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INSULAR CARCINOID PRIMARY I N T H E OVARY A Clinicopathologic Analysis of 48 Cases
STANLEY J. ROBBOY, MD, HENRY J. NORRIS, MD, AND ROBERT E. SCULLY, MD
Forty-eight cases of primary insular carcinoid of the ovary were analyzed from a clinicopathologic viewpoint. Sixteen (33%) were associated with preoperative clinical evidence of the carcinoid syndrome. At operation only one ovary was usually enlarged, but in 16% the contralateral ovary was also enlarged by either a dermoid cyst or a mucinoue cystadenoma or cystadenocarcinoma. The volume of the carcinoid was the most important determinant of whether the carcinoid syndrome was present. No patient had the syndrome whose carcinoid formed only a small portion of a teratoma. Pure tumors or components of teratomas be- tween 4 and 7 cm in diameter were associated with the syndrome in one-half, and larger carcinoids in two-third of the cases. Prominent acinar differentiation also correlated with the presence of the syndrome. Although the prognosis was nearly always favorable after the removal of the tumor, tricuspid valve damage con- tinued to progress and led to cardiac decompensation in one patient; fatal recur- rences developed in two others. The primary insular carcinoid should be dis- tinguished from carcinoid metastatic to the ovary, which is nearly always bilateral, is usually associated with the presence of peritoneal metastases, and has a poor prognosis.
Cancer 36:404-418, 1975.
INCE THE FIRST OVARIAN CARCINOID WAS S described in 1939,02 several types, both primary and metastatic, have been reported. The most common is primary in the ovary and composed wholly or largely of tumor cells growing in an insular p a t t e r n , ' ~ 3 ~ J ~ ~ ~ s ~ ~ ~ l l ~ ~ ~ l ~ ~
pattern typically observed in carcinoids aris- ing in the midgut derivatives (jejunum, ileum, and appendix). Most primary insular car- cinoids of the ovary have been components of teratomas, but some have occurred in ap- parently pure form. About a third of them have been associated with the carcinoid syn- drome. Very few have been clinically malig-
2 1 , 2 ~ 2 8 . 2 g 5 5 , 3 7 . 8 8 , 4 0 , 4 1 , ~ , 4 5 , 4 7 ~ ~ , 6 6 , 6 7 , 6 ~ , 8 2 ~ 7 the
From the Department of Pathology, Harvard Medical School and the James Homer Wright Pathology Labo- ratories of the Massachusetts General Hospital, Boston, MA, and Gynecologic Pathology Division, Armed Forces Institute of Pathology, Washington, DC.
Supported in part by a Junior Faculty Fellowship from the American Cancer Society to Dr. Robboy.
Address for reprints: S. J. Robboy, hfD, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114.
The opinions and assertations contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of De- fense.
Received for publication March 6, 1975.
nant, although the followup has been short in most reports.
Because no large series of ovarian car- cinoids has been analyzed, a clinicopathologic investigation of 147 cases has been underway in our laboratories for several years. An analy- sis of 35 carcinoids metastatic to the ovary has been published,= and studies of primary tra- becular carcinoids (tumors with a trabecular or ribbon pattern characteristic of carcinoids arising in derivatives of the foregut and hind- gut) and strumal carcinoids (trabecular car- cinoids mixed with thyroid tissue)62 are cur- rently in progress. The present article will analyze the clinical and pathologic features of 48 primary insular carcinoids of the ovary, raising the total in the literature to 70.
MATERIALS AND METHODS
The cases include 11 from the consultation files of two of the authors (S.J.R. and R.E.S.), 8 from the Armed Forces Institute of Pathol- ogy, 2 from the files of the Massachusetts General Hospital, and 2 from the Tumour Reference Collection, Imperial Cancer Re- search Fund, Lincoln's Inn Field, London. The remaining examples were included through the courtesy of the physicians who
404
No. 2 PRIMARY OVARIAN INSULAR CARCINOID * Robboy et al. 405 had previously reported t h e m . ~ ~ ~ ~ ~ ~ l l ~ l ~ l ~ ~ * ~ - l ~ ~
these were reviewed and additional data ob tained.
The number of available slides per tumor varied from 1 to 43. All were stained with hematoxylin and eosin (H & E); selected sec- tions were also stained for argentaffin granules by the ferric ferricyanide, Fontana-Masson, and/or diazo techniques.
2 ~ . 3 1 , 3 ~ 3 6 , 3 7 . 4 0 . 4 4 . 4 5 , 4 7 , ~ ~ , 5 7 , 5 ~ , ~ 2 , 0 5 The slides of
RESULTS
Preoperative Findings Evidence of the carcinoid syndrome was
present preoperatively in 16 of the 48 patients (3373. These patients were slightly older (mean age 64 years) than those in whom evi- dence of the syndrome was absent (mean age 57 years). Every patient with the carcinoid syndrome was at least 50 years of age (range 50-75 years), whereas a third of those without the syndrome were younger than 50 years of age (range 31-79 years). Seventythree percent of the patients were Caucasian and 27% were Negro. Every married patient for whom information was available was parous.
Cases with carcinoid syndrome: Of the 16 patients with one or more symptoms or signs of the carcinoid syndrome (Table l), 6 sought medical aid because of abdominal pain or en- largement or a disorder unrelated to the car- cinoid. In 2 of these 6 women, the combina- tion of a pelvic mass and a history of flushing or diarrhea created a suspicion of the correct diagnosis, but in the other 4 the significance of such symptoms was recognized only in retrcl spect. In 9 of the 10 patients in whom one or more symptoms of the syndrome prompted admission, the diagnosis of carcinoid was made preoperative1 y.
Flushing was the most frequent manifesta- tion of the syndrome (81%). Occasionally i t was misinterpreted as a symptom of the meno- pause, delaying the correct diagnosis by as many as 3 years. Usually the flush was erythe- matous, confined to the face, and lasted no more than 3 to 5 minutes, but occasionally it was violaceous and lasted 15 minutes or longer. One patient had telangiectases. In five patients, various stimuli such as the in- gestion of alcohol, tea, or food, and defecation repeatedly provoked attacks. Palpation of the ovarian tumor during a rectal examination precipitated the flush in one patient.
Sixty-two percent of the patients had diar-
rhea, but its significance was often appreciated only in retrospect because of its typically insidious onset. Cardiac murmurs were audible preoperatively in eight patients, but were identified specifically as those of pulmonary stenosis and/or tricuspid insufficiency in only five instances. Six (38%) of the patients with the syndrome had pedal edema. In five of them it was a major complaint: two of these patients also had ascites. Eight patients had lost 10 to 60 pounds. Hypertension was found in five patients; in one the blood pressure rose from 150/90 immediately before an episode of flushing to 220/110 during the at- tack.
Five-hydroxyindole acetic acid (5-HIAA) levels in the urine were measured in seven patients and ranged from 10 to 348 mg/24 hours (normal = less than 10 mg/24 hours in most laboratories). A roentgenographic study of the upper gastrointestinal tract was unre- markable in five patients, and a liver scan was negative in two individuals.
Cases without carcinoid syndrome: Thirty- two patients had no symptoms of the carcinoid syndrome (Table 2). Abdominal pain or en- largement (411%) were the most frequent com- plaints in this group. Some tumors were de- tected incidentally during a routine physical examination (9%) or during an operation for uterine leiomyomas (38%). Four patients had vaginal bleeding (12%): curettage disclosed an endometrial adenocarcinoma in one, and a normal endometrium in the others.
Operative Findings Forty-five of the 48 patients had an opera-
tive procedure during which the ovarian tu- mor was removed. In the other 3 patients the diagnosis was made only at autopsy; 2 were known to have a pelvic tumor during life, while in the 3rd it was an incidental finding.
T h e carcinoid was always unilateral, with the left ovary involved in 52% of the cases and the right in 48%. In 70% of the cases a uni- lateral tumor was apparent at operation. In 16% both ovaries contained tumors, only one of which proved to be a carcinoid. The contra- lateral ovary in such instances contained a dermoid cyst, mucinous cystadenoma or mu- cinous cystadenocarcinoma. The carcinoid tumor was not recognized by the surgeon but was an incidental finding in the pathologic specimen in the remaining 14%. Eight of the neoplasms were adherent to the omentum. pelvic peritoneum, or loops of small bowel.
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No. 2 PRIMARY OVARIAN INSULAR CARCINOID Robboy et al. 407
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The carcinoid nature of the tumor was rarely recognized at operation. When a cystic tumor that contained copious amounts of hair or sebum was opened in the operating room, the diagnosis of a dermoid cyst was made and the carcinoid component was usu- ally unsuspected until the time of microscopic examination. Sometimes the tumor was ini- tially considered to be a carcinoma because i t was solid, hair was not found in the specimen, and the carcinoid syndrome had not been suspected preoperatively.
Widespread tumor in the pelvis was oh served in one patient, but on microscopic ex- amination this proved to be a metastatic papil- lary adenocarcinoma rather than a carcinoid; no primary source for this tumor was dis- covered during the operation or at autopsy. A second patient had a mass localized to the head of the pancreas, which was shown to be a pancreatic adenocarcinoma on microscopic examination. A third patient had multiple small white nodules on the hepatic capsule but these were not biospied. Ascites was en- countered in four patients, two of whom had the syndrome.
Therapy Therapy consisted of unilateral salpingo-
oophorectomy (40%) or bilateral salpingo- oophorectomy with or without hysterectomy (50%). In one patient an obvious dermoid cyst that contained an unsuspected carcinoid was resected, preserving the adjacent ovarian tissue, while a second patient received pre- operative radiation therapy after percutaneous aspiration of the ovarian mass disclosed cells interpreted as malignant. Three patients with other cancers (endometrial adenocarcinoma, mucinous cystadenocarcinoma of the contra- lateral ovary, and peritoneal carcinomatosis from an undetermined primary site) received postoperative chemotherapy or radiation ther- apy in addition to bilateral salpingo-oopho- rectomy with hysterectomy.
Followup Within 1 day after the removal of the tu-
mor, episodic flushing and diarrhea ceased in every patient with the syndrome (Table 1). The intensity of the cardiac murmurs de- creased. Edema of the lower extremities dis- appeared; in 3 patients, blood pressure ele- vated before the operation fell afterwards to about 150/90. Postoperatively, the urinary
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No. 2 PRIMARY OVARIAN INSULAR CARCINOID - Robboy et al. 409
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5HIAA was normal in 17 patients, including 6 in whom it was elevated preoperatively.
Long-term followup data were available for the 42 patients who were treated by opera- tion with or without additional therapy (Fig. 1). Thirty-one are alive without evidence of disease 1 month to 18 years after the removal of the ovarian tumor, and 8 have died without evidence of carcinoid disease 4 months to 18 years postoperatively. Signs of progressive car- cinoid heart disease developed in 1 patient 3 years postoperatively (Case 13); they were apparently related to the original damage to the valves prior to removal of the primary tumor rather than to a recurrent neoplasm. T h e history of this woman u p to the time of oophorectomy has been reported in detail elsewhere;" only new data regarding the sub- sequent course are presented here:
Case 13. After the removal of a functioning ovarian carcinoid from a 65-year-old woman, all the signs and symptoms of the carcinoid syndrome disappeared, except for the murmur of tricuspid insufficiency. The 5-HIAA fell from 137 to 18 (12-22 mg/24 hours) in five assays from 5 to 30 days postoperatively. Three years later signs of "cardiac insufficiency" with pleural and pericardial effusion developed. The 5-HIAA was 15 md24 hours. During the next 6 months, tricuspid insuf- ficiency became much more severe, although there was no recurrence of the flush or diarrhea. She is to be admitted to the hospital for further study.
T h e carcinoid recurred in two patients (Cases 4 and 10) and subsequently proved fatal. In neither had metastases been apparent a t the time of the initial operation, either by
FIG. 1. Actuarial survival curve of primary insular carcinoid of the ovary. Excluded are patients who died from intercurrent disease or were lost to followup.
4 10 CANCER August 1975 Vol. 36
inspection of the peritoneum, palpation of the small bowel, or roentgenogram of the upper gastrointestinal tract. T h e carcinoid syndrome, which had been present preoperatively in both patients, disappeared once the tumor was re- moved with a fall to normal of elevated levels of 5-HIAA. Since portions of the histories of both patients have been reported in detail elsewhere,13.58 only new data regarding the recurrences are presented below.
Case 4. One year after a functioning ovarian carcinoid arising in a dermoid cyst was removed from a 56-year-old woman, she became constipated and experienced dull pain in the left flank. The urinary level of 5-HIAA, which had been negative on 10 determinations during the immediate post- operative period, became elevated, ranging between 38 and 55 mg/24 hours. At laparotomy, numerous pale grey, discrete subcapsular nodules, 1.5 cm in greatest diameter studded the liver. Examination of the entire small and large intestines and the pelvis disclosed no evidence of tumor. Biopsy of the hepatic nodules revealed metastatic carcinoid. Postoperatively the pain persisted, and the 5-HIAA values remained strongly positive. Flushing reap- peared and the patient was transferred to a nursing home, where she died 4 years later, 5 years after the primary ovarian tumor was removed. An au- topsy was not performed.
Case 10. After multiple negative determinations of urinary 5-HIAA following removal of a func- tioning ovarian carcinoid that a r m in a dermoid cyst, a routine examination 5 years postoperatively revealed 52 mg/24 hours. Although a faint murmur of tricuspid insufficiency had persisted after the removal of the ovarian tumor, the other symptoms of the syndrome had disappeared. Two months after the 5-HIAA level had risen, a mass appeared in the right iliac fossa. At laparotomy, carcinoid implants seeded the pouch of Douglas, the omen- tum, and the liver. Postoperatively she lost weight,
TABLE 3. Components of Tumors
Non- Functioning functioning
~ ~~ ~
Insular carcinoid (pure) 5 6 Insular carcinoid and
Insular carcinoid and
Dermoid cyst and insular
Mucinous cystadenoma
dermoid cyst* 5 2
mature solid teratoma' 3 3
carcinoid' 2 20
and insular carcinoid 1 1 TOTAL 16 32
* The predominant component of a germ cell tumor is named first, according to terminology of the World Health Organization.m
and died 9 months later, 6 years after the removal of the primary tumor. An autopsy was not per- formed.
T h e average postoperative survival of all 42 patients followed has been 6.9 years, with 12 patients having lived more than 10 years. Based on these data, an actuarial curve' in- dicates a survival of 95% at 5 years and 88% at 10 years (Fig. 1).
Ovarian Pathology T h e ovarian tumors including their t e ra te
matous components, when present, were 3 to 28 cm in greatest diameter, with a median diameter pf 10 cm. T h e capsular surface was usually smooth, but sometimes bosselated; fi- brous adhesions were noted occasionally. T u - mors associated with the syndrome were usu- ally large and predominantly or entirely solid (13 of the 16 tumors) (Table 3); cysts, if pres- ent, were generally less than 3 cm, but were occasionally as large as 10 cm in diameter. Most of the cysts were lined by carcinoid, but some were dermoid cysts containing hair and sebum. T h e carcinoid component itself was typically firm, homogeneous, and tan to yel- low; sometimes it had a whorled texture re- flecting its content of fibrous tissue, but only rarely was i t nodular. Foci of hemorrhage and necrosis were exceptional.
Sectioning of tumors not associated with the carcinoid syndrome usually disclosed a large unilocular cyst filled with hair and sebum (20 of 32 tumors) (Table 3). Commonly, a firm tan nodule of carcinoid less than 4 cm in diameter protruded into the lumen; rarely the carcinoid was incorporated diffusely in a wall that was several millimeters t o 2 cm thick (Fig. 2). I n 4 tumors, 2 of which contained dermoid cysts, other cysts 1 to 5 cm in diameter were filled with mucin.
T h e volume of the carcinoid in each tumor was calculated within the limits of the gross descriptions and available photographs (see footnote i n Table 1). T h e median diameter of the carcinoids associated with the syndrome was 9 cm and the range was 3 to 15 cm (Table 1); those tumors associated with minimal evi- dence of the syndrome were among the small- est. T h e carcinoids not associated with the syndrome had a median diameter of 3 cm (range 1 to 15 cm) (Table 2). Only 1 of the 20 tumors (5%) in which the carcinoid com- ponent was less than 4 cm in diameter was as- sociated with the syndrome, whereas 6 of 14 (43y0) between 4 and 7 cm and 9 of I 3 (69%)
No. 2 PRIMARY OVARIAN INSULAR CARCINOID Robboy et al. 41 1
FIG. cyst w (arror
2. Unilocular i th a carcinoid in v) (AFIP neg 61-51
derr the 15).
moid wall
greater than 7 cm were accompanied by the syndrome (x2 = 25 [2 d.f.1 p < .0005).
On microscopic examination, the carcinoid element was generally homogeneous, consist- ing entirely or predominantly of discrete masses and islands of cells separated by a fi- broma-like stroma, which ranged from negli- gible to extensive (Fig. 3). In two tumors the trabecular (ribbon) pattern of carcinoid was also seen. Acinus formation was observed in 93y0 of the functioning and 65y0 of the non- functioning tumors, either as isolated glands in the stroma or as multiple glands within an otherwise solid epithelial island, creating a cribiform pattern (Fig. 4). Glands were pres- ent in moderate to large numbers in the func- tioning tumors but were infrequent or absent in the nonfunctioning neoplasms. The basal nuclei of the glands were round and uniform in size, and were separated from the central lumens by abundant cytoplasm. A brush border was sometimes seen when the tumor was well fixed. Deeply eosinophilic, periodic- acid-Schiff (PAS)-positive secretion, which sometimes contained concentrically laminated or irregularly calcified concretions, occupied the lumens of the glands.
The central cells of the masses and islands were frequently hexagonal, and if well fixed, sometimes had distinct walls. The nucleus oc- cupied the center of the cell, was round, and contained coarsely and evenly clumped chro- matin (Fig. 5). Although the size and shape of the nuclei varied to some extent, mitoses
were rare. Frequently the basal cytoplasm of the cells lining acini or the peripheral row of cells in an island contained prominent red- dish-orange to brown granules when stained with H 8c E (Figs. 4 and 5). These were strongly positive when stained for argentaffin granules with the ferric ferricyanide,' the Masson- Fontana, and/or the diazo techniques. Fewer granules were usually dispersed in the cells oc- cupying the center of the islands. Granules were prominent in the H & E sections in 14 of the 15 (93Y0) functioning tumors. Although granules were also seen frequently in the non- functioning tumors (25 of 29 cases, 8673, they were generally more sparsely distributed.
Clusters of luteinized stromal cells were identified at the periphery of the tumor; plump theca externa-like cells were seen in the fibromatous strpma that separated the nests of tumor cells in 6% of neoplasms. No pa- tient was virilized or had other endocrine manifestations suggesting steroid hormone production by the tumor.
The carcinoid was intimately associated with other endodermal elements of teratomat- ous derivation in 26 cases. These included ciliated, pseudostratified columnar epithelium of the respiratory type in 13 tumors: in 6 of these the additional presence of cartilage and small mucous glands created a picture simulat-
Strong reducing agents stain blue, whereas weak reducing agents, which are more characteristic of trabecular carcinoid, stain green.
412 CANCER August 1975 Vol. 36
mors except for the absence of teratomatous elements, a fibromatous stroma, and luteinized stromal cells (Fig. 7).
Autopsy Findings Two of the three patients in whom the
ovarian carcinoid was first visualized at au- topsy had the carcinoid syndrome (Cases 5 and 11). Both had ascites and a thick, pearly- white, fibrous coating (“sugar-icing”) of much of the visceral and parietal peritoneal sur- faces. The pulmonary and tricuspid valves were stenotic and insufficient as a result of thickening of the cusps; the endocardium of
FIG. 3. Islands of carcinoid separated by varying amounts of fibromatous stroma (H & E, ~ 1 9 ) .
ing the wall of a bronchus. In 9 instances gas- trointestinal tissue contained various amounts of mucosa, submucosa, and circular and longi- tudinal smooth muscle; Auerbach’s plexus, Paneth’s cells, and argentaffin cells were also encountered. The carcinoid neoplasm did not appear to be associated topographically with neuroectodermal structures such as ganglia or nerve bundles; neuroepithelial rosettes of the type typically seen in immature teratomashl were conspicuously absent.
In four tumors the carcinoid was intimately admixed with or bordered on a mucinous cystadenoma; single argentaffin cells were identified among the mucinous cells in three of these (Fig. 6). One carcinoid arising in a dermoid cyst was associated with a large ipsi- lateral squamous cell carcinoma; in two other tumors microscopic foci of Brenner tumor were present. The contralateral ovary con- tained a dermoid cyst in five cases, and a mucinous cystadenoma, mucinous cystaden6 carcinoma, and small Brenner in one instance each.
The microscopic appearance of the recur- rences was similar to that of the primary tu-
FIG. 4. A (fop). Copious cytoplasm separates the h n e n from the nuclei and the basal minophilic granules. which appear black in this photograph of a function- ing carcinoid (H & E, ~ 4 9 0 ) . B (bottom). Functioning carcinoid with prominent acinar formation (H & E, x77; AFIP neg 72-6853).
No. 2 PRIMARY OVARIAN INSULAR CARCINOID . Robboy et al. 413
FIG. 5. Eosinophilic granules (black in photograph) are present in most of the cells in the island of carcinoid, but are most pronounced in the peripheral row (H & E, x380). Inset: nuclei with coarsely clumped chromatin (H & E, ~900).
the right ventricle and atrium were also focally fibrotic. The detailed gross and mi- croscopic findings in these cases and in car- cinoid heart disease in general have been described elsewhere.6~60~’J6~8’J
Ultrastructure Five of the carcinoids, two of which were
functional, were examined with the electron microscope; the results have been presented in detail elsewhere.81 The granules in each tumor were pleomorphic, being reniform, oval, biconcave, teardrop, or dumbbell-shaped; the average diameter was 210 nm and the range 90410 nm (Fig. 8). The granules were homogeneous and electron-dense without floc- culation. Sometimes a thin electron-lucent zone separated the core of the granule from its single limiting membrane.
Chemical-Pathologic Correlation The average ratio of the urinary 5-HIAA
level to the volume of carcinoid was 0.3 -C 0.1
FIG. 6. Individual argentaffin positive cells (arrow) in a mucinous cystadenoma associated with a carcinoid tumor (ferric ferricyanide stain, ~ 3 6 0 ) .
mg 5-HIAA/cma tumor/24 hours based upon five cases from the present study (Table 1) and four from the literature.32,*8.6”83
DISCUSSION
Primary insular carcinoid of the ovary is encountered in less than 1% of ovarian t e r a t o m a ~ , ~ ~ . ~ ~ and accounts for less than 1% of all carcinoids in the b0dy.2~~6~ Although no macroscopic feature permits a specific diag- nosis, this type of tumor can be suspected if homogeneous, firm, tan to yellow tissue protrudes as a knob into the cavity of a dermoid cyst or focally thickens its wall. A carcinoid must also be considered in the differential diagnosis of predominantly solid, yellow fibromatous tumors of the ovary with or without cysts.
Despite its distinctive microscopic charac- teristics, the insular carcinoid can be con- fused with several other ovarian tumors, especially the hanulosa cell tumor, the Ser- toli-leydig cell tumor, the Brenner tumor, and the metastatic carcinoid. Although the Call-Exner bodies of the granulosa cell tu- mor may simulate superficially the acini of a carcinoid, the former are seldom perfectly round, but have scalloped edges. They also contain watery eosinophilic material, occa- sionally with a few shrunken nuclei, which differs from the denser, often calcified se- cretion sometimes found within the lumen of a carcinoid acinus.63,SQ The granulosa cells surrounding a Call-Exner body lack the copious cytoplasm that separates the nuclei
414 CANCER August 1975 Vol. 36
FIG. 7 . Recurrent carcinoid in the omenturn. The primary carcinoid was associated with a dermoid cyst (H & E, X390).
from the lumen of a carcinoid acinus. The granulosa cells typically have pale, grooved nuclei that are haphazardly oriented in relation to one another and the lumen. Finally, carcinoid cells. when well fixed, may have distinct cell walls, which are not visible in granulosa cells unless they are luteinized. Unlike that of a granulosa cell tumor, the stroma of a carcinoid rarely undergoes lu- teinization, although luteinized stromal cells occasionally cluster at the periphery of the tumor.
Sertoli-Leydig tumors may contain hollow tubules lined by cells with basal nuclei and copious luminal cytoplasm, as well as solid tubules and rows of cells resembling testicu-
FIG. 8. Pleomorphic argentaffin granules (X26,OOO).
lar sex cords. These structures simulate the acini of insular carcinoids and the ribbon-like structures seen in trabecular carcinoids, re- spectively. Finally, both carcinoids and Sertoli- Leydig cell tumors may contain cysts lined by mucinous cells and scattered argentaffin cells. Despite these similarities, many distinctive features within the wide spectrum of patterns of Sertoli-Leydig cell tumors should permit their differentiation from insular carcinoids. Curiously, two cases of carcinoid arising within a Sertoli-Leydig tumor have been pub- lished.28*48
The Brenner tumor also poses a minor problem in the differential diagnosis of a carcinoid that has an abundant fibromatous stroma. The epithelial component of a Bren- ner tumor may contain acini, but the char- acteristic presence of mucinous cells lining the lumens creates an appearance unlike that of carcinoid glands. Most importantly, Bren- ner epithelium has a distinctive urothelial transi tional-cell appearance with longitudinal grooves in its nuclei. In two cases in this series Brenner tumors lay adjacent to car- cinoids, and in a third case one was found in the contralateral ovary.
Cytoplasmic argentaffin granules, which are reddish brown to orange with H & E staining, are the most specific diagnostic feature of the carcinoid. These are most conspicuous in the basal cytoplasm of cells lining glands or forming the outermost layer of a neoplastic mass or island. They may also occur in in- dividual cells in some mucinous cysts or cystadenomas.4~aOJ~ They were seen in three of the four mucinous cystadenomas contigu- ous with the carcinoid in this series of cases. The strong reducing agent in these granules results in a positive Prussian blue reaction with the ferric ferricyanide stain.
The primary insular carcinoid should be distinguished from the primary trabecular carcinoid and the strumal carcinoid of the ovary. The former is composed of ribbons of cells with central elongated nuclei and abundant cytoplasm at both poles. On oc- casion both the trabecular and insular pat- terns are found in a single tumor, which is named according to the pattern that pre- dominates. In this series 46 of 48 carcinoids were characterized exclusively by an insular pattern; in 2 of the 48 as well as in a re- ported case,41 a trabecular pattern was a minor feature. The strumal carcinoid is recognizable by the presence of thyroid acini in a carcinoid
No. 2 PRIMARY OVARIAN INSULAR CARCINOID Robboy et al. 4 15
that is most often of the trabecular type, but may be insular. One important reason for recognizing the strumal carcinoid is to avoid its misinterpretation as a malignant struma.
The tumor most difficult to distinguish from the primary insular carcinoid is the metastatic insular carcinoid, which is almost always of small intestinal origin. The criteria for distinguishing these have been discussed in detail elsewhere63 and are summarized in Table 4.
Sixteen of the 48 patients (33%) had evi- dence of the carcinoid syndrome. Although episodic flushing and diarrhea were marked in some cases, the clinical significance of these manifestations was not always obvious ini- tially. In some instances they had been present for years before the diagnosis of carcinoid was made, and in 5 cases the syndrome was recog- nized only in retrospect after the pathologist's diagnosis. Six patients had pedal edema; in 5 of them it was a major reason for their consulting a physician. Although this sign has been mentioned in several reviews of the carcinoid syndrome,13~22*63 most reports have ignored it. Its frequent presence in primary as well as metastatic ovarian car- cinoid63 indicates that it may be an important clue to the diagnosis. Three patients in this series, as well as 1 whose history was previously reported,54 had elevated blood pressure that fell after removal of the tumor; the signifi- cance of this is uncertain.
Most carcinoids arise in the small intestine, and their hormones, which are released into the portal circulation, are metabolized by the liver.2-23#42 Manifestations of the carcinoid syndrome do not occur until metastases are present in tissue with a venous drainage that bypasses the portal system. Because of the extraportal venous drainage of the ovary, the amount of tumor necessary to produce symp- toms of the carcinoid syndrome could be determined in the present series of cases as a mass 3 to 4 cm in diameter. In this size range the symptoms if present are usually minimal, whereas with increasing size a greater pro- portion of the tumors are associated with the syndrome, and its severity is apt to be greater.
In nine patients, correlation of the pre- operative level of 5-HIAA with the volume of carcinoid indicated that an average of 0.3 mg 5-HIAA/ml tumor was synthesized daily. On the basis of this figure, the urinary level of 5-HIAA would not be sumected to rise
the tumor is 3 to 4 cm in diameter. On microscopic examination, tumors that
were associated with the carcinoid syndrome had abundant acini, whereas large tumors that were clinically inactive had few i f any. The presence of the syndrome also correlated with the prominence of the argentaffin granules.
Although the primary insular carcinoid of the ovary behaves in a benign fashion in most cases,16 recurrences have been observed. Peritoneal and hepatic metastases developed 1 and 5 years after oophorectomy in two pa- tients in the series in whom the carcinoid was associated with a teratoma. There have been three additional reports of malignant behavior, but inadequate data were avail- able to evaluate one of the cases,m and review of the slides of the other tw010.3+3 indicated that the primary ovarian tumor was a small cell carcinoma resembling an oat cell car- cinoma and not insular carcinoid in the ac- cepted sense of the term. An unfavorable
TABLE 4. Differential Features of 42 Primary and 25 Metastatic Ovarian Carcinoids'
Primary Metastatic
Clinical data Preoperative carcinoid
Syndrome subsides after
Syndrome reappears within
5-HIAA positive within
syndrome 31% 40%
oophorectom y 14/14 4/4
6 mo 0/14 2 /4
6 mo 0/17 9/12 Operative findings
Extraovarian primary
Extraovarian carcinoid
Contralateral ovary
Contralateral ovarian
lesion 0% 76%
metastases 0% 92 %
enlarged 19%+ 56%
carcinoid 0% 96%
carcinoid in same ovary 76% 0%
Ovarian tumor Teratomatous tissue &
Appearance of carcinoid homogeneous nodular Amount of stroma small large Foci of atypical nuclei none to slight slight to
marked Argentaffin positivity 90% 70%
Prognosis Dead of carcinoid in 1 year 0% 34 % Dead of carcinoid in 4 years 0% 76% Recurrent or residual tumor 4% 96%
* Surgical cases only, adapted from Robboy et al." t Dermoid cyst, mucinous cystadenoma or carci- - .
to abnormal levels (> 10 mg/i4 hours) until noma, or Brenner tumor.
416 CANCER August 1975 Vol. 36
outcome is also possible if there has been valvular damage prior to removal of the tu- mor, and the damage progresses subsequently in the absence of recurrence.m In this series, signs of tricuspid insufficiency developed in one patient 3 years postoperatively without obvious recurrence of tumor.
The findings of this study have several implications regarding therapy. If an ovarian carcinoid is unilateral, associated with tera- tomatous elements, and not accompanied by obvious extraovarian tumor, it is almost cer- tainly primary. If the patient is menopausal or postmenopausal, bilateral salpingo-oopho- rectomy and hysterectomy is warranted. If she is young and preservation of ovarian function is important, the contralateral ovary
should be biopsied in an attempt to exclude its involvement before unilateral salpingo- oophorectomy is accepted as the definitive surgical procedure. If a unilateral carcinoid not associated with obvious teratomatous ele- ments is diagnosed or suspected by the path- ologist on a frozen section examination, care- ful evaluation of the intestinal tract as well as the opposite ovary is indicated before concluding that the tumor is primary in the ovary. The finding of an intestinal or mesenteric mass, bilateral ovarian involve- ment, or peritoneal metastases strongly sug- gests carcinoid metastatic to the ovary, the treatment of which usually includes bilateral salpingo-oophorectomy as well as some type of surgical approach to the primary tumor.
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APPENDIX
The authors wish to thank the following physicians who permitted us to review their cases: TRC-Tumour Reference Collection, Imperial Cancer Research Fund, Lincoln Inn’s Field, London, England; Case 1-Dr. S. Bruce Kephart, Bluffton, IN; Case 2- Dr. J. R. Betson, Jr., Costa Mesa, CA, and Monroe S. Samuels, New Orleans, LA; Case 3-Doctors D. P. Black, W. L. Cunn, and T. Stewart Perrett, Vancouver, BC, Canada; Case 5-Doctors Haw Chan and Mary L. Contakos, Walnut Creek, CA; Case 6-Dr. Winston Evans, David Lewis Northern Hos- pital, Liverpool, England; Case 7-Dr. Mal- colm Dockerty, Rochester, MN; Case 9- Doctors K. Chatterjee and J. C. Heather, Coventry and Warwickshire Hospital, Cov- entry, England; Case 10-Dr. Ansgar Torvik, Ulleval Hospital, Oslo, Norway; Case 11- Dr. Ralph Richart, New York, NY; Case 12-Dr. A. Mouchet, Hospital Foch, Surrenes, France; Case 13-Dr. Narciso S. Albarracin, Columbus, OH; Case 14-Dr. Elizabeth Yan- nello, New Britian, CT; Case 15-Doctors A. A. Kass and D. W. Penner, Winnipeg, Canada; Case 16-Dr. Howard Ulfelder, Bos- ton, MA, and Doctors Henry McDuff and Sumner I. Raphael, Providence, RI; Case 17-Dr. Edward Nissen, Anaheim, CA, and Doctors Umberto Villasanto and C. Wood, Baltimore, MD; Case 18-Dr. Sture Falkmer, University of Umea, Umea, Sweden; Case 19-Dr. J. Dossett, St. James Hospital, Leeds, Yorkshire, England; Case 20-Doctors Baldo Bertocchi and Henry Stoll, Brooklyn, NY; Case 21-Dr. Rupert Willis, “Inverdee,” Dela- vor Rd., Heswall, Cheshire, England; Case 23-Doctors Joseph F. Kerrans and George
Lauro, Attleboro, MA; Case 24-Dr. Christie E. McLeod, Middletown, CT; Case 25-Doc- tors James C. Beyer and William D. Dolan, Arlington, VA; Case 27-Dr. A. R. W. Climie, Detroit, MI; Case 28-see Case 7; Case 29- Dr. David F. Alstatt, Lafayette, IN; Case 30-Dr. Leszek Wozniak, Lodg, ul. Sterlinga 5, Osradek Naukowo-Badawcgy, Poland; Case 31-Dr. Leonard B. Kahn, University of Cape Town, Observatory C.P., South Africa, and Dr. Peter A. Trott, St. Paul’s Hospital, London; Case 32-Dr. Wm. M. Murphy, Val- ley Forge General Hospital, Phoenixville, PA; Case 34-Dr. Brian F. Quinn, Mater Misercordiae Hospital, N. Sydney, Australia; Case 35-Dr. John P. Decker, Philadelphia, PA; Case 36-Dr. Jack W. Doucette, Denver, CO. and Dr. John Shinner, St. Petersburg, FL; Case 37-Dr. John J. Anthony, Pitts- burgh, PA, and Dr. J. Donald Woodruff, Ovarian Tumor Registry (OTR), Baltimore, MD; Case 38-Doctors Richard Alt and Rob- ert Fienberg, Beverly, MA; Case 39-Dr. John Craig, Boston, MA; Case 40-see Case 21; Case 41-Doctors Rudolf O s g d and Wendell E. Smith, Attleboro, MA, and Dr. Henry W. Kolbe, Walpole, MA; Case 42- Dr. Peter E. Hughesdon, University College Hospital Medical School, London, England; Case 43-Dr. Theophilus W. Roberts, New York, NY, and Dr. Joseph V. Casella, Wil- mington, DE; Case 44-see Case 2; Case 45-Dr. Raymond C. Zastrow, Milwaukee, WI; Case 4 6 s e e Case 18; Case 47-Doctors F. Lamont Jennings and Richard B. Mar- shall, Galveston, TX; Case 48-Dr. Joseph F. Martin, Univ. Claude Bernard, Lyons, France.
