Intestinal Carcinomas 696

Krukenberg Tumor 699

Carcinoid Tumors 701

Breast Carcinoma 702

Tumors of the Pancreas, Biliary Tract, and Liver 703

Tumors of the Appendix 704

Renal Tumors 705

Tumors of the Urinary Tract 706

Adrenal Gland Tumors 707

Malignant Melanoma 707

Pulmonary and Mediastinal Tumors 707

Uterine Tumors 707

Lymphoma and Leukemia 709

Peritoneal Tumors 710

Extragenital Sarcomas 711

Intestinal Carcinomas

Most intestinal metastases originate in the large intestine and, much less frequently, in the small bowel. Whereas at autopsy metastases from intestinal carcinomas are less common than those from gastric carcinomas (14% vs 38%, respectively), at the time of operation metastases from intestinal carcinomas are almost five times as frequent as those from gastric carcinomas.²⁷ Up to 45% of colorectal metastases to the ovary are clinically thought to be primary ovarian tumors, and many are misinterpreted as such on microscopic examination.² Metastasis from the large bowel to the ovary is seen relatively more frequently when this cancer develops in women under 40 years of age. In one large series, one-fourth of patients were less than 40 years old²⁸ and in another about 43% were under 50 years.²⁹ In the latter study, it was found that patients initially presenting with an ovarian mass were significantly younger than those having ovarian spread in the setting of a known colorectal primary (average 48 vs 61 years). Not infrequently, patients have luteinized stromal cells in the ovarian tumor with resultant hormone production and endocrine symptoms.

The ovarian tumors are bilateral in approximately two-thirds of cases (Figure 30.1). Smaller tumors are usually solid, whereas larger tumors are composed of friable gray, yellow, or red tissue with cysts that contain necrotic tumor, mucinous fluid, or blood (Figure 30.2).^2,3

Microscopically, the metastatic tumors may be confused with primary endometrioid or mucinous carcinoma depending on whether the colonic carcinoma is predominantly non-mucinous or mucinous. Features that help distinguish colon cancer from endometrioid carcinoma include luminal necrotic debris (‘dirty necrosis’), focal segmental necrosis of the glands (Figures 30.3–30.5), occasional presence of goblet cells, and absence of müllerian features (squamous differentiation, an adenofibromatous component, or association with endometriosis). Also the nuclei lining the glands of metastatic colon carcinoma exhibit a higher degree of atypia than those of endometrioid carcinoma (Figure 30.5).^2,3 The stroma may be desmoplastic (Figure 30.6), edematous, or myxoid, but frequently resembles ovarian stroma. Stromal luteinization is most frequently found in metastatic colorectal carcinomas.³⁰

Metastatic tumors may also resemble closely primary mucinous ovarian tumors both grossly (Figure 30.7) and microscopically. The metastases may be moderately differentiated (Figure 30.8) or so well differentiated that they can be mistaken for mucinous borderline or less often benign ovarian tumors. Generous sampling (at least one block per 1–2 cm of tumor diameter) is recommended. Metastatic mucinous tumors to the ovary can originate in the large intestine, stomach, pancreas, gallbladder, biliary tract, appendix, and even, exceptionally, urachus and lung. Features supportive of the diagnosis of a metastasis already discussed include bilaterality, histologic surface involvement by epithelial cells (surface implants) (Figure 30.9), irregular infiltrative growth with desmoplasia (Figure 30.6), single cell invasion, signet-ring cells, vascular invasion (Figure 30.10), coexistence of benign-appearing mucinous areas with foci showing a high mitotic rate and nuclear hyperchromasia, and histologic surface mucin.³¹ In some cases, the intestinal metastases contain cells with abundant clear cytoplasm and may simulate either primary clear cell carcinoma or the secretory variant of endometrioid carcinoma (Figure 30.11).³²

Krukenberg Tumor

Krukenberg tumors are adenocarcinomas with a distinctive histologic appearance. They consist of mucin-filled signet-ring cells and a striking proliferation of the ovarian stroma. Signet-ring cell carcinomas are associated more often with ovarian metastasis than carcinomas of other histologic types. These tumors originate in the stomach, usually in the pylorus, in the vast majority of cases. It has been demonstrated that gastric signet-ring cell carcinomas metastasize to the ovary much more often than intestinal-type carcinomas of the stomach do.⁴³ Sometimes, the gastric cancer may be small and remains undetected for several years after oophorectomy. Much less frequently, the primary tumor is in the large intestine, breast, gallbladder, uterine cervix, appendix, or urinary bladder. In rare cases, the site of origin of the primary tumor is unknown and a diagnosis of ‘primary’ Krukenberg tumor has been proposed for those cases in which either the patient survives in good health for 10 years or longer or a thorough autopsy fails to reveal an extraovarian primary tumor.⁴⁴ Possibly, some of the cases reported in the older literature as primary Krukenberg tumors represent mucinous (goblet cell) carcinoids. Patients with Krukenberg tumors tend to be younger than most patients with metastatic carcinoma; most of them are between 40 and 50 years of age. Although the symptoms are usually nonspecific, most frequently abdominal pain and swelling, endocrine manifestations, such as virilization during pregnancy, may result from stromal luteinization.³

Krukenberg tumors are bilateral in 60–80% of the cases.³ They are typically solid masses with smooth nodular or bosselated outer surfaces (Figure 30.14). The cut surfaces are predominantly white or tan with areas of red or brown discoloration (Figure 30.15); the consistency may be firm, fleshy, or gelatinous. Because of the marked proliferation of the ovarian stroma, the tumors may resemble fibrothecomas on gross examination.

Microscopically, the plump, rounded carcinoma cells have a signet-ring appearance and are surrounded by a dense cellular stroma (Figure 30.16). The epithelial cells may appear singly or in nests (Figure 30.17) and tend to concentrate in the dense fibroblastic areas. In some cases, the stroma is less cellular, edematous (Figure 30.18), or fibrous. Isolated small glands are usually found⁴⁵ (Figure 30.19) and, occasionally, there is a predominant tubular architecture (tubular Krukenberg tumor) (Figure 30.20).⁶ The stromal cells are plump, spindle shaped, and are sometimes extensively luteinized.^3,6

Krukenberg tumors must be distinguished from primary and other metastatic ovarian tumors including clear cell adenocarcinoma, mucinous (goblet cell) carcinoid, and a variety of ovarian tumors that contain signet-ring-like cells filled with non-mucinous material. The presence of clear cells may raise the issue of clear cell carcinoma, but the clear cells in the latter contain glycogen; mucin, when present, is typically luminal and extracellular. Rarely, clear cell carcinoma may have a signet-ring cell component that simulates a Krukenberg tumor; however, the signet-ring cells of the former have a characteristic ‘targetoid’ cytoplasm (bull’s eye appearance), containing a large vacuole with a central eosinophilic body. In addition, the identification of a tubulocystic pattern, as well as the presence of hobnail cells, stromal hyalinization, and eosinophilic secretion, is helpful in establishing the diagnosis. In contrast, CK immunostains are not useful, as nearly half of gastric carcinomas metastatic to the ovary are CK7 positive/CK20 negative.³⁸ Mucinous carcinoid, either primary or metastatic, may contain large areas of signet-ring cells; the former neoplasms, however, frequently contain other teratomatous elements, and Grimelius stains as well as immunostains for chromogranin, synaptophysin are usually positive in both.

The tubular variant of Krukenberg tumor, sometimes associated with stromal luteinization, can be confused with a Sertoli–Leydig cell tumor (Figure 30.20); however, signet-ring cells are not a feature of the latter tumor except for the heterologous form that contains mucinous intestinal glands.⁶ Positive mucicarmine and periodic acid–Schiff (PAS) stains with diastase digestion (Figure 30.21) are of great value in establishing the diagnosis of a Krukenberg tumor.⁶ Occasional Krukenberg tumors may closely resemble fibromas on macroscopic examination and may have relatively few signet-ring cells. Bilaterality and positive mucin stains facilitate the differential diagnosis.

Almost all patients die within a year of the diagnosis of Krukenberg tumor, but rare patients have survived for 5 or more years after gastrectomy and bilateral oophorectomy.⁴⁶ Although exceptional, this outcome justifies removal of both the stomach and the ovarian metastases in cases in which the tumor appears limited to those organs. Also, in menopausal and postmenopausal women undergoing gastrectomy for carcinoma, the ovaries should be removed routinely to prevent the later development of ovarian metastasis and avoid another operation.

Carcinoid Tumors

Carcinoid tumors of the gastrointestinal tract, pancreas, or bronchus may metastasize to the ovary, and approximately half of the patients have the carcinoid syndrome.⁴⁷ The primary tumor is usually in the ileum. Whereas mucinous carcinoid tumors of the appendix spread to the ovary in approximately one-third of cases, typical carcinoid tumors of the appendix almost never metastasize to the ovary.³ In the largest series reported, the age of the 35 patients ranged from 21 to 82 years, with a median of 57 years.⁴⁷ Forty percent of the women had preoperative manifestations of the carcinoid syndrome. Some of them also had clinical evidence of intestinal or ovarian involvement. Extraovarian metastases were found in at least 90% of the cases, in contrast to the rarity of similar spread in cases of primary ovarian carcinoids.

Metastatic carcinoids are typically bilateral solid tumors with smooth or bosselated surfaces. The cut section often shows firm white or yellow confluent nodules, which may simulate fibromas or thecomas (Figure 30.22). Rare carcinoid tumors are predominantly cystic.³ Microscopically, the insular pattern is the most common, but trabecular and mucinous patterns may also be found. The carcinoid glands usually appear scattered in a dense fibrous stroma, which may be hyalinized (Figures 30.23 and 30.24). Focally, metastatic mucinous (goblet cell) carcinoids may resemble Krukenberg tumors. Immunostains for chromogranin and synaptophysin are often positive (Figure 30.25).

Metastatic carcinoids can be confused with primary carcinoids (Table 30.3), granulosa cell tumors, Sertoli–Leydig cell tumors, Brenner tumors, adenofibromas, or endometrioid carcinomas.^3,5 If the diagnosis of a carcinoid tumor is difficult in any of the previous situations, more thorough sampling, and immunohistochemical staining for neuroendocrine markers can be performed. Bilaterality, extraovarian extension, and absence of teratomatous elements are important features of metastatic carcinoids. CDX-2 does not distinguish between tumors of intestinal origin and primary ovarian carcinoids.⁴⁸

Breast Carcinoma

Ovarian involvement by breast cancer is usually an incidental microscopic finding without clinical significance (Figure 30.26). Historically, such tumors have been found in approximately 30% of patients who have had therapeutic oophorectomy for disseminated breast carcinoma and, at autopsy, in about 10% of cases of breast cancer. Bilateral involvement occurs in 60–80% of cases.³

Patients with breast cancer are at increased risk of developing primary ovarian, tubal, or pelvic peritoneal carcinoma, especially if they have a hereditary predisposition to breast and ovarian cancer due to BRCA1 or BRCA2 mutations. It is not surprising then that patients with a history of breast cancer who present with an adnexal or pelvic mass are more likely to have independent ovarian or tubal malignancy than metastases from the breast cancer by a 3 : 1 ratio.⁴⁹ The very rare cases of metastases that present clinically as primary ovarian tumors before the detection of the breast carcinoma often pose diagnostic difficulty.⁵⁰ The tumors are characteristically solid, multinodular, and firm (Figure 30.27). A larger percentage of cases of lobular carcinoma of the breast, including those of signet-ring cell type, metastasize to the ovary than do cases of ductal carcinoma; in an autopsy study 36% of the former metastasized to the ovaries in contrast to only 2.6% of the latter.⁵¹

Metastatic lobular carcinomas (Figure 30.28) usually show a diffuse pattern mimicking granulosa cell tumors, granulocytic sarcomas, or lymphomas, or even an insular pattern simulating carcinoid tumors. Rarely, metastatic ductal carcinomas may have an endometrioid-like appearance. Positive immunoreaction for gross cystic disease fluid protein (GCDFP-15) (Figure 30.29),⁵² estrogen (ERPr) (Figure 30.30), and progesterone receptor proteins (ER, PR), epithelial membrane antigen (EMA), and S-100 protein, and negativity for CA12.5, CA19.9,⁵³ α-inhibin, myeloperoxidase, and lymphoid markers favor metastatic breast carcinoma. Mammaglobin is expressed in about 50% of breast carcinomas.^54,55 However, its expression has been demonstrated in rare ovarian serous carcinomas and in endometrioid carcinomas of the uterine corpus.^54,56 WT1 is positive in >80% of serous carcinomas of the ovary, but it is rarely positive in breast carcinomas. PAX-8 immunoreaction is seen in greater than 88% of ovarian carcinomas but not in breast carcinomas.⁵⁷ Both breast and ovarian carcinomas may be positive for CK7.³⁶ A panel of markers is recommended as no currently available individual marker is entirely specific for breast or ovarian carcinomas.

Tumors of the Pancreas, Biliary Tract, and Liver

Although ovarian metastases are rarely found in patients with these carcinomas, they may strikingly mimic primary ovarian tumors both grossly and microscopically.58–60 Metastatic tumors from the pancreas are usually bilateral, large, cystic, and multiloculated (Figure 30.31), an appearance that may be indistinguishable from primary mucinous neoplasia, although in some cases surface nodules may be noted and raise suspicion for metastasis. The microscopic pattern varies considerably within individual tumors that may show areas resembling ovarian mucinous cystadenomas, borderline tumors (Figure 30.32), and well-differentiated cystadenocarcinomas as well as foci of irregular stromal infiltration.⁵⁸ In some cases, foci of high-grade adenocarcinoma appear admixed with more indolent low-grade cystic tumor and are a clue to the diagnosis. Four cases of ovarian involvement by acinar cell carcinoma of the pancreas have been recently reported⁶¹ (Figure 30.33). Metastatic adenocarcinomas of the gallbladder and extrahepatic bile ducts are very rare.⁵⁹ Recently, however, a series of cases has been reported.⁶² They are usually solid tumors that microscopically may simulate ovarian mucinous (Figure 30.34) or endometrioid carcinomas, or even cystadenofibromas.⁵⁹ Rarely, Krukenberg tumors originate in the pancreas or biliary tract.³ Features suggesting metastasis include bilaterality, extraovarian extension, ovarian surface implants, and vascular invasion. Like primary ovarian mucinous tumors, pancreatic carcinomas are diffusely immunoreactive for CK7 and MUC5AC and show focal to diffuse positivity for CK20 (Table 30.2); however, 46% of pancreatic carcinomas are negative for Dpc4.³⁵

Ovarian metastases from hepatocellular carcinomas are exceedingly rare and should be distinguished microscopically from primary hepatoid carcinomas (Chapter 27), and hepatoid yolk sac tumors (Chapter 29). HepPAR1 is not useful in distinguishing among metastatic hepatocellular carcinoma, hepatoid yolk sac tumor, and hepatoid ovarian carcinoma as it is expressed in all.⁶³ The presence of bile in the ovarian tumor favors metastatic hepatocellular carcinoma.⁶⁰

Tumors of the Appendix

Metastatic tumors from the appendix are rare and represent only 1–2% of ovarian metastases.¹ Most of these cases are mucinous tumors of borderline malignancy (low-grade mucinous tumors) associated with pseudomyxoma peritonei8,64,65 (see Chapters 26 and 31). Other appendiceal tumors that may spread to the ovary include mucinous (goblet cell) carcinoids^3,66 and, less frequently, adenocarcinomas of signet-ring cell (Figure 30.35), mucinous intestinal, and colorectal types (Figure 30.36).¹⁰ The ovarian metastases of mucinous carcinoids and signet-ring cell adenocarcinomas are generally of the Krukenberg type. The former tumors are clinically aggressive and often fail to show the characteristic immunoreactions of carcinoid tumors. A recent report on ovarian metastases of appendiceal carcinomas with neuroendocrine differentiation emphasized that the clinical features and pathologic findings support classifying the appendiceal tumors as carcinomas rather than goblet cell carcinoids. According to the authors, the presence of infiltrative and destructive growth justifies their designation as carcinomas.⁶⁷

In patients with pseudomyxoma peritonei, low-grade mucinous tumors of the appendix often coexist with histologically similar tumors in one or both ovaries. Although these tumors were traditionally considered as independent primary neoplasms, there is now convincing clinicopathologic, immunohistochemical, and molecular genetic evidence that in most cases the ovarian tumors represent metastases from the appendiceal lesions.8,9,64,65,68 In such cases, the ovarian tumors are frequently bilateral or, when unilateral, predominantly right-sided, and often exhibit pools of mucin dissecting through the ovarian stroma (‘pseudomyxoma ovarii’). In contrast, primary ovarian mucinous borderline tumors are usually unilateral and only occasionally associated with pseudomyxoma peritonei or ovarii, even when preoperative or surgical rupture has occurred. Additional features that support the secondary nature of the ovarian tumors associated with pseudomyxoma peritonei are their jelly-like consistency on gross examination (Figure 30.37), the finding of mucin and atypical mucinous cells on the ovarian surfaces, and the presence of very tall mucinous lining cells (Figure 30.38).³ Although appendiceal tumors are almost always diffusely positive for CK20, they may also be positive for CK7 in approximately one-third of cases.³⁵

At surgery, the primary appendiceal tumor is often overlooked because the ovarian tumors are usually much larger.¹⁰ Besides, the site of appendiceal rupture may be very small and require extensive sectioning to demonstrate it. Additionally, in some cases a rupture site heals over, and is represented only by fibrosis in the appendiceal wall.

Renal Tumors

Renal cell carcinoma rarely metastasizes to the ovaries; however, when it does, it must be distinguished from a primary clear cell carcinoma. Only 15 cases have been reported in detail.69–72 Most were unilateral tumors, often large (average 12.5 cm in greatest dimension), solid and cystic, and yellow to orange. Microscopically, they showed a prominent sinusoidal vascular pattern, a homogeneous clear cell pattern without hobnail cells, absence of hyalinized papillae, and the absence of intraluminal mucin (Figure 30.39).^3,72

A panel of antibodies may be helpful in the differential diagnosis: ovarian clear cell carcinomas are usually immuno- reactive for CK7 and mesothelin and negative for CD10 and RCCma (renal cell carcinoma marker), whereas renal cell carcinomas often show the opposite immunoprofile (CK7−/mesothelin−/CD10+/RCCma+).73–75 Although PAX2 may be a more sensitive marker than RCCma for metastatic renal cell carcinoma, it should be noted that about 40% of ovarian clear cell carcinomas also express PAX2.⁷⁶

Tumors of the Urinary Tract

Distinction between a transitional cell carcinoma of the urinary tract metastatic to the ovary (Figure 30.40) and a borderline or malignant Brenner tumor, or a primary ovarian transitional cell carcinoma, may be difficult.^77,78 Clinical information may be necessary to resolve the issue. In most borderline or malignant Brenner tumors, however, a benign Brenner tumor component can be found. Also, the presence of benign mucinous elements favors the diagnosis of a Brenner tumor. In contrast to primary transitional cell carcinomas of the ovary, urinary tract carcinomas are immunoreactive for CK13, CK20, uroplakin, and thrombomodulin⁷⁹ and they are typically negative for WT1.⁸⁰

Adrenal Gland Tumors

Neuroblastoma is the adrenal tumor that most frequently metastasizes to the ovary.81–83 The metastases must be distinguished from rare cases of primary ovarian neuroblastomas. In contrast to the metastatic tumors, the primary tumors are usually unilateral and are often associated with a teratoma. The prominent fibrillary background of neuroblastoma and the presence of pseudorosettes help in the distinction of metastatic neuroblastoma from other metastatic small cell tumors. Immunohistochemistry is also helpful. Metastases of adrenal cortical carcinomas to the ovary are exceedingly rare.⁸⁴ Pheochromocytomas spread to the ovary even less commonly.

Malignant Melanoma

Three series of melanomas metastatic to the ovary including 52 cases have been reported.85–87 In the ovary metastatic malignant melanoma may be confused with primary malignant melanoma; the latter is unilateral, usually associated with a dermoid cyst, and often nonpigmented. When a melanoma is composed predominantly of large cells, it may resemble a lipid-poor steroid cell tumor or a pregnancy luteoma; sometimes, it exhibits a follicle-like arrangement resembling juvenile granulosa cell tumor; when it is composed mainly of small cells it may be confused with a small cell carcinoma of the hypercalcemic type.⁸⁷ Positive stains for melanin, S-100 protein (Figure 30.41), Melan A, and/or HMB-45 should establish the diagnosis of melanoma.

Pulmonary and Mediastinal Tumors

Ovarian metastases from lung carcinomas account for less than 1% of ovarian metastases but are increasing in frequency as the disease becomes more common in women⁸⁸ (Figure 30.42). Most women present with symptoms of the pulmonary tumor and are subsequently found to have a pelvic tumor. All major histologic types of lung cancer can spread to the ovaries and potentially mimic a primary carcinoma. Squamous cell carcinomas, the most common form of lung cancer, rarely metastasize to ovaries.⁸⁸ Metastases from lung adenocarcinomas are slightly more frequent. Thyroid transcription factor-1 (TTF-1) immunoreactivity helps identify lungs as a potential primary site in cases of metastatic adenocarcinoma of unknown origin; it is reactive in 60–75% of primary lung adenocarcinomas, but not reactive in primary ovarian adenocarcinomas.⁸⁹ Undifferentiated small cell (oat cell) carcinomas of the lung, the most common type of pulmonary metastasis, should be distinguished from ovarian small cell carcinomas of either ‘hypercalcemic type’ or ‘pulmonary type’ (see Chapter 27), although all of the tumors have a poor prognosis. Ovarian small cell carcinomas of hypercalcemic type occur in young women and, like other ovarian tumors, are negative for TTF-1, while more than half of small cell lung carcinomas are reactive.^88,90 Primary ovarian small cell carcinoma of pulmonary type typically differs from metastatic small cell lung carcinoma in its tendency for peritoneal spread and its association with epithelial–stromal tumors, in particular endometrioid carcinoma. Interestingly, however, small cell carcinoma of the lung has been reported to metastasize to pre-existing ovarian tumors.^88,91

Metastatic large cell carcinomas must be distinguished from morphologically similar oxyphilic tumors, both primary and secondary, including melanoma. Bronchioloalveolar carcinomas rarely are metastatic to the ovaries.⁹²

Small cell carcinomas arising in sites other than lung, such as mediastinum, uterine cervix, and gastrointestinal tract, may also metastasize to the ovaries.93,94 Isolated cases with metastases include posterior mediastinal neuroblastoma⁸² and mediastinal thymoma.⁹⁵

Uterine Tumors

Ovarian involvement by endometrial carcinoma has been reported in 5–15% of hysterectomy specimens. The distinction between metastatic endometrial and primary endometrioid carcinoma of the ovary has been discussed in Chapter 27. Uterine sarcomas may metastasize to the ovary and may occasionally be discovered before the primary tumor.⁹⁶ Metastatic epithelioid leiomyosarcoma may have an appearance that simulates a carcinoma, a malignant lymphoma, or even a Sertoli cell tumor. A positive immunoreaction for desmin may facilitate the diagnosis. Distinction between metastatic low-grade endometrial–stromal sarcoma, primary ovarian low-grade endometrioid stromal sarcoma, and sex cord–stromal tumors has been discussed in Chapter 27.

Mucinous adenocarcinomas of the cervix coexist with ovarian tumors of similar type more frequently than other adenocarcinomas.97–99 Sometimes, it may be difficult to determine whether the tumors are metastatic from one organ to the other or independent primary neoplasms. The distinction is made by applying criteria similar to those used in diagnosing simultaneous ovarian and corpus carcinomas and in identifying metastatic tumors in general. However, the microscopic clue to the metastatic nature of the ovarian tumors is the ‘hybrid’ appearance of the epithelium with features of both endometrioid and mucinous differentiation, i.e., with low-power endometrioid-like features but with apical mucin seen on higher power. Additionally, the nuclei are hyperchromatic and more atypical than seen in true endometrioid or mucinous carcinomas with a similar glandular grade, and mitotic figures and apoptotic bodies are numerous (Figure 30.43).^100,101 Although nonspecific, a strong p16 immunoreaction (Figure 30.44) supports the metastatic nature of the ovarian tumor, which can be confirmed by detecting human papillomavirus (HPV) using in situ hybridization or polymerase chain reaction. In some cases, an occult primary cervical adenocarcinoma was discovered after resection of the ovarian metastases.¹⁰⁰ Subsequently, the question of whether ovarian conservation is justified in patients with cervical adenocarcinoma has been raised.

Cervical adenoma malignum may be associated with synchronous ovarian mucinous tumors, sometimes in the setting of Peutz–Jeghers syndrome. In this instance, assessing neither their HPV DNA status nor their CK immunoreactivity is of any help as adenoma malignum is not HPV related, and both primary cervical and ovarian tumors should be reactive for CK7 and unreactive for CK20.

Cervical squamous cell carcinomas metastasize to the ovary in less than 1% of cases.102,103 Most ovarian squamous cell carcinomas arise in dermoid cysts or endometriotic cysts. Adenosquamous, neuroendocrine, undifferentiated, and transitional cell carcinomas metastatic to the ovary have also been reported.¹⁰²

Uterine choriocarcinomas spread to the ovary in 22% of cases.⁵ It may be extremely difficult to distinguish a primary ovarian choriocarcinoma of either gestational or germ cell origin from a metastatic uterine choriocarcinoma in which regression of the primary tumor has occurred. The specimen should be thoroughly sampled in an attempt to discover teratomatous elements, thus establishing a germ cell origin of the neoplasm.

Carcinomas of the fallopian tube involve the ovary in approximately 13% of cases, usually by direct extension.¹ In such cases, it may be difficult to determine whether the tumor is primary in the tube or ovary. Although the problem is usually resolved on the basis of the gross pathologic findings, in questionable cases the tumor is classified as tubo-ovarian carcinoma.⁵¹ Most tubal carcinomas resemble high-grade serous carcinomas of the ovary, thus microscopic examination rarely helps in deciding a primary site.104,105 Recent studies have raised the possibility that a great number of high-grade serous carcinomas of the ovary, predominantly from BRCA-positive patients but also sporadic cases, may actually represent spread of fallopian tube cancers, especially those of the fimbria^106–109 (see Chapter 25).

Lymphoma and Leukemia

Although lymphoma and leukemia can involve the ovaries simulating various primary tumors, they rarely present clinically as an ovarian mass. In countries where Burkitt lymphoma is endemic, however, it accounts for approximately half the cases of malignant ovarian tumors in childhood.³ On pelvic examination, unilateral or bilateral adnexal masses are palpable. Approximately two-thirds of the patients have extraovarian disease frequently involving the fallopian tubes, and the pelvic or para-aortic lymph nodes. The Ann Arbor lymphoma stage provides more prognostic information than the International Federation of Gynecologists and Obstetricians stage. With modern combination chemotherapy, patient survival is greater than 50% and is comparable to that achieved overall in nodal lymphomas.¹¹⁰

Ovarian lymphomas have an average diameter of 10–15 cm.³ The external surface of the tumor is smooth, nodular, or bosselated. The cut surface is fleshy and tan, or gray (Figure 30.45). Microscopically, the tumor cells of Burkitt and Burkitt-like lymphomas grow in sheets punctuated by spaces that contain phagocytic histiocytes, creating a characteristic ‘starry sky’ appearance (Figure 30.46). The cells have scanty cytoplasm and uniform, round, medium size nuclei with coarse chromatin and 1–3 nucleoli. Mitotic figures are numerous. The tumor cells can infiltrate ovarian follicles without destroying them. In adults, large cell lymphoma is the most common type. The tumor cells show scanty to moderate amphophilic cytoplasm and round, oval, or cleaved nuclei (Figure 30.47). The nuclei are hyperchromatic with coarse chromatin or vesicular with a prominent central nucleolus. Mitotic figures are frequent. Other types of non-Hodgkin lymphoma, both follicular and diffuse, rarely involve the ovary.

Dysgerminoma is one of the most common and difficult differential diagnoses. The appearance of the cell nuclei is very important. Immunostains for lymphoid markers, such as CD45 (leukocyte common antigen), CD20 for B-cells (Figure 30.48), and CD3 for T-cells, and placental alkaline phosphatase, c-kit, and D2-40 for dysgerminoma are helpful. Dysgerminomas also react for pluripotency markers (transcription factors) SALL4 and OCT3/4. Most ovarian lymphomas have a B-cell phenotype.¹¹¹ The ‘single-file’ arrangement of lymphoma and leukemic cells may simulate metastatic lobular carcinoma of the breast; however, the cells of the latter tumors often contain small mucin-filled intracytoplasmic vacuoles and are immunoreactive for CKs. Carcinoid, granulosa cell tumor, or small cell carcinoma can also resemble lymphoma.

Myeloid neoplasms, including acute myeloid leukemia and myeloid (granulocytic) sarcoma, may involve the ovary and rarely constitute the initial clinical presentation of the disease. At the time of diagnosis of myeloid sarcoma, leukemia may or may not involve the peripheral blood and bone marrow; if not present, it usually develops subsequently. Some of these tumors exhibit a characteristic green color (‘chloroma’). Microscopic examination reveals a diffuse growth pattern with a prominent ‘single file’ arrangement of the tumor cells (Figure 30.49). In contrast to lymphoma cells, the cells of myeloid (granulocytic) sarcoma have more finely dispersed nuclear chromatin and more abundant cytoplasm. Myeloid differentiation can be demonstrated by the chloroacetate esterase stain. Immunostains for myeloperoxidase, lysozyme, and CD68 are positive.¹¹² B- and T-cell markers, such as CD20 and CD3, are negative.

Peritoneal Tumors

Secondary ovarian involvement by malignant mesothelioma is common and is usually limited to the surface of the ovary or the superficial stroma (Figure 30.50). Occasionally, however, the ovary is extensively involved and the clinical picture simulates that of ovarian cancer.¹¹³ Microscopically, malignant mesotheliomas are characterized by tubular, papillary, and solid patterns and relatively uniform cells with abundant eosinophilic cytoplasm (Figure 30.49). Rare tumors with an exclusive sheet-like pattern containing polygonal cells may be confused with ectopic decidual reaction. In routinely stained sections, mesotheliomas are usually readily distinguishable from serous carcinoma by their pattern of growth and cytologic features, although histochemical or immunohistochemical stains are sometimes necessary to confirm the diagnosis. In contrast to adenocarcinomas, mesotheliomas lack neutral mucins (digested PAS negative) and contain hyaluronic acid within vacuoles (Alcian blue positive, hyaluronidase sensitive). Hyaluronic acid, however, may leach from formalin-fixed tumors, resulting in false-negative staining. The most useful immunohistochemical markers are the BerEp4-defined surface glycoprotein, which is positive in serous carcinomas but negative in mesothelioma, and calretinin (Figure 30.51), CK5/6, and thrombomodulin, all three of which are positive in mesothelioma but negative in serous carcinomas.^114,115 Additionally, no reactivity for CEA, B72.3, Leu-M1, ER, PR, and CA125 favor a diagnosis of mesothelioma over carcinoma.

Extraovarian primary peritoneal serous carcinomas are tumors histologically identical to serous carcinomas of the ovary that present with peritoneal carcinomatosis and minimal or no ovarian involvement. Most peritoneal serous carcinomas are high grade and fundamentally different from low-grade peritoneal serous carcinomas. The latter tumors are distinguished from serous borderline tumors by the presence of invasion. Compared with ovarian high-grade serous carcinomas, the peritoneal tumors contain less ER and PR, and exhibit a stronger expression of Ki-67, and a higher overexpression of HER-2/neu.¹¹⁶

Although desmoplastic small round-cell tumors (DSRCTs) with divergent differentiation occur mainly in young males, a few of these tumors have developed in females and have presented clinically as primary ovarian tumors.117,118 At operation, there was extensive extraovarian disease in all the reported cases, and, despite combination chemotherapy, most patients died of tumor within 2 years of diagnosis. The tumor cells have the translocation t(11;22)(p13;q12), which results in fusion of the Ewing sarcoma and Wilms’ tumor genes (EWS–WT1).¹¹⁹ Microscopically, the metastatic tumor shows discrete aggregates of small cells surrounded by a desmoplastic stroma (Figures 30.52 and 30.53). The tumor cells are small with hyperchromatic nuclei, inconspicuous nucleoli, and scanty cytoplasm. Mitotic figures are numerous. Since many ovarian tumors are characterized by small cells, there is a wide range of differential diagnoses. A prominent nesting pattern of small cells in a desmoplastic stroma, as well as a young age of the patient, should lead to consideration of this tumor. The immunophenotype of the DSRCT is quite characteristic: the tumor cells stain for CKs (Figure 30.54) and epithelial membrane antigen, for neuron-specific enolase, and for desmin (Figure 30.55). Immunostain for actin is negative.

Unusual metastases to the ovary have included small cell carcinoma of the lung, adenoid cystic carcinoma of salivary gland origin, neuroblastoma, alveolar and embryonal rhabdomyosarcomas, leiomyosarcoma, angiosarcoma, Ewing sarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, and ependymoma (Figures 30.56 and 30.57).³

Extragenital Sarcomas

Sarcomas rarely metastasize to the ovaries and are more likely to be primary tumors at that site. An exception to this is the gastrointestinal stromal tumor.¹²⁰ The differential diagnoses include cellular and typical fibromas, smooth muscle tumors, and other primary soft-tissue-type tumors. In cases of bilateral tumors or extraovarian disease, immunohistochemistry for c-kit helps to rule out the possibility of a gastrointestinal stromal neoplasm. Leiomyosarcomas from stomach, small bowel, and retroperitoneum may occasionally metastasize to the ovary.⁹⁶ Also isolated examples of fibrosarcoma of the anterior abdominal wall, sarcoma of the mesentery, angiosarcoma of the heart, osteosarcoma of the maxilla, chondrosarcoma of the rib, Ewing sarcoma of a pubic bone, angiosarcoma,¹²¹ alveolar rhabdomyosarcoma,^82,122 Ewing sarcoma of the fibula,⁸² chordoma,¹²³ and malignant hemangiopericytoma.¹²⁴ In children, rhabdomyosarcoma is said to be the most common sarcoma to spread to ovary.⁸² Metastatic retinoblastoma is also known.^122,125

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