Metastatic Ovarian Carcinoma of Large Intestinal Origin Simulating Primary Ovarian Carcinoma

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1 ANATOMIC PATHOLOGY Original Article Metastatic Ovarian Carcinoma of Large Intestinal Origin Simulating Primary Ovarian Carcinoma A Clinicopathologic Study of 25 Cases DEAN DAYA, M.D., F.R.C.P.(C), LATIFA NAZERALI, M.D., F.R.C.P.(C), AND GEORGE L. FRANK, M.B., CH.B., F.R.C.P.(C) The distinction of metastatic ovarian carcinoma from a primary malignant ovarian neoplasm is crucial to its subsequent management. The most common metastatic carcinoma that mimics primary ovarian carcinoma is that of large bowel origin. The clinical and pathologic features of 25 cases of intestinal adenocarcinoma metastatic to the ovaries were analyzed. The patients ranged in age from 47 to 80 years (average age, 60 years). Most patients had abdominal pain and a pelvic mass. In 56%, the ovarian tumors and the large bowel carcinomas were discovered synchronously; 44% were metachronous. Seventy-five percent of the tumors were unilateral. Gross examination revealed that all the ovarian tumors were solid and cystic with smooth outer surfaces. Most of the tumors showed hemorrhage and necrosis. Histologic examination showed that 13 cases had a predominantly endometrioid-like pattern, four cases were predominantly mucinous, and the rest demonstrated a mixed pattern. The presence of a garland pattern with cribriform areas and "dirty" necrosis were the most distinctive features that were helpful in correctly differentiating these tumors from primary endometrioid ovarian carcinoma, with which they are often confused. Immunohistochemical stains for carcinoembryonic antigen showed strong intracytoplasmic positive staining in all the cases of intestinal adenocarcinoma metastatic to the ovaries, in contrast to primary ovarian endometrioid carcinoma, which stain negatively for carcinoembryonic antigen or show only intraluminal or apical positivity. As expected, intestinal adenocarcinoma metastatic to the ovaries had a very poor prognosis. Seventy percent of the patients died within a period of 1 to 19 months (average, 8.2 months). Its distinction from primary ovarian carcinoma is crucial because the management and prognosis of metastatic ovarian carcinoma of large intestine origin is different. (Key words: Metastatic ovarian carcinoma; Primary ovarian cancer; Endometrioid-like pattern; Carcinoembryonic antigen) Am J Clin Pathol 1992; 97: Although the clinical and pathologic features of Krukenberg tumor are well documented in the literature, 1 only one study has critically analyzed the clinical and pathologic features of ovarian metastases from carcinoma of the large intestine. 2 Approximately 7% of all ovarian masses encountered by the surgeon are metastatic, usually from the gastrointestinal tract. 3,4 Metastatic ovarian carcinomas from the large bowel simulate primary ovarian carcinomas, especially the endometrioid and mucinous types, when examined grossly and microscopically. Indeed, even after microscopic examination, some of these are misdiagnosed as primary epithelial ovarian cancer. 2 ' 4 This study was designed to analyze the clinical and pathologic features of 25 ovarian metastases from carcinoma of the large bowel and to characterize the salient features that might aid in differentiating such tumors from primary epithelial ovarian carcinomas. MATERIALS AND METHODS The cases were obtained from the surgical pathology From the Department of Pathology, Hamilton Civic Hospitals, Hen filederson General Division, and McMasler University, Hamilton, Ontario, Civic Hospitals, which were reported as metastatic car of the Henderson General Division of the Hamilton Canada. cinoma, and from the cases referred to the Hamilton Regional Cancer Centre, in which a diagnosis of primary Received July 23, 1991; received revised manuscript and accepted for publication September 16, versus secondary carcinoma was questioned. Only cases Address reprint requests to Dr. Daya: Section of Anatomic Pathology, Hamilton Civic Hospitals, Henderson General Division, 711 Concession with a documented primary carcinoma of large intestine Street, Hamilton, Ontario, L8V 1C3, Canada. metastatic to the ovaries were selected for this study. 751

2 752 ANATOMIC PATHOLOGY Article Twenty-five cases were identified. Between 10 and 15 hematoxylin-and-eosin-stained slides were available for review in each case. In addition, special stains for periodic acid-schiff, with and without diastase digestion (PAS-D), and mucicarmine were performed. Immunohistochemical stains for polyclonal adsorbed carcinoembryonic antigen (CEA) (Dako, Carpenteria, CA; 1:25) using the peroxidase anti-peroxidase method (PAP) were performed in 17 cases. Appropriate positive and negative control tests were performed. Follow-up was available in 20 of the 25 cases. Clinical Features RESULTS The patients ranged in age from 47 to 80 years (average age, 60 years). The most common symptom was abdominal pain, occurring in 18 patients. Ten patients had a pelvic mass; eight patients had signs and symptoms of intestinal obstruction. Other problems that prompted medical attention occurred in a few cases and included changes in bowel habit (two cases), anemia (two cases), rectal bleeding (one case), ascites (one case), and urinary symptoms (one case). In two patients, the tumor was detected as an incidental finding one during hysterectomy for endometrial hyperplasia and the other during resection of a colonic polyp in a patient with previously diagnosed large bowel adenocarcinoma. In 14 cases (56%), the ovarian tumor and the large bowel carcinoma were discovered synchronously. Eleven cases were diagnosed after surgical resection of the intestinal adenocarcinoma. In these metachronous cases, the time interval between the primary and secondary tumor ranged from 2 months to 2 years (average interval, 11 months). In three cases the ovarian tumor was diagnosed as primary endometrioid carcinoma at the time of frozen section. This diagnosis was changed after clinical information became available. Thirty-five percent of the primary intestinal carcinomas occurred in the rectosigmoid area and an equal percentage occurred in the cecum. Other sites included splenic flexure, transverse colon, and descending colon (8.7% in each of these areas). Liver metastasis was documented at the time of operation in 50% of the patients. All the patients were managed surgically; in addition, eight patients received postoperative adjuvant chemotherapy or radiotherapy, except one patient who was given cyclophosphamide and cisplatin. This case was misdiagnosed as primary papillary serous carcinoma of the ovary. The treatment was discontinued after three cycles of chemotherapy when signs and symptoms of renal failure occurred. FIG. 1. Gross appearance of metastatic ovarian carcinoma of large intestinal origin showing a solid and cystic pattern. Follow-up information, which was available in 20 of 25 cases, revealed that 14 of the 20 patients (70%) died within a period of 1 to 19 months (average, 8.2 months). Three patients were alive and well; three other patients had recurrences after a period of 3 to 14 months. PATHOLOGIC FINDINGS Gross Features The tumors ranged in size from 2.5 to 25 cm (average, 15 cm) in greatest dimension. The outer surfaces were described as being smooth and glistening, sometimes with serosal congestion and hemorrhage. All the tumors were solid and cystic (Fig. 1). The cut surface revealed hemorrhage and necrosis in 70% of the cases, accompanied by friable, mushy, yellow, red, or gray areas. Ten percent of the tumors ruptured during removal. Seventy-five percent of the tumors were unilateral. Microscopic Features The major histologic features are listed in Table 1. Three subtypes were identified. Thirteen cases had a predominantly endometrioid-like pattern (Fig. 2), four cases were A.J.C.P. June 1992

3 DAYA, NAZERALI, AND FRANK 753 Metastatic Ovarian Carcinoma TABLE 1. MAJOR MICROSCOPIC FINDINGS IN 25 CASES OF METASTATIC OVARIAN CARCINOMA OF LARGE INTESTINAL ORIGIN Histologic Features Garland Cribriform Dirty necrosis Intraluminal Segmental Confluent Endometrioid Type (n = 13) 92% Mucinous Type (n = 4) 50% Mixed Type (n = 8) 43% 71% 86% predominantly mucinous carcinomas (Fig. 3), and the others showed a mixed pattern. Necrosis, exhibiting several different patterns, i.e., intraluminal, segmental, and confluent, was a diagnostically constant feature of these tumors (Fig. 4). A particularly useful feature was the presence of so-called "dirty" necrosis (Fig. 5), consisting of eosinophilic karyorrhectic debris due to breakdown of carcinoma cells within the glandular lumens, which was noted in of endometrioid type, in 50% of the mucinous type, and in 86% of the mixed type. A garland pattern that contained necrotic debris surrounded by an array of round tubular glands was noted in every case (Fig. 6). Another feature that was present in 90% of the cases was a cribriform pattern (Fig. 2), showing uniformly sized glands with rounded edges. In the endometrioidlike type of these tumors, there were often many mitoses per unit area of the tissue, even in the architecturally welldifferentiated component of the tumor (Fig. 7). Mucinous tumors showed abundant extracellular mucin extruding from the mucinous glands. These glands were lined by stratified, atypical, tall columnar, mucin-producing cells. Besides the obvious cytologically malignant mucinous epithelium, approximately 20% of the cases showed a rather banal mucinous epithelium (Fig. 8), although this was a minor component of the tumor. Table 2 is a list of minor microscopic findings. Two cases had focal areas showing a distinct papillary pattern (Fig. 9). Stromal luteinization of varying degrees showing round or polyhedral cells with eosinophilic to pale cytoplasm was noted in one half of the cases. This was seen mainly in tumors showing an endometrioid-like pattern but was also present in mixed and mucinous types. Signet ring cells were focally present in 10% of the cases. None of the cases showed squamous metaplasia. Histochemical stains for mucin (PAS-D and mucicarmine) showed strong positive intraluminal and intracytoplasmic staining in all of the four pure mucinous types. Tumors that showed endometrioid-like patterns demonstrated intraluminal and apical mucin. Intracytoplasmic mucin in this type was detected only in cells showing goblet cell and signet ring differentiation. The mixed type had a staining pattern showing luminal, apical, and intracytoplasmic features corresponding to the histologic appearance. Immunohistochemical stain for CEA showed marked intraluminal and intracytoplasmic positivity (Fig. 10) in all 17 cases, although the distribution of intracytoplasmic positivity was focal in some cases. DISCUSSION The frequency and distribution of metastatic ovarian carcinoma will depend on several factors, including the incidence of primary cancer in the general population as well as the demographic and epidemiologic characteristics of the population studied. For example, ovarian metastases from intestinal carcinoma have been reported to be less common than those from gastric carcinoma at autopsy: 14% versus 38%, respectively. 5 However, when malignant ovarian tumors encountered at the time of operation are studied, metastases from intestinal carcinomas are almost five times as frequent as those from gastric carcinomas. 6 " 10 In one large series of 357 patients with secondary ovarian carcinoma, Webb and associates 8 found the largest group (47.3%) to be primary in the gastrointestinal tract, of which 38% were colorectal and 8.1% were from the stomach. Up to 10% of patients with intestinal carcinoma have ovarian metastases at some time during the course of their disease."" 17 Patients with intestinal adenocarcinoma metastatic to the ovary may be classified as follows: (1) those in whom an intestinal carcinoma precedes the detection of ovarian tumor, (2) those in whom the ovarian involvement is detected synchronously at the time of operation for large FIG. 2. Metastatic ovarian carcinoma of large intestinal origin showing an endometrioid-like pattern. The glandular structures are rounded and also show a cribriform pattern (hematoxylin and eosin, XI00). Vol. 97 No. 6

4 754 ANATOMIC PATHOLOGY Original Article FIG. 3 (upper left). Metastatic ovarian carcinoma, of large intestinal origin, showing mucinous differentiation (hematoxylin and eosin, X100). FIG. 4 (upper right). Segmental necrosis (hematoxylin and eosin, XI00). FIG. 5 (lower left). Intraluminal "dirty" necrosis consisting of karyorrhectic debris (hematoxylin and eosin, XI00). FIG. 6 (lower right). Garland pattern: cystically dilated glandular structures containing "dirty" necrosis (hematoxylin and eosin, XI00). A.J.C.P.-June 1992

5 755 DAYA, NAZERALI, AND FRANK Metastatic Ovarian Carcinoma» # > i^iji^l <3 :v ^ >, < * :>?,' **tfk -i/k "* <ft' ;$ /) t *..;m X <t * ~ i,9."* FIG. 8 (upper right). Mucinous subtype of intestinal?; adenocarcinoma metastatic to the ovary showing a rather banal mucinous epithelium (hematoxylin and eosin, X250). 9 %\ '-^ T_. FIG. 9 (lower left). Intestinal adenocarcinoma metastatic to the ovary, mixed type, showing papillary pattern simulating primary serous carcinoma of the ovary (hematoxylin and eosin, XI00). FIG. 10 (lower right). Immunohistochemical stain with adsorbed polyclonal anti-cea antiserum showing strong positive luminal and intracytoplasmic staining in an endometrioid-like intestinal adenocarcinoma metastatic to the ovary (hematoxylin and eosin, X400). tf % "» > A. * ^ ^, * f t. y» t Yl V *"& * o^- *V f ',# V*. 1 FIG. 7 (upper left). Highpower view of endometrioid type of intestinal adenocarcinoma metastatic to the ovary showing many mitoses in the purely glandular component (hematoxylin and eosin, X250). v,,f ~.»»' :-'.V ^!.»'.:.' > i, '..Hr.*... ' ;^"^C"^y-, X '. r " '. ;. v - rjf.- ' *.* t ' E *. * * e ' ; '?<.» T* *- >, ' ; 'V, r VrS " ' i ' ' V r? u ' *" ' i M.7 * ' *. '.... <;'? ". 'v :? :r-i}}..,'.-f^ ' i- i i'' v* <i' ^ Vol. 97 No. 6!

6 756 ANATOMIC PATHOLOGY Original Article TABLE 2. MINOR MICROSCOPIC FINDINGS IN 25 CASES OF METASTATIC OVARIAN CARCINOMA OF LARGE INTESTINAL ORIGIN Finding Desmoplasia Stromal luteinization Goblet cells Signet ring cells Papillary pattern Microcalcification Foci of banal epithelium Percentage bowel carcinoma, and (3) those whose initial manifestations are those of an ovarian tumor (3% to 20%). 18 ~ 20 From a clinical standpoint, it is important to emphasize that a thorough clinical history will help to resolve the distinction between primary and secondary ovarian carcinomas in most cases. However, it is not uncommon that a complete history is not made available to the pathologist before or at the time of surgery. Sometimes, even the surgeon may not be aware that the patient has had a previous operation for carcinoma of the large bowel. In 1987, Lash and Hart 2 described the clinical and pathologic features of 22 cases of metastatic intestinal adenocarcinoma to the ovaries. On gross examination, almost all of the tumors were solid and cystic, had a smooth outer surface, and one half were at least partly necrotic and had hemorrhagic areas. Fifty-seven percent of their cases were unilateral. Seventy-five percent of cases in our series were unilateral and the gross appearance of these tumors was similar to their findings. From the gross viewpoint it is important to emphasize that intestinal adenocarcinoma metastatic to the ovaries mimics primary ovarian carcinoma. Unlike Krukenberg tumors, which, in most cases, are bilateral and have a solid and multinodular appearance, ovarian metastases from large bowel are often solid and cystic with a smooth outer surface. Roughly 60% of the tumors described by Lash and Hart 2 were discovered synchronously at the time of operation for resection of primary bowel carcinoma, and 40% were metachronous. The corresponding figures in our series are 56% and 44%, respectively. Histologically, the predominant type in their study showed an endometrioidlike pattern. The authors emphasized the presence of garland formation, "dirty" necrosis, and a cribriform pattern as distinctive features that help to separate them from primary endometrioid ovarian carcinoma. The histologic features in our series confirm these findings. In addition, in metastatic intestinal adenocarcinoma, the glands are lined by more poorly differentiated cells that are more highly stratified, and contain more mitoses per unit area than those of primary endometrioid ovarian carcinoma. Also, extensive necrosis is more common in metastatic intestinal adenocarcinomas but uncommon in glandforming endometrioid carcinomas. 21 Although these histologic features are not pathognomonic of intestinal adenocarcinoma metastatic to the ovaries, their presence is highly predictive of metastatic carcinoma. Young and Scully 22 have reported similar histologic features in ovarian metastases from carcinomas of the gallbladder and extrahepatic bile ducts and from pancreatic carcinomas. 23 The authors emphasize that such tumors are bilateral in most cases and show multinodularity and surface implants. Two of our cases showed a distinct papillary configuration and both were diagnosed erroneously as primary papillary serous carcinoma of the ovary. In these two cases, the papillary component of the tumor was focal but other areas of the tumor showed "dirty" necrosis and garland formation, typical of intestinal adenocarcinoma metastatic to ovaries. Another useful feature is the presence of squamous metaplasia, which occurs in up to 50% of primary endometrioid ovarian carcinoma 24 but is distinctly rare in metastatic intestinal adenocarcinoma of the ovaries. Squamous metaplasia was not present in any of the cases in our series not in that reported by Lash and Hart. 2 We have seen only one case of squamous metaplasia in metastatic ovarian carcinoma from the large bowel, and in this case the primary intestinal carcinoma also showed pronounced squamous differentiation. Stromal luteinization was present in 50% of our cases, similar to the findings of Scully and Richardson. 7 This is a nonspecific feature that is also frequently present in primary mucinous and endometrioid ovarian carcinoma. 24 The distinction of metastatic ovarian carcinoma of the mucinous type from a primary ovarian mucinous carcinoma can be very difficult. Aside from the clinical history, the presence of glands and cysts lined by endocervicaltype mucinous cells with basal nuclei strongly favors a primary mucinous carcinoma. Although most cases of metastatic ovarian carcinomas show cytologically malignant mucinous epithelium, 25% of our cases and 4 of the 23 cases by Lash and Hart 2 showed benign-appearing mucinous epithelium. These changes have been described by other authors. 4 ' 24 We have seen one case in which a diagnosis of benign mucinous cystadenoma was made in a patient who first came to us with a unilateral ovarian cyst. On review, this case also showed histologic changes consistent with mucinous cystadenoma of borderline malignancy with large amounts of colloid material. A year later, she had abdominal pain and change in bowel habits. Laparotomy revealed that the sigmoid colon contained a palpable mass, which was resected. Pathologic examina- A.J.C.P..June 1992

7 DAYA, NAZERALI, AND FRANK 757 Metastatic Ovarian Carcinoma tion showed a large colloid carcinoma of the sigmoid colon. The contralateral ovary showed features of a mucinous cystadenocarcinoma with histologic features of benign, borderline, and invasive mucinous adenocarcinoma of the ovary. A review of the slides of the ovarian tumor showed "dirty" necrosis and a garland pattern reminiscent of metastatic ovarian carcinoma from the large bowel. Although goblet cells are encountered more commonly in primary mucinous carcinomas, they also may be seen in metastatic mucinous tumors. Special stains for mucin are not very helpful in distinguishing primary from secondary lesions because mucin is present intraluminally and within the cytoplasm in primary and secondary tumors of the mucinous type. In tumors showing an endometrioid-like pattern, mucin positivity is primarily intraluminal and found on the surfaces of the cells. Intracytoplasmic mucin is seen only in a few cells and in those that show goblet cell differentiation. Primary endometrioid ovarian carcinomas also may show a similar staining pattern for mucins. 24 Immunohistochemical staining for CEA is useful in differentiating primary endometrioid ovarian carcinomas from metastatic cancers in that metastatic carcinomas show very strong positive staining of both intraluminal and intracytoplasmic areas. 2,25 " 28 Primary endometrioid ovarian carcinomas may show focal positive intracytoplasmic staining, but never to the degree seen in metastatic carcinoma from the large bowel. Unfortunately, the use of CEA in the mucinous type of metastatic ovarian carcinoma is not helpful because primary and secondary mucinous ovarian carcinomas stain very strongly positive for CEA. 2 It is crucial that an accurate diagnosis be made because the management and treatment of primary epithelial carcinoma is different from metastatic carcinoma. In some centers, patients with primary ovarian carcinomas receive cisplatin-based chemotherapy after surgery, whereas patients with intestinal adenocarcinoma metastatic to the ovaries are treated with radiotherapy and chemotherapy, which often includes 5-fluorouracil. 29 The prognosis of metastatic intestinal adenocarcinoma to the ovaries is dismal. Seventy percent of the patient in our series died of the disease within a period of 1 to 19 months (average, 8.2 months). On the other hand, primary endometrioid ovarian carcinoma (Stages I and II), with which this entity may be easily confused both clinically and pathologically, has a very good prognosis, with a 5-year survival rate of up to 80%. 30 If a pathologist is confronted with a unilateral ovarian mass that is cystic and solid at the time of frozen section and shows the distinctive histologic features mentioned above, the surgeon should be asked if the patient has had a previous colonic carcinoma. Even with a negative history it would be prudent for the surgeon to palpate the large bowel carefully for a possible primary colon carcinoma because the microscopic features described may be the first indication that the patient has a metastatic ovarian malignancy. Furthermore, the presence of hepatic metastases also would favor intestinal adenocarcinoma metastatic to the ovary because primary ovarian carcinomas rarely demonstrate clinically apparent liver metastasis, even in Stage III and Stage IV. REFERENCES 1. Holtz, F. Hart WR. Krukenberg tumors of the ovary: A clinicopathologic analysis of 27 cases. Cancer 1982;50: Lash RH, Hart WR. Intestinal adenocarcinomas metastatic to the ovaries: A clinicopathologic evaluation of 22 cases. Am J Surg Pathol 1987;11: Santesson L, Kottmeier HL. General classification of ovarian tumors. In: Gentil F, Junqueira AC, eds. Ovarian Cancer (UICC Monograph Series, volume 11). Berlin: Springer-Verlag, 1968, pp Ulbright TM, Roth LM, Stehman FB. 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