Carcinoid metastatic to the ovary.A clinicopathologic analysis of 35 cases

CARCINOID METASTATIC T O T H E OVARY A Clinicopathologic Analysis of 35 Cases

HENRY J. NORRIS, MD

STANLEY J. ROBBOY, MD (MAJOR, hlC), ROBERT E. SCULLY, MD, AND

Thirty-five cases of carcinoid metastatic to the ovary were analyzed from a clinicopathologic viewpoint. In 25 patients the ovarian tumors were discovered at laparotomy; in the remaining cases, t he ovarian involvement was detected only at autopsy as a manifestation of widespread metastasis. Although one ovary was almost always enlarged, the opposite ovary was frequently enlarged also. Both ovaries contained tumor with only two exceptions. Abnormal urinary levels of 5-hydroxyindole acetic acid were of ten detected within several months after the operation. In al l but five cases evidence for a pr imary carcinoid in the intestine or elsewhere was found. The prognosis was poor, with one-third of the patients dying within 1 year, and two-thirds within 4 years af ter the diagnosis of ovarian involvement. Although a metastatic ovarian carcinoid is of ten misinterpreted as a Brenner tumor or granulosa cell tumor, the most difficult diagnosis t o exclude is primary carcinoid, which, in an unpublished series of 34 cases, was always unilateral and was usually associated with the presence of other teratomatous elements within the tumor.

VARIAN CARCINOIDS ARE RARE, ESPECIALLY 0 the metastatic forrns,l4 which almost always originate in the intestine. In a recent review, Shuster et al.25 found only 8 cases of metastatic ovarian carcinoid reported since 1955; a more complete survey of the literature has revealed a total of 25 cases.2-8,10,11,16,17,19, 20,22,24,26-29 When the ovarian tumor is dis-

From the Department of Pathology, Harvard Med- ical School, James Homer Wright Pathology Labora- tories, Massachusetts General Hospital, Boston; De- partment of Pathology, US. Ireland Army Hospital, Ft. Knox, Ky.; and Gynecologic and Breast Pathology Branch, Armed Forces Institute of Pathology, Wash- ington, D.C.

Supported in part by a Junior Faculty Fellowship from the American Cancer Society to Dr. Robboy.

Addrcss for reprints: S. J. Robboy, MD, Department of Pathology, Massachusetts General Hospital, Boston, Mass. 02114.

T h e opinions or assertions contained herein are the private views of the authors and are not to be con- strued as official or as reflecting the views of the De- partment of the Army or the Department of Defense.

T h e authors wish to thank the following physicians for permitting us to review their cases and providing additional clinical information and followup history: Case 1: Dr. Kenneth E. Droulard, Nampa-Canyon, Id., and Dr. J. Lesley Montgomery, Caldwell, Id.; Casc 4: Dr. Orn Arnar, Dr. Jonas Hallgrimsson, and Dr. Tomas A. Jonasson, Medical School, University of Ice- land, Reykjavik. Iceland; Case 5: Dr. David F. Alstott, Lafayette, Ind.; Case 6: Dr. R. T. J. Holl-Allen, T h e Queen Elizabeth Hospital, Edgbaston, Birmingham, England; Case 7: Dr. B. F. Quinn, Mater Misericordiae Hospital, North Sydney, Australia: Dr. Lillian Pang and Dr. Stretton Young, Tumour Reference Collection, Imperial Cancer Research Fund, Lincoln’s Inn Field,

covered at autopsy as a manifestation of wide dissemination of a known carcinoid, the correct diagnosis is straightforward. I n contrast, the microscopic appearance of an ovarian carcinoid has often been misinterpreted in patients who present with a pelvic mass, ex- hibit no clinical evidence of the carcinoid syndrome,30 and have a small primary tumor

London, England; Case 8: Dr. Mary Ellen Kirk, Mon- treal General Hospital, Montreal, Quebec, Canada; Case 9: Dr. E. B. Price, Jr., Dr. Giles D. Toll, and Dr. W. Donald Woodard, Denver, Colo.; Case 11: Major Bruce A. Friedman, 121 Evacuation Hospital, Seoul, Korea; Major Jaime Diaz, 406th Medical Lab- oratory, Camp Zama, Japan; Case 12: Dr. Gieuseppe G. Pietra and Dr. Alma L. Young, Philadelphia, Pa.; Case 13: Dr. R. F. Chard, Stockton, Calif.; Case 14: Dr. R. G. Carlstein and Dr. Martin Bradford, Norwood, Mass: Case 15: Dr. David J. Pines, Farmington, Mich.; Dr. Murray R. Abell, Ann Arbor, Mich.; Case 16: Dr. Joseph V. Casella, Wilmington, Del.; Case 17: Dr. Robert J . Mulvey, Naval Hospital, St. Albans. Queens, New York; Case 18: Dr. Malcolm B. Dockerty, Ro- chester, Minn.; Case 19: Dr. J. w . Beattie, Lawrence, Mass.; Dr. Julius Kay and Dr. David W. Wallwork, North Andover, Mass.; Case 2 0 Dr. George W. Evans and Dr. George A. Marks, Winchester, Mass.; Dr. Max J. Klainer, Stoneham, Mass.; Case 21: Dr. A. L. Wick- ens, Mt. Clcmens, Mich.; Dr. Floyd A. Poetter, Toledo, Oh.; Casc 22: Dr. Alfred T. Joseph and Dr. Morris W. Shapiro, Lexington, Mass.; Dr. William Dowd, Arling- ton, Mass.: Case 23: Dr. Joseph Tarride, Fort Worth, Tex.; Case 24: Dr. Jack Garfinkle, Sherman Oaks, Calif.; Case 25: Dr. Ludwig Gross, Dr. Rudolf Howard, and Dr. Vincent Kogan, Staten Island, N.Y.; Case 27: Dr. Marvin Shuster, Perth Amboy, N.J.; Case 29: Dr. Richard A. MacDonald, Worcester, Mass.; Cases 32-34: Dr. William C. Roberts, Bethesda, Md.

Received for publication July 3, 1973.

No. 3 CARCINOID METASTATIC TO OVARY - Robboy et nl. 799

of the intestine that escapes detection at operation. In some cases of this type, the correct diagnosis has not been made until a subsequent operation or autopsy has revealed the primary tumor.30 This report analyzes the clinical and pathologic features of 35 cases of metastatic ovarian carcinoid. In 30 cases a primary tumor outside the ovary has been found; in the remaining 5 cases, the site of the origin of tlie tumor has not been identified up to the present time.

MATERIALS AND METHODS

The files of the Massachusetts General Hos- pital yielded six cases?-fiJ7,Zi and that of the Armed Forces Institute of Pathology, nine cases. Eleven other tumors had been seen in private consultation by two of the authors. The microscopic slides and clinical data per- taining to the remaining nine cases were ob- tained ihrough the courtesy of the physicians who had already reported them in the litera-

The number of paraffin blocks ranged from 1 to 68 (median: 5) per case. Slides prepared from them were stained with hematoxylin and eosin (H & E); many of the sections were also stained for argentaffin granules by the ferric ferricyanide and Masson-Fontana techniques.

~~~~~0,10,15,10,20,2~-25,27.28

1<ESU I.TS

Age and Race The age at the time of discovery of ovarian

involvement ranged from 21 to 82 years. The median age was 57; only 3 patients were under 40. Ninety-three percent of the women were Caucasian and the remainder, Negro.

Symptoms and Past Medical History The 35 cases were divided into four groups.

The 10 patients in Group 1 (29%) had signs and symptoms of the carcinoid syndrome prior to the operation that revealed ovarian involvement (Table 1). The 15 patients in Groups 2 and 3 (427,) presented no evidence of this syndrome preoperatively. Evidence for a primary tumor in the intestine or pancreas was present in the 10 patients in Group 2 (Table 2), but not in the 5 in Group 3 (Table 3). The ovarian involvement was discovered in the 10 patients in Group 4 (297,) only at autopsy (Table 4); 8 of these patients had had the carcinoid syndrome.

Nine of the 10 women in Group 1 (Table

1) had intermittent diarrhea for 1 to 4 years. In 2 of them it had become progressively more severe during the several months prior to admission. Ankle edema of a few weeks’ to more than 6 months’ duration had developed in 4 patients. Two women experienced in- voluntary weight losses of 15 to 35 pounds, while another 2 had cardiac murmurs ascrib- able to carcinoid heart disease. Four patients complained of abdominal pain, and 1 had intestinal obstruction. A 5-hydroxyindole acetic acid (5-HIAA) test was not performed preoperatively in any of the cases. Only 2 of these 10 women (Cases 1 and 2) had under- gone a laparotomy within the 5 years prior to admission; ileal carcinoids had been discovered in both and segmental resection of the ileum had been performed.

The 15 patients without the carcinoid syndrome (Groups 2 and 3) had similar symptoms and signs prior to the operation at which ovarian involvement was discovered (Tables 2 and 3). The most common chief complaints, abdominal swelling and abdominal or back pain (7 cases), were related to the presence of a pelvic or abdominal mass. The tumor was detected on a routine physical examination in 5 cases. One patient had melena, and 2 intestinal obstruction. One patient (Case 14), who was shown subsequently to have an elevated urinary 5-HIAA level, had ankle edema but no other symptoms or signs of the carcinoid syndrome. Two patients had had a laparotomy during the previous year. In one (Case 16) no abnormality was detected. In the other (Case 17), metastatic carcinoid was found on the uterine serosa, but nowhere else; a test for urinary 5-HIAA was negative in this patient.

None of the 10 patients in Group 4 had symptoms or signs related to the presence of the ovarian tumor, but 8 of them had the carcinoid syndrome, 8 with diarrhea, 7 with cardiac abnormalities, and 6 with flushes (Table 4). Determinations of 5-HIAA, performed in 4 cases, were strongly positive (200-1250 mg/24 hr). Six patients had had a laparotomy 1 month to 9 years before death, at which time a primary carcinoid with extensive spread was found, but ovarian involvement was not yet apparent.

Findings and Therapy at Time Ovarian Metastases were Detected

Operative findings: The operative findings in the 25 patients with (Group 1) and without

, H, i

(no A)

+ 0 + 0

lo); p

n., tu

, H, r

t. ile

e z 2 0 L

) b7 ;." 2 0" z

802 CANCER March 1974 Vol. 33

TABLE 3. Patients without Carcinoid Syndrome Prior t o Surgical Discovery of Ovarian hfetastases; Primary Carcinoid not Identified

Operative findings and treatment

Max. ovarian Pelvic 5-HIAA diam. perit. Other (mg/24 hr)

Case # Age R , L (cm) tumor tumor Therapy (time postop.) Followu~i

AFIP 1219829

21. SCS-1031 26 5, 6 0 None BSO, H , A N D \i7e11 5.2 yr

22. SCS-586 73 12, 12 0 Mes., small BSO N D D 3.5 yr, ? cause

23. SCS-2668 82 7, 10 f Extens. perit., BSO N D D 0.2 yr (no A)

24. SCS-897 21 8, 10 0 Perit., liver BSO oment., 99 (2 mo) --t Pulm. murm. 2.2 yr ;

25. A F I P 55 4, 13 0 Large mass BSO, H , N D Diar. 1.6 yr; alive 1337703 base mes., chemorx., with distant met.

intest., perit. (110 A)

liver, tube

chemorx. 164 (5 mo) D 2.8 yr

liver X-ray rx. 1.9 yr

(Groups 2, 3) the carcinoid syndrome were similar in most respects (Tables 1-3). When the laparotomy was performed because of a pelvic mass, one ovary was usually appreciably larger than the other (14 2 4 vs. 6 rt 4 cm average greatest diameter). In contrast, when the operation was performed for reasons other than a pelvic mass, the involved ovaries were generally smaller and differed less in size (7 vs. 5 cm average greatest diameters). Peri- ovarian “adhesions” were observed in a third of the patients and sometimes contained tumor.

In addition to the 2 cases in which the primary tumor had been removed previously, it was identified or its presence was strongly inferred at laparotomy in 11 of the remaining 23 patients. In 7 cases (Cases 5, 6, 8, 11, 13, 17, and 18), the primary tumor was examined

microscopically, These patients had a nodule or thickening in the ileum, appendix, or cecum; a clue to the site of the primary tumor was gross enlargement of the adjacent mesenteric lymph nodes. In the remaining 4 patients, the diagnosis was only strongly inferred at the time of laparotomy. In 2 cases, the cecum was indurated. In one it was in direct continuity with the right ovary (Case 14), but was not removed. In the other case a subsequent operation established the presence of the primary carcinoid in the cecum (Case 7). I n the final 2 cases a segment of ileum was stretched around and obstructed by a mesenteric mass, 8 cm in diameter (Case ZO), or was obstructed by a group of smaller lymph nodes containing tumor (Case 19). The ileum was not removed in either case, but an intestinal bypass operation was performed.

TABLE 4. Patients in which Ovarian Metastases Were Discovered a t Autopsy

Max. ovarian Time of diagnosis Carcinoid 5-HIAA diam.

Case # Age of carcinoid syndrome* (mg/24 hr) R , L (cm) Primary tumor

26. MGH-A52032*4~6 27. ShusterZ5 28. Ritchiez2 29. M a c D ~ n a l d ~ ~ ~ ’ ~

31. AFIP-290508 32. Roberts ( # 8 ) 2 3

33. Roberts (#2)Z3

34. Roberts (#7)23 35. MGH-A234065

30. MGH-A2385924

43 49 58 46 72 64 52 50

Autopsy Autopsy Autopsy Arltopsy

Lap., 17 d. Lap., 2 yr. Lap., 2 yr. Lap., 2 yr.

Lap., 3 yr. Lap., 9 yr.

D H D F H D F H D D F H D F H

N D 4, 4 Ileum N D 2 , 2 Ileum N D 2, 2 Ileum ND 4, 4 Ileum POS 11, 5 Cecum N D AR, 2 t Appendix ( ? ileum) >200 AR, 4 Jejunum 294 -+ ?, 3 Ileum 1250 2 74 AB, 5 Ileum NeF: 5 , 1’ Cecum

* D = diarrhea, F = flush, H = heart + AB = surgically absent f no tumor identified

No. 3 CARCINOID METASTATIC TO OVARY - Robboy et al. 803

The followup section below presents the data for the seven patients in whom the primary tumor was found at a subsequent operation, and for the five in whom it has not been discovered to date.

Extensive seeding of the pelvic peritoneum was observed in 5 of the 10 patients with, but in only 2 of the 15 without, the carcinoid syndrome (x” = 4.0, p < 0.05). In another 7 cases (2 with ancl 5 without the syndrome) only isolated foci were found.

Abdominal metastases affecting the intestinal mesentery, omentum, and peritoneal surfaces were widespread in 16 (64%) of the 25 patients. In another 5 cases (20y0) the amount of tumor in the abdominal cavity was much less. Although no abdominal tumor was recorded in the remaining 4 patients (If?%), 2 had pelvic implants and inadequate information was available in the other 2 cases (Cases 16 and 21). Of importance, only rare or no liver metastases were detected by visual inspection in 5 of the 10 patients with the carcinoid syndrome. Ascitic fluid in amounts varying from “little” to several liters was observed in 24y0 of the patients; occasionally it was serosanguineous or dark brown.

Surgical therapy: Bilateral salpingo-oophorectomy was performed in 20 patients (SOYo) in Groups 1-3 (Tables 1-3). Of the 5 women (28%) who had only a unilateral salpingo- oophorectomy or a biopsy, the contralateral ovary obviously contained tumor in 2 cases (Cases 3 and 8 ) and was buried in adhesions and could not be identified in 1 (Case 14). A dermoid cyst was enucleated from the contralateral ovary, leaving “normal” tissue in place in 1 patient (Case IS), while in the last case (Case 11) no information was available about the opposite ovary.

In four patients, intestinal bypass operations were done because of obstruction by non-resectable mesenteric masses up to 12 cm in diameter. In another four patients bowel resections ranged in extent from the removal of the involved segment to a resection of the ileum and hemicolectomy; partial omentec- tomy was often performed, and other metastases (hepatic, omental, lymph-nodal, or pelvic-peritoneal) were frequently biopsied.

Followup of Patients with Ovarian Metastases Detected at Operation

Postoperative followup information of varying detail and duration was available for 24 of the 25 patients in Groups 1-3. In at least

10 patients, abnormal urinary levels of 5- HIAA or signs of the carcinoid syndrome persisted, recurred, or developed postoperatively.

Urinary 5-HIAA determinations were done in 12 of the patients, 1 week to 2 months after the ovarian carcinoid was discovered. The initial levels were definitely elevated in 5, possibly elevated in 1, and normal in 6 patients. The negative results may have been due to surgical extirpation of the bulk of the tumor, in view of the fact that diarrhea ceased promptly postoperatively in 4 patients with preoperative evidence of the carcinoid syndrome (Cases 4, 6, 7, and 9). In 4 of the 7 patients whose first postoperative tests were negative or only possibly elevated, a second test was done within the next 4 months and was positive in 2 (Cases 7 and 9); in a third patient (Case 8 ) the test became positive on a third determination 3 weeks postoperatively.

In only one patient (Case 3), the carcinoid syndrome persisted postoperatively, but no tumor had been removed at laparotomy since it was considered inoperable. Immediately after the operation, the 5-HIAA was elevated and cardiac catheterization disclosed pul- monic stenosis, tricuspid regurgitation and stenosis, and right-sided heart failure. In four patients, the full-blown carcinoicl syndrome recurred (Cases 6 and 9) or developed for the first time (Cases 12 and 24) up to 3 years after the ovarian tumors were removed. In a final case (Case 25) intermittent diarrhea was the only postoperative manifestation of the syndrome.

A primary carcinoid was not identified in 12 of the 25 patients either before or at the operation in which the ovarian involvement was detected. During the followup period it was found in 7 of these patients. In 4 (Cases 4, 9, 15, and 16) a large mesenteric mass developed 3 months to 3 years postoperatively, and in 2 patients caused intestinal obstruction; the presence of the primary carcinoid was confirmed on microscopic examination of the adjacent loop of intestine in all 4 cases. In the other 3 cases, the primary carcinoid was found at autopsy (Cases 3, 10, and 12). The remaining 5 patients (Group 3 , Table 3) , in whom the primary carcinoid has not been identified, had no subsequent operations.

After the operation in which the ovarian involvement was discovered, 8 of the 25 patients underwent a later exploration for intestinal obstruction that developed either be-

804 CANCER Murch 1974 V O l . 33

cause of a mesenteric mass (6 cases) or adhesions (2 cases). Several of these patients had additional operations for subsequent episodes of obstruction.

Of particular interest, 6 of the 25 patients became and remained asymptomatic, even though 4 had extensive residual tumor. Two of these patients died without autopsy 3!/2 to 11 years after laparotomy, 1 (Case 22) of unknown cause, and the other (Case 20) from a putative cerebrovascular accident. T h e remaining 4 patients are alive ?,$, 5, 6, and 29 years postoperatively (Cases 2, 18, 19 and 21).

Shortly after the operation, three patients received radiation therapy and another three, chemotherapy. There were no objective signs of remission in any of the patients receiving radiation, two of whom died within 5 months. In contrast, two of the three patients who received chemotherapy for widespread tumor were benefitted. One (Case 25) received 5- fluorouracil (5-FU) and thiotepa; after 9 months, administration of the latter was omitted, and methotrexate and cyclophospha- mide were added to the regimen with a subsequent marked reduction in size of the palpable abdominal tumor and a decrease in the diarrhea that had appeared several months before. A second patient (Case 24) received chlorambucil and methotrexate with no ef- fect. The administration of 5-FU 9 months postoperatively was followed by a striking shrinkage of the abdominal tumor.

According to an actuarial survival curve, 65% of the patients survived 1 year, 50% 21/* years, and 25y0 5 years postoperatively (Fig. 1). No differences in the length of sur-

viva1 were apparent between patients with (Table 1) and those without (Tables 2 and 3) the carcinoid syndrome at the time the ovarian metastases were detected, nor between patients in whom the primary carcinoid was (Tables 1 and 2) or was not (Table 3) found.

Pathology Ovarian metastnses detected at operation:

In at least 22 of the 25 surgical cases the ovarian metastases were bilateral (Tables 1-3). Inadequate information in the other 3 cases precluded a confident determination of the status of the opposite ovary. In Case 14 the contralateral ovary was buried in adhesions and could not be seen at operation. In Case 18 the conserved portion of the contralateral ovary, from which a dermoid cyst was enucleated, was not biopsied. In Case 11 the operative findings and followup were unknown.

The greatest diameters of the involved ovaries varied from 1-20 cm. The average difference in the largest diameter of the two ovaries was 8 cm. Typically the external surface was smooth with a few bosses (Fig. 2 right); occasionally these were numerous cre- ating a knobby appearance (Fig. 2 left). Some tumors were adherent to the omentum, loops of bowel, 01 the abdominal or pelvic wall, and several were covered by gray-white plaques. On section the tumor was usually firm and coniposed of a confluence of tan, gray, or bright yellow nodules, 0.1 to 4 cm in diameter (Fig. 3). Cysts, which were usually less than 2 cm in diameter and were filled with clear, thin fluid and foci of necrosis and hemorrhage were occasionally present.

On low-power microscopic examination, sharply demarcated islands of tumor cells of varying sizes and shapes typically lay in a fibromatous stroma (Fig. 4 left), which ranged from a small to the major component of the mass. Within a single specimen and even on a single microscopic slide, the appearance of the tumor often varied greatly (Fig. 4 left). For example, whereas one of three nodules in a single slide had the typical insular appearance of a mid-gut carcinoid (Fig. 4 t op right), a second nodule contained nests of cells with hemorrhagic centers (Fig. 4 middle right), and a third was characterized by atypical irregular A 4 5 6 + A /o k2 cords (Fig. 4 bottom right). Sometimes a rib- bon pattern typical of a foregut or hindgut

posed of tubules within a ,fibromatous stroma

SURVIVAL /YEARS/

FIG. 1 . Actuarial survival after detection of ovarian carcinoid was evident, Or the tumor was com- metastases.

No. 3 CARCINO~D METASTAT~C TO OVARY - Robboy e l al . 805

FIG. 2. llilaleral ovarian metastases. The generally smooth capsule of the right ovary dis- plays one nodular protrusion; the small left ovary is multi- nodular (Case 5 , AFIP Neg 57- 16044).

that lacked a diagnostically specific appearance. In one unusual tumor (Case 25) nodules of typical carcinoid were adjacent to, but not intermixed with broad zones of typical Bren- ner tumor.

Two additional features observed on low power examination were acini (52%) and calcified bodies (20%). The cells lining the acini had basal nuclei and abundant cytoplasm bordering the lumen (Fig. 5). Homo- geneous eosinophilic intraluminal secretions, when present, were often calcified. In some instances the calcific deposits were laminated concentrically to form psammoma bodies. Oc- casionally the calcific concretions lay in the stroma without surrounding epithelial cells (Fig. 6).

On high-power examination the neoplastic cells were typically small and of uniform size. The nucleus was central and contained highly characteristic coarsely and evenly clumped chromatin. A slight variation in nuclear size was not uncommon, and on occasion a gigantic nucleus or multiple nuclei were seen (Fig. 7). An occasional cell was in mitosis. The cell borders were often distinct in well-fixed specimens (Figs. 5 and 7). Although the cytoplasm of most of the cells was eosinophilic and non- granular, in some specimens red-brown or orange (eosinophilic and phloxine-positive), argentaffin (Fig. 8) granules were conspicuous either in the basal cytoplasmic rims of cells lining acini or diffusely throughout the cyto-

plasm if the cells were arranged in solid nests (72%). The correlation coefficient between eosinophilic and argentaffin granules was high (r = +0.90).

The stroma of the tumor was most often composed of spindle cells with prominent nuclei (Fig. 4 top right), the growth pattern of which resembled that of an ovarian fibroma. In some instances the cells were plump resembling theca externa cells (Fig. 9), while on occasion foci of lutein cells resembling luteinized theca interna cells or the luteinized cells of the ovarian stroma were also observed (Fig. 8). The stroma was sometimes hypocel-

FIG. 3. Nodules visible on sectioned surface of ovarian metastasis (Case 21, AFIP Neg. 72-6874, H & E, x4).

806 CANCER March 1974 VOl. 33

FIG. 4 (left). Three metastatic nodules in ovary, each with a different microscopical pattern (Case 7, AFIP Neg 72-6869, H & E, X24). ( top right) Nests of uniform polygonal cells with acinus formation lying in a fibromatous stroma (AFIP Neg. 60-3337, H 8c E, x70). (middle right) Large nests with hemorrhagic centers (H PC E, ~140). (bottom right) Irregular branching cords (H & E, X140).

lular and had a diffuse hyalinized appearance. Clusters of tumor cells were occasionally found in blood vessels.

Slides from the intestinal primary tumor were available in 12 cases. Its pattern was typical for carcinoid. Acini were observed frequently: when numerous they often contained intraluminal calcifications morphologi- cally identical to those in the ovarian metastases (Fig. 6). Eosinophilic, argentaffin cytoplasmic granules were present in 50% of the tumors. Although the stroma was generally scant in the primary tumors (Fig. 6 inset), it was sometimes abundant and fibrous in the lymph node metastases. Large plaques of hyalinized collagen overlay tumor-infil- trated lymph nodes or foci of tumor on serosal surfaces in 3 cases (25%) (Fig. lo).

Autopsy findings: The postmortem findings in the 10 patients whose ovarian tumors were first detected at autopsy (Group 4, Table 4) were similar to those in the 4 women whose metastases had been found at laparotomy.

The tumor was bilateral in 6 of the 10 cases. In 3 of the remaining 4 cases the contralateral ovary had been removed previously for unknown reasons. In the fourth case (Case 35), one ovary was apparently free of tumor; but only 1 section was available for review. The ovarian tumors were usually small (median: 4 cm in greatest diameter) in contrast to most discovered at operation. Tumor was found in the regional lymph nodes in all the cases and throughout the abdominal cavity in all but one case. T h e liver was almost always (goyo) involved. The lesions of carcinoid heart disease (endocardia1 fibrous plaques, or thickening of the tricuspid and/or pulmonary valves, stenosis or regurgitation) occurred in 70y0 of the patients.

If the findings of the 4 patients in Groups 1-3 who had an autopsy are added to those of the 10 patients in Group 4, organs other than the ovary that contained metastases were: spleen (48%), heart (40%), pancreas (40%), adrenal (24y0), uterus (24y0), lung (16%),

No. 3 CARCINOID METASTATIC TO OVARY - Robboy et al. 807

gallbladder (16y0), fallopian tube (16%), breast (870), pituitary (8%), and skin (8%).

DISCUSSION

Metastases LO the ovary of all types coni- prise approximately 7% of malignant ovarian tumors encountered at operation,24 and of these, less than 2% are metastatic carcinoids.29 Thus, the approximate incidence of metastatic carcinoitl is O.lyO of all malignant ovarian tumors encountered at operation. From another viewpoint, the data of Moertel et al.1" and Bates' suggest that only about 2y0 of intestinal carcinoids larger than 1 cm in diarneter give rise to ovarian metastases.

Several types of ovarian tumor can be con- fused with the metastatic carcinoid on pathologic examination. On gross examination, the appearance oC a solid tumor that is firm, and gray, tan, or yellow may suggest one of the more common solid ovarian tumors such as a

Frc. 6. Metastatic carcinoid with many psammonia hodies within acini and in stioma (Case 16, H & E, ~ 3 4 0 ) . Inset: primary ileal carcinoid with calcifying secretion within acini (Case 17, AFIP Neg. 72-6844, X22.5).

Brenner tumor, fibroma, or thecoma. The high incidence of bilaterality and the fre- quent multinoclularity of the metastatic carcinoid, however, are clues to the diagnosis. When cysts are present, a mistakcn gros5 diagnosis of adenofibroma may be entertained.

The most common referral diagnosis after microscopic examination in these case5 sub- mitted for consultation was Brenner tumor, either benign, of borderline malignancy (proliferative), or malignant (379b) . Other mis- diagnoses were granulosa cell tumor, adenofibroma, adenocarcinoma, and primary carcinoid. Brenner tumors, like many metastatic carcinoids, contain nests of epithelial cells in a fibromatous stroma, derived from the ovarian stroma, but these nests are composed of cells of urothelial type with oval, pale, grooved nuclei instead of cells with round

F ~ G . 5 . Metastatic carcinoid characterized by small nuclei containing coarse chromatin; no eosinopliilic argentaffin granules are present in the cytoI.'lasm. The glandular and cystic

round nuclei with clumped chromatin, occasional larger nuclei, and prominent cytoplastic borders of \ome cells. T h e acini have basal nuclei (Case 16, H & E, x600). rpaces encountered in some Brenner tumors

808 CANCER March 1974 VOl. 33

mon epithelial tumor of the ovary (serous, mucinous, or endometrioid).

The tumor that is most difficult to dis- tinguish from the metastatic carcinoid is the primary ovarian carcinoid. When other teratomatous elements are present, the correct diagnosis is obvious, but a problem exists when neither an obvious teratomatous element nor an intestinal primary tumor has been demonstrated. In an attempt to resolve this problem in differential diagnosis, the data from the present study were combined with unpublished data from 34 cases of carcinoid (31 surgical and 3 autopsy cases) that were considered to be definitely or probably primary and in which both ovaries were examined microscopically. T h e total number of cases was divided into four categories (Table 5): Category 1-cases of unilateral tumor with a teratomatous component (25 cases); Category 2-cases of unilateral tumor without a demonstrated teratomatous component (1 1 cases);

FIG. 7. Metastatic carcinoid with giant nuclei, mitoses (arrow), and multiple nuclei (arrow). Also note irregular size of cells and distinct cell borders (Case 18, AFIP Neg. 72-6837, H & E, ~ 1 9 0 ) .

may be lined by mucin-filled cells, ciliated cells, or epithelial cells of a non-specific type, all of which differ from the cells lining the acini of carcinoids. Finally, the calcific deposits occurring in some Brenner tumors are typically sharply etched stromal plaques, and not concretions lying in the lumens of acini.

The granulosa cell tumor may form nests or sheets of cells sometimes perforated by tiny cavities, Call-Exner bodies. The latter are not perfectly round or sharply outlined, but are surrounded by haphazardly arranged cells with generally scant cytoplasm and grooved nuclei oE irregular shape. Granulosa cell nuclei do not have the coarse chromatin pattern of carcinoid nuclei and the cytoplasmic margins are generally not distinct except in ' - 1 teinized areas of the tumor.

adenofibromas and FIG. 8. Metastatic carcinoid. The outer rims of acini well-differentiated adenocarcinomas may SU- are black due to positive argentafin staining. Calci- pepficially resemble a metastatic carcinoid but fied secretions are present in several acinar lumens,

and the stroma is composed of poorly stained luteinized these generally have cells (Case 24, AFIP Neg 72-6858, Fontana-Masson, characteristic of one of the forms of com- ~ 1 2 0 ) .

'eni%n and

No. 3 CARCINOID METASTATIC TO OVARY - Robboy et al.

Category 3-cases of bilateral tumor in which the presence of a primary tumor in the intestine or another organ was confirmed microscopically or strongly suggested by the operative findings (23 cases); and Category 4-cases of bilateral tumor in which no evidence for a primary tumor has appeared up to the present time (5 cases).

On the basis of an analysis of the clinical and pathologic data it is evident that the cases of unilateral tumor with and without teratomatous elements were similar to one another in most respects, but differed from the two groups of cases of bilateral tumors (with and without demonstrated primary tumors), which also presented features similar to one another.

Patients with unilateral tumors sometimes had the carcinoid syndrome (26 and 33%; Categories 1 and 2), which, if present, disap peared within 24 hours after the operation, along with a permanent return to normal of 5-HIAA levels, i f elevated preoperatively. At operation only one patient with a unilateral

FIG. 10. Collagenous plaque on peritoneum. Several tiny foci of metastatic carcinoid are nearby (arrow) (Case 16, H 8c E, x42).

ovarian carcinoid had a primary carcinoid in the intestine (Case 18); possibly, bilateral ovarian involvement might have been established in that case if the portion of the conserved ovary adjacent to an enucleated dermoid cyst had been biopsied.

Usually only one ovary was enlarged in the cases of unilateral carcinoid, but if the opposite ovary was also enlarged, it usually contained a dermoid cyst (6 cases). Grossly the cut surface of the unilateral ovarian carcinoid was typically homogeneous and not composed of nodules. The prognosis of the patients with unilateral carcinoids was excel- lent. Recurrent tumor developed in only 2 cases in category 1 ( 1 and 5 years postoperatively); both patients died of widespread metastases after 5 and 6 years, respectively.

In contrast, although signs and symptoms of the carcinoid syndrome usually disappeared within 24 hours, 5-HIAA levels either remained or became positive within several

FIG. 9. Metastatic carcinoid. The stroma contains cells resembling both theca externa and luteinized theca interna cells. A rare mitosis is present (arrow) (Case 21, AFIP Neg. 72-6842, H & E, x350).

postoperativeiy in patients with bilateral tumors (700j,-Categories 3 and 4)- At operation, peritoneal metastases were al-

810 CANCER March 1974 Vol. 33

TABLE 5 . Differential Features of linilateral and Bilateral Ovarian Carcinoids that Suggest Their Respective Primary and Metastatic Natures*

Unilateral Bilateral

Teratomatous elements Primary lesion Present Absent Found Not found

(Category 1) (Category 2 ) (Category 3 ) (Category 4)

Total number of cases Number surgical cases Teratomatous structure Extraovarian 1’ lesion Carciiioid syndromet

Preoperative Disappear immediately after

Reappear within 6 months 5-HIAA positive within 6 months

Extraovarian carcinoid

Asci tes Contralateral ovary enlarged

Ovarian tumor Cut surface Stromal component Foci of atypical nuclei Argentafin positive

Dead of carcinoid in 1 year Dead of carcinoid in 4 years Recurrence or known residual

oophorectomy

Operative findingst

metastases

Prognosis’

carcinoid

0% 1 1 % 5

21%: 20%: occasional occasional

usually homogeneous usually small bu t variable usually 0 to 1 +

14/15 617

0% 0% 0% 0%

8% 1 1 % ’

23 5 17 >

0% 0% + -

59% 0%

94% 80%

44 % 80% occasional occasional

usually nodular usually large but variable usually 1 + to 3+

10/13 2 /4

38% 77%

20% 75%

80% * Includes only cases in which both ovaries were examined microscopically. Cases were eliminated in which one

+ Considers surgical cases only. f The contralateral ovary contained a dermoid cyst or mucinous cystadenoma. * Case 18 11 Case 3 5 .

ovary was absent, its status was unknown, or i t was examined only grossly.

most always present (94%). One-third of the patients were dead within 1 year, and three- fourths within 4 years of discovery of the ovarian tumors.

The conclusion drawn from this analysis is that in the absence of a demonstrable intestinal primary tumor, a unilateral ovarian carcinoid is in all probability primary even though teratomatous elements are not demonstrable, whereas bilateral carcinoid tumors are metastatic until proven otherwise. Re- stated, the two most useful clues to the diagnosis of a primary ovarian carcinoid at operation are unilateral ovarian involvement and the absence of extraovarian tumor. Bi- lateral ovarian involvement and extraovarian tumor suggest metastases.

T h e published records of 5 patients in this series with established intestinal primary tumors (Cases 6,9 18,’O 32,23 34,23 and 355) de- scribed only unilateral ovarian involvement, appearing to contradict our conclusion that unilateral tumors are always primary, but

several explanations can be offered to explain this apparent discrepancy: (1) Metastasis was present in the contralateral ovary on microscopic examination, but was not reported apparently because it was small (Case 6); (2) The contralateral ovary had been removed many years before for unknown reasons (Cases 32 and 34); (3) Microscopic sampling was incom- plete: only one section was made from the contralateral ovary in Case 35, while in Case 18 a dermoid cyst was enucleated but residual grossly normal ovarian tissue was left in place and not biopsied. This case underscores the importance for microscopic examination of both ovaries even though one appears “normal” or only “equivocally enlarged.”

The findings of this study have several im- plications regarding therapy. If an ovarian carcinoid unassociated with teratomatous elements is diagnosed or suspected by the pa- thologist on frozen section examination, the intestinal tract should be explored for a primary tumor and the opposite ovary carefully

No. 3 CARCINOID METASTATIC TO OVARY Robboy et al . 81 1

evaluated. If an operable intestinal tumor is found, removal of i t and its regional lymph nodes may prevent future episodes of intestinal obstruction; removal of the contralateral ovary, whether demonstrably involved or not, may eliminate the necessity of a future operation when i t becomes overtly involved. If a unilateral carcinoid without teratomatous elements is found in a young woman in whom there is no extraovarian tumor and in whom the preservation of fertility is important, the contralateral ovary should generally be biopsied in an attempt to exclude the presence of metastases before unilateral salpingo- oophorectomy is accepted as the definitive surgical procedure. Finally, if a primary carcinoid of the bowel is encountered at opera-

tion in a menopausal or postmenopausal woman even in the absence of demonstrable ovarian involvement, prophylactic oophorectomy will prevent the subsequent develop- ment of ovarian metastases,21 which has occurred in 3 patients (Cases 1 and 2 and ref. 3).

Postoperatively, signs of the carcinoid syndrome or an elevated level of 5-HIAA are indicative of residual or recurrent metastatic tumor. In these cases chemotherapy may be effective, causing shrinkage of the tumor and relief of symptoms. The death of most patients within 4 years after the discovery of ovarian involvement reflects its common association with widespread metastases, and the association of the latter with short survival.l2,18~?3

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13. Lincoln, J. C. R.: Malignant argentaffinoma with metastases to the ovaries. Br. .I. Surg. 53:1071-1073, 1966.

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Carcinoid metastatic to the ovary.A clinicopathologic analysis of 35 cases

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