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. 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. 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 old and in another about 43% were under 50 years. 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 ).

Metastatic carcinoma from the colon. Solid and cystic tumor with extensive necrosis and focal hemorrhage.

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 ). 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.

Metastatic adenocarcinoma from the colon. Garland-like glandular pattern with focal segmental necrosis of glands and abundant necrotic debris.

Metastatic adenocarcinoma from the colon. Focal segmental necrosis of glands and luminal necrotic debris (‘dirty necrosis’).

Metastatic adenocarcinoma from the colon. The glandular epithelium shows papillary growth and striking nuclear atypia (grade 3).

Metastatic adenocarcinoma from the colon. Neoplastic glands lying in a desmoplastic stroma.

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. 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 ).

Metastatic carcinoma from the cecum. Multilocular mucinous cystic tumor with focal necrosis simulating an ovarian mucinous cystadenocarcinoma.

Metastatic adenocarcinoma from the colon. The mucinous glands are indistinguishable from those of a primary ovarian mucinous carcinoma. Mitotic figures are seen.

Metastatic adenocarcinoma from the colon. Ovarian surface involvement by mucinous epithelial cells (surface implant).

Krukenberg tumor. Vascular space invasion. Numerous signet-ring cells lie in the ovarian stroma.

Metastatic adenocarcinoma from the small intestine. (A) Tubular glands lined by vacuolated cells resembling those of a secretory endometrioid carcinoma. Note the presence of stromal luteinization. (B) Typical Krukenberg tumor component encountered after additional sampling. Numerous signet-ring cells with eccentric nuclei and pale vacuolated cytoplasm are seen.

Immunohistochemistry

Immunohistochemical stains can be helpful in distinguishing primary adenocarcinoma of the ovary from metastatic colorectal adenocarcinoma ( Table 30.2 ). Cytokeratin (CK) immunostains are the most commonly used. Primary ovarian carcinomas are almost always immunoreactive for CK7 whereas colorectal adenocarcinomas are usually CK7 negative. Mucinous adenocarcinomas of the ovary may be immunoreactive for CK20, but the reaction is typically weak and focal. Endometrioid adenocarcinomas are almost invariably CK20 negative. In contrast, colorectal adenocarcinomas are diffusely and strongly reactive for CK20. Therefore, a CK7-positive/CK20-negative immunoprofile favors a primary ovarian carcinoma, whereas a CK7-negative/CK20-positive immunoprofile suggests metastatic adenocarcinoma ( Table 30.2 ). Although the vast majority of colorectal adenocarcinomas express CK20, poorly differentiated and right-sided tumors can be CK20 negative. Furthermore, adenocarcinomas of the appendix, small intestine, and stomach can be CK7 positive. Thus, immunostains for CK7 and CK20 should be interpreted with caution, always in the light of all clinical information, and with the understanding that no tumor shows absolute consistency in its staining with these markers.

Table 30.2

Primary Ovarian Carcinomas versus Metastatic Gastrointestinal Carcinomas (Immunophenotypes)

Tumor	CK7	CK20	CA125	MUC5AC	CEA	CDX2	ER
Ovarian Carcinoma
Serous	+	−	+
Mucinous	+	+	±	±	+	±
Endometroid	+	−	+		−	±	+
Metastatic Carcinoma
Colon–rectum	−	+	−	−	+	+	−
Stomach	+	±	−	+	+	+
Appendix	±	+	−	±	+	+
Pancreas	+	+	−	+	+	+

 

CK7, cytokeratin 7; CK20, cytokeratin 20; + usually positive; − usually negative; ± can be positive or negative, but often positive; ± can be positive or negative, but often negative.

Other immunohistochemical stains have greater overlap in their expressions and should not be used individually in this differential diagnosis. Nevertheless, after taking into account the clinicopathologic findings and the results of the CK immunostains, negative stainings for vimentin CA125 and gastric mucin gene MUC5AC , and strongly positive staining for carcinoembryonic antigen (CEA) ( Figure 30.12 ) favor metastatic colorectal cancer over primary ovarian adenocarcinoma ( Table 30.2 ). Likewise, strong immunoreactivity for P53 ( Figure 30.13 ) supports the colonic origin of the neoplasm. CDX2 is often strongly and diffusely positive in colorectal carcinomas, but it can also be positive in ovarian mucinous and endometrioid tumors. Estrogen receptors (ERs) may be helpful for distinguishing endometrioid adenocarcinomas from metastatic intestinal carcinomas, as the former are usually positive and the latter are negative.

Metastatic adenocarcinoma from the colon. Strong immunoreaction for CEA.

Metastatic adenocarcinoma from the colon. Positive immunoreaction for P53.

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. 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. 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.

Krukenberg tumors are bilateral in 60–80% of the cases. 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.

Krukenberg tumor. Bilateral multinodular tumors.

Krukenberg tumor. The cut surface shows solid beige-yellow tissue with small foci of hemorrhage.

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 found ( Figure 30.19 ) and, occasionally, there is a predominant tubular architecture (tubular Krukenberg tumor) ( Figure 30.20 ). The stromal cells are plump, spindle shaped, and are sometimes extensively luteinized.

Krukenberg tumor. Numerous signet-ring cells with pale cytoplasm are arranged irregularly within a cellular stroma.

Krukenberg tumor. The signet-ring cells have eosinophilic cytoplasm and are distributed singly or in nests.

Krukenberg tumor. The ovarian stroma shows extensive edema.

Krukenberg tumor. Small glands lined by moderately atypical epithelial cells are admixed with signet-ring cells.

Tubular Krukenberg tumor. The tubular glands are lined by markedly atypical cells. The intervening clusters of luteinized stromal cells contribute to the resemblance to a Sertoli–Leydig cell tumor.

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. 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. 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. 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.

Krukenberg tumor. A PAS–diastase stain demonstrates the mucin in the vacuolated tumor cells.

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. 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. 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. In the largest series reported, the age of the 35 patients ranged from 21 to 82 years, with a median of 57 years. 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. 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 carcinoid tumor from the pancreas. The sectioned surfaces are solid and white-yellow simulating those of a fibroma or thecoma.

Metastatic mucinous carcinoid tumor from the appendix. The ovary is partly replaced by a nodule of dense fibrous tissue containing scattered small glands.

Metastatic mucinous carcinoid tumor from the appendix. Small glands lined by flat to cuboidal mucinous epithelium and occasional goblet cells. The intervening stroma appears fibromatous.

Metastatic mucinous carcinoid tumor from the appendix. Positive chromogranin immunoreaction.

Metastatic carcinoids can be confused with primary carcinoids ( Table 30.3 ), granulosa cell tumors, Sertoli–Leydig cell tumors, Brenner tumors, adenofibromas, or endometrioid carcinomas. 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.

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.

Metastatic carcinoma from the breast. Several nests of carcinoma cells are seen in the highly vascular theca layer of a Graafian follicle.

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. The very rare cases of metastases that present clinically as primary ovarian tumors before the detection of the breast carcinoma often pose diagnostic difficulty. 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.

Metastatic carcinoma from the breast. The sectioned surface appears solid and multinodular.

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 ), 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, α-inhibin, myeloperoxidase, and lymphoid markers favor metastatic breast carcinoma. Mammaglobin is expressed in about 50% of breast carcinomas. However, its expression has been demonstrated in rare ovarian serous carcinomas and in endometrioid carcinomas of the uterine corpus. 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. Both breast and ovarian carcinomas may be positive for CK7. A panel of markers is recommended as no currently available individual marker is entirely specific for breast or ovarian carcinomas.

Metastatic carcinoma from the breast, lobular type. The tumor cells show a single-file arrangement.

Metastatic carcinoma from the breast, lobular type. Scattered tumor cells are immunoreactive for gross cystic disease fluid protein (GCDFP-15).

Metastatic carcinoma from the breast. Positive immuno­reaction for estrogen receptor protein (ERPr).

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. 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. 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 reported ( Figure 30.33 ). Metastatic adenocarcinomas of the gallbladder and extrahepatic bile ducts are very rare. Recently, however, a series of cases has been reported. They are usually solid tumors that microscopically may simulate ovarian mucinous ( Figure 30.34 ) or endometrioid carcinomas, or even cystadenofibromas. Rarely, Krukenberg tumors originate in the pancreas or biliary tract. 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.

Metastatic carcinoma from the pancreas. Multiloculated cystic tumor simulating a primary mucinous tumor.

Metastatic carcinoma from the pancreas. The lining epithelium resembles that of a mucinous intestinal borderline tumor. Note the condensation of the ovarian stroma adjacent to the tumor.

Metastatic acinar cell carcinoma from the pancreas. High-power view of typical small acini and cystic glands.

Metastatic intrahepatic cholangiocarcinoma. (A) Proliferation of mucinous epithelium with filiform branching papillae simulating an ovarian mucinous borderline tumor. (B) The mucinous intestinal epithelium shows stratified cells with moderate nuclear atypia.

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. The presence of bile in the ovarian tumor favors metastatic hepatocellular carcinoma.

Tumors of the Appendix

Metastatic tumors from the appendix are rare and represent only 1–2% of ovarian metastases. Most of these cases are mucinous tumors of borderline malignancy (low-grade mucinous tumors) associated with pseudomyxoma peritonei (see Chapters 26 and 31 ). Other appendiceal tumors that may spread to the ovary include mucinous (goblet cell) carcinoids and, less frequently, adenocarcinomas of signet-ring cell ( Figure 30.35 ), mucinous intestinal, and colorectal types ( Figure 30.36 ). 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.

Metastatic adenocarcinoma from the appendix, signet-ring cell type.

Metastatic adenocarcinoma from the appendix, colorectal type.

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. 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 ). Although appendiceal tumors are almost always diffusely positive for CK20, they may also be positive for CK7 in approximately one-third of cases.

Metastatic low-grade mucinous tumor from the appendix. Multiloculated cystic tumor with abundant mucoid material.

Metastatic low-grade mucinous tumor from the appendix. (A) The mucinous cells are tall and lack nuclear atypia. (B) Mucin appears to be discharged from the apical pole of the columnar cells.

At surgery, the primary appendiceal tumor is often overlooked because the ovarian tumors are usually much larger. 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. 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 ).

Metastatic papillary renal cell carcinoma. (A) The renal clear cell carcinoma lacks hobnail cells, hyalinized papillae, and intraluminal mucin. (B) Lymph node metastasis showing a strong racemase immunoreaction.

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+). 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.

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. 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 thrombomodulin and they are typically negative for WT1.

Metastatic transitional cell carcinoma from the renal pelvis. This tumor is indistinguishable from a primary transitional cell carcinoma.

Adrenal Gland Tumors

Neuroblastoma is the adrenal tumor that most frequently metastasizes to the ovary. 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. Pheochromocytomas spread to the ovary even less commonly.

Malignant Melanoma

Three series of melanomas metastatic to the ovary including 52 cases have been reported. 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. Positive stains for melanin, S-100 protein ( Figure 30.41 ), Melan A, and/or HMB-45 should establish the diagnosis of melanoma.

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