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Carcinoid tumor and pregnancy
CURRENT DEVELOPntllENTS
Carcinoid tumor and pregnancy JOHN Wheeling,
W. West
DURKIN,
JR.,
M.D.
Virginia
THIS IS A review of pregnant patients with carcinoid tumor. It has been noted that carcinoid tumors do not influence an intrauterine gestation when present. This may be true, but this review suggests a slightly different perspective. Carcinoid tumors and pregnancy are obviously not incompatible, but the chances for fetal wastage may be increased. The clinical encounter with a young pregnant woman with a carcinoid tumor prompted this review. The patient presented the classic situation in which a mother is confronted by two proliferating systems: a tumor and a fetus. Obviously, the first system demands control and elimination if possible. The second system hopefully can be preserved and salvaged.* During the care of this patient we reviewed the effects of serotonin (5-hydroxytryptamine, 5-HT) during gestation, as well as observations relative to serotonin in normal human pregnancy and in complications of pregnancy. The outcome of similar cases of carcinoid tumor and pregnancy retrieved from the medical literature were reviewed also.
Animal studies In 1955, Page and Glendening2 published their studies of serotonin (5-HT), which produced renal cortical
From the Defwtmnt of Obstetrics and Gynecology, Ohio Vu@ Medic& Center and West Virginia University School of Medicine (Wheeling Division). Presented in part at the annual meeting of the American College of Obstetri&lzs and Gyrzecologistr, West Virginia Section, in Huntington, West Virginia, September 19, 1981. Reprint Medical
requests: John W. Durkin, Jr., M.D., Ohio Valley Center, Wheeling, West Virginia 26003.
necrosis when given to rats, guinea pigs, mice, and rabbits. They postulated this small molecular hormone might play a role in eclampsia and placental abruption. Poulson and associates3 gave mice a single dose of 5-HT early in gestation. This resulted in death for 22% of the fetuses. Five percent of the survivors displayed anencephaly, anophthalmia, hydrocephalus, polydactyly, syndactly, and phocomelia. These findings could be grouped in two main categories: severe central nervous system anomalies and limb disturbances. Robson and Sullivan’ also caused fetal death in mice by dosing the mothers with serotonin. Fahim and Botrosj also conducted studies using serotonin in rats and rabbits. They noted serotonin caused vascular occlusion and thrombosis of placental vessels. Serotonin also caused myometrial contractions that affected the vascular supply to the uterus to produce fetal death. They did not believe this was either a hormonal action or a direct lethal action on the fetus. Craig6 conducted similar studies in rats in which serotonin produced vasoconstriction of uterine vessels and contraction of the myometrium. This decreased maternal blood flow to the placenta to render the fetus acutely anoxic, thus causing death or possible disturbances in growth and development. Pfeifer and colleagues7 also conducted studies in rats with similar fmdings. In summary these animal studies showed serotonin could reduce uterine blood flow and affect fetal nutrition. There is a spectrum of fetal effects ranging from congenital anomalies to growth retardation to death. The seriousness of the effects depended on the duration of gestation at the time of the insult and the severity of fetal deprivation caused by the vascular and myometrial reactions to serotonin. 757
758
Durkin
Human studies In 1959, Israel and associates8 noted that serotonin neither fell nor increased during labor. Platelet levels of serotonin were not altered. Specimens of myometrium were obtained from nonpregnant patients as well as from patients undergoing cesarean section with or without labor. There was no difference in the serotonin content in the myometrium studied. Another study involved the measurement of 5-hydroxyindoleacetic acid (5-HIAA) in 7,000 urine specimens obtained from 141 women.9 The daily range of excretion of 5-HIAA (1 .O to 5.8 mg) in normal pregnant women showed a high degreee of constancy. There was no change as pregnancy advanced to term. A few patients who had habitual abortion (9 to 25 weeks) excreted 30 to 40 mg per day. This level of 5-HIAA suggested a carcinoid tumor, but none was ever diagnosed. In 1965, Koren and his groupi measured 5-HT in various placentas, fetal tissue, and a few uteri. They stated 5-HT gradually increased from early pregnancy to delivery. However, no other study appears to have obtained similar findings. Southgate and Sandier” studied 23 women, four of whom were toxemic, throughout pregnancy. They found a slight increase in tryptamine values. However, values throughout pregnancy for 5-HT, 5-HIAA, indoleacetic acid, tyramine, vanillylmandelic acid, and homovanillic acid were more or less constant. Values in the toxemic women did not show any differences.
Clinical reports There have been 13 reports in the medical literature involving 18 patients with carcinoid tumors during 25 pregnancies. Most of the reports concern one patient during one pregnancy. The exceptions are Banner and associates12 who described three patients; Berrios and co-workers13 who described four patients in their article: and Reddy and colleaguesr4 and Luosto and his group’j who, in each case, described one patient with four different pregnancies. A brief summary of these reports follows: The first report found in the literature describing carcinoid tumor and pregnancy was virtually buried in an article originating from the Mayo Clinic.12 The authors incidentally noted three such patients while giving only sparse details. One patient, age 36 years, underwent operation with a diagnosis of acute appendicitis. She was found to have a carcinoid tumor of the appendix as well as an ectopic pregnancy in the right uterine tube. Another patient, 20 years of age, had the sudden onset of pain in the right lower quadrant on her eleventh post-
March Am. J, Obstet.
15, lYX3 Gynecd
partum day. The preoperative diagnosis was acute appendicitis. Laparotomy disclosed a gangrenous appendix with a carcinoid tumor at its tip. The patient recovered uneventfully and subsequently completed another pregnancy successfully. The third patient was noted to have had a carcinoid tumor of the appendix removed in the sixth month of gestation. The pregnancy was completed uneventfully. Duturmeny and Rufi’described a 36-year-old woman who presented with pain in the right lower abdomen at about 6 weeks gestation. Laparotomy resulted in an appendectomy. The pathology report was carcinoid tumor of the appendix. The patient aborted at 15 weeks of gestation. In a review of pregnant patients with cancer seen at Charity Hospital in New Orleans, Betson and GoldenI reported on a 32-year-old patient who was diagnosed as having acute appendicitis 1 month after spontaneous vaginal delivery. Exploratory laparotomy resulted in an appendectomy. The lesion was reported as a carcinoid tumor (argentaffinoma of the appendix). The patient was lost to follow-up after 5 years of normality. Based on the natural history of this tumor, the authors believed the lesion coexisted with at least the last pregnancy. Another report was that of a young black woman found to have a small rectal nodule on examination at 28 weeks of gestation. i* The tumor was removed under saddle block anesthesia. The mass was reported as carcinoid tumor. There was no apparent effect on the pregnancy. In 1963, Reddy and colleaguesr4 reported on an unusual patient who arrived in the hospital at 35 years of age with an acute abdominal problem. She had a 15year history of flushing. During that time she had four pregnancies with no living children. Three of the neonates were born between 30 and 34 weeks of gestation. All died of respiratory difficulty and cyanosis 2 to 36 hours after birth. In the last pregnancy a stillborn infant with multiple congenital anomalies was delivered at 34 weeks. All these births occurred in a small community hospital, no postmortem examinations were done, and the authors could not secure further details. At surgery this woman was found to have a carcinoid tumor of the distal ileum with multiple metastases to the liver and regional lymph nodes. The patient sub sequently developed congestive heart failure associated with tricuspid insufficiency and pulmonary stenosis. In a report from a military hospital, four different cases were described. I3 One patient displayed symptoms of acute appendicitis at 2 months of gestation. An appendectomy revealed a carcinoid tumor of the appendix. The patient was delivered of an infant at 41
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weeks of gestation. A second patient required a cesarean section during unsuccessful labor at term. An apparently abnormal appendix was removed and a carcinoid tumor was found. A third patient was suspected of having an ectopic pregnancy after a period of amenorrhea. Laparotomy disclosed an intrauterine pregnancy of 10 weeks’ duration and a bleeding corpus luteum cyst, and an incidental appendectomy was carried out. A carcinoid tumor was found in the appendix. The last patient underwent elective cesarean section and sterilization performed at 38 weeks of gestation. A firm mass was noted in the appendix. The appendix was removed and subsequently noted to contain a carcinoid tumor. At North Carolina Baptist Hospital, McCullough and on 22 patients, eight of whom were MyersI reported female, with carcinoid tumors. One of the eight women was noted to be pregnant. This woman began to have symptoms of flushing and diarrhea at age 31 years after the birth of twins. At age 34 years the patient was evaluated and a diagnosis of carcinoid syndrome with liver nodules was made. No primary tumor was noted. During another successful pregnancy her symptoms seemed to abate slightly. After the pregnancy, however, her disease progressed: she died 4 years after diagnosis and 7 years after onset of symptoms. Mattingly and associatesZo described a woman who had symptoms beginning at age 10 years, whose condition confounded prominent medical figures at several centers until a diagnosis was finally made at age 38 years. Her heart murmur was attributed at various times to either a congenital lesion or possibly rheumatic fever. It is interesting that the murmur was first recognized and termed functional during a pregnancy when this woman was in her late twenties. Studies at the National Institutes of Health subsequently confirmed a functioning carcinoid tumor with syndrome. When she died at age 45 years, postmortem examination confirmed carcinoid tumor in the distal ileum and 90% of her liver had been replaced by tumor masses. Apparently her earlier pregnancy was unaffected at the time. Leeper and colleagues”’ reported on a 15-year-old white girl who presented with weakness, fatigue, diarrhea, and a nontender abdominal mass. Laparotomy revealed metastatic liver lesions. A liver biopsy was described as adenocarcinoma not definitive in structure for diagnosis of tumor type. Three years later, in 1958, the patient developed a macular rash on her shoulders and face. By 1960, she had a generalized rash, as well as systolic and diastolic murmurs at the base of the heart. In 1960, a kidney stone was removed. A urine 5-HIAA test was reported as positive. On reevaluation the patient was considered to have a carcinoid tumor. In
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1962, she became pregnant and spontaneously aborted the fetus at 10 weeks of gestation. No fetal anomalies were noted. Hoch and co-workers” reported a .%)-year-old woman who had prolapse of the umbilical cord during labor in her third pregnancy. An immediate cesarean section resulted in the birth of a healthy neonate. It was noted the left ovary was completely replaced by a tumor which measured 15 by 10 by 5 cm. .4n additional left salpingo-oophorectomy was followed bv an uneventful recovery. The diagnosis was carcinoid tumor in a benign cystic teratoma. On review it was noted the woman had sudden attacks of Hushing, tachycardia, and severe dyspnea on occasions for 3!/2 years prior to the pregnancy. A diagnosis was not made at the time, and only symptomatic therapy had been administered. Postoperatively her symptoms disappeared and she remained I’rine studies, symptom fi-ee for 2 years’ tbllow-up. chest x-rays, and liver scan were reported as normal. Luosto and associates’” described a nllrse whose third pregnancy was terminated by cesarean section in 1966 because of fetal distress. During the pregnancy a chest x-ray revealed a peripheral solitary nodule in the upper lobe of the right lung. The patient was asymptomatic. A review of x-rays revealed this lesion had been present in previous x-rays (1955, 1956. 1961) through two other pregnancies. Post partutu. the lesion appeared smaller and the patient reiilsed rhoracotomv. She subsequently became pregnant again. A period of antituberculous therapy was administered without effect. Some 5 years alter the last deli\ery the patient underwent thoracotomv. The lesion was a bronchial adenoma, carcinoid type. Six months after the operation. the patient was well and her chest x-ra) was normal. Another patie&” was found to have an exophytic mass involving the entire cervix at 28 weeks’ gestation. A diagnosis of’ cervical malignancy w-as tnade. At 33 weeks of gestation a living newborn intan was delivered by cesarean section, and the operation was extended as a Wertheim hysterectomy. The patient died approximately 1 months after surgery. Postmortem examination resulted in a final diagnosis of the cervical lesion as tnalignant apudoma (argyrophil carcinoma). The last reported patient’” was a 25-year-old woman who presented with menometrorrhagia of several months’ duration. Examination disclosed an intrauterine pregnancy of 10 weeks’ duration as well as a cervical mass diagnosed initially as poorly differentiated squamous cell carcinoma. Therapy was carried out with &-platinum, but repeat biopsy showed no definitive change. Two weeks later radical hysterectomy and pel-
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vie lymph node dissection were performed, followed by external radiation to the pelvic field. Special stains and electron microscopy of the tissue resulted in a diagnosis of oat cell carcinoma, a malignant variant of the carcinoid tumor. The patient was reported as well 9 months after surgery. A concise description of the problems of the index patient which prompted this review follows: In 1971, at the age of 18 years, this young white woman was delivered of a son uneventfully in a community hospital in another state. Some 18 months later (in the autumn of 1972) she entered a community hospital in West Virginia with a possible small bowel obstruction that resolved with conservative therapy. Some 5 weeks later (December, 1972) she was readmitted to the same hospital with findings associated with small bowel obstruction. An exploratory laparotomy resulted in mobilization of the third portion of the duodenum, the removal of compressing lymph nodes in the retroperitoneal space near the superior mesenteric artery, reduction of an ileal intussusception, ileotomy, and appendectomy. The pathology report for the lymph nodes removed was carcinoid tumor with no primary origin recognized. Over the next 4 years this patient was admitted to several hospitals on more than 30 occasions for recurrent symptoms of palpitations, sweating, dizzy spells, abdominal pain, and diarrhea. Repeated tests for 5-HIAA were reported as within normal limits. During this period at least six laparotomies were done, mainly for the release of bowel adhesions. One hospitalization at a university medical center resulted in removal of a mass, again from the retroperitoneal area. It was reported as consistent with carcinoid tumor, but islet cell tumor was mentioned as a possibility. The last laparotomy was done in January, 1977, at yet another community hospital. In addition to lysis of adhesions, a biopsy of a liver nodule was diagnosed as carcinoid tumor. On October 20, 1977, this woman arrived in the Ohio Valley Medical Center Emergency Department on referral from another area hospital. The patient complained of vomiting, diarrhea, and pain over the entire upper abdomen. Examination revealed an alert, emaciated, cooperative white woman weighing 97 pounds who was obviously pregnant. She had lost 20 pounds in the previous 6 months. Her last menstrual flow was March 6, 1977; the uterine fundus measured 25 cm above the symphysis pubis; and a fetal heartbeat was heard in the left lower quadrant of the abdomen. There was no evidence of labor. The clinical diagnoses were: intrauterine pregnancy, 32 weeks; carcinoid tumor: and anemia. Urine tests for
15, 1989 Gynecol.
5-HIAA were within the normal range. On October 24, 1977, a sonogram revealed the fetal size to be consistent with 32 to 33 weeks of gestation. Hyperalimentation was instituted to improve the patient’s nutritional status. Intubation was carried out when the patient had a hematemesis on her eighth hospital day. Labor ensued and fetal monitoring disclosed fetal distress with late decelerations. An emergency cesarean section was unsuccessful and revealed an abruptio placentae. A stillborn female infant, 3 pounds and 15 ounces, was delivered. No gross abnormalities were noted. The operative report noted 1,000 ml of ascitic fluid, but none was taken for cytology. Massive bowel adhesions were also described as well as multiple liver nodules. The patient had a stormy postoperative course complicated by pneumonia and peritonitis. She received several blood transfusions and was treated with a variety of antibiotics. When the patient’s condition stabilized she was given a course of chemotherapy without response. In April, 1978, she was transferred to a chronic care facility in her own community. During 1978, she was hospitalized on three occasions, including one for pneumonia caused by Klebsiella. In January, 1979, this young woman entered the hospital for the final time in an emaciated state, weighing 75 pounds. The patient died in early February, 1979, at the age of 25 years. The findings at autopsy were widespread involvement of the liver by cells consistent with carcinoid tumor and gastrointestinal bleeding secondary to ulcer of the duodenum. No primary tumor site could be determined.
Comment At one point Berrios and colleaguesr3 noted a total of six patients with carcinoid tumor and pregnancy reported in the medical literature (they apparently were unaware of the “obscured” cases reported by Banner and co-workerP). A statement was made that such a small number of cases did not reflect a true incidence of this combination. This statement probably is still in order today. It is unlikely such a combination would be overlooked, but cases may not be reported. In the discussion that followed the presentation of this paper, a physician reported that his wife had had a bronchial adenoma, carcinoid type, with a massive hemoptysis during late pregnancy. 25 After successful completion of the pregnancy, this woman underwent thoracotomy with complete removal of the tumor. An extensive review noted carcinoid tumors occur in about 1% of all people and may be slightly more common in women than men.26 The cells which give rise to carcinoid tumors appear to be ubiquitous. They are
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derived from Kulchitsky cells or analogous cells, which embryologically arise from neural crest cells. Thus these cells may be considered primitive with multiple potential for differentiatiomz7’ 28 Carcinoid tumors are slow growing and may present with dramatic endocrine manifestations. Usually they are progressive with marked fibroplastic reactionszgS 3o that can cause intestinal obstruction and adhesions as noted in the index patient. Curative therapy requires complete surgical removal of the tumor. However, if the syndrome is already present owing to liver involvement, it appears that debulking and symptomatic therapy may be in order. Further therapy to date with various modalities, including ex-
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tensive surgery, radiation, and chemotherapy, has not been effective. A more recent publication suggests reconsideration of radiation therapy for some patients.3’ In another monograph it was noted: “I ;arcinoids do not influence an intrauterine gestation when present”.32 This may be true, but this review suggests a slightly different perspective. Carcinoid tumors and pregnancy are obviously not incompatible, but the chances for fetal wastage may be increased. The author acknowledges the translation of reference 23 by Ladislav Boehm, M.D. Mrs. Eleanor Shonn assisted in the translation of parts of rcaferences 13 and 27.
REFERENCES 1.
2.
3. 4.
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Smith, R. B. W., Sheehy, T. W., and Rothberg, H.: Hodgkin’s disease and pregnancy, Arch. Intern. Med. 102:?77, 1958. . Parze. E. W.. and Glendeninz. M. D.: Production of renal co%al nekosis with serot&n (5 hydroxytryptamine): Theoretical relationship to abruptio placentae, Obstet. Gynecol. 5:781, 1955. _ . Poulson. E.. Robson. 1. M.. and Sullivan. F. M.: Teratogenie effect of 5-hydroxytryptamine in mice, Science 141:717, 1963. Robson, J. M., and Sullivan, F. M.: Mechanism of lethal action of 5-hydroxytryptamine on the foetus, J. Endocrinol. 25:553, 1963. Fahim, I., and Botros, M.: Possible mechanism of action of 5-hydroxytryptamine in interruption of pregnancy, Obstet. Gynecol. 24:575, 1964. Craig, 1. M.: Mechanism of serotonin induced abortion in rats,-Aqch. Pathol. 81:257, 1966. Pfeifer. Y.. Sadowskv. R.. and Sulman, F. G.: Prevention of serotonin abortion in pregnant rats by five serotonin antagonists, Obstet. Gynecol. 33:709, 1969. Israel, S. L., Seligson, H. T., Stroup, P. E., and Seligson, D.: Serotonin in pregnant and parturient women, Obstet. Gynecol. 13:672, 1959. Sadowsky, A., Pfeifer, Y., Sadowsky, E., Tsur, C., and Sulman, F. G.: Serotonin metabolism in habitual abortion, Obstet. Gynecol. 22:778, 1963. Koren, Z., Pfeifer, Y., and Sulman, F. G.: Serotonin content of human placenta and fetus during pregnancy, AM. J. OBSTET. GYNECOL. 93:411, 1965. -Southgate, J., and Sandier, M.: 5-Hydroxyindole metabolism in pregnancy, Adv. Pharmacol. (Suppl.) 6:179, 1968. Banner, E. A., Hunt, A. B., and Dixon, C. F.: Pregnancy associated with carcinoma of the large intestine, Surg. Gynecol. Obstet. 80:211, 1945. Birrios, J. R., Dunnihoo, D. E., Gibbs, C. E., and Moore, S. F.: Appendiceal carcinoid tumors in pregnancy, Ob stet. Gynecol. 26:428, 1965. Reddy, D. V., Adams, F. H., and Baird, C.: Teratogenic effects of serotonin, I. Pediatr. 63:394, 1963. Luosto, R., Koikkai&en, K., and Sipponen, P.: Spontaneous regression of a bronchial car&&id tumor fofiowinp oreznancv, Ann. Chir. Gvnaecol. Fenn. 63:342.1974. D%rGeny, k., and Ruf, J.:‘Epithelioma argentaffine de l’appendice chez une femme enceinte, Bull. Fed. Gynecol. Obstet. Fr. 9:377, 1957. ,
,.J
,I
17. Betson, J. R., Jr., and Golden, M. L.: Cancer and pregnancy, AM. J. OBSTET. Gm~co~.81:718, 1961. 18. Monteagude, F. P.: Rectal carcinoid associated with pregnancy, J. Int. CoH. Surg. 35:205, 1961. 19. McCullough, D. L., and Myers, R. T.: Carcinoid tumors and the carcinoid syndrome, N. C. Med. J. 26: 198, 1965. 20. Mattingly, T. W., Andrus, E. C., Biorck, G., and Manion, W. C.: The functioning carcinoid tumor. Trans. Am. Clin. Climatol. Assoc. 75190, 1965. 21. Leerier. S. W.. Brown. H.. and Rosenberrr. H. S.: Spontaneous abortion in the carcinoid syndrome, AM. . 1. L
OBSTET.
GYNECOL.
94:340,
1966.
22. Hoch. Z.. Lichtiz. C.. Peretz. A. B.. Paldi. E.. Pascal, B.. Fuchs, K:, and &&es, J. M.: Ov&ian carcinoid tumor and term pregnancy, AM. J. ORSTET. GYNECOL. 1 IO: 1141, 1971.
23. Kodousek, R., Gazarek, F., Dusek, J., and Dostzal, S.: Malignant apudoma (argyrophil carcinoma) of’ the uterine cervix in a 24 year old woman in .pregnancl Ctzsk. Patol. ., 12:37, 1976. ’ 24. Jacobs, A. J., Marchevsky, A., Gordon, R. E.. Deppe. G., and Cohen. C. 1.: Oat cell carcinoma of the uterine cervix in a pregnant woman treated with cis-diamminedichloroplatinum, Gynecol. Oncol. 9:405, 1980. 25. Dickie, H. G.: Personal communication. 26. Jagar, R. M., and Polk, H. C., Jr.: Carcinoid apudomas, Curr. Probl. Cancer 1:1, 1977. 27. Huebschmann, P.: Sur le carcinome primitif. de l’appendice vermiculaire, Rev. Med. S&se Romande 30:317, 1910. of 28. Weston, J. A.: The migration and differentiation neural crest cells, in Abercrombie, M., Bracket, J., and King, T. L., editors: Advances in Morphogenesis, vol. 8, New York, 1970, Academic Press, Inc. 29 Moertel, C. G., Sauer, W. G., Dockertv, M. B., and Baggenstoss, A. H.: Life history of the carcinoid rumor of the small intestine, Cancer 14:901, 1961. 30 Horsley, B..L, and Baker, R. R.: Fibroplastic response to intestinal carcinoid, Am. Surg. 36:676, 1970. 31. Krohel, G. B., Perry, S., and Hepler. R. S.: Acute hypertension with orbital carcinoid tumor. Arrh. Ophthalmol. 100:106, 1982. 32. McGowan, L.: Cancer in Pregnancy, Springfield, 1967, Charles C Thomas, Publisher. p. 41.
Carcinoid tumor and pregnancy JOHN Wheeling,
W. West
DURKIN,
JR.,
M.D.
Virginia
THIS IS A review of pregnant patients with carcinoid tumor. It has been noted that carcinoid tumors do not influence an intrauterine gestation when present. This may be true, but this review suggests a slightly different perspective. Carcinoid tumors and pregnancy are obviously not incompatible, but the chances for fetal wastage may be increased. The clinical encounter with a young pregnant woman with a carcinoid tumor prompted this review. The patient presented the classic situation in which a mother is confronted by two proliferating systems: a tumor and a fetus. Obviously, the first system demands control and elimination if possible. The second system hopefully can be preserved and salvaged.* During the care of this patient we reviewed the effects of serotonin (5-hydroxytryptamine, 5-HT) during gestation, as well as observations relative to serotonin in normal human pregnancy and in complications of pregnancy. The outcome of similar cases of carcinoid tumor and pregnancy retrieved from the medical literature were reviewed also.
Animal studies In 1955, Page and Glendening2 published their studies of serotonin (5-HT), which produced renal cortical
From the Defwtmnt of Obstetrics and Gynecology, Ohio Vu@ Medic& Center and West Virginia University School of Medicine (Wheeling Division). Presented in part at the annual meeting of the American College of Obstetri&lzs and Gyrzecologistr, West Virginia Section, in Huntington, West Virginia, September 19, 1981. Reprint Medical
requests: John W. Durkin, Jr., M.D., Ohio Valley Center, Wheeling, West Virginia 26003.
necrosis when given to rats, guinea pigs, mice, and rabbits. They postulated this small molecular hormone might play a role in eclampsia and placental abruption. Poulson and associates3 gave mice a single dose of 5-HT early in gestation. This resulted in death for 22% of the fetuses. Five percent of the survivors displayed anencephaly, anophthalmia, hydrocephalus, polydactyly, syndactly, and phocomelia. These findings could be grouped in two main categories: severe central nervous system anomalies and limb disturbances. Robson and Sullivan’ also caused fetal death in mice by dosing the mothers with serotonin. Fahim and Botrosj also conducted studies using serotonin in rats and rabbits. They noted serotonin caused vascular occlusion and thrombosis of placental vessels. Serotonin also caused myometrial contractions that affected the vascular supply to the uterus to produce fetal death. They did not believe this was either a hormonal action or a direct lethal action on the fetus. Craig6 conducted similar studies in rats in which serotonin produced vasoconstriction of uterine vessels and contraction of the myometrium. This decreased maternal blood flow to the placenta to render the fetus acutely anoxic, thus causing death or possible disturbances in growth and development. Pfeifer and colleagues7 also conducted studies in rats with similar fmdings. In summary these animal studies showed serotonin could reduce uterine blood flow and affect fetal nutrition. There is a spectrum of fetal effects ranging from congenital anomalies to growth retardation to death. The seriousness of the effects depended on the duration of gestation at the time of the insult and the severity of fetal deprivation caused by the vascular and myometrial reactions to serotonin. 757
758
Durkin
Human studies In 1959, Israel and associates8 noted that serotonin neither fell nor increased during labor. Platelet levels of serotonin were not altered. Specimens of myometrium were obtained from nonpregnant patients as well as from patients undergoing cesarean section with or without labor. There was no difference in the serotonin content in the myometrium studied. Another study involved the measurement of 5-hydroxyindoleacetic acid (5-HIAA) in 7,000 urine specimens obtained from 141 women.9 The daily range of excretion of 5-HIAA (1 .O to 5.8 mg) in normal pregnant women showed a high degreee of constancy. There was no change as pregnancy advanced to term. A few patients who had habitual abortion (9 to 25 weeks) excreted 30 to 40 mg per day. This level of 5-HIAA suggested a carcinoid tumor, but none was ever diagnosed. In 1965, Koren and his groupi measured 5-HT in various placentas, fetal tissue, and a few uteri. They stated 5-HT gradually increased from early pregnancy to delivery. However, no other study appears to have obtained similar findings. Southgate and Sandier” studied 23 women, four of whom were toxemic, throughout pregnancy. They found a slight increase in tryptamine values. However, values throughout pregnancy for 5-HT, 5-HIAA, indoleacetic acid, tyramine, vanillylmandelic acid, and homovanillic acid were more or less constant. Values in the toxemic women did not show any differences.
Clinical reports There have been 13 reports in the medical literature involving 18 patients with carcinoid tumors during 25 pregnancies. Most of the reports concern one patient during one pregnancy. The exceptions are Banner and associates12 who described three patients; Berrios and co-workers13 who described four patients in their article: and Reddy and colleaguesr4 and Luosto and his group’j who, in each case, described one patient with four different pregnancies. A brief summary of these reports follows: The first report found in the literature describing carcinoid tumor and pregnancy was virtually buried in an article originating from the Mayo Clinic.12 The authors incidentally noted three such patients while giving only sparse details. One patient, age 36 years, underwent operation with a diagnosis of acute appendicitis. She was found to have a carcinoid tumor of the appendix as well as an ectopic pregnancy in the right uterine tube. Another patient, 20 years of age, had the sudden onset of pain in the right lower quadrant on her eleventh post-
March Am. J, Obstet.
15, lYX3 Gynecd
partum day. The preoperative diagnosis was acute appendicitis. Laparotomy disclosed a gangrenous appendix with a carcinoid tumor at its tip. The patient recovered uneventfully and subsequently completed another pregnancy successfully. The third patient was noted to have had a carcinoid tumor of the appendix removed in the sixth month of gestation. The pregnancy was completed uneventfully. Duturmeny and Rufi’described a 36-year-old woman who presented with pain in the right lower abdomen at about 6 weeks gestation. Laparotomy resulted in an appendectomy. The pathology report was carcinoid tumor of the appendix. The patient aborted at 15 weeks of gestation. In a review of pregnant patients with cancer seen at Charity Hospital in New Orleans, Betson and GoldenI reported on a 32-year-old patient who was diagnosed as having acute appendicitis 1 month after spontaneous vaginal delivery. Exploratory laparotomy resulted in an appendectomy. The lesion was reported as a carcinoid tumor (argentaffinoma of the appendix). The patient was lost to follow-up after 5 years of normality. Based on the natural history of this tumor, the authors believed the lesion coexisted with at least the last pregnancy. Another report was that of a young black woman found to have a small rectal nodule on examination at 28 weeks of gestation. i* The tumor was removed under saddle block anesthesia. The mass was reported as carcinoid tumor. There was no apparent effect on the pregnancy. In 1963, Reddy and colleaguesr4 reported on an unusual patient who arrived in the hospital at 35 years of age with an acute abdominal problem. She had a 15year history of flushing. During that time she had four pregnancies with no living children. Three of the neonates were born between 30 and 34 weeks of gestation. All died of respiratory difficulty and cyanosis 2 to 36 hours after birth. In the last pregnancy a stillborn infant with multiple congenital anomalies was delivered at 34 weeks. All these births occurred in a small community hospital, no postmortem examinations were done, and the authors could not secure further details. At surgery this woman was found to have a carcinoid tumor of the distal ileum with multiple metastases to the liver and regional lymph nodes. The patient sub sequently developed congestive heart failure associated with tricuspid insufficiency and pulmonary stenosis. In a report from a military hospital, four different cases were described. I3 One patient displayed symptoms of acute appendicitis at 2 months of gestation. An appendectomy revealed a carcinoid tumor of the appendix. The patient was delivered of an infant at 41
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weeks of gestation. A second patient required a cesarean section during unsuccessful labor at term. An apparently abnormal appendix was removed and a carcinoid tumor was found. A third patient was suspected of having an ectopic pregnancy after a period of amenorrhea. Laparotomy disclosed an intrauterine pregnancy of 10 weeks’ duration and a bleeding corpus luteum cyst, and an incidental appendectomy was carried out. A carcinoid tumor was found in the appendix. The last patient underwent elective cesarean section and sterilization performed at 38 weeks of gestation. A firm mass was noted in the appendix. The appendix was removed and subsequently noted to contain a carcinoid tumor. At North Carolina Baptist Hospital, McCullough and on 22 patients, eight of whom were MyersI reported female, with carcinoid tumors. One of the eight women was noted to be pregnant. This woman began to have symptoms of flushing and diarrhea at age 31 years after the birth of twins. At age 34 years the patient was evaluated and a diagnosis of carcinoid syndrome with liver nodules was made. No primary tumor was noted. During another successful pregnancy her symptoms seemed to abate slightly. After the pregnancy, however, her disease progressed: she died 4 years after diagnosis and 7 years after onset of symptoms. Mattingly and associatesZo described a woman who had symptoms beginning at age 10 years, whose condition confounded prominent medical figures at several centers until a diagnosis was finally made at age 38 years. Her heart murmur was attributed at various times to either a congenital lesion or possibly rheumatic fever. It is interesting that the murmur was first recognized and termed functional during a pregnancy when this woman was in her late twenties. Studies at the National Institutes of Health subsequently confirmed a functioning carcinoid tumor with syndrome. When she died at age 45 years, postmortem examination confirmed carcinoid tumor in the distal ileum and 90% of her liver had been replaced by tumor masses. Apparently her earlier pregnancy was unaffected at the time. Leeper and colleagues”’ reported on a 15-year-old white girl who presented with weakness, fatigue, diarrhea, and a nontender abdominal mass. Laparotomy revealed metastatic liver lesions. A liver biopsy was described as adenocarcinoma not definitive in structure for diagnosis of tumor type. Three years later, in 1958, the patient developed a macular rash on her shoulders and face. By 1960, she had a generalized rash, as well as systolic and diastolic murmurs at the base of the heart. In 1960, a kidney stone was removed. A urine 5-HIAA test was reported as positive. On reevaluation the patient was considered to have a carcinoid tumor. In
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1962, she became pregnant and spontaneously aborted the fetus at 10 weeks of gestation. No fetal anomalies were noted. Hoch and co-workers” reported a .%)-year-old woman who had prolapse of the umbilical cord during labor in her third pregnancy. An immediate cesarean section resulted in the birth of a healthy neonate. It was noted the left ovary was completely replaced by a tumor which measured 15 by 10 by 5 cm. .4n additional left salpingo-oophorectomy was followed bv an uneventful recovery. The diagnosis was carcinoid tumor in a benign cystic teratoma. On review it was noted the woman had sudden attacks of Hushing, tachycardia, and severe dyspnea on occasions for 3!/2 years prior to the pregnancy. A diagnosis was not made at the time, and only symptomatic therapy had been administered. Postoperatively her symptoms disappeared and she remained I’rine studies, symptom fi-ee for 2 years’ tbllow-up. chest x-rays, and liver scan were reported as normal. Luosto and associates’” described a nllrse whose third pregnancy was terminated by cesarean section in 1966 because of fetal distress. During the pregnancy a chest x-ray revealed a peripheral solitary nodule in the upper lobe of the right lung. The patient was asymptomatic. A review of x-rays revealed this lesion had been present in previous x-rays (1955, 1956. 1961) through two other pregnancies. Post partutu. the lesion appeared smaller and the patient reiilsed rhoracotomv. She subsequently became pregnant again. A period of antituberculous therapy was administered without effect. Some 5 years alter the last deli\ery the patient underwent thoracotomv. The lesion was a bronchial adenoma, carcinoid type. Six months after the operation. the patient was well and her chest x-ra) was normal. Another patie&” was found to have an exophytic mass involving the entire cervix at 28 weeks’ gestation. A diagnosis of’ cervical malignancy w-as tnade. At 33 weeks of gestation a living newborn intan was delivered by cesarean section, and the operation was extended as a Wertheim hysterectomy. The patient died approximately 1 months after surgery. Postmortem examination resulted in a final diagnosis of the cervical lesion as tnalignant apudoma (argyrophil carcinoma). The last reported patient’” was a 25-year-old woman who presented with menometrorrhagia of several months’ duration. Examination disclosed an intrauterine pregnancy of 10 weeks’ duration as well as a cervical mass diagnosed initially as poorly differentiated squamous cell carcinoma. Therapy was carried out with &-platinum, but repeat biopsy showed no definitive change. Two weeks later radical hysterectomy and pel-
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vie lymph node dissection were performed, followed by external radiation to the pelvic field. Special stains and electron microscopy of the tissue resulted in a diagnosis of oat cell carcinoma, a malignant variant of the carcinoid tumor. The patient was reported as well 9 months after surgery. A concise description of the problems of the index patient which prompted this review follows: In 1971, at the age of 18 years, this young white woman was delivered of a son uneventfully in a community hospital in another state. Some 18 months later (in the autumn of 1972) she entered a community hospital in West Virginia with a possible small bowel obstruction that resolved with conservative therapy. Some 5 weeks later (December, 1972) she was readmitted to the same hospital with findings associated with small bowel obstruction. An exploratory laparotomy resulted in mobilization of the third portion of the duodenum, the removal of compressing lymph nodes in the retroperitoneal space near the superior mesenteric artery, reduction of an ileal intussusception, ileotomy, and appendectomy. The pathology report for the lymph nodes removed was carcinoid tumor with no primary origin recognized. Over the next 4 years this patient was admitted to several hospitals on more than 30 occasions for recurrent symptoms of palpitations, sweating, dizzy spells, abdominal pain, and diarrhea. Repeated tests for 5-HIAA were reported as within normal limits. During this period at least six laparotomies were done, mainly for the release of bowel adhesions. One hospitalization at a university medical center resulted in removal of a mass, again from the retroperitoneal area. It was reported as consistent with carcinoid tumor, but islet cell tumor was mentioned as a possibility. The last laparotomy was done in January, 1977, at yet another community hospital. In addition to lysis of adhesions, a biopsy of a liver nodule was diagnosed as carcinoid tumor. On October 20, 1977, this woman arrived in the Ohio Valley Medical Center Emergency Department on referral from another area hospital. The patient complained of vomiting, diarrhea, and pain over the entire upper abdomen. Examination revealed an alert, emaciated, cooperative white woman weighing 97 pounds who was obviously pregnant. She had lost 20 pounds in the previous 6 months. Her last menstrual flow was March 6, 1977; the uterine fundus measured 25 cm above the symphysis pubis; and a fetal heartbeat was heard in the left lower quadrant of the abdomen. There was no evidence of labor. The clinical diagnoses were: intrauterine pregnancy, 32 weeks; carcinoid tumor: and anemia. Urine tests for
15, 1989 Gynecol.
5-HIAA were within the normal range. On October 24, 1977, a sonogram revealed the fetal size to be consistent with 32 to 33 weeks of gestation. Hyperalimentation was instituted to improve the patient’s nutritional status. Intubation was carried out when the patient had a hematemesis on her eighth hospital day. Labor ensued and fetal monitoring disclosed fetal distress with late decelerations. An emergency cesarean section was unsuccessful and revealed an abruptio placentae. A stillborn female infant, 3 pounds and 15 ounces, was delivered. No gross abnormalities were noted. The operative report noted 1,000 ml of ascitic fluid, but none was taken for cytology. Massive bowel adhesions were also described as well as multiple liver nodules. The patient had a stormy postoperative course complicated by pneumonia and peritonitis. She received several blood transfusions and was treated with a variety of antibiotics. When the patient’s condition stabilized she was given a course of chemotherapy without response. In April, 1978, she was transferred to a chronic care facility in her own community. During 1978, she was hospitalized on three occasions, including one for pneumonia caused by Klebsiella. In January, 1979, this young woman entered the hospital for the final time in an emaciated state, weighing 75 pounds. The patient died in early February, 1979, at the age of 25 years. The findings at autopsy were widespread involvement of the liver by cells consistent with carcinoid tumor and gastrointestinal bleeding secondary to ulcer of the duodenum. No primary tumor site could be determined.
Comment At one point Berrios and colleaguesr3 noted a total of six patients with carcinoid tumor and pregnancy reported in the medical literature (they apparently were unaware of the “obscured” cases reported by Banner and co-workerP). A statement was made that such a small number of cases did not reflect a true incidence of this combination. This statement probably is still in order today. It is unlikely such a combination would be overlooked, but cases may not be reported. In the discussion that followed the presentation of this paper, a physician reported that his wife had had a bronchial adenoma, carcinoid type, with a massive hemoptysis during late pregnancy. 25 After successful completion of the pregnancy, this woman underwent thoracotomy with complete removal of the tumor. An extensive review noted carcinoid tumors occur in about 1% of all people and may be slightly more common in women than men.26 The cells which give rise to carcinoid tumors appear to be ubiquitous. They are
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derived from Kulchitsky cells or analogous cells, which embryologically arise from neural crest cells. Thus these cells may be considered primitive with multiple potential for differentiatiomz7’ 28 Carcinoid tumors are slow growing and may present with dramatic endocrine manifestations. Usually they are progressive with marked fibroplastic reactionszgS 3o that can cause intestinal obstruction and adhesions as noted in the index patient. Curative therapy requires complete surgical removal of the tumor. However, if the syndrome is already present owing to liver involvement, it appears that debulking and symptomatic therapy may be in order. Further therapy to date with various modalities, including ex-
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tensive surgery, radiation, and chemotherapy, has not been effective. A more recent publication suggests reconsideration of radiation therapy for some patients.3’ In another monograph it was noted: “I ;arcinoids do not influence an intrauterine gestation when present”.32 This may be true, but this review suggests a slightly different perspective. Carcinoid tumors and pregnancy are obviously not incompatible, but the chances for fetal wastage may be increased. The author acknowledges the translation of reference 23 by Ladislav Boehm, M.D. Mrs. Eleanor Shonn assisted in the translation of parts of rcaferences 13 and 27.
REFERENCES 1.
2.
3. 4.
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Smith, R. B. W., Sheehy, T. W., and Rothberg, H.: Hodgkin’s disease and pregnancy, Arch. Intern. Med. 102:?77, 1958. . Parze. E. W.. and Glendeninz. M. D.: Production of renal co%al nekosis with serot&n (5 hydroxytryptamine): Theoretical relationship to abruptio placentae, Obstet. Gynecol. 5:781, 1955. _ . Poulson. E.. Robson. 1. M.. and Sullivan. F. M.: Teratogenie effect of 5-hydroxytryptamine in mice, Science 141:717, 1963. Robson, J. M., and Sullivan, F. M.: Mechanism of lethal action of 5-hydroxytryptamine on the foetus, J. Endocrinol. 25:553, 1963. Fahim, I., and Botros, M.: Possible mechanism of action of 5-hydroxytryptamine in interruption of pregnancy, Obstet. Gynecol. 24:575, 1964. Craig, 1. M.: Mechanism of serotonin induced abortion in rats,-Aqch. Pathol. 81:257, 1966. Pfeifer. Y.. Sadowskv. R.. and Sulman, F. G.: Prevention of serotonin abortion in pregnant rats by five serotonin antagonists, Obstet. Gynecol. 33:709, 1969. Israel, S. L., Seligson, H. T., Stroup, P. E., and Seligson, D.: Serotonin in pregnant and parturient women, Obstet. Gynecol. 13:672, 1959. Sadowsky, A., Pfeifer, Y., Sadowsky, E., Tsur, C., and Sulman, F. G.: Serotonin metabolism in habitual abortion, Obstet. Gynecol. 22:778, 1963. Koren, Z., Pfeifer, Y., and Sulman, F. G.: Serotonin content of human placenta and fetus during pregnancy, AM. J. OBSTET. GYNECOL. 93:411, 1965. -Southgate, J., and Sandier, M.: 5-Hydroxyindole metabolism in pregnancy, Adv. Pharmacol. (Suppl.) 6:179, 1968. Banner, E. A., Hunt, A. B., and Dixon, C. F.: Pregnancy associated with carcinoma of the large intestine, Surg. Gynecol. Obstet. 80:211, 1945. Birrios, J. R., Dunnihoo, D. E., Gibbs, C. E., and Moore, S. F.: Appendiceal carcinoid tumors in pregnancy, Ob stet. Gynecol. 26:428, 1965. Reddy, D. V., Adams, F. H., and Baird, C.: Teratogenic effects of serotonin, I. Pediatr. 63:394, 1963. Luosto, R., Koikkai&en, K., and Sipponen, P.: Spontaneous regression of a bronchial car&&id tumor fofiowinp oreznancv, Ann. Chir. Gvnaecol. Fenn. 63:342.1974. D%rGeny, k., and Ruf, J.:‘Epithelioma argentaffine de l’appendice chez une femme enceinte, Bull. Fed. Gynecol. Obstet. Fr. 9:377, 1957. ,
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17. Betson, J. R., Jr., and Golden, M. L.: Cancer and pregnancy, AM. J. OBSTET. Gm~co~.81:718, 1961. 18. Monteagude, F. P.: Rectal carcinoid associated with pregnancy, J. Int. CoH. Surg. 35:205, 1961. 19. McCullough, D. L., and Myers, R. T.: Carcinoid tumors and the carcinoid syndrome, N. C. Med. J. 26: 198, 1965. 20. Mattingly, T. W., Andrus, E. C., Biorck, G., and Manion, W. C.: The functioning carcinoid tumor. Trans. Am. Clin. Climatol. Assoc. 75190, 1965. 21. Leerier. S. W.. Brown. H.. and Rosenberrr. H. S.: Spontaneous abortion in the carcinoid syndrome, AM. . 1. L
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22. Hoch. Z.. Lichtiz. C.. Peretz. A. B.. Paldi. E.. Pascal, B.. Fuchs, K:, and &&es, J. M.: Ov&ian carcinoid tumor and term pregnancy, AM. J. ORSTET. GYNECOL. 1 IO: 1141, 1971.
23. Kodousek, R., Gazarek, F., Dusek, J., and Dostzal, S.: Malignant apudoma (argyrophil carcinoma) of’ the uterine cervix in a 24 year old woman in .pregnancl Ctzsk. Patol. ., 12:37, 1976. ’ 24. Jacobs, A. J., Marchevsky, A., Gordon, R. E.. Deppe. G., and Cohen. C. 1.: Oat cell carcinoma of the uterine cervix in a pregnant woman treated with cis-diamminedichloroplatinum, Gynecol. Oncol. 9:405, 1980. 25. Dickie, H. G.: Personal communication. 26. Jagar, R. M., and Polk, H. C., Jr.: Carcinoid apudomas, Curr. Probl. Cancer 1:1, 1977. 27. Huebschmann, P.: Sur le carcinome primitif. de l’appendice vermiculaire, Rev. Med. S&se Romande 30:317, 1910. of 28. Weston, J. A.: The migration and differentiation neural crest cells, in Abercrombie, M., Bracket, J., and King, T. L., editors: Advances in Morphogenesis, vol. 8, New York, 1970, Academic Press, Inc. 29 Moertel, C. G., Sauer, W. G., Dockertv, M. B., and Baggenstoss, A. H.: Life history of the carcinoid rumor of the small intestine, Cancer 14:901, 1961. 30 Horsley, B..L, and Baker, R. R.: Fibroplastic response to intestinal carcinoid, Am. Surg. 36:676, 1970. 31. Krohel, G. B., Perry, S., and Hepler. R. S.: Acute hypertension with orbital carcinoid tumor. Arrh. Ophthalmol. 100:106, 1982. 32. McGowan, L.: Cancer in Pregnancy, Springfield, 1967, Charles C Thomas, Publisher. p. 41.