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