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Nonspecific Tumors of the Ovary, Including Mesenchymal Tumors

  • Lauren E. SchwartzEmail author
  • Russell Vang
Living reference work entry

Abstract

The tumors discussed in this chapter comprise a heterogeneous group of neoplasms many of which are not specific to the ovary. Most are uncommon in this location, occurring much more frequently in other parts of the body. Consequently, whenever they are encountered in the ovary, these tumors pose difficult problems in diagnosis, histogenesis, behavior, and therapy for the pathologist and clinician. These neoplasms must be differentiated from primary ovarian neoplasms containing mesenchymal tissue, as well as from metastatic and disseminated neoplasms affecting the ovary. Thus, mesenchymal neoplasms nonspecific to the ovary must be differentiated primarily from teratomatous neoplasms containing large amounts of mature or immature mesenchymal elements and from carcinosarcoma (malignant mixed mullerian tumor), which are composed of different malignant mesenchymal elements in addition to their malignant epithelial components. Tumors of teratomatous origin containing mesenchymal tissue are described in chapter “Germ Cell Tumors of the Ovary”, and carcinosarcomas, endometrioid stromal sarcomas, and adenosarcoma are discussed in chapter “Surface Epithelial Tumors of the Ovary”.

In addition to the mesenchymal neoplasms nonspecific to the ovary, adenomatoid tumor, which is of mesothelial origin, Wolffian tumors, ovarian neoplasms of neural origin, hepatoid carcinoma of the ovary, small cell carcinoma of the ovary (pulmonary type), and tumors of salivary gland type are included. Although small cell carcinoma of hypercalcemic type is listed in the miscellaneous ovarian tumor category in the 2014 WHO classification (Kurman RJ, Carcangiu ML, Simon Herrington C, Young RH. WHO classification of tumours of female reproductive organs, 4th edn. IARC Press, Lyon, 2014), that tumor is discussed in chapter “Sex Cord-Stromal, Steroid Cell, and Other Ovarian Tumors with Endocrine, Paraendocrine, and Paraneoplastic Manifestations”. Lastly, solid pseudopapillary neoplasm of the ovary (Deshpande V, Oliva E, Young RH, Am J Surg Pathol 34(10):1514–1520, 2010) is also listed in the miscellaneous ovarian tumor category in the 2014 WHO classification (Kurman RJ, Carcangiu ML, Simon Herrington C, Young RH. WHO classification of tumours of female reproductive organs, fourth edn. IARC Press, Lyon, 2014) but will not be discussed.

Keywords

Ovary Mesenchymal Muscle Mesothelial Wolffian 

Mesenchymal Tumors Nonspecific to the Ovary

Mesenchymal neoplasms that arise in the ovary are rare and thought to arise from connective tissue found in the ovary, rather than thought to be of teratomatous or surface epithelial–stromal (müllerian) origin. Teratomatous origin or origin from surface epithelial-stromal (mullerian) origin cannot be excluded in a number of cases. The neoplasms discussed here are composed of a single neoplastic mesenchymal element, either benign or malignant, in contrast to teratomatous tumors or carcinosarcomas, which are usually composed of a number of tissue elements.

Some issues of classification and histogenesis may not be resolvable in view of the possibility of a monomorphic teratoma. Thus, although some of these neoplasms can be shown to originate directly from ovarian tissue, a considerable number of cases are of indeterminate histogenesis and origin. Mesenchymal neoplasms of the ovary can be benign or malignant, just like their counterparts that arise in other areas of the body, and are classified on the basis of the tissue of origin.

Low–Grade Endometriod Stromal Sarcoma

Low grade endometrioid stromal sarcoma (LGESS), primary to the ovary is a rare neoplasm with less than 100 cases reported (Oliva et al. 2014; Young et al. 1984; Chang et al. 1993; Masand et al. 2013). The patients are of variable age with the majority of tumors occurring during the fifth and sixth decades (Oliva et al. 2014; Chang et al. 1993). Clinically patients tend to present with non-specific symptoms including abdominal distension and/or pain. The neoplasms have been noted to predominately be unilateral, with some cases being bilateral in nature. Macroscopically the tumors range in size with a mean size close to 10 cm (Oliva et al. 2014) Macroscopically the lesions vary from predominately cystic to predominately solid. The cut surface is typically tan-yellow with areas of hemorrhage and/or necrosis. Microscopically the tumor appears similar to its uterine counterpart and consists of sheets of small, closely packed cells resembling proliferative phase endometrial stroma (Figs. 1 and 2). Mitotic figures are variable and the vasculature seen is similar to that described in uterine endometrial stroma sarcomas (see chapter “Mesenchymal Tumors of the Uterus”). In some cases sex-cord differentiation and smooth muscle metaplasia have been identified. In the majority of reported cases, intermixed endometriosis has been identified suggesting the tumor arises from endometriosis rather than ovarian stroma. Immunohistochemically these tumors tend to exhibit strong and diffuse positivity for CD10. Further like in the uterine counterpart, JAZF1-SUZ12 gene fusions and PHF1 have been detected in some of these tumors (Amador-Ortiz et al. 2011; Chiang et al. 2011).
Fig. 1

Low grade endometroid stromal sarcoma (low power)

Fig. 2

Low grade endometroid stromal sarcoma (high power)

The differential diagnosis of these lesions consists of metastatic lesions, sex cord stromal tumors and other less common entities. Endometrioid stromal sarcomas are for the most part considered primary to the ovary if the uterus is uninvolved after extensive evaluation, the largest mass is in the ovary, and presentation is similar to ovarian cancer (Oliva et al. 2014). Besides metastatic endometrial stromal sarcoma from the uterus, metastatic gastrointestinal stromal tumors (GIST) should enter the differential diagnosis as these tumors tend to occur in similar aged patients. Histologically metastatic GISTs are more likely to show nuclear palisading and the absence of the typical vasculature seen in LGESS. Further, immunohistochemical stains should help to evaluate this differential as GISTS should show positivity for c-kit, DOG-1 and/or CD34.

Myxoma

Primary myxoma of the ovary is a very rare neoplasm: only a very small number of cases have been reported in the literature (Brady et al. 1987; Eichhorn and Scully 1991; Scully et al. 1998; Roth et al. 2013). The patients were aged 12–80 years, with only one being regarded as post-menopausal. In each case the adnexal mass was unilateral (Brady et al. 1987; Eichhorn and Scully 1991; Scully et al. 1998; Roth et al. 2013). Macroscopically, the tumors measured from 3.5 to 22 cm in greatest dimension (Eichhorn and Scully 1991; Scully et al. 1998; Roth et al. 2013; Dutz and Stout 1961). The tumors were described as encapsulated, gray-white, and soft; on cut section, they were found to be partly cystic. Solid areas were slimy and mucinous, whereas the cystic spaces contained a viscous, glassy, gelatinous material.

Microscopically, the tumors showed the typical appearance of myxomas seen in other locations. They were composed of loose myxomatous stroma within which there were scattered stellate or spindle-shaped cells, some of which contained hyperchromatic nuclei. There was no nuclear pleomorphism, and mitotic activity was absent. The tumors varied from poorly vascularized, containing only a few capillary blood vessels and showing absence of plexiform vessels, to tumors with prominent capillary vessels within the tumor, and larger vessels with muscular walls at its periphery. The myxomatous stroma stained positively with alcian-blue stain and contained a network of fine reticulum fibers. Stains for fat were negative. In some areas, fibrosis was present. There were no other connective tissue elements, and the tumors had a homogeneous appearance. Myxoma is immunoreactive for vimentin and focally for actin, but negative for desmin, inhibin cytokeratins, vascular markers, S-100, and neurofilaments (Eichhorn and Scully 1991; Roth et al. 2013; Costa et al. 1993).

In a relatively recent review of ovarian myxomas, three ovarian myxoma cases were noted to have occurred within ovaries also containing additional sex cord stromal tumors (Roth et al. 2013). Two cases showed a sclerosing stromal tumor, whereas the other showed a luteinized theca cell tumor. This led the authors to speculate as to whether these ovarian myxomas arose from the other stromal lesions, suggesting two distinct pathways for the development of ovarian myxoma, one from ovarian myxoid connective tissue and the other from other sex cord stromal neoplasms (Roth et al. 2013). The authors advocate for mentioning a myxomatous component if it is distinct and measures >1 cm in greatest (Roth et al. 2013). More research is needed to further investigate the various origins of these tumors.

Although myxoma is considered a benign neoplasm, because of its viscous nature it is difficult to excise it completely, and recurrences are not uncommon unless the entire adnexa bearing the tumor are excised. All the known patients treated by unilateral adnexectomy, in which the diagnosis of myxoma was confirmed, and for whom there is follow-up information are free of disease after 1–21 years (Roth et al. 2013; Costa et al. 1993).

The differential diagnosis for an ovarian myxoma is broad. Most importantly myxomas must be distinguished from sarcomas, including myxoid liposarcoma and embryonal rhabdomyosarcoma. Myxoid liposarcoma which contains fat, is more vascularized, and shows lipoblasts at least in some areas. Embryonal rhabdomyosarcoma shows less of a uniform appearance, displays greater cellular and nuclear pleomorphism, and contains rhabdomyoblasts. In addition, embryonal rhabdomyosarcoma shows immunohistochemical staining for muscle-specific actin, desmin, and myogenin. Even focal atypia should raise suspicious for a low grade sarcoma and the differential should be investigated.

The differential diagnosis for myxoma also contains various benign entities. These include fibroma with myxoid degeneration, which contains normal fibrous tissue in some areas, and massive edema of the ovary (see chapter “Nonneoplastic Lesions of the Ovary”) (Young and Scully 1984; Kalstone et al. 1969). The patients with massive edema usually are younger, and the lesion shows entrapment of follicular derivatives, which is not observed in ovarian myxoma. Lastly, myxoma must be differentiated from mucinous cystadenomas and carcinomas, either primary or metastatic, which contain epithelial cells, show absence of stellate and spindle-shaped cells, and may show glandular differentiation. Cytokeratin stains should help with this diagnosis.

Undifferentiated Sarcoma

Some ovarian tumors are poorly differentiated, and although a diagnosis of sarcoma can be made, the tumor does not exhibit further differentiation beyond showing its mesenchymal origin. Careful and extensive gross sampling and histologic examination in such cases are helpful and may result in finding better-differentiated areas, which will yield a more accurate diagnosis. Immunohistochemical investigations may be very helpful in accurately detecting the tissue of origin and should be undertaken in all such cases. In some cases, a more precise diagnosis cannot be made despite very extensive investigations.

Tumors of Muscle Differentiation

Leiomyoma

Primary leiomyoma of the ovary is uncommon (Scully et al. 1998; Doss et al. 1999; Kandalaft and Esteban 1992; Lerwill et al. 2004; Prayson and Hart 1992). A small number of cases are on record, but it is likely that many cases are not reported, especially when the tumor is small and is discovered incidentally. Primary ovarian leiomyoma probably originates from smooth muscle present in the walls of blood vessels in the cortical stroma, in the corpus luteum, and in the ovarian ligaments at their point of attachment to the ovary; its precise histogenesis is uncertain, however. This tumor usually is found in menopausal and postmenopausal women, but sometimes occurs in young women. The age of patients ranged from 3 to 65 years. Clinically, many patients are asymptomatic, and the tumor is discovered incidentally. When symptoms are present, they are related to the presence of an adnexal mass, often accompanied by abdominal swelling and pain. The latter may be acute because of torsion. Ascites is rare, and hydrothorax has not been reported. The uterus usually contains leiomyomas.

Ovarian leiomyoma is usually unilateral, although a single case of large bilateral ovarian leiomyomas occurring in a 21-year-old woman has been reported (Kandalaft and Esteban 1992). Macroscopically the tumors are solid, firm, and round or oval masses having a smooth surface. On cut section they have a white or gray-white solid whorled surface.. Cyst Coagulative type necrosis should not be identified. Microscopically, the tumor shows typical appearances of a leiomyoma, as observed in the uterus, the tumor being composed of smooth muscle cells that are uniformly spindle-shaped or elongated and contain elongated blunt-ended or cigar-shaped nuclei (Fig. 3). Palisading of the nuclei may be present and may be prominent. Mitotic activity is absent or very low, and cellular and nuclear pleomorphism is not a feature. Most leiomyomas are of the typical type, but cellular, mitotically active, myxoid, epithelioid types and other subtypes can be seen. The tumor cells form bundles intersected by fibrous septa that may be wide and show marked hyalinization. Other degenerative changes seen in uterine leiomyomas also may be present. Occasionally a leiomyoma may show an epithelioid pattern, which may cause some diagnostic problems. Immunohistochemical expression of smooth muscle actin, muscle-specific actin, desmin, ER, and PR can be seen. In four tumors that we have studied, this was further confirmed ultrastructurally.
Fig. 3

Primary leiomyoma of the ovary. The tumor shows an appearance similar to the much more common uterine leiomyoma

A well-documented case of a large ovarian lipoleiomyoma occurring in a 63-year-old woman has been reported (Mira 1991). The tumor replaced nearly the entire ovary. The adipose tissue was found replacing and dissecting the smooth muscle within the tumor. There was no associated uterine leiomyomatosis.

Primary ovarian leiomyoma must be differentiated from pedunculated subserosal (parasitic) uterine leiomyoma, which has lost its attachment and instead has become attached to the ovary, from which it draws its blood supply. Leiomyoma also must be differentiated from ovarian fibroma as the latter is much more common. There is a tendency to diagnose leiomyoma as a fibroma, but use of immunohistochemical stains for this distinction should be used with caution since fibromas can also show expression of muscle markers (Costa et al. 1993; Tiltman and Haffajee 1999). The treatment is excision of the affected adnexa.

Leiomyosarcoma

Primary leiomyosarcoma of the ovary is very rare. These tumors usually are found in postmenopausal women, but sometimes may be seen in younger women (Lerwill et al. 2004; Vijaya Kumar et al. 2015; Balaton et al. 1987). The tumors usually are large and solid, and patients have symptoms and signs related to the presence of an abdominal or pelvic mass. The tumors are gray-yellow, soft, fleshy, and frequently associated with hemorrhage and necrosis.

Microscopically, they differ from a leiomyoma by the presence of a variable combination of mitotic activity, cellular and nuclear pleomorphism, and necrosis (Figs. 4 and 5). It has been proposed that leiomyosarcoma should be diagnosed when ≥2 of the following histologic features are present: significant nuclear atypia, mitotic index ≥10 mitotic figures/10 high-power fields, and tumor cell necrosis; it has also been suggested that a smooth muscle tumor with nuclear atypia can qualify as a leiomyosarcoma if the mitotic index is ≥5 mitotic figures/10 high-power fields, even if tumor cell necrosis is not present (Lerwill et al. 2004). The diagnosis of “smooth muscle tumor of uncertain malignant potential” can be used for tumors with histologic features intermediate between leiomyoma and leiomyosarcoma.
Fig. 4

Primary leiomyosarcoma of the ovary. Low magnification. Note the similarity to the leiomyoma seen in Fig. 3

Fig. 5

Primary leiomyosarcoma of the ovary. High magnification. Note the marked cellular and nuclear pleomorphism

Most leiomyosarcomas are of the conventional type, but occasional ovarian leiomyosarcomas may be of the myxoid or epithelioid type. It is important to recognize these unusual variants, which are similar to their counterparts in the uterus. Primary leiomyosarcoma of the ovary metastasizes via the bloodstream; the prognosis is generally unfavorable. Primary leiomyosarcoma of the ovary must be distinguished from carcinosarcomas containing a prominent leiomyosarcomatous component. Primary leiomyosarcoma also should be distinguished from immature teratoma with a prominent leiomymatous tissue component. It also must be distinguished from metastatic leiomyosarcoma of uterine or other origin, as well as from poorly differentiated sarcomas and carcinosarcomas, both primary and metastatic to the ovary.

Rhabdomyoma

No well-documented case of pure ovarian rhabdomyoma has been recorded. A case of mural nodules of rhabdomyoma within a serous cystadenoma in a 48 year old has been reported (Huang et al. 2005).

Rhabdomyosarcoma

Primary rhabdomyosarcoma of the ovary is uncommon. A small number of cases have been reported in the literature. A careful review of the literature shows that some cases, such as the frequently quoted case reported by Sandison (1955), were not pure rhabdomyosarcomas but rather examples of carcinosarcoma or teratomas with a marked rhabdomyoblastic component. Therefore, before a diagnosis of primary ovarian rhabdomyosarcoma can be made, the tumor must be sampled carefully and extensively to exclude the presence of other neoplastic elements, the presence of which would preclude a diagnosis of a pure rhabdomyosarcoma of the ovary.

The diagnosis of an embryonal rhabdomyosarcoma in a young patient should raise consideration for DICER1 syndrome as these tumors may be a manifestation of this syndrome (Stewart et al. 2016; de Kock et al. 2015).

The histogenesis of primary rhabdomyosarcoma of the ovary is uncertain. These tumors may originate from the connective tissue of the ovary, as a one-sided development of a teratoma, as a result of malignant transformation of a mature cystic teratoma with the malignant element overgrowing the tumor, or as a one-sided development of a carcinosarcoma.

The age of patients with ovarian rhabdomyosarcoma ranged from 2.5 to 84 years. The small number of cases makes it impossible to state whether there is a predilection for any particular age group, but, as with rhabdomyosarcomas occurring in other locations, the pleomorphic type occurs in older patients, whereas the embryonal and alveolar types occur in young women and children (Chan et al. 1989). Patients with ovarian rhabdomyosarcoma usually have symptoms associated with the presence of a large, usually rapidly growing, abdominal mass, often associated with hemorrhagic ascites. Metastases frequently are seen at presentation.

Macroscopically, the tumors are unilateral, but metastatic involvement of the contralateral ovary may be present and should be differentiated from bilateral involvement. The tumors usually are large, exceeding 10 cm in diameter. They are solid, soft, fleshy, and gray-pink to yellow-tan, with areas of hemorrhage and necrosis that may be prominent.

Microscopically, the tumors may be of the embryonal (including the botryoid type), alveolar, or pleomorphic type and contain variable numbers of rhabdomyoblasts (Figs. 6, 7, and 8). Tumors composed of the former types occur in children and young adults, whereas those of the pleomorphic type are observed in older women. The diagnosis of pleomorphic rhabdomyosarcoma should not present undue difficulty, because of the presence of at least some typical rhabdomyoblasts showing cross-striations. In cases of embryonal rhabdomyosarcoma, the diagnosis is much more difficult because the tumor cells are poorly differentiated, making rhabdomyoblastic differentiation discernible only with difficulty. Furthermore, it is necessary to recognize the distinctive alveolar or botryoid patterns, which also may not be easy.
Fig. 6

Primary rhabdomyosarcoma of the ovary. This portion of the tumor contains a significant spindle cell component

Fig. 7

Primary rhabdomyosarcoma of the ovary. Distinctive cross-striations are seen (arrow)

Fig. 8

Primary rhabdomyosarcoma of the ovary. The tumor contains abundant rhabdomyoblasts, each of which have an ample amount of bright eosinophilic cytoplasm and eccentric nuclei

The embryonal rhabdomyosarcoma is composed of small round primitive cells having a narrow rim of cytoplasm. They are poorly differentiated rhabdomyoblasts in various stages of differentiation. Therefore, the lesion is difficult to distinguish from poorly differentiated small cell carcinoma, lymphoma/leukemia, or even neuroblastoma (Scully et al. 1998; Nielsen et al. 1998; Nunez et al. 1983). Among the small round cells are scattered occasional rhabdomyoblasts, which are better-differentiated large cells with bright eosinophilic cytoplasm and eccentric nuclei (Fig. 8). Presence of these cells and their recognition may provide a diagnostic clue. Occasionally, large, more typical rhabdomyoblasts may be seen. The presence of cross-striations is not necessary for diagnosis, but the cells comprising the tumor may be well-enough differentiated to exhibit cross-striations (Fig. 7). Demonstration of Z bands or their precursors by electron microscopy is helpful in making the diagnosis. Immunohistochemical demonstration of myoglobin, desmin, muscle-specific actin, and myogenin are helpful in this respect (Fig. 9). The tumor is frequently affected by edema, hemorrhage, and necrosis, making the diagnosis even more difficult. Therefore, thorough examination and sampling of the tumor are essential to make the correct diagnosis. The tumor may be more common than has been hitherto believed, but because of its poor differentiation, it may have been either assigned to the group of undifferentiated ovarian tumors or misdiagnosed. In some cases, the tumor infiltrated the bone marrow and was originally diagnosed as leukemia (Nunez et al. 1983). It is therefore emphasized that embryonal rhabdomyosarcoma must be considered in the differential diagnosis of undifferentiated small round cell tumor of the ovary in a young patient. The presence of other neoplastic elements always must be excluded when making this diagnosis.
Fig. 9

Primary rhabdomyosarcoma of the ovary showing diffuse expression of myogenin

The importance of making the correct diagnosis is not only academic but practical, in view of the advances that have been made in the therapy of embryonal rhabdomyosarcoma during the past few decades. In the past, the prognosis was poor, and in most reported cases, the patients died of extensive metastatic disease within 1 year of diagnosis. Recently, patients with embryonal rhabdomyosarcoma, some of whom had metastases, are well and disease-free after surgery, chemotherapy, and radiotherapy.

Myofibroblastoma

A well-documented case of an ovarian myofibroblastoma has been reported recently (Rhoades et al. 1999). A 22-year-old woman who was involved in an automobile accident was found to have an enlarged right ovary but refused laparotomy. Over the next 3 years the mass gradually increased in size, and laparotomy was performed. A 9 × 8.5 × 6 cm, right-sided ovarian tumor weighing 215 g and adherent to the right fallopian tube and omentum was found and excised. The tumor was solid, white-tan, and on sectioning revealed whorled areas and focal calcification. Microscopically, it was composed of uniform bland-looking spindle cells arranged haphazardly in fascicles separated by bands of hyalinized collagen. In some areas there was increased vascularity. There was no atypia or mitotic activity. The tumor cells showed vimentin, smooth muscle actin, and muscle-specific actin positivity. There was no immunoreactivity with desmin and cytokeratin. The patient was well and disease-free 21 months after treatment. Myofibroblastoma is a benign lesion, and complete excision results in cure.

Tumors of Vascular and Lymphatic Differentiation

Hemangioma

Hemangiomas, cavernous type, capillary type and anatomosing type, are found only occasionally in the ovary with less than 100 cases reported in the literature (Ziari and Alizadeh 2016; Lawhead et al. 1985; Talerman 1967; Dundr et al. 2017) Rare patients with this lesion present with clinical findings suspicious for a malignant process (Schoolmeester et al. 2015). The origin of ovarian hemangioma, in common with hemangioma in general, is a matter of controversy; it is considered either a hamartomatous malformation or a true neoplasm. It is likely that both modes of origin are responsible for their formation. The reported age of patients with ovarian hemangioma ranges from 4 months to 81 years (Ziari and Alizadeh 2016), and does not show a predominance in any decade. In most patients, ovarian hemangioma has been noted as an incidental finding at operation or autopsy (Talerman 1967). In a few cases, the lesion was large and the patient had abdominal enlargement because of the presence of an ovarian mass (Gehrig et al. 2000; Mann and Metrick 1961; Mc and Trumbull 1955) or had acute abdominal pain associated with torsion of the tumor (Mann and Metrick 1961; Shaffer and Cancelmo 1939). In some cases, there was ascites, which resolved following removal of the lesion (Gehrig et al. 2000; Mc and Trumbull 1955; Savargaonkar et al. 1994). The lesions usually are unilateral, although in four patients they were bilateral (Talerman 1967). Ovarian hemangiomas have been noted in patients with generalized hemangiomatosis (Lawhead et al. 1985) and in patients with hemangiomas in other parts of the genital tract (Lawhead et al. 1985; Talerman 1967). Further, ovarian hemangiomas have also been linked to various syndromes including Kasabach-Merritt syndrome and pseudo-Meigs syndrome and have also been seen patient’s with elevated CA-125 (Schoolmeester et al. 2015).

Macroscopically, the lesions are small, red or purple, round or oval nodules, measuring from a few millimeters to 24 cm in diameter. On cut section, they usually are spongy and show a honeycomb appearance. Although they have been found in different parts of the ovary, the medulla and the hilar region appear to be the most common sites (Talerman 1967).

Microscopically, ovarian hemangioma is of the cavernous, mixed capillary-cavernous type or anastomosing type. Generally, hemangiomas consist of collections of vascular spaces, which may vary in size but usually are small, lined by a single layer of endothelial cells, and usually contain red blood cells in their lumens (Fig. 10). The anastomosing hemangioma, which has been recently described in the ovary, consists of a non-lobular vascular proliferation of capillary sized vessels which are usually intermixed with a larger vessel (Dundr et al. 2017; Kryvenko et al. 2011). Occasionally, in hemangiomas thrombosis may be seen. In a few reported cases, the hemangioma was associated with the presence of luteinized cells in the stroma of the lesion. In one such case, there was evidence of hormonal function (Savargaonkar et al. 1994).
Fig. 10

Hemangioma of the ovary. The tumor is composed of numerous small blood vessels, some of which contain red blood cells in their lumens

Hemangioma must be differentiated from proliferations of dilated blood vessels, frequently seen in the hilar region of the ovary. Although a very small hemangioma may not be easily distinguished from such vascular proliferations, the hemangioma usually forms a nodule or a small mass. The presence of a circumscribed nodule composed of vascular spaces tends to distinguish hemangioma from vascular proliferations, which usually are smaller and more diffuse. The presence of numerous blood cells within the vascular spaces and the absence of pale eosinophilic homogeneous material usually distinguish hemangioma from the less common lymphangioma, but immunohistochemical stains including CD31, CD34, ERG, and FLI-1 can also be used (Schoolmeester et al. 2015). Hemangioma also must be distinguished from teratoma with a prominent vascular component. In such cases, careful sampling will detect other teratomatous elements, the presence of which distinguishes the lesion from a hemangioma. The differential diagnosis for hemangiomas of the ovary, especially anastomosing hemangiomas, also includes well differentiated angiosarcoma and Kaposi sarcoma. Unlike these two malignant entities, hemangiomas lack cytologic atypia and tend to be small and somewhat lobulated (Kryvenko et al. 2011).

The treatment of choice is oophorectomy.

Angiosarcoma

Angiosarcoma is a very rare ovarian neoplasm (Scully et al. 1998; Nielsen et al. 1997; Nucci et al. 1998; Kruse et al. 2014; Yaqoob et al. 2014). In some reported cases, the angiosarcoma had arisen within a mature cystic teratoma or may have been associated with an immature teratoma. Such cases are considered as germ cell tumors and are excluded from consideration here. The age of the patients with angiosarcoma varied from 19 to 77 years. The tumor usually is unilateral, but bilateral tumors have been recorded. Bilaterality must be differentiated from metastatic spread to the contralateral ovary. The histogenesis of primary ovarian angiosarcoma is uncertain. It may originate from the vascular tissue present in the ovary, as a one-sided development of a teratoma, or from a teratoma in which the vascular component has overgrown the other parts of the tumor. Patients usually have symptoms related to the presence of a lower abdominal mass, which may be associated with torsion and rupture of the tumor and hemorrhage.

Macroscopically, the tumors usually are large, blue-brown, hemorrhagic, soft, and friable. They may be confined to the ovary, but often are associated with invasion of the surrounding structures.

Microscopically, they are composed of vascular spaces of varying size and appearance, lined by endothelial cells that usually are large, showing atypical appearance, bizarre nuclei, and mitotic activity (Figs. 11 and 12). In some areas, the tumor may contain a considerable amount of connective tissue interspersed between the vascular spaces. Fine papillary projections lined by atypical endothelial cells may be seen and are prominent. Some tumors are composed of small closely packed spaces lined by atypical cells with a suggestion of a solid pattern (Nucci et al. 1998).
Fig. 11

Primary angiosarcoma of ovary. The tumor contains closely packed vessels forming a solid spindle cell pattern (top). More typical vascular pattern is seen below

Fig. 12

Primary angiosarcoma of ovary. The tumor is composed of dilated vascular spaces lined by enlarged hyperchromatic cells

Angiosarcoma of the ovary must be distinguished from immature teratomatous neoplasms with a prominent vascular component. The presence of other neoplastic germ cell elements distinguishes teratoma from primary angiosarcoma. Immunohistochemical stains for CD31, CD34, and ERG are useful in confirming the diagnosis of angiosarcoma when the tumor is poorly differentiated, especially when showing a solid pattern.

The tumor invades locally and metastasizes via the bloodstream. Prognosis is poor, especially in patients who have metastases at the time of presentation. When the tumor is confined to the ovary, the prognosis is better and a few survivors have been reported. Recent studies have shown some improved survival with adjuvant chemotherapy (Kruse et al. 2014).

Lymphangioma

Lymphangioma of the ovary is very rare (Singer et al. 2010; Radhouane et al. 2016). The tumors tend to be small and found incidentally. They are slow growing and often remain asymptomatic for a long time. The tumor is usually unilateral but bilateral lesions have been reported. Macroscopically, the tumor is small with a smooth, gray surface. On cut section, it is yellow, honeycombed, and composed of numerous small cystic spaces exuding clear yellow fluid.

Microscopically, lymphangioma of the ovary is composed of closely packed, thin-walled vascular spaces lined by flattened endothelial cells and containing pale, homogeneous eosinophilic fluid (Fig. 13). Lymphocytes may be seen within the vascular spaces. The histogenesis is a matter of controversy. Some investigators consider these lesions as malformations and some as neoplasms. Both modes of histogenesis are likely.
Fig. 13

Primary ovarian lymphangioma. The tumor is composed of large and closely packed thin-walled lymphatic spaces lined by flattened endothelial cells and contains pale eosinophilic fluid

Lymphangioma is differentiated from a teratoma with a prominent vascular component by the absence of other germ cell elements. Lymphangioma also must be distinguished from hemangioma and an adenomatoid tumor that contains thin-walled, vessel-like spaces. In contrast to hemangioma, lymphangioma does not contain blood cells in the vascular spaces and shows D2–40 staining. Adenomatoid tumor has solid areas, and the cells lining the vessel-like spaces show immunohistochemical expression of cytokeratin and calretinin.

Tumors of Cartilage Differentiation

Chondroma

Only a few reports of ovarian chondroma are available, and documentation in most cases is unsatisfactory. One well-documented case considered to originate from the ovarian stroma has been reported (Nogales 1982). The tumor, which measured 4 × 3 × 3 cm and was composed entirely of mature cartilage, was found incidentally. Although chondroma may originate from the connective tissue of the ovary by a process of metaplasia, it is more likely that most ovarian tumors described as chondroma were either fibromas showing cartilaginous metaplasia or teratomas having a prominent cartilaginous component.

Chondrosarcoma

Pure chondrosarcoma of the ovary (Figs. 14 and 15) is rare. In one report (Talerman et al. 1981), a 61-year-old woman had an abdominal mass that on extensive microscopic examination proved to be a pure, well-differentiated chondrosarcoma. The patient was well and disease-free 6 years after one-sided oophorectomy. The histogenesis of this tumor is uncertain, but the age of the patient and the histologic appearances of the tumor point to an origin in a dermoid cyst with malignant transformation and overgrowth by the malignant cartilaginous component (Talerman et al. 1981). Well-documented cases of mature cystic teratoma (dermoid cyst) with malignant transformation of the cartilaginous element have been reported (Yasunaga et al. 2011; Climie and Heath 1968). In malignant ovarian tumors with cartilaginous differentiation, additional sampling is recommended in order to exclude a teratomatous background or a carcinosarcoma.
Fig. 14

Primary ovarian chondrosarcoma. Low magnification

Fig. 15

Primary ovarian chondrosarcoma. Marked nuclear atypia

Tumors of Bone Differentiation

Osteoma

Few documented examples of osteoma occurring in the ovary exist. Although an origin from ovarian stroma is possible, most such lesions probably were examples of osseous metaplasia occurring in fibromas or leiomyomas, or possibly examples of metaplasia or heterotopia and not neoplasia occurring in the connective tissue of the ovary. Teratomatous origin is also possible. The lesions usually are small, but may be large, and are histologically composed of dense cortical bone.

Osteosarcoma

Few cases of pure extraskeletal osteosarcoma of the ovary have been reported. Patients range in age from 24 to 76 years (Lacoste et al. 2015). The tumor is frequently associated with extensive metastatic disease. Survival is poor. In one case metastatic tumor deposits affecting the abdominal cavity were excised at operation, and the patient was treated with triple chemotherapy consisting of cyclophosphamide, mitomycin C, and bleomycin (Hirakawa et al. 1988). The tumor recurred, and cisplatin and doxorubicin were added to the chemotherapeutic regimen. In spite of this, the tumor progressed and the patient died 8 months after diagnosis. Currently, only two patients have been reported as long term survivors (greater than 3 years disease free). Both received doxorubicin and cisplatin after complete surgical resection (Lacoste et al. 2015).

Histologically, the tumors show typical appearances of osteosarcoma occurring in the skeleton. Although it was believed that the tumors originated directly from ovarian stroma, their histogenesis is uncertain. Occasional cases of osteosarcoma originating in ovarian teratoma have been recorded (Stowe and Watt 1952), but such cases should not be confused with pure ovarian osteosarcoma or with cases of carcinosarcoma with a prominent osteosarcomatous component.

Tumors of Neural Differentiation

Ovarian tumors originating from neural tissue are rare. The presenting symptoms usually are related to the presence of an intraabdominal mass. The tumors are solid and usually are small. The histogenesis is uncertain and probably is similar to that of other mesenchymal tumors of the ovary.

Neurofibroma

Several cases of neurofibroma of the ovary have been reported in patients with generalized neurofibromatosis (von Recklinghausen’s disease) (Hegg and Flint 1990; Smith 1931; Protopapas et al. 2011). Histologically, the tumors resembled neurofibroma occurring elsewhere.

Schwannoma (Neurilemmoma)

Three cases of ovarian schwannoma have been reported (Meyer 1943; Mishura 1963). In one case, the tumor was large (Mishura 1963). The tumors were solid, and the patients were well and disease-free after the excision of the tumor. Histologically, the tumors resembled schwannoma occurring in other locations.

Malignant Peripheral Nerve Sheath Tumor

One case of “malignant neurilemmoma” (malignant schwannoma) of the ovary has been reported (Stone et al. 1986). The affected patient, a 71-year-old nulliparous woman, was admitted for evaluation of lower abdominal enlargement and pain. There were no stigmata of generalized neurofibromatosis. At laparotomy, a 15 cm, firm, somewhat hemorrhagic tumor was found arising from the left ovary. There were numerous tumor deposits involving the peritoneal cavity. A debulking procedure was performed, and the ovarian tumor was excised together with the omentum. Histologic and ultrastructural examinations revealed that the tumor was a malignant neurilemmoma. After surgery, the patient was treated with combination chemotherapy consisting of doxorubicin and cyclophosphamide, but the disease progressed and she died 5 months after surgery of extensive intraabdominal metastatic disease (Stone et al. 1986). One case of “neurofibrosarcoma” occurring in a 38-year-old woman with generalized neurofibromatosis (von Recklinghausen’s disease) has been described (Dover 1950). The tumor was an incidental finding and had replaced the ovary. It was solid, and histologically showed the typical appearance of a neurofibrosarcoma with a moderate degree of nuclear pleomorphism and mitotic activity. There was no evidence of metastases, and the patient was well and disease-free 1 year after diagnosis (Dover 1950). A malignant epithelioid schwannoma of the ovary has been reported (Laszlo et al. 2006).

Paraganglioma

Paraganglioma (extra-adrenal pheochromocytoma) of the ovary is rare with very few cases reported in the literature. Several patients presented with hypertension. The lesions usually follow a benign course (Schuldt et al. 2015). In a report of three cases, patients ranged in age from 22 to 68 years (McCluggage and Young 2006); however a younger patient aged 15 was described in a separate report (Fawcett and Kimbell 1971). Tumors are characterized by the “zellballen” growth pattern seen in primary non-ovarian paragangliomas. With immunohistochemical stains, tumors are positive for neuroendocrine markers and negative for cytokeratin. Sustentacular cells can show expression of S-100. It should be noted that inhibin expression has been observed, which may create diagnostic confusion if a sex cord–stromal tumor, especially a Sertoli cell tumor, is in the differential diagnosis.

Ganglioneuroma

A single case of ovarian ganglioneuroma occurring in a 4-year-old girl has been reported (Schmeisser and Anderson 1938). The child had abdominal enlargement. The tumor was solid, weighing 200 g, and replaced nearly the whole ovary. Histologically, the tumor was composed of well-differentiated ganglion cells. There was a recurrence after the excision of the tumor. True ganglioneuroma must be differentiated from teratomas showing prominence of ganglion cells and from proliferations of ganglion cells occasionally seen in the hilar region of the ovary; the latter are nonneoplastic and probably hamartomatous in nature. However, ganglioneuroma has been reported as arising from a teratoma (Coy et al. 2018).

Tumors of Adipose Tissue Differentiation

Collections of adipose cells forming islands of fatty tissue that are not encapsulated are seen occasionally within ovarian tissue and are attributed to metaplasia of connective tissue of the ovary. These collections have been described as adipose prosoplasia. Benign adipose tissue seen in the ovary may be part of a teratoma with a prominent adipose tissue component. Pure benign fatty tumors in the ovary are very rare. A single case of a pure lipoma has been reported (Zwiesler et al. 2008). Malignant adipose tissue may be part of a carcinosarcoma with a prominent liposarcomatous component, or it may represent metastases from a liposarcoma occurring at another location. Rare myxoid liposarcomas have been reported in the ovary (Liang et al. 2015; Tirabosco et al. 2010).

Tumors of Mesothelial Differentiation

Adenomatoid Tumor

Adenomatoid tumor, which in females is found most frequently in the fallopian tubes and broad ligament and occasionally in the uterus near the serosal surface, is found only rarely in the ovary (see chapters “Mesenchymal Tumors of the Uterus” and “Diseases of the Fallopian Tube and Paratubal Region”). Although its histogenesis was long disputed, it is now considered to be of mesothelial origin, as is supported by morphologic, histochemical, immunohistochemical, and ultrastructural observations. Adenomatoid tumorsare benign and, therefore, are considered a benign mesothelioma.

Few cases of ovarian adenomatoid tumor have been recorded, most of which occurred in patients in the third and fourth decades (Scully et al. 1998; Young et al. 1991; Phillips et al. 2007). The lesions, which are small, round or oval, and 0.5–3 cm in diameter, usually are found in the hilus of the ovary as incidental findings. In two cases the tumors were larger, measuring 6 and 8 cm in the longest diameter, respectively, and were symptomatic.

Histologically, the tumors show similar appearances to adenomatoid tumors occurring in other locations and are composed of clefts and spaces lined by cuboidal, low columnar, or flattened epithelial-like cells (Fig. 16) and of solid aggregates of similar cells surrounded by connective tissue that varies from loose and edematous to dense and hyalinized. The epithelial-like cells may exhibit marked vacuolation. An oxyphilic variant has been described (Phillips et al. 2007). They exhibit positive staining with alcian blue, which is digestible with hyaluronidase, and similarly staining material is present in the clefts and spaces. Occasionally, the cells may show weak PAS staining. The tumor cells show strong positive immunohistochemical staining for low molecular weight cytokeratin, WT-1, calretinin, and D2-40. ER, PR, and Ber-EP4 are negative. Ultrastructural observations support the mesothelial origin of this lesion and show an abundance of microvilli, bundles of cytoplasmic filaments, tight junctional complexes, and intercellular spaces. The lesion is benign, and its excision results in a complete cure.
Fig. 16

Adenomatoid tumor. The tumor has numerous clefts and small round spaces lined by a single layer of flattened cells

The differential diagnosis for adenomatoid tumor in the ovary can be broad. Adenomatoid tumor may be confused with yolk sac tumor (YST) because the clefts and spaces may resemble the microcystic pattern of YST, but the nuclear appearances are totally different. The nuclei of adenomatoid tumor are bland and generally small and flattened, differing from the larger round and ovoid vesicular nuclei of YST, which exhibit brisk mitotic activity. The absence of other patterns associated with YST helps to distinguish adenomatoid tumor from YST. Lymphangioma may simulate adenomatoid tumor. Immunohistochemical studies can be helpful in differentiating between these two entities. Lymphangioma is low molecular weight cytokeratin negative, whereas adenomatoid tumor is strongly positive. Vascular markers such as factor VIII, CD34, and CD31 show negative reactions with adenomatoid tumor and positive staining with lymphangioma. Calretinin and WT-1 are also expressed in adenomatoid tumor but negative in lymph-vascular tumors.

Peritoneal Malignant Mesothelioma

Occasionally, peritoneal mesothelioma may involve the surface of the ovary (see chapter “Diseases of the Peritoneum”). When the tumor affects the ovary, confusion with primary ovarian neoplasms (serous borderline tumor with implants, low-grade serous carcinoma, and high-grade serous carcinoma) or benign conditions may occur (Talerman et al. 1985). The involvement of the ovary may be very extensive, and the presentation is that of a primary ovarian neoplasm. In one series of nine malignant peritoneal mesotheliomas presenting as ovarian masses, two tumors were considered as primary ovarian malignant mesotheliomas because the tumors were confined to the ovary (Scully et al. 1998; Clement et al. 1996). The histologic and immunohistochemical features, and distribution of the lesion are helpful in making the correct diagnosis (Scully et al. 1998; Talerman et al. 1985; Clement et al. 1996; Bollinger et al. 1989; Ordonez 1998; Vang and Ronnett 2009). Most patients with malignant peritoneal mesothelioma are middle-aged or elderly adults. Very rarely, it may occur in children (Talerman et al. 1985). The exact association with asbestos exposure is unclear.

Additionally, malignant mesothelioma should be distinguished from well-differentiated papillary mesothelioma, which also can involve the ovary.

Wolffian Tumor (Formally Known as Female Adnexal Tumor of Probable Wolffian Origin (FATWO))

In the original report describing tumors of this type (Kariminejad and Scully 1973), all the tumors were located within the leaves of the broad ligament or were attached to it or to the fallopian tube; this also applied to subsequent reports dealing with this entity. Subsequently, a small number of ovarian tumors of probable wolffian origin were reported (Devouassoux-Shisheboran et al. 1999; Hughesdon 1982; Young and Scully 1983), indicating that tumors of this type also occur in the ovary. In the 2014 WHO Classification Femael Adnexal Tumors of Probable Wolffian Origin (FATWO) are not classified as Wolffian tumors (Kurman 2014).

The age of most patients ranged from 28 to 79 years. Some patients had abdominal enlargement, and in other patients, the tumor was found on physical examination (Hughesdon 1982; Young and Scully 1983). All the tumors were unilateral. In most cases, they were confined to the ovary, but in one case metastatic deposits in the abdominal cavity were reported. In the latter case, the tumor contained foci of undifferentiated carcinoma (Young and Scully 1983). Most tumors ranged in size from 2 to 20 cm in the largest diameter. They are smooth and often lobulated and are either solid or solid and cystic. The cysts vary in size and may range up to 11 cm (Young and Scully 1983).

Microscopically, the tumor is composed of relatively uniform epithelial cells that line cysts and tubules, sometimes forming a sieve-like pattern. The tumor cells also may form closely packed tubules, grow in a diffuse pattern, or fill tubules or tubular spaces (Fig. 17). They have uniform round or oval nuclei, and there is low mitotic activity. The tumor cells do not contain mucin but occasionally may contain glycogen. The amount of intervening connective tissue varies from imperceptible to considerable, forming fibrous bands separating the islands of tumor cells and producing a lobular pattern (Young and Scully 1983). In two patients in whom the tumors were associated with aggressive behavior, there was brisk mitotic activity with 10 or more mitoses (MF)/10 high-power fields (HPF), and in one of these patients, there was nuclear pleomorphism. Details of immunohistochemistry can be found in chapter “Diseases of the Fallopian Tube and Paratubal Region”.
Fig. 17

Ovarian tumor of probable wolffian origin. The tumor is composed of closely packed tubules and clefts with adjacent solid patterns containing spindle cells

Two patients have subsequently developed metastases (Young and Scully 1983). Eight patients were known to be alive and disease-free from 1 to 15 years postoperatively, and one was lost to follow-up (Young and Scully 1983), indicating that in most cases the tumor is not associated with an aggressive course. It is also of note that there is a good correlation between the mitotic activity and the behavior of this neoplasm.

Wolffian tumors may be confused with sex cord–stromal tumors, especially various types of Sertoli–Leydig cell tumors and surface epithelial–stromal tumors (see chapter “Sex Cord-Stromal, Steroid Cell, and Other Ovarian Tumors with Endocrine, Paraendocrine, and Paraneoplastic Manifestations”). The presence of the typical features of this tumor described here and the absence of the various patterns observed in Sertoli–Leydig cell tumors differentiate it from the latter. Wolffian tumors with a prominent spindle cell component may mimic cellular fibroma (Fanghong et al. 2008). The Wolffian tumor is distinguished from the various surface epithelial–stromal tumors of the ovary by the absence of cellular and nuclear pleomorphism, papillary pattern, and intraluminal and intracellular mucin.

Lesions of the Rete Ovarii

Rete cysts/cystadenomas are uncommon, although probably more common than realized. The average age of patients with tumors of the rete ovarii is 59 years (range, 23–80 years). Patients can present with abdominal discomfort, pelvic pressure, virilization, postmenopausal bleeding, and/or hirsutism (Rutgers and Scully 1988). Most tumors are unilateral, and the average size is 9 cm. They may be uni- or multicystic, and the internal lining is usually smooth.

The rete lesions range in histologic type and include cyst, cystadenoma, adenoma, adenomatous hyperplasia, and adenocarcinoma (Rutgers and Scully 1988; Heatley 2000; Nogales et al. 1997). Most are cysts/cystadenomas. Rete lesions are either found within the ovarian hilus or are anatomically related to the rete ovarii. The distinction between cyst and cystadenoma is arbitrary, but an upper limit of 1 cm for cysts has been proposed. The epithelial lining of the rete cyst/cystadenoma is simple, non-ciliated, and bland and characterized by irregular crevices (Fig. 18). The periphery of rete adenoma is well circumscribed, and the tumor contains crowded tubules and papillae. The tubules and papillae have a simple layer of bland epithelial cells. Adenomatous hyperplasia is histologically similar to adenoma; however, the former is not well circumscribed.
Fig. 18

Rete cyst with cuboidal epithelium

Rete adenocarcinoma is rare and ill-defined. Only one well-documented case of adenocarcinoma of rete ovarii occurring in a 52-year-old woman with abdominal enlargement and ascites has been reported (Rutgers and Scully 1988). The patient had bilateral, partly solid and partly cystic tumors without specific macroscopic features. The tumor showed a predominant pattern of branching tubules and cysts containing simple papillae with fibrovascular or hyalinized cores. Some cysts contained eosinophilic material. Focally the tumor showed a solid tubular pattern. The cells lining the tubules and papillae were cuboidal, nonciliated, and atypical. Focally, they were multilayered and stratified. There was brisk mitotic activity. Adenocarcinoma of rete ovarii can only be diagnosed if the tumor is small enough to appreciate a hilar location and is composed of collections of slit-like retiform tubules and cysts containing papillae lined by cells similar to those of normal rete ovarii (Scully et al. 1998; Rutgers and Scully 1988).

Rete cysts/cystadenomas are benign. The data on adenoma and adenocarcinoma is limited; thus, the behavior of these lesions is uncertain.

The most common lesion to histologically mimic rete cystadenoma is serous cystadenoma, but this is not a clinically important distinction. Rete cystadenoma is favored based on location in the hilus or anatomic connection with the rete ovarii, cyst lining with crevice-like contours, absence of ciliated cells, and smooth muscle and hilus cells within the cyst wall. Confusion may occur with retiform Sertoli–Leydig cell tumor, but the latter is likely to show other patterns of Sertoli–Leydig cell tumor and stain positively for inhibin and SF-1. Some small serous carcinomas may also resemble adenocarcinoma of the rete ovarii, but they tend to be found in a cortical location, generally do not show the fine slit-like papillae, and exhibit much greater nuclear pleomorphism. Immunohistochemically, rete ovarii are positive for PAX-8, while negative for PAX-2 and GATA-3. SF-1 is noted to show weak diffuse nuclear staining. These stains may help to distinguish rete ovarii lesions from Wolffian tumors and sex cord stromal tumors; however, morphology is of the utmost importance especially with relation to lesions of mullerian origin (Goyal et al. 2016), and the immunophenotype of Wolffian tumors can be non-specific in some cases.

Primary Ovarian Tumors of Uncertain Histogenesis

Hepatoid Carcinoma

In 1987, Ishikura and Scully (1987) described five cases of ovarian carcinoma with hepatoid features, three of them primary and two probably primary. Since then, the number of cases reported in the literature still remains less than 50. The age of reported patients ranges from 35 to 78 years (Randolph et al. 2015) and, thus, differs considerably from patients with YST with a hepatoid pattern, which is usually seen in children, adolescents, and young women although yolk sac tumor can uncommonly arise in postmenopausal women. The age range as well as the histologic appearances of the tumors showed considerable similarity to gastric carcinomas with hepatic features described some years earlier (Ishikura et al. 1986). Unlike YST with a hepatoid pattern, which may be pure, mixed with other YST patterns, or combined with other germ cell tumors, hepatoid carcinoma of the ovary occurs in pure form, although occasionally it is associated with serous adenocarcinoma or other types of ovarian surface epithelial–stromal tumors (Scurry et al. 1996, 1998; Pitman et al. 2004; Tochigi et al. 2003). Hepatoid carcinoma of the ovary (Ishikura and Scully 1987; Pitman et al. 2004; Tochigi et al. 2003)], like YST with hepatoid pattern and gastric adenocarcinoma with hepatoid features (Ishikura et al. 1986), is associated with alpha-fetoprotein (AFP) secretion, and AFP can be demonstrated within the tumor cells by immunohistochemical techniques. In several cases, high levels of serum AFP were noted, and serum AFP was used to monitor the disease activity. Serum CA-125 also appears to be increased in patients (Randolph et al. 2015).

Clinically, patients present with symptoms and signs related to the presence of an adnexal mass. Abdominal enlargement, which may be associated with pain, malaise, and weight loss, is the main presenting sign (Ishikura and Scully 1987). In several cases the tumor was bilateral at presentation (Randolph et al. 2015).

Hepatoid carcinomas of the ovary are large and are associated with metastatic tumor deposits within the abdominal cavity (stage III) in most cases (Ishikura and Scully 1987). Histologically, the tumor shows a close resemblance to hepatocellular carcinoma (Fig. 19), and is composed of solid sheets or aggregates of uniform cells with moderate or abundant eosinophilic cytoplasm, distinct cell borders, and centrally located nuclei with prominent nucleoli (Ishikura and Scully 1987; Pitman et al. 2004; Tochigi et al. 2003). Mitotic activity generally is brisk, and abnormal forms are seen. In some parts of the tumor there may be a considerable degree of nuclear pleomorphism, and multinucleated giant cells may be seen (Ishikura and Scully 1987). PAS-positive diastase-resistant hyaline globules may be seen, and glycogen can be demonstrated within the cytoplasm of the tumor cells. Histologic patterns seen in germ cell tumors or surface epithelial–stromal tumors are not detectable when the tumor is seen in pure form (Scully et al. 1998; Ishikura and Scully 1987).
Fig. 19

Hepatoid carcinoma of the ovary. Note the close resemblance to hepatocellular carcinoma

Immunohistochemical studies demonstrate the presence of AFP and hepatocyte paraffin 1 (Pitman et al. 2004) in a considerable number of tumor cells (Fig. 20). In addition, the tumor cells are immunoreactive for albumin, alpha 1-antitrypsin, and alpha 1-antichymotrypsin. Focal positive immunostaining for carcinoembryonic antigen (CEA) also is seen (Ishikura and Scully 1987).
Fig. 20

Hepatoid carcinoma of the ovary showing expression of alpha-fetoprotein (AFP)

Hepatoid carcinoma of the ovary is a highly malignant neoplasm (Scully et al. 1998; Ishikura and Scully 1987). The histogenesis of hepatoid carcinoma of the ovary has not been established. Unlike YST with hepatoid pattern, it is thought not to be of germ cell origin, as it occurs in older patients, is not associated with other neoplastic germ cell elements, and is not found in patients with gonadal dysgenesis. Because of the age distribution and the occasional association with ovarian surface epithelial–stromal tumors, it is likely that it is a metaplastic tumor and represents a variant of a surface epithelial–stromal tumor (Scurry et al. 1996, 1998; Ishikura and Scully 1987; Randolph et al. 2015; Pitman et al. 2004; Tochigi et al. 2003).

Hepatoid carcinoma of the ovary must be distinguished from YST with hepatoid pattern. It can be distinguished clinically by its occurrence in older, usually postmenopausal patients (although some yolk sac tumors also arise in postmenopausal women), and by its presentation in a more advanced clinical stage, usually stage III. Histologically, hepatoid carcinoma shows a greater degree of cellular and nuclear pleomorphism, and tumor giant cells are much more frequently seen.

In most cases demonstration of positive immunocytochemical staining for AFP in the tumor cells and elevated levels of serum AFP differentiate hepatoid carcinoma from other ovarian tumors such as undifferentiated adenocarcinomas, endometrioid adenocarcinomas with marked squamous differentiation, and steroid cell tumors (Ishikura and Scully 1987). One case of hepatoid carcinoma without AFP staining has been reported (Sung et al. 2013). Primary hepatoid carcinoma of the ovary also must be differentiated from hepatocellular carcinoma metastatic to the ovary (Young et al. 1992). Although the latter is uncommon, this possibility must be carefully excluded before the diagnosis of primary hepatoid carcinoma of the ovary is made.

Small Cell Carcinoma, Pulmonary Type (Neuroendocrine Type)

Eichhorn et al. (1992) have reported 11 primary ovarian tumors that resembled small cell carcinoma of the lung and differed both clinically and histologically from primary small cell carcinoma of the ovary of hypercalcemic type (Young et al. 1994). The age of the patients ranged from 28 to 85 years (Eichhorn et al. 1992). Most patients presented with abdominal enlargement. Six of the tumors were unilateral, and five were bilateral. Spread beyond the ovary was noted in seven tumors. None of the patients had distant metastases at presentation (Eichhorn et al. 1992). The tumors measured from 4.5 to 26 cm in the greatest dimension; they were mostly solid with a variable minor cystic component (Eichhorn et al. 1992).

Histologically, the tumor is composed of small to medium-sized round to spindle-shaped cells with scanty cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli forming sheets, large aggregates, and closely packed nests (Fig. 21). Sometimes an insular or a trabecular pattern was seen (Eichhorn et al. 1992). In four tumors a component of endometrioid carcinoma was present, one tumor showed focal squamous differentiation, two tumors were associated with Brenner tumor, and one contained a cyst lined by atypical mucinous cells (Young and Scully 1984). In two of six tumors, argyrophil granules were demonstrated. In nine cases, immunohistochemical studies were performed that demonstrated positive staining for cytokeratin in six cases, epithelial membrane antigen (EMA) in five, and chromogranin in two. All nine tumors were vimentin-negative. In a small number of cases evaluated, perinuclear dot-like staining for CK20 and variable TTF-1 expression have been observed (Carlson et al. 2007; Rund and Fischer 2006). Flow cytometric studies performed on eight tumors showed that five tumors were aneuploid and three were diploid (Eichhorn et al. 1992). It is important to note that tumors can be diagnosed in the absence of neuroendocrine maker positivity if morphology is typical.
Fig. 21

Small cell carcinoma, pulmonary type. (a) Solid growth pattern containing abundant geographic necrosis. (b) Small to medium-sized round cells with hyperchromatic nuclei, absence of nucleoli, scant cytoplasm, and numerous apoptotic bodies and mitotic figures. (Case courtesy of Dr. Robert H. Young, Boston, MA)

The tumors were aggressive, and of the nine patients with known follow-up, five died of the disease 1–13 months after diagnosis, one died after an unknown interval, and two had recurrent disease 6 and 8 months after surgery. Five of the patients with stage III tumors and two with stage I tumors were treated with combination chemotherapy, which included cisplatin in all cases and doxorubicin in most cases; one of these treated patients was alive at 7.5 years (Eichhorn et al. 1992).

Aggressive treatment with agents effective in treating small cell pulmonary carcinoma appears to be the treatment of choice.

Primary ovarian small cell carcinoma (pulmonary type) must be distinguished from pulmonary small cell carcinoma metastatic to the ovary, which shows both clinical and pathologic differences (Young and Scully 1985; Irving and Young 2005). It also must be differentiated from primary ovarian small cell carcinoma of hypercalcemic type (Scully et al. 1998; Young et al. 1994) (see chapter “Sex Cord-Stromal, Steroid Cell, and Other Ovarian Tumors with Endocrine, Paraendocrine, and Paraneoplastic Manifestations”). The patients with primary ovarian small cell carcinoma of pulmonary type are older. The tumor is seen either in perimenopausal or postmenopausal women (Scully et al. 1998; Eichhorn et al. 1992). Hypercalcemia is absent. The tumors are bilateral in 45% of cases, whereas in the hypercalcemic type, bilaterality is seen only rarely (1% of cases) (Eichhorn et al. 1992).

Histologically, the cells of primary ovarian small cell carcinoma of pulmonary type differ from those of the hypercalcemic type in having finely dispersed chromatin and inconspicuous nucleoli, whereas the latter is composed of cells with nuclei showing clumped chromatin and prominent nucleoli, as well as showing the presence of larger cells with abundant eosinophilic cytoplasm in 40% of cases (Eichhorn et al. 1992). Follicle-like spaces are frequently seen in the hypercalcemic type and are virtually absent in the pulmonary type of small cell carcinoma (Eichhorn et al. 1992). It is important to recognize that small cell carcinoma of pulmonary type is a neuroendocrine carcinoma whereas the hypercalcemic type is not. Immunohistochemically, the pulmonary type usually but not always expresses chromogranin and synaptophysin while the hypercalcemic type does not express these markers. Conversely, the hypercalcemic type shows complete loss of BRG1. Although data are limited, it would be expected that the pulmonary type retains expression of this marker. Endometrioid and Brenner tumor components are present in more than half the small cell carcinomas with pulmonary differentiation and are absent in the hypercalcemic type. The former also tend to be more frequently aneuploid (Eichhorn et al. 1992)

Although the histogenesis of the primary ovarian small cell carcinoma of pulmonary type has not been established, the frequent association with endometrioid and Brenner tumors points toward a surface epithelial–stromal origin, as is supported further by the age range of the patients (Eichhorn et al. 1992).

Neuroendocrine Carcinoma, Non-Small Cell Type

A small number of ovarian tumors composed of solid sheets, nests, cords, trabeculae, or solid islands of cells showing neuroendocrine differentiation have been reported (Scully et al. 1998; Eichhorn et al. 1996; Veras et al. 2007). These tumors can be associated with either a surface epithelial-stromal or possibly germ cell component (Collins et al. 1991; Agarwal et al. 2016). The age of reported patients ranges from 22 to 77 years. Some tumors were stage I, but in spite of this the prognosis was poor. Several cases presented with advanced stage disease, and the tumors demonstrated aggressive behavior, in common with neuroendocrine tumors occurring in other sites.

Histologically, the neuroendocrine component of the tumor consisted of solid islands or cords of medium to large epithelial cells with variable amount of cytoplasm and large nuclei, some of which had prominent nucleoli. Mitotic activity was variable but frequently high. The cellular islands and cords were surrounded only by a small amount of connective tissue. Immunohistochemical stains were frequently positive for pan-cytokeratin, CK7, CK20, chromogranin, and synaptophysin (Veras et al. 2007) Other neurohormonal polypeptides were also detected in some of the tumors (Eichhorn et al. 1996).

The neuroendocrine component of the tumor may resemble insular carcinoid tumor of the ovary, but the cells are usually larger and show much greater degree of cellular and nuclear pleomorphism. The presence of the surface epithelial–stromal component also helps to differentiate between these two entities. The distinction between them is very important because the prognosis of patients with neuroendocrine carcinoma is by far worse than that of patients with carcinoid tumors. The size of the tumor cells, proliferative index, and the strong positive immunohistochemical reactions distinguish this tumor from the ovarian carcinoma of the small cell pulmonary type. Another tumor in the differential is adult granulosa cell tumor. Immunohistochemistry should help to resolve this differential as neuroendocrine carcinoma should be negative for inhibin and calretinin (Agarwal et al. 2016), as well as SF-1. The presence of the surface epithelial–stromal component confirming the ovarian origin differentiates this tumor from metastatic small cell tumors to the ovary (Eichhorn et al. 1996).

Salivary Gland-Like Carcinomas

Ovarian tumors resembling salivary gland carcinomas are rare, but a series of 12 tumors has been reported (Eichhorn and Scully 1995). The tumors in six cases resembled adenoid cystic carcinoma. Most of the tumors also exhibited a minor component of surface epithelial–stromal neoplasia. The latter were of various histologic types and included serous, endometrioid, and clear cell carcinomas. The affected patients were elderly; nearly all were in the seventh or eighth decade. Most of the tumors were associated with extensive metastatic disease and the prognosis was poor, except for one case where the tumor was in pure form and another in which the associated surface epithelial–stromal component was of the serous borderline type. Histologically, the tumors showed architectural patterns seen in adenoid cystic carcinoma of the salivary glands (Fig. 22). The tumor cells resemble myoepithelial cells, although this has not been confirmed immunohistochemically because in the majority of cases the cells did not stain positively for actin and S-100 protein (Scully et al. 1998; Eichhorn and Scully 1995). Histogenetically, these tumors are probably of surface epithelial–stromal origin because they are usually associated with a surface epithelial–stromal component or recurred as an adenoid cystic carcinoma in a patient for whom the original tumor was an endometrioid carcinoma.
Fig. 22

Ovarian carcinoma resembling adenoid cystic carcinoma. (Case courtesy of Dr. Robert H. Young, Boston, MA)

The ovarian tumors in the remaining six cases from the study mentioned above showed basaloid or ameloblastomatous features (Scully et al. 1998; Eichhorn and Scully 1995). The age distribution was wide, ranging from 19 to 65 years. Most of the tumors were confined to the ovary (stage IA), and the prognosis was excellent after excision of the tumor although some of the follow-up periods were relatively short, varying from 16 to 71 months. Histologically, the tumors showed either a basaloid or ameloblastomatous pattern (Fig. 23). Several of them showed focal squamous and glandular differentiation, and one showed a minor component of endometrioid adenocarcinoma (Scully et al. 1998; Eichhorn and Scully 1995). The histogenesis of this neoplasm is uncertain, but surface epithelial–stromal origin, particularly endometrioid carcinoma, appears to be most likely.
Fig. 23

Ovarian carcinoma with basaloid appearance. Note peripheral palisading at interface between neoplastic epithelium and fibrovascular cores. (Case courtesy of Dr. Robert H. Young, Boston, MA)

Nephroblastoma (Wilms Tumor)

Less than 10 cases of ovarian nephroblastoma have been reported. Patients range in age from 1 year to 36 years. Pure nephroblastomas of the ovary as well as nephroblastomas arising in conjunction with an ovarian teratoma have been documented (Alexander et al. 2017). The tumors show typical features of well-differentiated nephroblastoma with glomeruloid formations, small tubules, and prominent blastema (Alexander et al. 2017; Sahin and Benda 1988). Although the tumors were described as primary ovarian nephroblastomas, their histogenetic origin is uncertain. It is thought that these tumors either arise from mesonephric remnants or teratomas (Alexander et al. 2017). Occasionally, retiform Sertoli–Leydig cell tumors, because of the presence of tubules and papillary pattern resembling glomeruloid formations, have been misdiagnosed as ovarian nephroblastomas. Careful sectioning and examination of the tumor for the presence of other patterns associated with Sertoli–Leydig cell tumors and absence of renal blastema are helpful in differentiating between these two entities. Demonstration of positive inhibin and SF-1 staining using immunohistochemistry further supports the diagnosis of Sertoli–Leydig cell tumor.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicinePerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Pathology, Division of Gynecologic PathologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA

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