fatty tissue. Endodermal tissue is represented by gastrointestinal and bronchial epithelium and glands, thyroid, and salivary gland tissue. In a careful study of 100 cases, ectodermal structures were found in 100%, mesodermal in 93%, and endodermal in 71% of cases (Blackwell et al. 1946). Rare tissues, such as prostate, have been reported (Halabi et al. 2002). The various tissues present in mature cystic teratoma show an orderly organoid arrangement forming cutaneous, bronchial, and gastrointestinal tissues, as well as bone and other structures. Although these tissues may be scattered diffusely, they do not exhibit the disorderly haphazard arrangement that is observed in immature teratoma.
With the exception of thyroid tissue, the presence of endocrine tissue is distinctly uncommon in mature cystic teratoma, but pituitary, adrenal, and parathyroid tissues have been documented. Occasionally functioning endocrine tissue, forming an adenoma, may be found in a mature cystic teratoma (Roth and Talerman 2006; Scully et al. 1998). Mature cystic teratoma must be differentiated from the rare cases of fetus in fetu, considered most likely to be caused by an inclusion of a monozygotic diamniotic twin (Brand et al. 2004). Fetus in fetu can be distinguished from a teratoma by its location in the retroperitoneal space, presence of vertebral organization with formation of limb buds, and a well-developed organ system. Fetus in fetu shows better organization than the most differentiated teratomas. Like mature cystic teratoma, fetus in fetu is a benign lesion (Brand et al. 2004).
Clinical Behavior and Treatment
Mature cystic teratoma of the ovary may be associated with various complications. In view of the fact that in many of these cases the condition is amenable to cure, their recognition is of considerable importance. These complications include (1) torsion, (2) rupture, (3) infection, (4) hemolytic anemia, (5) paraneoplastic encephalitis, and (6) development of malignancy.
Torsion is the most frequent complication (Ayhan et al. 2000; Caruso et al. 1971; Pantoja et al. 1975a; Peterson et al. 1955), occurring in 16.1% of cases in one large series (Peterson et al. 1955). This complication tends to be more common during pregnancy and puerperium (Malkasian et al. 1967; Peterson et al. 1955). Mature cystic teratoma is said to comprise from 22% to 40% of ovarian tumors in pregnancy, and from 0.8% to 12.8% of reported cases of mature cystic teratoma have occurred during pregnancy (Caruso et al. 1971; Peterson et al. 1955). The fact that these tumors, when they occur during pregnancy, are more liable to be associated with torsion is of considerable importance. Torsion is also more common in children and younger patients (Pantoja et al. 1975a; Peterson et al. 1955). The patients usually have severe acute abdominal pain, and the condition is an acute abdominal emergency. Excision of the affected ovary or salpingo-oophorectomy is the treatment of choice.
Torsion tends to predispose to rupture of the tumor. Rupture of mature cystic teratoma is an uncommon complication, occurring in approximately 1% of cases (Malkasian et al. 1967; Peterson et al. 1955). The immediate result of the rupture may be shock or hemorrhage, especially during pregnancy or labor, but the prognosis even in these cases is usually favorable. Rupture of the tumor into the peritoneal cavity may be followed by chemical peritonitis caused by the spillage of tumor contents. It produces a marked granulomatous reaction and leads to the formation of dense adhesions throughout the peritoneal cavity. Rupture of the tumor occasionally may be followed by the development of glial implants on the peritoneum. This condition occurs when the tumor contains mature neuroglial elements, and spillage leads to deposition of numerous small nodules composed of mature glia in the peritoneal cavity. Despite the wide dissemination of these deposits throughout the peritoneal cavity, the prognosis is favorable, and simple surgical excision of the primary tumor is considered to be adequate therapy (Robboy and Scully 1970). Mature cystic teratoma may rupture not only into the peritoneal cavity but also into adjacent organs, usually the bladder or the rectum. Several such cases have been reported (Dandia 1967). Infection is an uncommon complication and occurs in approximately 1% of cases (Malkasian et al. 1967). The infecting organism is usually a coliform, but Salmonella infection causing typhoid fever has also been reported (Hingorani et al. 1963).
Autoimmune hemolytic anemia has been noted occasionally in patients with teratoma of the ovary, mainly mature cystic teratoma. A small number of mature cystic teratomas and other cystic ovarian tumors associated with this complication have been reported (Bernstein et al. 1974; Payne et al. 1981). The patients have symptoms and signs of progressive anemia, which may be moderate or severe; it is accompanied by reticulocytosis, spherocytosis, and increased osmotic fragility. Normoblasts may be present in the peripheral blood. The indirect serum bilirubin is elevated, and the direct antiglobulin test (Coombs test) is positive, indicating the presence of autoantibodies that react with the patient’s red blood cells. The platelets are normal in number. The spleen may be palpable but is only slightly enlarged. Steroids are only transiently effective in treating the disease, and splenectomy has no effect on the progress of the disease (Bernstein et al. 1974; Payne et al. 1981). Excision of the ovarian tumor leads to the permanent disappearance of the anemia (Bernstein et al. 1974; Dawson et al. 1971; Payne et al. 1981). The following possible pathogenetic mechanisms have been suggested (Bernstein et al. 1974) (1) Presence in the tumor of substances that are antigenically different from the host and that stimulate the production of antibodies by the host, which cross-react with the patient’s own red blood cells; (2) Antibody production by the tumor directed specifically against the host’s red blood cells resembling the graft-versus-host reaction; and (3) Coating of red blood cells with products secreted by the tumor, resulting in changed red blood cell antigenicity. In view of this, pelvic and radiologic examination is indicated in a young woman with autoimmune hemolytic anemia that does not respond to steroid treatment, as it may help detect an ovarian teratoma and prevent an unnecessary splenectomy (Payne et al. 1981).
A syndrome of paraneoplastic limbic encephalitis has been reported in multiple cases of both mature and immature teratoma and has been demonstrated to be secondary to antibodies against subunits of the N-methyl-D-aspartate (NMDA) receptor; these subunits are expressed in the neural and/or squamous tissue of the associated teratomas (Clark et al. 2014; Dalmau et al. 2007; Gultekin et al. 2000; Vitaliani et al. 2005). The syndrome is characterized by acute psychiatric symptoms, seizures, memory deficits, altered level of consciousness, central hypoventilation, and inflammatory abnormalities in the cerebrospinal fluid (Vitaliani et al. 2005), and the responsible antibodies can be isolated from the serum and the cerebrospinal fluid (Dalmau et al. 2007). Encephalitis-related tumors show an increased intratumoral lymphoid infiltrate associated with mature neuroglial elements, including reactive germinal centers, diffuse lymphoplasmacytic infiltrates, and degenerative neuronal changes (Dabner et al. 2012). Treatment consists of tumor resection and immunotherapy, which is effective in the majority of cases (Dalmau et al. 2007).
The treatment of choice for an uncomplicated mature cystic teratoma in young patients is excision of the cyst with conservation of part of the ovary if possible. This treatment usually results in a complete cure. Local recurrences after conservative treatment for mature cystic teratoma are uncommon and occur in less than 1% of cases.
Mature Cystic Teratoma (Dermoid Cyst) with Malignant Transformation
Malignant transformation is an uncommon complication of mature cystic teratoma. It occurs in approximately 2% of cases (Ayhan et al. 2000; Krumerman and Chung 1977; Malkasian et al. 1967; Park et al. 2008; Peterson 1957; Roth and Talerman 2006; Scully et al. 1998; Stamp and McConnell 1983), although in one report the frequency was almost 4% (Pantoja et al. 1975b). The age of patients with this complication as reported in the literature ranges from 19 to 88 years (Peterson 1957), but this tumor usually is observed in postmenopausal patients (Krumerman and Chung 1977; Malkasian et al. 1967; Pantoja et al. 1975b; Peterson 1957; Stamp and McConnell 1983). The most common presenting symptom is abdominal pain (Chen et al. 2008).
While this tumor cannot always be readily clinically differentiated from an uncomplicated mature cystic teratoma, features such as larger tumor size (>10 cm), older patient age (>50 years), and elevated tumor antigens, in particular CA125 and SCC antigen, have been demonstrated to be predictive of malignancy (Chen et al. 2008; Dos Santos et al. 2007; Hackethal et al. 2008). Certain imaging findings on Doppler ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) have also been shown to have predictive value for malignancy (Chiang et al. 2011; Dos Santos et al. 2007). Sometimes, the tumor may be an incidental finding.
Clinical Behavior and Treatment
The mode of spread of the malignant tumor differs from that observed in other tumors of germ cell origin. The tumor spreads by direct invasion and peritoneal implantation and generally does not metastasize to the lymph nodes (Krumerman and Chung 1977; Peterson 1957). Extensive local invasion and absence of lymph node involvement usually is observed at laparotomy (Pantoja et al. 1975b; Stamp and McConnell 1983). Hematogenous dissemination is uncommon.
The prognosis of patients with mature cystic teratoma with malignant transformation is unfavorable (Krumerman and Chung 1977; Pantoja et al. 1975b; Peterson 1957; Stamp and McConnell 1983); only 15–48.4% of patients survive 5 years (Chen et al. 2008; Krumerman and Chung 1977; Peterson 1957). Better prognosis has been reported when the malignant element is a squamous cell carcinoma confined to the ovary and is excised without spillage of the contents. In such cases, the reported 5-year survival is 75.7% (Chen et al. 2008).
Treatment is hysterectomy and bilateral adnexectomy (Krumerman and Chung 1977; Stamp and McConnell 1983). Because the tumors are usually unilateral, in cases where there is no penetration of the capsule and no involvement of the adjacent structures, a more conservative surgical procedure may be just as effective. However, because malignant transformation of a mature cystic teratoma usually occurs in postmenopausal women, total hysterectomy and bilateral salpingo-oophorectomy is performed. If the tumor has spread beyond the confines of the ovary and there is involvement of the adjacent structures, a more radical procedure with resection of the tumor and the involved structures or viscera is advocated (Pantoja et al. 1975b). For squamous cell carcinoma, adjuvant chemotherapy has been demonstrated to improve survival, in particular for higher-stage patients (Chen et al. 2008). Some authors have reported a benefit with whole pelvic radiation, while others have not confirmed the utility of this treatment modality (Chen et al. 2008; Chiang et al. 2011; Dos Santos et al. 2007; Hackethal et al. 2008). Poor prognostic factors include higher stage at presentation, older patient age, larger tumor size, and positive serum tumor markers (Chen et al. 2008).
Mucinous Tumors Arising in Mature Cystic Teratoma
In general, the vast majority of primary ovarian mucinous tumors are of epithelial origin, but a subset is of germ cell origin. In the cases studied, 2–11% of ovarian mature cystic teratomas are associated with a mucinous tumor, and many of the latter in this setting are likely of germ cell origin.
Further evidence for this concept is provided by the occurrence of occasional teratomatous tumors composed mainly of mucinous (intestinal-type) epithelium of endodermal derivation and only a small amount of other teratomatous elements, as well as the presence of intestinal-type mucinous epithelium as the only other tissue element present in association with some cases of struma ovarii and strumal carcinoid. In 21% of cases, the epithelium lining mucinous tumors of the ovary contains argyrophil and argentaffin granules, and Paneth cells are also present in a considerable number of cases. These findings are considered to be a strong argument in favor of the derivation of at least some mucinous ovarian tumors from intestinal-type epithelium of teratomatous (germ cell) origin. A number of molecular studies have provided evidence that at least a subset of mucinous tumors associated with teratomas are of germ cell origin (Fujii et al. 2014; Kerr et al. 2013; Magi-Galluzi et al. 2001; Snir et al. 2016; Wang et al. 2015).
Primary ovarian mucinous tumors associated with a mature cystic teratoma show a spectrum of histologic appearances (McKenney et al. 2008; Vang et al. 2007). At the lower end of the spectrum, tumors display a cystadenomatous pattern. Proliferative tumors with architectural complexity and epithelial stratification resemble atypical proliferative (borderline) mucinous tumor of ovarian epithelial origin or low-grade adenomatous mucinous neoplasm of the appendix. Pseudomyxoma ovarii can be seen with some cystadenomatous and proliferative neoplasms. Compared to tumors without pseudomyxoma ovarii, neoplasms with pseudomyxoma ovarii more closely resemble lower gastrointestinal tract adenomatous tumors and tend to have hypermucinous columnar epithelium and abundant goblet cells. Other tumors may show goblet cell carcinoid-like morphology. At the upper end of the spectrum, the carcinomatous neoplasms may be of glandular (Fig. 40) or signet ring cell type. Pseudomyxoma ovarii can also be associated with goblet cell carcinoid-like tumors or carcinoma.
Immunohistochemical Features and Differential Diagnosis
Immunohistochemical stains for CK7 and CK20 show variable coordinate expression profiles (Vang et al. 2007). Tumors without pseudomyxoma ovarii and having cystadenomatous or proliferative patterns show a variety of CK7/CK20 profiles, including a CK7 diffuse/CK20 variable pattern (a pattern frequently seen in ovarian epithelial tumors). Those with pseudomyxoma ovarii and having cystadenomatous, proliferative, or goblet cell carcinoid-like patterns characteristically display a CK7(−)/CK20 diffuse or CK7 focal/CK20 diffuse profile (patterns typical of lower gastrointestinal tract tumors). A minority of these tumors histologically and immunohistochemically resembling lower gastrointestinal tract adenomatous tumors can have the clinical syndrome of pseudomyxoma peritonei without a tumor in the appendix. Parenthetically, it should be emphasized that although nearly all cases of pseudomyxoma peritonei are of appendiceal origin, rare cases are of primary ovarian origin due to an appendiceal-type mucinous tumor arising within a mature cystic teratoma. The carcinomas can have variable CK7/CK20 profiles, but some will show a CK7(−)/CK20 diffuse or CK7 focal/CK20 diffuse pattern.
Ovarian mucinous tumors of germ cell origin with histologic and immunohistochemical features typical of primary lower gastrointestinal tract tumors can be misclassified as metastatic or secondary tumors involving the ovary. Thus, it is important to search for focal teratomatous components in such ovarian mucinous tumors in order to suggest a possible primary ovarian origin. Nonetheless, when problematic mucinous neoplasms in ovarian mature cystic teratomas histologically and immunohistochemically resemble lower gastrointestinal tract tumors, extensive sampling of the gross specimen and further clinical evaluation to exclude the rare possibility of a similar primary mucinous tumor in the appendix or colorectal region as part of a tumor-to-tumor metastasis (e.g., a primary lower gastrointestinal tract tumor with a metastasis to a coexisting ovarian teratoma) are recommended.
Primary ovarian mucinous tumors arising in a teratoma, which histologically and immunohistochemically resemble lower gastrointestinal tumors, are considered to be of germ cell origin. Tumors that are histologically and immunohistochemically analogous to ovarian epithelial mucinous cystadenoma or atypical proliferative (borderline) mucinous tumor may have developed in the same ovary containing a teratoma as an independent tumor; however, it should also be considered that some of those mucinous tumors could be of germ cell origin, having potentially arisen from upper gastrointestinal/pancreaticobiliary or sinonasal tissue in a teratoma, which would have histologic and immunohistochemical features similar to mucinous tumors of ovarian epithelial origin.
For primary ovarian mucinous tumors histologically and immunohistochemically resembling lower gastrointestinal tract tumors, descriptive terminology that parallels the nomenclature for tumors in lower gastrointestinal sites (e.g., low-grade adenomatous mucinous neoplasm for ovarian tumors histologically and immunohistochemically analogous to those of the appendix) is preferred, considering that (a) terms such as borderline tumor and atypical proliferative tumor are used for primary epithelial tumors of the ovary, (b) these mucinous tumors are of germ cell rather than epithelial origin, and (c) they resemble their counterparts in the lower gastrointestinal tract.
Clinical Behavior and Treatment
Data on the behavior of mucinous ovarian tumors of germ cell origin are limited, but in the series of McKenney et al. and Vang et al., patients with cystadenomatous and proliferative/low malignant potential tumors on follow-up remained well and disease-free (McKenney et al. 2008; Vang et al. 2007). In the same series, mucinous carcinomas showed variable outcomes but exhibited the potential for aggressive behavior. However, Ueda et al. (1993) reported a case of a patient with an adenocarcinoma arising in a mature cystic teratoma who has survived for more than 15 years.
Thyroid tissue is a relatively frequent constituent of mature cystic teratoma and has been demonstrated in 5–20% of cases. Struma ovarii is considered a one-sided development of a teratoma in which the thyroid tissue has overgrown all other tissues or one in which only the thyroid tissue has developed. The term struma ovarii should be reserved for tumors composed either entirely or predominantly of thyroid tissue (Roth and Talerman 2006; Roth and Talerman 2007; Scully et al. 1998).
Struma ovarii is uncommon; it comprises nearly 3% of ovarian teratomas. The age distribution of patients with struma ovarii is generally the same as that of patients with mature cystic teratoma and ranges from 6 to 74 years. Most patients are in the reproductive years (Roth and Talerman 2006; Roth and Talerman 2007; Woodruff et al. 1966). There are usually no specific symptoms; the clinical findings are similar to those observed in patients with mature cystic teratoma. The only differences are that in some cases struma ovarii is associated with enlargement of the thyroid gland and in other cases there is clinical evidence that the struma ovarii is responsible for the development of thyrotoxicosis, although this has not been confirmed preoperatively by laboratory tests (Smith 1946; Woodruff et al. 1966). The ectopic thyroid tissue present within struma ovarii, therefore, may be subject to the same physiologic and pathologic changes as the eutopic thyroid gland (Smith 1946).
Struma ovarii is usually unilateral but is often associated with mature cystic teratoma and rarely with a cystadenoma in the contralateral ovary (Roth and Talerman 2006; Roth and Talerman 2007; Scully et al. 1998; Woodruff et al. 1966). In some cases, the teratoma present in the contralateral ovary also contained thyroid tissue.
Struma ovarii varies in size, but usually measures less than 10 cm. The surface is usually smooth, and, before sectioning, the tumor resembles a mature cystic teratoma. Occasionally, adhesions may be present. The cut surface of the tumor may be composed entirely of light tan, glistening thyroid tissue. Hemorrhage, necrosis, and foci of fibrosis may be present. Solid tumors with small amounts of colloid appear less glistening and more fleshy. Some tumors may be cystic (Szyfelbein et al. 1994).
Microscopic and Immunohistochemical Features
Clinical Behavior and Treatment
Most cases of struma ovarii are benign and can be treated by excision of the ovary or by unilateral salpingo-oophorectomy. In a small number of cases, there are complications, the most important being the development of malignancy (Devaney et al. 1993; Garg et al. 2009; Rose et al. 1974; Roth and Talerman 2006; Roth and Talerman 2007). In one series (Devaney et al. 1993), proliferative struma ovarii was benign; however, in another series 26% of cases were clinically malignant, but the entire cohort of proliferative struma ovarii had good overall survival (98% survival at 10 years, 92% at 25 years) (Robboy et al. 2009). However, due to the lack of clarity as to which morphologic features predict malignancy, some authors have advocated regarding all proliferative struma as having malignant potential (Robboy et al. 2009; Shaco-Levy et al. 2012).
Another complication is the presence of ascites or ascites associated with pleural effusion producing a pseudo-Meigs syndrome (Kawahara 1963). Ascites may be found in 17% of cases of struma ovarii, and its presence does not indicate that the tumor is malignant (Smith 1946). The cause of the ascites and pleural effusion has not been fully elucidated. In most reported cases, excision of the tumor led to complete remission.
Occasionally, struma ovarii may be associated with extra-ovarian extension caused either by rupture of the tumor or by local spread. In such cases, the peritoneal cavity contains tumor deposits, which may be numerous and are composed of mature thyroid tissue. The condition is thought by some to be benign and is termed benign strumosis (Karseladze and Kulinitch 1994), although some authorities believe that it represents a very well-differentiated follicular carcinoma (Rose et al. 1974; Roth and Karseladze 2008). This condition is only rarely associated with untoward side effects, which are mainly caused by the formation of adhesions. As most patients with this rare condition have been treated by excision of the tumor deposits and by administration of radioactive iodine (131I) with successful outcomes, or have been lost to follow-up after varying periods of time with no ill effects, it is not possible to resolve this controversy. However, rare patients with strumosis have died of disease (Rose et al. 1974).
Malignancy Arising in Struma Ovarii
Malignant change in struma ovarii, in which the tumor shows histologic/cytologic features of thyroid carcinoma (“malignant struma ovarii”), is uncommon (3% of all cases of struma ovarii in one study (Robboy et al. 2009)). A number of reported cases of malignant struma ovarii were actually examples of strumal carcinoid. Patients with malignant struma ovarii are relatively young. The mean ages of women with the different types of thyroid carcinoma arising in struma ovarii range from 38 to 46 years (Roth et al. 2008). Most patients with papillary thyroid carcinoma and typical follicular carcinoma present with stage I disease.
In a number of reported cases, the diagnosis was based on the histology of the tumor, and there were no metastases or other features of malignancy (Devaney et al. 1993; Roth et al. 2008; Roth and Talerman 2007). Whether malignant struma ovarii should be diagnosed based on the same criteria used for tumors in the eutopic thyroid gland is unclear. Application of the eutopic thyroid diagnostic criteria for the follicular variant of papillary thyroid carcinoma (FVPTC) in struma ovarii (optically clear nuclei, overlapping nuclei, nuclear pseudoinclusions, nuclear grooves (Robboy et al. 2009)) may be difficult given the recognized interobserver variability in diagnosis for tumors in eutopic thyroid locations. It should be noted that even ovarian tumors with subtle atypical nuclear features, which are suggestive of but not fully diagnostic for the FVPTC, still have the ability to metastasize (Garg et al. 2009) and that the usual nuclear features distinguishing benign from malignant thyroid tissue (clearing, grooves, pseudoinclusions, and overlap) are not necessarily reliable in distinguishing cases of clinically benign vs. malignant struma (Robboy et al. 2009; Shaco-Levy et al. 2012). Therefore, it has been recommended that whenever an ovarian follicular thyroid-type tumor with cytologic features borderline for the FVPTC is encountered, it should be reviewed by at least two surgical pathologists with experience in thyroid pathology in order to prevent under- or overdiagnosis (Garg et al. 2009). Additionally, it is not yet clear if and how the evolving terminology for the FVPTC, many cases of which are now termed “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) based on their indolent clinical behavior (Nikiforov et al. 2016), should be applied to struma ovarii.
Application of eutopic thyroid criteria for the diagnosis of follicular carcinoma in struma ovarii (tumor invasion of cortex with growth on ovarian serosa and vascular invasion (Robboy et al. 2009)) is also problematic, particularly because the ovary lacks a true capsule; additionally, vascular invasion has not been found to be a good predictor of clinically benign vs. malignant struma ovarii (Robboy et al. 2009; Shaco-Levy et al. 2012). Furthermore, ovarian tumors that histologically qualify as struma ovarii but which have an extra-ovarian metastasis or recurrence that histologically resembles nonneoplastic thyroid tissue have been designated “highly differentiated follicular carcinoma” (Roth and Karseladze 2008). Thus, this form of follicular carcinoma can only be diagnosed when an extra-ovarian lesion is identified. It should be noted, however, that this entity is controversial and considered “peritoneal strumosis” by others. However, tumor deposits of obviously malignant papillary thyroid carcinoma and typical follicular carcinoma should be diagnosed as such.
For any ovarian tumor featuring a problematic proliferation of thyroid tissue, extensive sampling is strongly suggested. In rare and unusual cases (especially those with bilateral tumors), it may be necessary to recommend further clinical evaluation in order to exclude the possibility of a metastasis from the thyroid gland with secondary involvement of the ovary.
Clinical Behavior and Treatment
See above section on Struma Ovarii for behavior of proliferative struma ovarii. Metastases of malignant struma ovarii are uncommon (Garg et al. 2009; Roth et al. 2008; Shaco-Levy et al. 2012). In addition to peritoneal involvement, other routes of spread are via the lymphatics to the para-aortic and other lymph nodes and via the bloodstream to the lungs and bones (Roth et al. 2008). The disease is treatable with good outcome in most cases, including those with metastatic disease. Only 7%, 14%, and 0% of patients with papillary thyroid carcinoma, typical follicular carcinoma, and “highly differentiated follicular carcinoma,” respectively, in struma ovarii died of disease (Roth et al. 2008). A recent analysis of the SEER database also demonstrated excellent disease-specific survival, with an overall survival of 96.7%, 94.3%, and 84.9% at 5, 10, and 20 years, respectively (Goffredo et al. 2015). In a study by Robboy et al. of all histologically malignant thyroid-type tumors in struma ovarii, 81% and 60% of patients were alive at 10 years and 25 years, respectively (Robboy et al. 2009). In that study, malignant struma ovarii was assessed for pathologic features that might predict aggressive behavior, and the size of the strumal component correlated with malignant outcome. It was also demonstrated that abundant peritoneal fluid, numerous adhesions, and ovarian serosal defects were more common in clinically malignant tumors. In general, however, it is not possible to reliably determine which cases will develop progressive disease.
Treatment of malignant struma ovarii should consist of at least oophorectomy but may also include thyroidectomy, radioactive iodine (131I), and follow-up with serum thyroglobulin measurement. Long-term follow-up is important as metastases can occur decades later.
Carcinoid tumors of the ovary may be primary or metastatic. Primary carcinoids are subdivided into four categories: (1) insular, (2) trabecular, (3) strumal, and (4) mucinous. In the 2014 WHO classification, carcinoids are also referred to as “well-differentiated neuroendocrine tumor, grade 1” (Prat et al. 2014). Mixed types also occur (composed of any combination of the pure types). The latter are uncommon and often associated with a mature cystic teratoma. Of the metastatic carcinoids, the insular carcinoid tumor is the most common, followed by the trabecular and mucinous types. Metastatic carcinoid tumors of the ovary are discussed in Metastatic Tumors of the Ovary.
Insular carcinoid tumor, considered to be of midgut derivation, is the most common type of primary ovarian carcinoid tumor. It usually arises in association with gastrointestinal or respiratory epithelium present in a mature cystic teratoma. It may also be observed within a solid teratoma, a mucinous tumor, in association with a Sertoli–Leydig cell tumor (Young et al. 1982), or may occur in a pure form (Robboy et al. 1975; Soga et al. 2000; Talerman 1984). The latter is considered to arise either as a one-sided development of a teratoma or from enterochromaffin cells present within the ovary. The former is much more likely. Approximately 40% of ovarian insular carcinoids occur in pure form; the remaining 60% are combined (Scully et al. 1998; Soga et al. 2000).
More than 200 cases of primary ovarian insular carcinoid tumors have been reported (Davis et al. 1996; Robboy et al. 1975; Scully et al. 1998; Soga et al. 2000). The age of patients ranges from 31 to 83 years, but most patients are either postmenopausal or perimenopausal (Davis et al. 1996; Robboy et al. 1975; Soga et al. 2000). One third of the reported cases have been associated with the typical carcinoid syndrome, despite the absence of metastases (Davis et al. 1996; Robboy et al. 1975; Soga et al. 2000). This is in contrast to intestinal carcinoids, which are associated with the syndrome only when there is metastatic spread to the liver. The reason for this difference is that the blood flow from the ovary goes directly into the systemic circulation and does not pass through the liver, which inactivates the serotonin produced by the tumor. The presence or absence of symptoms of carcinoid syndrome is also dependent on the number of secreting tumor cells.
Functioning ovarian carcinoid tumors, with only one exception, have all measured approximately 10 cm in greatest dimension, whereas intestinal carcinoids are usually smaller. Thus, there is a good correlation between the size of the tumor and the presence of carcinoid syndrome. The excision of the tumor is associated with rapid remission of the symptoms, disappearance of 5-hydroxyindoleacetic acid (5-HIAA) from the urine (Robboy et al. 1975), and marked decrease of serum serotonin. Determination of serum serotonin and urinary 5-HIAA may be used to monitor disease activity and response to therapy. If the tumor is nonfunctioning, there is no specific presentation.
The tumor shows similar appearances to those of mature cystic teratoma, within which it is usually found. The same applies if the tumor is associated with a solid teratoma or a mucinous tumor. If the carcinoid is not associated with other tissue elements, the tumor is solid. The carcinoid may vary from microscopic to 20 cm in greatest dimension and is solid and homogeneous. Its color may vary from light brown to yellow or pale gray. Primary ovarian carcinoids are practically always unilateral, although they may be associated with a mature cystic teratoma in the contralateral ovary.
Immunohistochemical Features and Differential Diagnosis
Primary insular carcinoid of the ovary must be differentiated from metastatic insular carcinoid of the ovary, which is usually of gastrointestinal origin. Metastatic carcinoid nearly always affects both ovaries (Robboy et al. 1974), unlike primary ovarian carcinoid, which is unilateral (Robboy et al. 1975). Macroscopically, the metastatic carcinoid is composed of tumor nodules, whereas primary ovarian carcinoid forms a single homogeneous mass. The presence of other teratomatous elements associated with an ovarian carcinoid confirms that it is primary (Robboy et al. 1975; Soga et al. 2000). Immunohistochemical studies are generally not helpful for this distinction, as metastatic midgut carcinoids and insular ovarian carcinoids demonstrate similar staining profiles, including CDX2 positivity (Rabban et al. 2009).
Primary ovarian carcinoid sometimes may be confused with Brenner tumor, but the appearances of the cell nests and the grooved coffee bean nuclei of the cells of Brenner tumor militate against the diagnosis of a carcinoid, whereas the typical small acinar pattern and expression of chromogranin A favor diagnosis as a carcinoid. Confusion with granulosa cell tumor may also arise because Call–Exner bodies may be mistaken for carcinoid acini, but the cells of the carcinoid tumor usually show an acinar pattern and contain more cytoplasm and argentaffin granules (Robboy et al. 1975). Cystic areas that may be present in a granulosa cell tumor are nearly always absent in a carcinoid. The presence of nuclear grooves typical of adult granulosa cell tumor further supports this diagnosis. Inhibin and calretinin are typically negative in carcinoid (Zhao et al. 2007).
Occasionally, ovarian carcinoid may be confused with a Krukenberg tumor, but the latter is usually bilateral and larger. The cells of Krukenberg tumor tend to merge with the stroma, are larger, and show greater pleomorphism, at least focal signet ring appearance, and more brisk mitotic activity. An acinar pattern is less evident. Demonstration of chromogranin and synaptophysin expression supports a diagnosis of carcinoid.
Clinical Behavior and Treatment
Although insular carcinoid tumors of the ovary are considered to be malignant, they are slow growing and only occasionally associated with metastases. Metastases have been observed in 11 patients, 7 of whom died with metastatic disease (Davis et al. 1996; Robboy et al. 1975); this includes six patients with metastatic disease from a series of nine cases of insular carcinoid tumors of the ovary collected over 40 years by Davis et al. (1996). This series suggested that metastatic disease may be more frequent than generally reported. Although the malignant potential of insular carcinoid should not be minimized, it is considered that the series of Davis et al. (1996) was somewhat selective for metastasizing tumors and lethal outcome.
In occasional patients, features of carcinoid syndrome, such as tricuspid incompetence resulting in right-sided heart failure, may progress after the excision of the tumor and lead to the death of the patient, as has been observed in two cases (Robboy et al. 1975). In most patients with the carcinoid syndrome, the symptoms and signs of the syndrome observed preoperatively disappear or regress during the postoperative period (Robboy et al. 1975). Because nearly all patients with this tumor are postmenopausal or perimenopausal, bilateral salpingo-oophorectomy and hysterectomy is the treatment of choice. Surgical excision of foci of extra-ovarian spread if present is indicated. There is little experience with chemotherapy. Estimation of serum serotonin and 5-HIAA in the urine may be used to monitor the progress of the disease.
Trabecular carcinoid includes carcinoid tumors of hindgut or foregut derivation. Primary trabecular or ribbon carcinoid usually arises in association with teratomatous elements (Robboy et al. 1977; Soga et al. 2000), but in a later study of four cases of trabecular carcinoid, two tumors were pure and not associated with teratomatous elements (Talerman and Evans 1982).
Trabecular carcinoid is rare. Patient age varies from 24 to 74 years, with most patients being postmenopausal (Davis et al. 1996; Robboy et al. 1977; Soga et al. 2000; Talerman and Evans 1982). Trabecular carcinoid is a slowly growing neoplasm that can reach a large size. None of the known cases have been associated with the carcinoid syndrome. In three patients whose urine was examined immediately after surgery, 5-HIAA was normal (Robboy et al. 1977).
The appearance of trabecular carcinoid depends on whether the tumor is associated with teratomatous elements. When associated with teratoma, the appearance is similar to that of a mature cystic teratoma. When the tumor is pure, it is a solid, firm to hard, round or ovoid mass with a smooth outline and a tan to yellow cut surface. Reported cases have always been unilateral (Robboy et al. 1977; Soga et al. 2000; Talerman and Evans 1982), but occasionally have been associated with mature cystic teratoma in the opposite ovary (Robboy et al. 1977; Soga et al. 2000). In the reported cases, the tumors measured from 4 to 25 cm in greatest dimension (Robboy et al. 1977; Soga et al. 2000; Talerman and Evans 1982).
Immunohistochemical Features and Differential Diagnosis
See section on Insular Carcinoid for details of immunohistochemistry. Immunohistochemical staining demonstrates a much wider range of neurohormonal polypeptides than insular carcinoids; these include serotonin, pancreatic polypeptide, glucagon, enkephalin, gastrin, vasoactive intestinal polypeptide, and calcitonin (Sporrong et al. 1982).
Primary trabecular carcinoid must be distinguished from metastatic trabecular carcinoid, which is usually bilateral and frequently associated with metastases elsewhere. The presence of teratomatous elements, which are found frequently in the primary lesion, helps distinguish a primary from a metastatic lesion. Immunohistochemistry is not useful in this distinction, as metastatic hindgut or foregut carcinoids and ovarian trabecular carcinoids demonstrate a similar staining pattern, including CDX2 negativity (Rabban et al. 2009). Trabecular carcinoid sometimes may exhibit an insular pattern in foci, but unless this is a major component the tumor need not be classified as a mixed carcinoid.
The presence of thyroid follicles indicates that the tumor is a struma ovarii and carcinoid (strumal carcinoid), and their presence must be excluded before a diagnosis of trabecular carcinoid is made. Occasionally, trabecular carcinoid must be distinguished from a Sertoli–Leydig cell tumor showing a cord-like pattern. In contrast to a Sertoli–Leydig tumor, trabecular carcinoid lacks tubules. Immunohistochemical expression of chromogranin and synaptophysin and lack of staining for inhibin and calretinin confirm the diagnosis of carcinoid.
Clinical Behavior and Treatment
The prognosis of patients with trabecular carcinoid of the ovary is favorable because these tumors are not associated with metastases (Davis et al. 1996; Robboy et al. 1977; Talerman and Evans 1982). In one case, a peritoneal implant was found 2 years after bilateral salpingo-oophorectomy and hysterectomy (Robboy et al. 1977). The optimal treatment is the excision of the affected adnexa, which results in a complete cure, but follow-up of the patient is advisable.
Mucinous Carcinoid (Goblet Cell Carcinoid)
Mucinous carcinoid is a variant of carcinoid tumor that has been encountered mainly in the vermiform appendix (Klein 1974; Subbuswamy et al. 1974; Warkel et al. 1978) and occasionally has been observed in the ovary (Alenghat et al. 1986; Baker et al. 2001; Soga et al. 2000). However, it should be noted that at least some of the tumors described as primary Krukenberg tumors of the ovary may have been examples of this entity. Also, it should be emphasized that before establishing a diagnosis of primary ovarian mucinous carcinoid, a metastatic appendiceal carcinoma with goblet cell carcinoid-like features must be excluded. A number of the latter have been reported (Hristov et al. 2007), and several more are known to the authors. It is likely that a proportion of “primary ovarian” mucinous carcinoids reported in the literature really represent metastases from an occult appendiceal primary.
The age of patients ranges from 14 to 74 years. Mucinous carcinoid is usually observed in pure form but may be seen in association with mature cystic teratoma. The tumor is unilateral but may be associated with metastases in the contralateral ovary (Alenghat et al. 1986; Baker et al. 2001; Soga et al. 2000).
Macroscopically, the tumor is usually of considerable size, ranging from 4 to 30 cm, and most of the tumors have been more than 8 cm in greatest dimension. The tumor is gray–yellow, firm, and usually solid but may contain cystic areas (Alenghat et al. 1986; Baker et al. 2001; Soga et al. 2000). Similar appearances are encountered when the tumor forms part of a mature cystic teratoma.
In some tumors, such appearances may predominate. This second pattern resembles Krukenberg tumor and is described as atypical or Krukenberg tumorlike pattern. Sometimes mucinous carcinoid showing either the typical or atypical pattern or both merges with intestinal-like adenocarcinoma showing numerous neuroendocrine cells; this is regarded as a third pattern present in this tumor. Some mucinous carcinoids may be admixed with other types of carcinoid tumor, such as insular or trabecular, forming a mixed carcinoid tumor. Thus, primary ovarian mucinous carcinoid tumors can be divided into four histologic types. In a study of 17 mucinous carcinoid tumors, 6 were of the typical type, 4 of the atypical or Krukenberg tumorlike type, 5 were admixed with intestinal-like adenocarcinoma, and 2 were of the mixed type (Baker et al. 2001). The cytoplasm of the tumor cells may exhibit orange–red granules and may even be bright red. Argyrophil and argentaffin granules are always present and, in some tumors, may be abundant (Alenghat et al. 1986; Baker et al. 2001; Soga et al. 2000).
Ultrastructurally, neurosecretory granules are present in some cells and absent in others. The tumor cells may contain both neurosecretory granules and mucinous material. The neuroendocrine nature of the tumor cells is further confirmed using immunohistochemical stains.
Immunohistochemical Features and Differential Diagnosis
Primary mucinous carcinoid tumor of the ovary must be differentiated from metastasis, including secondary involvement by an appendiceal carcinoma with goblet cell carcinoid-like features (Hristov et al. 2007; Soga et al. 2000). Metastatic mucinous carcinoid, in common with other types of carcinoid metastatic to the ovary, is nearly always bilateral and instead of forming a single tumor mass shows multiple scattered tumor deposits within ovarian tissue. Depending on their size, these deposits may form tumor nodules observed macroscopically or may be detectable only microscopically. Histologically, they may have appearances indistinguishable from a primary tumor. The presence of teratomatous elements supports primary ovarian origin.
Mucinous carcinoid must be distinguished from other mucinous tumors of the ovary, particularly, a mucinous carcinoma with goblet cell carcinoid-like features arising in a teratoma. That is especially so when the carcinoid tumor is composed of large acini, shows increased mucin production, and exhibits a pleomorphic pattern. Occasionally, confusion may arise with well-differentiated endometrioid tumors of the ovary, which may resemble mucinous tumors.
Mucinous carcinoid must also be distinguished from a Krukenberg tumor. The differentiation between these two entities may be difficult, especially if the mucinous carcinoid assumes a predominantly Krukenberg-like pattern or if the Krukenberg tumor contains numerous argentaffin and argyrophil granules. The presence of these granules as well as of the neurosecretory granules observed ultrastructurally cannot be used for differentiation between these two entities. Involvement of both ovaries and the presence of primary extra-ovarian signet ring or mucinous adenocarcinoma are indicative of Krukenberg tumor.
Clinical Behavior and Treatment
Primary mucinous carcinoid of the ovary behaves in a somewhat more aggressive manner than other types of primary ovarian carcinoid tumors (Alenghat et al. 1986; Baker et al. 2001; Soga et al. 2000), similar to the behavior of mucinous carcinoid tumors of the vermiform appendix (Klein 1974; Subbuswamy et al. 1974; Warkel et al. 1978). The tumor tends to spread mainly via the lymphatics, and metastases may be present at the time of initial laparotomy. Patients who do not exhibit metastatic disease at the time of diagnosis have a much better prognosis compared to those who have metastases, however small, at the time of diagnosis (Alenghat et al. 1986; Baker et al. 2001; Soga et al. 2000). A series of 17 patients has been reported (Baker et al. 2001). Six patients with mucinous carcinoid of the typical or classical type had tumors confined to the ovary, and all five with available follow-up (27–147 months) were well and disease-free after excision of the tumor. Three patients with mucinous carcinoid of the atypical type had tumors confined to the ovary and were well and disease-free after excision of the tumor (follow-up, 36–168 months). Of the eight women with carcinoma arising in mucinous carcinoid, six were stage I, one was stage II, and one was stage III. Seven had available follow-up. Two patients died of disease at 9 and 12 months, respectively. Four were alive and well with 48–120 months of follow-up, and a fifth patient died of other causes at 36 months.
The treatment is surgical, depending on the extent of the disease. In postmenopausal women, patients with involvement of the contralateral ovary and patients who do not want to retain fertility, hysterectomy, bilateral salpingo-oophorectomy, and omentectomy, as well as excision of all the tumor deposits, are indicated. Para-aortic lymph node dissection may be necessary because metastatic tumor deposits may be present. Surgery may be followed by combination chemotherapy, including 5-fluorouracil, although the efficacy of this mode of therapy is not proven. Premenopausal patients with tumors localized to the ovary may be treated by unilateral salpingo-oophorectomy with careful follow-up.
Strumal carcinoid is an uncommon ovarian tumor composed of thyroid tissue intimately admixed with carcinoid tumor, showing a ribbonlike or cord-like pattern. Other teratomatous elements are also present in most of the tumors (Robboy and Scully 1980). Tumors showing the histologic pattern of what is now regarded as strumal carcinoid were historically interpreted as carcinoma arising in struma ovarii, although the resemblance to a carcinoid tumor had been noted in some cases.
More than 60 cases have been reported (Robboy and Scully 1980; Snyder and Tavassoli 1986; Soga et al. 2000), and there are probably as many unreported cases. The age distribution is similar to struma ovarii, ranging from 21 to 77 years. The tumor is usually not associated with any specific clinical findings. In one reported case, it was associated with virilization. Like hindgut carcinoids and unlike the primary ovarian insular carcinoid, strumal carcinoid is not, as a rule, associated with the carcinoid syndrome (Robboy and Scully 1980; Snyder and Tavassoli 1986; Soga et al. 2000) although this association has been described in a single case (Ulbright 2005).
Macroscopically, this tumor, if pure, may be similar to struma ovarii or carcinoid. If the tumor is a part of a teratoma, it manifests as a yellow nodule within the teratoma (Robboy and Scully 1980; Snyder and Tavassoli 1986).
Microscopic and Immunohistochemical Features
Argyrophil and argentaffin granules are identified in the carcinoid cells (Robboy and Scully 1980; Snyder and Tavassoli 1986; Stagno et al. 1987), as well as in some cells lining the thyroid follicles, both histochemically and immunohistochemically. Chromogranin and synaptophysin are expressed in the carcinoid component. TTF-1 and CK7 are usually expressed in the strumal component with no expression in the carcinoid component (Rabban et al. 2009); however, we have seen cases with focal TTF-1 expression in the carcinoid component. Ultrastructural examination demonstrates neurosecretory granules in the carcinoid component and in some of the thyroid follicular cells (Snyder and Tavassoli 1986; Stagno et al. 1987). In two tumors, amyloid deposits were identified and were verified both immunohistochemically and ultrastructurally (Arhelger and Kelly 1974; Dayal et al. 1979).
Some investigators consider that strumal carcinoid is a carcinoid tumor and that the thyroid tissue only resembles thyroid (Hart and Regezi 1978). Other investigators have conclusively demonstrated thyroglobulin and TTF-1 within the thyroid component of the tumor, thus indicating its thyroid nature (Rabban et al. 2009; Robboy and Scully 1980; Snyder and Tavassoli 1986). It is, therefore, considered that in verified cases of strumal carcinoid, the tumor consists of thyroid tissue intimately admixed with a carcinoid. Strumal carcinoid should be distinguished from carcinoma of the thyroid arising in struma ovarii, with which it has often been confused. The carcinoma has the typical appearances observed in the eutopic thyroid and usually exhibits a follicular or papillary pattern.
Clinical Behavior and Treatment
Strumal carcinoid has been associated with metastases in only one reported case, and even in this case the patient was apparently cured by a combination of surgery and radiation therapy (Robboy and Scully 1980). All other cases have followed a benign course (Robboy and Scully 1980; Snyder and Tavassoli 1986).
Monodermal Teratomas with Neuroectodermal Differentiation
Monodermal Teratoma Composed of Vascular Tissue
Another type of monodermal teratoma is represented by neoplasms composed entirely or predominantly of immature vascular tissue. These occur in children and young adults, and the patients present with symptoms and signs suggestive of an ovarian tumor. The tumors may vary in size, are smooth, soft, solid, and gray–pink, and may be hemorrhagic. Microscopically, they consist of collections of small vascular spaces lined by immature endothelial cells and surrounded by connective tissue, which varies from loose and edematous to dense and fibrous. The lining of the vascular spaces may be multilayered, and the endothelial cells may form small projections bulging into the lumen. Small collections of endothelial cells, some forming abortive lumina and some devoid of a lumen, are also seen within the connective tissue and may predominate.
The endothelial cells show a considerable degree of cellular and nuclear pleomorphism, and mitotic activity is usually evident. Occasionally, hematopoietic activity may be seen within some of the vascular spaces. When these tumors contain small teratomatous foci, their nature is more readily apparent, but when they occur in pure form, especially when the endothelial cells form a more solid pattern with fewer obvious vascular spaces, the nature of the lesion is more difficult to recognize. Occasionally, these tumors may be composed of immature pericytes and resemble a hemangiopericytoma. Further sampling of the tumor, which may reveal a more typical vascular pattern, and immunohistochemical stains for CD31 and CD34 as well as for factor VIII may be helpful in reaching the correct diagnosis. This distinction is important because monodermal teratomas composed of immature vascular tissue or with a predominant vascular component behave on the whole in a less aggressive manner compared with high-grade immature teratomas and angiosarcomas of the ovary, with which they tend to be confused. As in most immature teratomas, the grade of the tumor is an important prognostic feature.
Baker et al. have reported a series of teratomas containing prominent benign vascular proliferations associated with neural tissue (Baker et al. 2002). The underlying tumors were either mature cystic teratoma, immature teratoma, or a mixed germ cell tumor. The vascular proliferations consisted of long, thin-walled, and curved vessels or rounded cellular aggregates with glomeruloid patterns. Small vessels could be seen arranged in whorls, and focally, a trabecular pattern was present.
Monodermal Teratoma with Sebaceous Differentiation
Sebaceous tumors resulting from one-sided development of a teratoma or arising in mature cystic teratomas with other components are rare (Chumas and Scully 1991). The reported cases showed an age range from 31 to 79 years at presentation, but the majority of patients were older than 49 years. All presented with lower abdominal enlargement. The ovarian tumors found at laparotomy were large, ranging from 10 to 35 cm. Some of the patients were found to have a mature cystic teratoma in the contralateral ovary. The tumors were mainly cystic. Partly solid yellow and tan masses protruded into the cysts. The latter contained necrotic or cheesy material (Chumas and Scully 1991).
Microscopically, the tumors consisted of sebaceous adenoma, basal cell carcinoma with sebaceous differentiation, and sebaceous carcinoma (Chumas and Scully 1991). The adenomas were all composed of nodules or lobules of proliferating normal sebaceous cells showing various degrees of maturity, with mature cells predominating. The basal cell carcinomas with sebaceous differentiation were composed of masses or nests of malignant basal cells containing collections of mature sebaceous cells. The sebaceous carcinoma was composed of sebaceous cells showing marked cellular and nuclear pleomorphism growing in an infiltrative pattern. The tumor cells had the typical appearance of sebaceous cells. Lipid stains were strongly positive in all the tumors, confirming the diagnosis (Chumas and Scully 1991).
The patients were treated either by excision of the affected adnexa or by hysterectomy and bilateral salpingo-oophorectomy (Chumas and Scully 1991). The outcome was favorable; only one tumor was known to have recurred. The tumor, a basal cell carcinoma with sebaceous differentiation, recurred in the pelvis; further follow-up was not available. One patient had, in addition to the sebaceous adenoma, a squamous cell carcinoma arising in the same ovary and died as a result of disseminated disease 1 year after the diagnosis. All the other patients were well and disease-free for periods ranging from 1.5 to 6 years postoperatively. The patient with sebaceous carcinoma was well and disease-free 6 years after diagnosis (Chumas and Scully 1991). Two other reported cases of sebaceous carcinoma treated with surgical resection also described good patient outcomes, with no recurrence at 19 months in one case and 32 months in the other (Moghaddam et al. 2013; Venizelos et al. 2009).
Other Types of Monodermal Teratoma
Some mucinous tumors of germ cell origin arising in mature cystic teratomas may overgrow the background teratomatous component and appear to be entirely composed of a mucinous tumor (see section on “Mucinous Tumors Arising in Mature Cystic Teratoma”) (Vang et al. 2007). This phenomenon is similar to the situation in which thyroid tissue in a pure struma ovarii or carcinoid has developed in a pure form or has overgrown all the other tissues. At least a subset of pure mucinous tumors of the ovary are thought to derive from teratomas and therefore represent a type of monodermal teratoma.
Other rare examples of monodermal teratomatous neoplasms observed in the ovary include the epidermoid cyst, which is lined by epidermis without appendages; the melanotic tumor, resembling the retinal anlage tumor (King et al. 1985); and the possible benign cystic counterpart of the latter (Anderson and McDicken 1971). Monodermal teratomatous origin of some malignant connective tissue tumors is difficult to prove because of the occurrence of connective tissue neoplasms derived from normal ovarian tissue. Monodermal teratomatous origin of tumors derived from ectodermal or endodermal tissues is more easily acceptable, and there may be as yet undescribed tumors of this type.
Mixed Germ Cell Tumors
Although many ovarian tumors belonging to this group are classified according to the predominant element present, it is emphasized that all areas of varying appearance should be sampled carefully. All the neoplastic germ cell elements observed within the tumor, however small, should be reported and described and, if possible, their size or relative proportion estimated. This is important because the behavior and treatment of these neoplasms vary considerably, and the presence of a small area composed of a more malignant element may alter the therapeutic approach and prognosis. This is especially true in children (Heifetz et al. 1998) where most immature teratomas behave in a nonaggressive manner; however, the presence of small foci of yolk sac tumor in an immature teratoma is associated with aggressive behavior.
Even though the presence of very small foci of yolk sac tumor or high-grade immature teratoma may not alter the behavior of a mixed germ cell tumor largely composed of less aggressive components, the presence of larger amounts of more malignant elements within a tumor is usually associated with a more aggressive behavior. Before the introduction of effective combination chemotherapy, the presence of yolk sac tumor or other more aggressive elements was associated with an unsatisfactory response to therapy and poor prognosis (Asadourian and Taylor 1969; Kurman and Norris 1976c; Talerman et al. 1973). The clinical course in most patients with tumors composed of yolk sac tumor associated with dysgerminoma or other germ cell elements usually does not differ materially from that observed in patients with pure yolk sac tumor (Gershenson 1993; Peccatori et al. 1995). The different response to treatment and the different behavior of some cases of dysgerminoma described in the past may have been a result of the presence of other germ cell elements that were not identified.
Clinical and Pathologic Features of Tumors Composed of Germ Cells and Sex Cord–Stromal Derivatives
In 1953, Scully (1953) described two patients with a distinctive gonadal tumor, which he designated gonadoblastoma. The tumor was composed of germ cells and sex cord–stromal derivatives, resembling immature granulosa and Sertoli cells. One of the tumors also contained stromal elements indistinguishable from lutein or Leydig cells. Both tumors occurred in phenotypic females who showed abnormal sexual development. The older patient, who was postpubertal, showed virilization, and it was postulated that the tumor was capable of steroid hormone secretion. The tumors were located at the site of normal ovaries, but normal ovarian tissue was not discernible, and the exact nature of the gonads in which the tumors had originated could not be determined. Both patients had bilateral tumors that were partly overgrown by dysgerminoma. The tumor was designated gonadoblastoma because it appeared to recapitulate the development of the gonads and because it occurred in individuals with abnormal sexual development and in gonads of uncertain nature (Scully 1970a). It was subsequently demonstrated that both patients were sex chromatin negative (indicative of an XY karyotype).
The neoplastic nature of gonadoblastoma has been questioned because some lesions are very small and may undergo complete regression by hyalinization and calcification. Furthermore, when malignancy supervenes, it manifests itself as germ cell neoplasia despite the fact that gonadoblastoma is composed of two or three different cell types. When the tumor has metastasized, gonadoblastoma as such has never been observed in the metastases. Nevertheless, gonadoblastoma shows exactly the same pattern in the very small lesions as in the large ones, including mitotic activity in the germ cell element and early overgrowth by dysgerminoma. The association with dysgerminoma is seen in 50% of cases and with other more malignant germ cell neoplasms in an additional 10% (Scully 1970a). In view of this, the concept that gonadoblastoma represents an in situ germ cell malignancy is considered to be justified.
Genetic and Molecular Features
Gonadoblastoma occurs almost entirely in patients with pure or mixed gonadal dysgenesis or in male pseudohermaphrodites. Occasional patients are of short stature and may have other stigmata of Turner syndrome (Brant et al. 2006; Schellhas 1974b; Shah et al. 1988). Nearly all patients with gonadoblastoma whose karyotype was recorded (96%) were found to have a Y chromosome (Schellhas 1974b), with the most frequent karyotype being 46,XY (found in half of cases), followed by 45,X/46,XY mosaicism (found in a quarter of cases) (Schellhas 1974b). A small subset of patients had a 46,XX karyotype (Bergher De Bacalao and Dominguez 1969; Erhan et al. 1992; Nakashima et al. 1989; Obata et al. 1995; Talerman et al. 1990; Zhao et al. 2000), some of whom were fertile (Bergher De Bacalao and Dominguez 1969; Erhan et al. 1992; Nakashima et al. 1989; Talerman et al. 1990; Zhao et al. 2000). The remainder showed many different forms of mosaicism, including 45,X/46,XX mosaicism (Schellhas 1974b; Scully 1953). Six patients with morphologic abnormalities of the Y chromosome were reported.
The similarity between the distribution of the karyotypes in patients with gonadoblastoma and patients with dysgerminoma and gonadal dysgenesis is striking. In one review, 24 of 25 patients with dysgerminoma and gonadal dysgenesis had a Y chromosome. The karyotype was 46,XY in 60%, followed by 45,X/46,XY in 24%, and the remainder showed various forms of mosaicism (Schellhas 1974b). One patient had 45,X monosomy and Turner syndrome. All other patients with features of Turner syndrome had various forms of mosaicism containing a Y chromosome. Gonadal dysgenesis and dysgerminoma have also been reported in a female with a 46,XX karyotype who had no evidence of Y chromosomal DNA (Letterie and Page 1995). Gonadoblastoma was not detected in the affected gonad, but the authors suggested that it was probably overgrown by the dysgerminoma. The reported cases suggest that gonadoblastoma and gonadal dysgenesis may infrequently occur in patients who do not have Y chromosomal DNA. However, some authors have postulated that such reports represent undetected mosaicism, with the dysgenetic gonads containing cells with at least some Y chromosome material (Ulbright and Young 2014).
Family history of gonadal dysgenesis has been noted in at least ten reports of patients with gonadoblastoma (Allard et al. 1972; Anderson and Carlson 1975; Boczkowski et al. 1972; Talerman 1971). Evidence of gonadal dysgenesis affecting three generations of the family of a patient with gonadoblastoma was obtained in two instances (Allard et al. 1972; Bartlett et al. 1968). Gonadoblastoma has been reported in one pair of twins (Frasier et al. 1964) and in four pairs of siblings (Allard et al. 1972; Anderson and Carlson 1975); Boczkowski et al. 1972; Talerman 1971). All these patients had 46,XY karyotypes. It has been postulated that the mode of inheritance is either an X-linked recessive gene or an autosomal sex-linked mutant gene (Bartlett et al. 1968; Schellhas 1974a, b). The TSPY gene, located on the GBY locus of the Y chromosome, has been postulated to play a role in the pathogenesis of gonadoblastoma (Hertel et al. 2010; Lau et al. 2009).
The association of gonadoblastoma with certain endocrine abnormalities was noted in one of the two cases first reported (Scully 1953). In view of the fact that gonadoblastoma occurs almost entirely in patients with gonadal dysgenesis, the defective gonadal development present in these patients should not be confused with the presence of endocrine effects that are associated with the tumor. Although the virilization produced by the tumor may regress after excision, there is no further gonadal development, and the gonadal abnormalities remain. Although the exact source of the steroid hormone production was not originally known, the interstitial cells resembling Leydig or lutein cells were considered to be the most likely source of the androgens (Scully 1953). Further observations have shown that the presence of Leydig or lutein-like cells is not always associated with the presence of virilization, although they are encountered more frequently in tumors from virilized phenotypic female patients than in those from non-virilized patients. The possibility that the tumor may secrete estrogens, as evidenced by complaints of hot flushes and other menopausal symptoms after excision of the tumor, has also been noted (Scully 1970a). Originally the evidence of hormone secretion was mainly clinical, usually evidenced by virilization occurring after puberty and manifesting itself as masculine body contour, hirsutism, and clitoromegaly. Slight elevation of the urinary 17-ketosteroid excretion was noted in some cases. The gonadotropins, when measured, were usually elevated.
Subsequently, it has been shown that gonadoblastoma is capable of producing testosterone and estrogens from progesterone in vitro (Anderson and Carlson 1975; Rose et al. 1974). Evidence of testosterone secretion in vivo in patients with gonadal dysgenesis has been presented (Judd et al. 1970). Androgen and estrogen formation from progesterone in vitro has been demonstrated in a streak gonad that did not contain any Leydig and lutein cells microscopically, but which, based on the description, may have contained a small burnt-out gonadoblastoma (Mackay et al. 1974). Although in vitro testosterone formation has been ascribed to the Leydig or lutein-like cells present in gonadoblastoma (Rose et al. 1974), the demonstration of steroid production by a streak gonad that did not contain Leydig or lutein cells indicates that the nondescript stromal tissue also has the capability of steroid synthesis (Mackay et al. 1974).
Despite the advances in the understanding of the hormonal aspects of gonadoblastoma and dysgenetic gonads, a number of questions remain, the most important being why some patients become virilized and others do not. Although there is an approximate relationship between virilization and the presence of Leydig or lutein-like cells in the tumor, this relationship is not constant. It may be that the amount of steroid secretion is inadequate to produce virilization in some cases because of a small cell mass. Another possible explanation is that the steroid metabolic pathways may be different and that some gonadoblastomas may produce hormones that are metabolically nonfunctioning, whereas other gonadoblastomas produce metabolically active steroids.
The exact prevalence of gonadoblastoma is not known, but it is certainly uncommon. Gonadoblastoma is reported to occur in approximately one third of patients with 45,X/46,XY mosaicism (Coyle et al. 2016; Zelaya et al. 2015) and in approximately 5% of all phenotypically female patients with disorders of sex development (Jiang et al. 2016). Gonadoblastoma is usually seen in young patients, occurring most frequently in the second decade and somewhat less frequently in the third and first decades, in that order. With a few exceptions, all the reported cases occurred in patients under 30 years of age. Patients with gonadoblastoma usually have primary amenorrhea, virilization, or developmental abnormalities of the genitalia. The discovery of gonadoblastoma is made in the course of investigating these conditions. Another mode of presentation is the presence of a gonadal tumor. The gonadoblastoma forms part of the tumor in these cases and is discovered on histologic examination. Most patients with gonadoblastoma (80%) are phenotypic females, and the remainder are phenotypic males with cryptorchidism, hypospadias, and female internal secondary sex organs. Among the phenotypic females, 60% are virilized and the remainder are normal in appearance (Scully 1970a).
Most of the phenotypic female patients exhibit abnormal genital development, and breast development is often diminished even among the non-virilized females. Although primary amenorrhea is a common presenting symptom among phenotypic females with gonadoblastoma, a few patients have episodes of spontaneous cyclical bleeding, and occasional patients menstruate normally (Scully 1970a). The virilization present in phenotypic female patients with gonadoblastoma usually does not regress after excision of the tumor, although this has been seen in occasional cases, and in a few additional cases there was partial regression.
Although most patients have gonadal dysgenesis, gonadoblastoma has been described in patients who have had normal pregnancies. These include patients with a 46,XX karyotype (Bergher De Bacalao and Dominguez 1969; Erhan et al. 1992; Nakashima et al. 1989; Zhao et al. 2000) and true hermaphrodites (Talerman et al. 1990).
At least eight true hermaphrodites with gonadoblastoma have been described. Of these, two had a 46,XX karyotype (McDonough et al. 1976; Talerman et al. 1981), four had 46,XY (Damjanov and Klauber 1980; Park et al. 1972; Quigley et al. 1981; Szokol et al. 1977), and two had 46,XX/46,XY mosaicism (Radharrishnan et al. 1978; Talerman et al. 1990). Gonadoblastoma has also been diagnosed in five males with normally descended testes (Hughesdon and Kumarasamy 1970; Talerman and Dlemarre 1975), some of whom fathered children subsequent to the excision of the testis bearing the lesion.
Gonadoblastoma has been found more often in the right gonad than in the left and has been bilateral in 40% of cases or higher (Scully 1970a; Talerman and Roth 2007). Although some tumors are recognized on gross examination, in a number of cases the lesion is detected only on histologic examination; this may be the case with bilateral tumors, only one of which may be recognized macroscopically. In most cases, the gonad of origin is indeterminate because it is overgrown by the tumor. When the nature of the gonad can be identified, it is usually a streak or a testis. The contralateral gonad in these cases may be a streak or a testis, and the former is more likely to harbor a gonadoblastoma (Scully 1970a; Talerman and Roth 2007). Occasionally gonadoblastoma has been found in otherwise normal ovaries (Nakashima et al. 1989; Nomura et al. 1999; Pratt-Thomas and Cooper 1976).
Pure gonadoblastoma varies from a microscopic lesion to 8 cm, with most tumors measuring a few centimeters. When gonadoblastoma becomes overgrown by dysgerminoma or other malignant germ cell elements, much larger tumors may be observed (Scully 1970a; Talerman 1974; Talerman and Roth 2007). The macroscopic appearance of the tumor varies to some extent according to the presence of hyalinization and calcification, as well as overgrowth by dysgerminoma.
Although the external sex organs in patients with gonadoblastoma present a wide variety of appearances ranging from normal to completely ambiguous, the secondary internal sex organs almost always include a uterus, which is hypoplastic in most cases, and two or occasionally one normal fallopian tube; this is also seen in the phenotypic males. Male secondary internal sex organs, such as the epididymis, vas deferens, and prostate, are found occasionally in the virilized phenotypic females and are always found in the phenotypic male pseudohermaphrodites (Scully 1970a).
Microscopic and Immunohistochemical Features
The germ cells show mitotic activity, which may be marked in some cases. They are intimately admixed with immature sex cord cells, which are smaller, round or oval, epithelioid cells with dark, oval, or slightly elongated carrot-shaped nuclei. Mitotic activity is not seen in these cells. The immature sex cord cells are arranged within the cell nests in three typical patterns: (1) along the periphery of the nests in a coronal pattern, sometimes with a palisading arrangement, (2) surrounding individual or collections of germ cells in the same way as the follicular epithelium surrounds the ovum of the primary follicle, or (3) surrounding small round spaces containing amorphous hyaline, eosinophilic, and PAS-positive material, resembling Call–Exner bodies.
The connective tissue stroma surrounding the cellular nests frequently contains collections of cells indistinguishable from Leydig cells or luteinized stromal cells. There is considerable variation in the number of these cells from case to case; in some cases they are numerous, in others they are identified with difficulty, or they may be absent.
Although in many cases the cells are indistinguishable from Leydig cells and may contain lipochrome granules, Reinke crystals, which are specifically diagnostic of Leydig cells, have never been identified in their cytoplasm. The Leydig or lutein-like cells are identified in 66% of cases, and they are present nearly twice as frequently in older patients as in those 15 years of age or younger (Scully 1970a). The presence of Leydig or lutein-like cells is not necessary for the diagnosis of gonadoblastoma. The connective tissue stroma surrounding the cellular nests may be scanty or abundant and may vary from dense and hyalinized to cellular, resembling ovarian stroma. These latter appearances are more common in tumors that either have arisen in or are suspected to originate in a gonadal streak (Scully 1970a). Occasionally, the stroma may be loose and edematous.
The basic composition of gonadoblastoma, consisting of the two cell types present within the cellular nests and with the Leydig or lutein-like cells present in the stroma, has been confirmed by electron microscopy (Garvin et al. 1976; Ishida et al. 1976; Mackay et al. 1974). Although there is agreement concerning the nature of the germ cells, the nature of the sex cord–stromal cells is in dispute. They are considered by some to be Sertoli cells or granulosa cells or their precursors (Mackay et al. 1974), whereas others consider them to be primitive sex cord–stromal cells and are unable to differentiate them further (Scully 1970a; Talerman 1980). The latter view is more widely accepted. Recent immunohistochemical studies demonstrating more consistent and extensive expression of FOXL2 compared to SOX9 suggest differentiation toward granulosa cells; however, the presence of some co-expression lends support to the idea of incompletely differentiated sex cord elements with hybrid features (Kao et al. 2014; Ulbright and Young 2014). The nature of the amorphous, hyaline, and eosinophilic material forming Call–Exner-like bodies also was a matter of dispute. It was considered to be either of basement membrane origin (Ishida et al. 1976; Mackay et al. 1974) or composed of fibrillar material formed by the stromal cells before they undergo fragmentation and cell death. The former view is supported by most investigators.
The basic histologic appearance of gonadoblastoma may be altered by three processes: hyalinization, calcification, and overgrowth by dysgerminoma (Scully 1970a; Talerman 1980; Talerman and Roth 2007). Hyalinization takes place by coalescence of the hyaline Call–Exner-like bodies within the nests and of the basement membrane-like band of similar material present around the nests. The hyaline material replaces the tumor cells, and the whole nest may be replaced. Calcification is a common feature (Fig. 54) and is seen microscopically in 81% of cases; it usually begins in the Call–Exner-like bodies with formation of small calcific spherules that are frequently laminated, resembling psammoma bodies. The process continues with enlargement and fusion of the calcified bodies and calcification of the hyalinized material, resulting in formation of a calcified mass embracing the whole nest. The process may extend to the stroma, which may also undergo hyalinization and calcification. In such cases, tumor cells become very scarce or absent, and the presence of smooth, rounded, and calcified masses may be the only evidence that gonadoblastoma was present (Fig. 6). Although this finding is not considered to be diagnostic of gonadoblastoma, it has been called a burnt-out gonadoblastoma (Scully 1970a; Talerman 1980; Talerman and Roth 2007) and is a strong argument in favor of the diagnosis, indicating that a careful search should be made for more viable areas of the tumor.
Gonadoblastoma is frequently overgrown by dysgerminoma, as is seen in 50% of cases (Scully 1970a; Talerman 1980; Talerman and Roth 2007). The overgrowth may vary from the presence of a small collection of malignant germ cells in the stroma outside the gonadoblastoma nests to massive overgrowth of the whole tumor, in which occasional nests of gonadoblastoma may be seen. The dysgerminoma in these cases shows the typical appearances of pure dysgerminoma or seminoma – histologically, histochemically, immunohistochemically, and ultrastructurally. It should be noted that when gonadoblastoma becomes overgrown by dysgerminoma, the germ cell component present within the gonadoblastoma nests shows marked proliferative activity and overgrows the sex cord elements. When gonadoblastoma undergoes regressive changes, they manifest first as a decrease in germ cells. Gonadoblastoma may also be associated with, and overgrown by, other more malignant germ cell neoplasms, such as immature teratoma, yolk sac tumor, embryonal carcinoma, and choriocarcinoma, as occurs in 10% of cases (Scully 1970a; Talerman 1980; Talerman and Roth 2007). A gonadoblastoma overgrown by dysgerminoma and containing a proliferation of sex cord elements resembling a Sertoli cell tumor has been reported in the dysgenetic gonad of a 19-year-old phenotypic female with 46,XY karyotype (Nomura et al. 1999). Although it has been postulated that gonadoblastoma may coexist with mixed germ cell–sex cord–stromal tumor, the two cases describing such an association (Bhathena et al. 1985; Cholafranceschi and Massi 1995) were in reality typical gonadoblastomas and not combined tumors.
Dissecting Gonadoblastoma and Undifferentiated Gonadal Tissue
In 2006, Cools and colleagues introduced the concept of undifferentiated gonadal tissue (UGT), which they defined as an admixture of germ cells and sex cord cells arranged in cords rather than tubules or follicles and/or with an unorganized pattern in a background of fibrous stroma (Cools et al. 2006). This tissue was found adjacent to gonadoblastoma in the majority of cases studied (67%), and it was postulated to represent a precursor to gonadoblastoma (Cools et al. 2006). The proposed model of gonadoblastoma tumorigenesis begins with abnormal development of Sertoli cells due to SOX9 deficiency, possibly due to upstream mutations. In the absence of normal Sertoli cells, the germ cells fail to mature, as evidenced by the expression of fetal germ cell markers such as OCT-3/4. The immature germ cells may then transform into the neoplastic germ cells of gonadoblastoma and may eventually form organized nests with the sex cord cells, resulting in the appearance of classic gonadoblastoma (Cools et al. 2006; Ulbright 2014).
Dr. Scully recognized an entity demonstrating overlapping features with UGT, which he termed “dissecting gonadoblastoma” and which has been described in detail by his colleagues in recent reviews (Kao et al. 2016; Ulbright and Young 2014). Dissecting gonadoblastoma contains the same cellular elements as classic gonadoblastoma, but displays an infiltrative or a diffuse pattern. Like UGT, dissecting gonadoblastoma is frequently found in gonads with classic gonadoblastoma, lending support to the idea that it represents a precursor lesion (Kao et al. 2016). Almost all cases described occurred in phenotypic females, with karyotypes of 46,XY, 45,XO/46,XY, or 46,XX, in order of decreasing frequency (Kao et al. 2016). The clinical presentation is similar to that of classic gonadoblastoma. Microscopically, a few different patterns are described, and these frequently coexist. The solid/expansile pattern, occurring in 68% of cases, consists of large nests of germ cells with a minor component of sex cord cells, often with intervening fibrovascular septa. The classic round deposits of basement membrane material are less conspicuous in this pattern. The anastomosing pattern, found in 63% of cases, consists of small interconnected nests of germ cells with surrounding sex cord cells, often with conspicuous deposits of basement membrane material and with cellular background stroma. Finally, the cord-like pattern, present in 58% of cases, demonstrates irregularly distributed cords of germ cells and small nests of sex cord cells, also within a cellular stroma. Calcifications are rare in the first two patterns and absent in the cord-like pattern (Kao et al. 2016). The germ cells demonstrate a variable appearance, ranging from spermatogonia-like to germinoma-like; only the latter expressed OCT-3/4. The sex cord cells are small, with dark ovoid or angulated nuclei and inconspicuous nucleoli, and stain similarly to the sex cord cells in classic gonadoblastoma, with positivity for inhibin, SF-1, and FOXL2 and only focal/weak expression of SOX9 (Kao et al. 2016).
The cord-like and anastomosing patterns of dissecting gonadoblastoma are essentially identical to UGT, and the high frequency of associated gonadoblastoma supports that these lesions are precursors to classic gonadoblastoma. The solid/expansile pattern, in contrast, has been suggested as the immediate precursor to invasive dysgerminoma, with classic gonadoblastoma representing an intermediate lesion (Kao et al. 2016).
Gonadoblastoma, because of its distinctive histologic appearance and its cellular composition, cannot be easily confused with any of the well-recognized gonadal neoplasms. Gonadoblastoma may be confused with the mixed germ cell–sex cord–stromal tumor (Talerman 1971; Talerman 1972a), which shares with gonadoblastoma the unique distinction of being composed of germ cells and sex cord–stromal derivatives. The mixed germ cell–sex cord–stromal tumor shows a less uniform appearance, absence of a nest-like pattern, absence of calcification and hyalinization, more pronounced proliferative activity involving also the sex cord–stromal derivatives, the tendency to occur in normal gonads, and other genetic, endocrine, and somatic differences. Another lesion resembling gonadoblastoma is the ovarian sex cord tumor with annular tubules (Scully 1970b), which is frequently found in patients with Peutz–Jeghers syndrome. This lesion, which is also frequently bilateral, is composed of tubules lined by Sertoli and granulosa-like cells; contains similar round, eosinophilic, and hyaline Call–Exner-like bodies; and tends to calcify in the same manner as gonadoblastoma. The basic difference from gonadoblastoma is the absence of germ cells (see “Sex Cord-Stromal, Steroid Cell, and Other Ovarian Tumors with Endocrine, Paraendocrine, and Paraneoplastic Manifestations”). Sertoli cell nodules with intratubular germ cell neoplasia may also mimic gonadoblastoma; however, the sex cord cells in intratubular germ cell neoplasia demonstrate full Sertoli cell differentiation, with positivity for SOX9 and no expression of FOXL2 (Hersmus et al. 2008; Kao et al. 2014). Immunohistochemistry for these two markers can, therefore, assist in the distinction from gonadoblastoma.
The solid/expansile pattern of dissecting gonadoblastoma may be mistaken for dysgerminoma, given the presence in both of large nests and sheets of germ cells separated by fibrovascular septa. However, the presence of sex cord cells indicates that the tumor is a gonadoblastoma, and immunohistochemistry for SF-1 can assist in highlighting these cells in difficult cases (Kao et al. 2016).
Clinical Behavior and Treatment
The prognosis of patients with pure gonadoblastoma is excellent, provided the tumor and the contralateral gonad, which may be harboring an undetectable gonadoblastoma, are excised. When gonadoblastoma is associated with dysgerminoma, the prognosis is still very good. Metastases tend to occur later and more infrequently than in dysgerminoma that is not associated with a gonadoblastoma. All patients with gonadoblastoma and dysgerminoma with known follow-up, including the occasional cases with metastases (Hart and Burkons 1979; Schellhas et al. 1971; Scully 1970a), are alive and well after treatment, with the exception of two patients who died of disseminated dysgerminoma (Hart and Burkons 1979; Teter 1970). The prognosis is different when gonadoblastoma is associated with more malignant germ cell neoplasms, such as embryonal carcinoma, yolk sac tumor, choriocarcinoma, and immature teratoma. In the past, none of these patients survived longer than 18 months (Talerman 1974). Subsequently, the administration of combination chemotherapy used successfully in the treatment of malignant germ cell tumors has markedly improved the prognosis, which with adequate treatment is now favorable.
Because gonadoblastoma occurs almost entirely in patients with dysgenetic gonads, which are not capable of normal function, and as the gonadoblastoma may act as a source from which malignant germ cell neoplasms may originate (Schellhas 1974b), there is general agreement that excision of the gonads is the treatment of choice (Schellhas 1974a; Scully 1970a; Talerman 1980; Talerman and Roth 2007). This consensus applies not only to a contralateral gonad that appears to be abnormal but also, in most cases, to a normal-appearing gonad. Routine resection of the uterus or other müllerian duct derivatives, which may rarely give rise to malignancy, is not recommended in asymptomatic patients with intersex disorders (Hughes et al. 2006; Mouriquand et al. 2014).
Mixed Germ Cell–Sex Cord–Stromal Tumor
The descriptive term mixed germ cell–sex cord–stromal tumor originally was intended to embrace all the tumors composed of these cell types, including gonadoblastoma. In view of the fact that the latter term is now so well established, the term mixed germ cell–sex cord–stromal tumor should be reserved for tumors composed of these cell types that exhibit distinctive histologic appearances differing from those of gonadoblastoma (Talerman 1972a, b). The WHO classification designates these tumors as “mixed germ cell-sex cord-stromal tumor, unclassified.”
Genetic and Molecular Features
Nearly all female patients with this neoplasm have had genotype and karyotype determinations and have been found to have the normal female chromosome complement of 46,XX. All the patients with this tumor showed normal somatosexual development. There is no evidence that patients with this tumor have chromosomal abnormalities or gonadal dysgenesis, except for a single patient reported to have monosomy 22 (Speleman et al. 1997). In a small number of tumors studied, a subset of neoplasms showed amplification of chromosome 12p, and no mutations of the c-kit or PDGFRA genes were identified (Michal et al. 2006).
Most patients with mixed germ cell–sex cord–stromal tumor do not exhibit any clinical manifestations of endocrine abnormalities. In most cases, tests of hormonal function have not been performed preoperatively. In cases in which tests have been performed postoperatively, function has been found to be normal. In one case, the patient, an 8-year-old girl, exhibited signs of precocious pseudopuberty manifesting as mammary development and menstrual bleeding for 3 years before the discovery of a large ovarian tumor (Talerman and van der Harten 1977). There was increased urinary estrogen excretion. After excision of the ovarian tumor, the uterine bleeding ceased and the urinary estrogens became normal (Talerman and van der Harten 1977). Another similar case involved a 4-year-old girl with a 46,XX karyotype who presented with precocious puberty and elevation of estradiol, progesterone, testosterone, and androstenedione (Metwalley et al. 2012). She was found to have a mixed germ cell–sex cord–stromal tumor and yolk sac tumor and had resolution of symptoms and hormone levels following excision of the tumor.
Isosexual precocious pseudopuberty has been seen in ten other patients in the first decade, including four infants less than 1 year of age, who exhibited mammary development and vaginal bleeding (Lacson et al. 1988; Metwalley et al. 2012; Michal et al. 2006; Zuntova et al. 1992). The urinary estrogens were elevated, and vaginal smears showed estrogen effect. After excision of the tumor, there was a complete return to normality. There was no evidence of virilization in any of the patients. These findings indicate that female patients with this neoplasm either do not have any associated endocrine abnormalities or, if these are present, that they are manifested as feminization. One reported patient with a mixed germ cell–sex cord–stromal tumor excised at the age of 10 years (Talerman 1972a) developed normally and commenced menstruating at age 15. She was well and disease-free 12 years after excision of the tumor.
These neoplasms are rare. A number of adequately documented cases have been reported (Arroyo et al. 1998; Lacson et al. 1988; Michal et al. 2006), but it is likely that some cases may not have been recognized and have been included with tumors of germ cell origin or with sex cord–stromal tumors. Tumors of this type have been observed more frequently in normal phenotypic female patients but have also been encountered in normal adult males. Most of the reported cases in females were encountered in children in the first decade. More than a dozen cases occurred in infants less than 1 year of age (Talerman 1972b, 1980). In three cases, the tumor occurred in women aged 26, 31, and 43 years, who had normal pregnancies (Talerman 1980). In the ovary, the tumor is most common in the first decade, followed by the second and third, and is uncommon thereafter. Therefore, the age distribution of patients with this neoplasm differs from that of patients with gonadoblastoma (Talerman 1980).
The tumors encountered have been relatively large, varying from 7.5 to 18 cm and weighing from 100 to 1050 g. The tumor was found to be unilateral in all except two patients, and the contralateral gonad has always been described as a normal ovary. In some cases in which excision or biopsy was performed, this was confirmed on microscopic examination.
The tumor is usually round or ovoid, firm in consistency, and surrounded by a smooth, slightly glistening, gray or gray–yellow capsule. In most cases, the tumor is solid (Michal et al. 2006; Talerman 1972a, b; Talerman and Roth 2007), but in some cases it is partly cystic (Talerman and van der Harten 1977). The cut surface of the tumor is uniformly gray, pink, or yellow to pale brown. Neither calcified areas nor foci of necrosis have been observed on gross examination. The fallopian tubes and the uterus have always been found to be normal. There have been no abnormalities affecting the external genitalia.
Microscopic and Immunohistochemical Features
The third pattern consists of scattered collections of germ cells surrounded by sex cord elements that may be very abundant. The germ cells admixed with sex cord derivatives may also be scattered individually and in small groups within connective tissue stroma. Sometimes there may be a suggestion of an insular pattern with islands of various sizes surrounded by fine fibrovascular stroma coalescing and forming aggregates or occasionally being separated by large amounts of connective tissue and forming a more pronounced insular pattern. Admixture with all these patterns is often seen. The typical nest-like pattern present in gonadoblastoma is not observed. In only one case were a few small collections of Leydig or lutein-like cells observed (Talerman 1972a), but in all the remaining cases, these cells were not identified.
The two cellular elements present in the tumor, the germ cells and the sex cord derivatives, are intimately admixed. The sex cord derivatives are arranged peripherally in a single file, forming long rows at the periphery of the cords or peripherally lining the tubular structures, as well as surrounding individual or groups of germ cells within the small clusters or larger aggregates. The sex cord derivatives generally tend to resemble Sertoli cells more than granulosa cells. They show variable degrees of mitotic activity. The germ cells resemble those observed in dysgerminoma and gonadoblastoma in all respects, including ultrastructural, histochemical, and immunohistochemical (CD117[+] and OCT-4[+]) features. In some cases, a number of the germ cells present in this tumor appear more mature than the germ cells observed in gonadoblastoma or dysgerminoma and tend to resemble primordial germ cells. In view of this, it is possible that they may represent a later stage in the maturation of the germ cell than that seen in gonadoblastoma or dysgerminoma. The germ cells show brisk mitotic activity.
The tumor does not show hyalinization, calcification, or the regressive changes observed in gonadoblastoma and appears to be actively proliferative. There is some variation in the cellular content in some parts of the tumor; in some areas there is a preponderance of germ cells, whereas in others the sex cord derivatives predominate. However, the intimate admixture of these two cell types is seen everywhere. Most tumors show a solid pattern, although occasional small clefts lined by sex cord elements may be present. In some tumors, cystic spaces of varying sizes either lined by sex cord derivatives or flattened epithelial-like cells or devoid of lining may be observed (Talerman and van der Harten 1977; Tavassoli 1983; Tokuoka et al. 1985); they closely resemble the cystic spaces observed in some retiform Sertoli–Leydig cell tumors (Talerman 1987; Talerman and Haije 1985; Young and Scully 1983) or cystic sex cord–stromal tumors. In occasional tumors, this pattern may be pronounced and may suggest that the tumor contains epithelial cells in addition to germ cells and sex cord derivatives (Tavassoli 1983). It is considered, however, that these cells are in fact sex cord derivatives and that the tumor exhibits a retiform and/or cystic pattern similar to that seen in some pure sex cord tumors.
Normal ovarian tissue, as evidenced by the presence of normal ovarian stroma and at least some primordial follicles, has been identified in all cases, including a case in which it could not be identified in the original sections available (Talerman 1972a). In a number of cases, graafian follicles also are present (Talerman 1972b; Talerman and van der Harten 1977). In other cases, tumor deposits are found very close to the surface of the ovary, obliterating primordial and graafian follicles.
Histologically, this tumor is most likely to be confused with gonadoblastoma. In contrast to gonadoblastoma, this tumor lacks the typical nest-like pattern, has greater proliferative activity of both the germ cell and sex cord component, and lacks calcification, hyalinization, and in most cases Leydig or lutein-like cells. Macroscopically, the tumors are larger. The gonad of origin is a normal ovary, and there is no evidence of gonadal dysgenesis or any somatosexual abnormalities. The patients have a normal female 46,XX karyotype. There is no evidence of virilization, and if there are signs of abnormal endocrine activity, they manifest as feminization.
Occasionally, if the germ cells are relatively scanty, the tumor may be confused with pure sex cord–stromal tumors of the ovary, but the presence of germ cells should alert the observer to the true identity of the tumor. If the sex cord derivatives are few in number, are missed, or are disregarded, the tumor may be misclassified as a germ cell tumor, but the presence of sex cord elements intimately admixed with the germ cells should indicate its true identity. The presence of prominent clefts and cystic spaces, especially when the latter contain papillary projections, may cause confusion with Sertoli–Leydig cell tumors showing a retiform pattern or even with serous papillary tumors. The presence of germ cells admixed with sex cord derivatives indicates that the tumor is a mixed germ cell–sex cord–stromal tumor, irrespective of its pattern.
Clinical Behavior and Treatment
The prognosis of patients with mixed germ cell–sex cord–stromal tumor of the ovary occurring in pure form is favorable. In the great majority of known cases when the tumor was confined to the ovary and not associated with other malignant neoplastic germ cell elements, there has been no recurrence or metastases after excision of the affected adnexa. The patients are well and disease-free for periods varying from 1 to 15 years (Michal et al. 2006; Talerman 1980; Talerman and Roth 2007). Accordingly, after a unilateral salpingo-oophorectomy, careful examination of the abdominal cavity is recommended. If the contralateral ovary shows signs of abnormality, biopsy is advisable. After this procedure, the patient should have chromosome studies. If the karyotype is 46,XX and if no other abnormalities are detected, further therapy is not necessary, although careful long-term follow-up is essential.
One well-documented case of metastasizing mixed germ cell–sex cord–stromal tumor occurring in a 5-year-old girl has been reported (Lacson et al. 1988). The metastases were found in the para-aortic lymph nodes and in the peritoneal cavity. The patient was well and disease-free 2 years after excision of the affected adnexa, para-aortic lymphadenectomy, excision of peritoneal metastases, and a course of cisplatin-based combination chemotherapy (Lacson et al. 1988). Another case of metastasizing mixed germ cell–sex cord–stromal tumor showing an unusual SCTAT-like pattern and occurring in a 30-year-old woman has been reported (Arroyo et al. 1998). Three years after excision of a right-sided ovarian tumor, a large tumor mass was noted in the region of the uterine fundus. The mass and a number of peritoneal implants were excised together with the uterus and the left ovary. The primary and the metastatic tumors showed identical appearances. The left ovary was normal. The patient was well and disease-free 1 year after excision of the metastases and administration of combination chemotherapy.
In three patients in their 20s, one in her early 30s, and one in her early 40s, the mixed germ cell–sex cord–stromal tumor was associated with dysgerminoma. There was no evidence of metastases. The patients were well and disease-free from 2 to 7 years after unilateral adnexectomy and radiation therapy (Talerman 1980).
In five children, aged 4–16 years, the tumor was overgrown by other malignant germ cell elements, including choriocarcinoma and yolk sac tumor. In three of these cases, the tumor metastasized and resulted in the death of the patient. The metastases were composed of the malignant germ cell elements. Two patients treated with cisplatin-based chemotherapy were alive and well at follow-up intervals of 5 years and 8 months (Metwalley et al. 2012). When the tumor is associated with malignant germ cell elements, the patient should be treated with the appropriate combination chemotherapy used in treatment of non-dysgerminomatous malignant germ cell tumors, in addition to excision of the affected adnexa. This is of particular concern in postmenarchal women, in whom there is an increased possibility that the tumor may not present in pure form but be associated with other neoplastic germ cell elements.
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