- Email: [email protected]
Cancer of the Ovary
CANCER OF THE OVARY NEIL
W.
SWINTON AND CHARLES
R.
YANCEY
MALIGNANT tumors of the ovary comprise approximately 4 per cent9 of malignant disease found in women. Eighty-nine patients wit!l ovarian malignancy have been seen at the clinic during the past fifteen years. A review of these cases at this time reveals that frequentl~ a diagnosis of cancer was not made before operation and even at operation in certain cases the presence of malignancy was not suspected. In an attempt to make earlier diagnoses of ovarian malignant disease, obtain data on potentially malignant ovarian tumors, further information on the detection of malignant change in these tumors aJ the time of operation and to determine the type of treatment indicated when ovarian cancer is encountered, we have reviewed the 64 cases of ovarian cancer in which we have complete data at this time and also have reviewed the recent literature on the subject.
TABLE 1 INCIDENCE OF VARIOUS TUMORS IN (After Bernsteinl )
1101
CASES
Follicle cysts ........................................ Dennoid cysts ....................................... Serous papillary cystadenocarcinomas ................... Corpus luteum cysts .................................. Pseudomucinous papillary cystadenomas ................. Endometriosis of the ovary ............................ Serous papillary cystadenomas .........................
Per cent . 36 . 16 . 14 . 11 6 . 4 . 3 .
In a collected series of 160,324 admissions to gynecologic clinics, an incidence of ovarian tumors of 2.8 per cent was found. IS Table 1 represents a typical distribution in a reported series of 1101 ovarian tumors of various types. 1 Approximately 15 per cent of these tumors were malignant, of which 50 per cent were bilateral. Considering ovarian tumors of all types, it was found that they are most commonly observed in women between 30 and 40 years of age. 1 In a survey of 2,083 cases of ovarian cancer reported, however, the average age was estimated to be between 49 and 52 years. 9 Cases of malignant disease of the ovary have been reported in children and in patients over 80. In our series the youngest was 5 years old and the oldest 77 years. It is not the purpose in this report to review in detail the vari(lli's classifications of ovarian tumors which have been presented or to go into detail on the histology of the various types of ovarian tumors. 681
682
NEIL W. SWINTON, CHARLES R. YANCEY
TABLE 2 CLASSIFICATION OF OVARIAN TuMoRS ACCORDING TO NOVAK1o
Benign Tumors 1. Cystic a. Non-neoplastic Follicle cysts Lutein cysts Corpus luteum cysts (including corpus albicans cysts) Theca lutein cysts Germinal inclusion cysts Endometrial cysts b. Neoplastic Cystadenoma Pseudomucinous simple papillary Serous simple papillary Dermoid 2. Solid a. Papilloma, fibroma-adenoma, fibroma, fibromyoma, angioma, lymphangioma, chondroma, osteoma b. Brenner tumors c. Adrenal tumors (masculinovoblastoma) Malignant Tumors 1. Carcinoma
2.
3. 4. 5.
a. Primary solid carcinoma Adenocarcinoma Nonpapillary Papillary Medullary carcinoma Carcinoma simplex Scirrhous carcinoma Alveolar carcinoma Plexiform carcinoma Mesonephroma (not clearly established as yet) Embryonic or dysontogenetic Granulosa-ceIl carcinoma (often cystic) Arrhenoblastoma Dysgerminoma (seminoma) Chorionepithelioma b. Cystic carcinoma Pseudomucinous cystadenocarcinoma Serous papillary cystadenocarcinoma Epidermoid carcinoma arising in dermoid cyst Secondary or Metastatic Carcinoma a. Adenocarcinoma, simple b. Krukenberg tumor c. Epidermoid carcinoma d. Chorionepithelioma e. Hypernephroma Teratoma (including struma ovarii) Sarcoma (round-cell, spindle-cell, mixed-cell) Melanoma
CANCER OF THE OVARY
683
Ewing 5 has stated that "ovarian tumors present a wider scope of structure, greater individual variation and a more complex embryologic and histogenic basis than those of any other organ .. For these reasons they have escaped satisfactory classification. In a substantial proportion of ovarian tumors as they actually occur, the diagnosis is largely a matter of arbitrary decision on the part of the observer." In spite of the many different classifications of ovarian tumors that have been presented, however, it is important to classify such tumors in some manner for purposes of discussion. The classification of Novak, 10 using the benign or malignant nature of the tumor as the most important criterion, has seemed the most practical to us. This classification of ovarian tumors is presented in Table ~. CYSTIC BENIGN TUMORS OF THE OVARY
The non-neoplastic tumors, which comprise the common cystic tumors of the ovary, are not related to the subject of malignancy except in the differential diagnosis, and will not be reviewed. The neoplastic group, the cystadenomas and the dermoids, however, have a definite relation to ovarian malignancy and, for a clear understanding of many of the problems connected with the diagnosis and treatment of ovarian cancer, must be thoroughly understood. Cystadenomas may be classified as either serous or pseudomucinous. The pseudomucinous cystadenomas may attain enormous size and in general are larger than the serous variety. Characteristically, they contain a thick, pseudomucinous fluid. They usually consist of large, rounded, cystic compartments of varying thicknesses. The large majority of tumors of this type are of the simple variety and not directly related to the development of malignancy. Approximately 10 per cent are of the papillary variety,2 which is much more important from the standpoint of malignant degeneration. MeyerS believes that approximately 5 per cent of these pseudomucinous cysts may become malignant. Of particular importance in this type of tumor is the pseudo'myxoma peritonei resulting from rupture of tumors of this type. Rupture of these tumors is followed by the implantation of pseudomucinous epithelium throughout the peritoneal cavity. They may penetrate the liver and other organs and set up various sources of secreting cells. Although these tumors are not truly malignant and are slow to develop, this complication invariably results in an eventually fatal outcome. Serous cystadenomas occur slightly less frequently than the pseudomucinous, may attain a large size but in general are smaller than the pseudomucinous variety. They characteristically contain a strawcolored fluid except when discolored by hemorrhage. The cysts are usually multilocular but may be made up of only a few large compartments. A much higher percentage of cystadenomas of this type may show papillary excrescences on the exterior of the cyst wall and,
684
NEIL W. SWINTON, CHARLES R. YANCEY
even more common, in the interior of the tumor. Of particular importance in the consideration of malignancy are those tumors showing a papillomatous growth, and Curtis 3 emphasized that every tumor of the ovary with a papillomatous growth upon the outer surface must be regarded as a malignant tumor, irrespective of its histologic characteristics. Curtis further stated that a benign papillary growth confined within a heavy capsule is relatively harmless; when the tumor has but a thin capsule, when there has, been leakage of the cyst contents from tapping or following rupture or, most importantly, when there are papillomatous growths on the surface, the prognosis is more serious. When papillary growths are fQund on the surface of these tumors, peritoneal implants occur in at least 25 per cent of the cases. Even though these implants may regress following removal of the primary lesion, ultimate death is the usual eventuality. Furthermore, the histologic differentiation between the papillary cystadenoma and cystadenocarcinoma frequently is very difficult and at times impossible. It may thus be seen from this discussion of the cystadenomas that a large percentage of these tumors making up the papillomatous variety must be considered as definite premalignant tumors. Thus, an early diagnosis of the cystadenomas and their treatment constitute a very important aspect of our attack on ovarian cancer. The differential diagnosis of minute cystomas from simple retention cysts is primarily an academic one and of no particular significance. When tumors attain any appreciable size, however, the detection of a papillomatous growth is very important. These latter tumors are usually of greater weight than the simple cysts. There is more of a tendency to fix~tion and they have' a nodular, firm surface. Nodules in the cul-de-sac are suggestive of a papillary growth. Although ascites may be found with the simple cyst variety, usually the presence of ascites indicates a more serious prognosis. It is unfortunately common that many of the cystadenomas do not cause early symptoms; however, disturbances of menstruation are frequent although sterility is rare. Pain in the pelvis and sensations of weight and pressure may occur. On physical examination, cystic ovarian tumors usually are found anterior to the uterus, which is an important differential point in diagnosing inflammatory cysts. The latter are usually lateral and posterior to the fundus. It must be remembered that the boggy, painless swelling of a tubal pregnancy may also be commonly found anterior to the uterus. The surface of a cystadenoma is usually lobulated and the tumor firm. A twisted ovarian pedicle is common with cystadenoma and is more frequent with the pseudomucinous type. It must be carefully remembered, however, that there are no preoperative criteria which will establish a definite diagnosis of the cystadenomatous group of benign ovarian tumors. Final diagnosis
CANCER OF THE OVARY
685
must await the intra-abdominal examination of the tumor by the surgeon and usually a histologic examination of the tumor by a pathologist. All patients with an ovarian cystic tumor 7 cm. or more in diameter should be carefully observed. A thin-walled, soft cyst will usually prove not to be a cystadenoma and may vary in size on repeated examinations or actually disappear. The persistence of the tumor, its firmness, induration, nodules, heaviness, pain, increase in size and demonstrable ascites are indications for exploration and probable removal. In discussing the treatment of the cystadenomas, the prevention of any spilling of the tumor content is to be particularly emphasized because of the danger of implants. The tapping of cysts is to be avoided whenever possible. Dermoid cysts occur frequently, comprising, according to Curtis,4 approximately 10 per cent of all ovarian tumors. They are the most common tumor found in children, sarcoma being the next most frequent. They may attain considerable size, develop slowly and are usually not found until adult life. The usual contents of dermoids found elsewhere, hair and teeth and other epithelial structures, are common. Torsion of the pedicle occurs frequently; associated ascites is rare. The importance of bowel perforation as a result of the extension or perforation of the dermoid ovarian cyst has been mentioned in the literature. These tumors may develop malignancy, although malignant degeneration probably does not occur in over 1 or 2 per cent of tumors· of this type. 14 Dermoid tumors frequently are bilateral and when such tumors are found, careful inspection of the opposite ovary must be made as the tumor in the adjacent ovary may be very small and frequently not detected unless a careful search is made. In such instances bilateral oophorectomy is indicated. DIAGNOSIS OF CANCER OF THE OVARY
The age incidence in the group of 64 cases of carcinoma of the ovary reported in this series is presented in Table 3. In this group of patients, 15 or 24 per cent had never married. Twenty-nine patients, or 45 per cent, had borne an average of three children. Twenty, or 31 per cent, were married but had never been pregnant. Unfortunately, and it has been generally recognized, there is no early characteristic symptomatology of carcinoma of the ovary. In our series of cases, 26 patients, or 40 per cent, came to the clinic for examination because of an abdominal enlargement and a feeling of a lump in the lower abdomen. This is the usual first sign of an ovarian tumor. This enlargement may be associated with a feeling of heaviness and pressure in the pelvis and occasionally with pain. Two patients particularly mentioned associated pain. Fifteen patients, or 23 per cent, came primarily because of pain or distress in the lower ab-
686
NEIL W. SWINTON, CHARLES R. YANCEY
domen without recognized abdominal enlargement. Eleven presented varying gynecologic complaints. Of the latter group, the most common were menorrhagia and metrorrhagia. Ten or 15 per cent were detected on routine pelvic examination (Table 4). Amenorrhea may occur.6 In the literature, hyperplasia of the mammary gland, even accompanied by lactation, virilization and various other endocrine changes have been described. 12 It is recognized that fertility is TABLE 3 ACE INCIDENCE
Age Group Number 5- 30 ........................ 4 31-40 ........................ 7 41-50 ........................ 21 51- 60 ........................ 18 Over 60 ........................ 14' Total .... , .... .... ......... 64 Average, 50.0 years
Per Cent 6.2 10.9 32.6 28.1 21.8
definitely decreased in the presence of ovarian carcinoma, and one of our patients came to the clinic primarily because of sterility. The symptoms caused by metastasis of ovarian tumors are common and deserve no special emphasis. Ascites is frequent. Hydrothorax is frequently noted. Anemia, fever and emaciation are usually found only in the late stages of the disease. In establishing the diagnosis of carcinoma of the ovary, it is to be remembered that malignant tumors are usually lateral to or behind TABLE 4 CHlEF COMPLAINT
Number Abdominal pain ....................... 15 Abdominal enlargement ................ 26 Pain and enlargement .................. 2 Incidentally discovered on routine pelvic examinaton ......................... 10 Various gynecologic complaints (menorrhagia, metrorrhagia, sterility) ......... 11 Total .......................... 64
Per Cent 23 40 3
15
17
the uterus, whereas simple cysts and tubal pregnancies are found anterior to the uterus. The malignant growth is firm and nodular, and any solid ovarian tumor should be considered as potentially malignant. Induration, fixation and the pJ;esence of bilateral tumors should suggest malignancy. Induration and nodules in the cul-de-sac are common. Of particular significance is bleeding after the menopause in patients in whom curettage has ruled out the presence of malignant disease in the uterus. Frequently, these tumors are small, but careful
CANCER OF THE OVARY
687
and repeated examinations of the ovary must be made with the possibility of a neoplasm in the ovary considered. The presence of ascites, hydrothorax and other signs suggestive of ovarian metastases must be borne in mind. In the differential diagnosis, particularly in bilateral tumors, the possibility of metastatic Krukenberg's tumors from the gastrointestinal tract must be remembered. The differentiation from diverticulitis and carcinoma of the sigmoid for masses in the left pelvis must be ruled out. Peritoneoscopy may be of assistance in establishing the diagnosis. In many of these cases, however, particularly in the benign but definitely premalignant papillary cystadenomas, the diagnosis will be made only at operation. A careful and complete abdominal exploration must, of course, first be made, the presence of ascites, the presence of peritoneal, omental or other implants or metastases noted, both ovaries must be inspected, and it must be remembered that 50 per cent of malignant tumors occur in both ovaries. Before the ovary is removed, all abdominal contents should be carefully walled off to avoid the danger from spilling of cystic content. All ovarian tumors following removal should be sectioned in the operating room by an assistant and the contents of the tumor noted. When there is any question of malignancy, histologic examination by means of a frozen section by a competent pathologist should be made immediately. It is only in this way in many of these patients that a diagnosis will be made and radical surgery carried out when indicated. TREATMENT
The treatment of the benign papillary cystadenoma is excision. Even during the child-bearing period when the tumors are bilateral, careful consideration must be given to the bilateral removal of these definitely premalignant tumors. When malignancy can be established, radical surgery must be carried out as in any other type of malignant disease. The operation should consist of a radical resection of the tumor; when necessary, isolation of the ureter, removal of both the fundus and cervix, and because of the high incidence of bilateral ovarian cancer, removal of both ovaries is included. Pemberton l l has emphasized the importance of routine resection of the omentum in these patients because of the high incidence of omental metastases. This custom has not been followed in our series but certainly merits careful consideration when the procedure does not add an undue risk to the patient. The types of operation carried out in our series are tabulated in Table 5. It is to be noted that in several of these cases, the radical type of operation which we now believe essential was not carried out. In the majority of instances this was because histologic examination of the tumor was not made at the time of operation and the presence of a definite ovarian malignancy was not demonstrated.
688
NEIL W. SWINTON, CHARLES R. YANCEY
The majority of observers advise the use of deep radiation therapy in addition to surgery in the treatment of these cases. TABLE 5 TYPES OF OPERATIONS IN GROUP
I
Dead or RecurNo Recurrence rence at Last Examination (5 Years) 4 Unilateral oophorectomy ................... 1 8 Bilateral oophorectomy ..................... 0 Supravaginal hysterectomy and bilateral oophorec7 tomy ................................ Complete hysterectomy and bilateral oophorec2t tomy .................................. 1 5 Exploratory laparotomy .................... 0 <> Six of these were done in the presence of demonstrable peritoneal implants. t Done in the presence of demonstrable peritoneal implants.
It has been our policy following operation for cancer of the ovary to give patients deep radiation therapy; 2000 r is given through each of two portals anteriorly and two portals posteriorly. The entire pelvis is covered. Forty-one of our patients received radiation therapy. TABLE 6 RESULTS
Group I (Operated on prior to March 1942) No Recurrence (5 Years) Number .......... 9 Per cent .......... 14
Known Dead or No Recent Recurrence Follow-up 27 9 42 14
Total
45
Group II (Operated on Mter March 1942) No Recurrence after 1 Yr. 2 Yrs. 3 Yrs. 4 Yrs. 6 2 Number 3 Per cent .......... · 9
Known Dead or No Recent Recurrence Follow-up Total 19 4 7 6 10
Various end-result studies have been reported in the literature, recording five-year survival rates varying from 14 to 32 per cent. 7 ,11 The end results in our series ~re reported in Table 6. Of 45 patients operated on' prior to 1942, 9 have survived without evidence of recurrence for five or more years. This is an incidence of 14 per cent.
CANCER OF THE OVARY
689
SUMMARY AND CONCLUSIONS
1. Characteristically, ovarian cancer does not cause early symptoms. An abdominal enlargement, lower abdominal pain and disturbances of menstruation are the common symptoms noted. 2. The importance of the premalignant, benign neoplastic ovarian tumors, . that is the papillary cystadenomas, must be appreciated and the tumors removed when found. Unfortunately, the papillary cystadenomas also do not present characteristic early symptoms. 3. Because of the absence of early symptoms in carcinoma of the ovary and the potentially malignant ovarian tumors, the importance of routine pelvic examinations in women during the child-bearing and postmenopausal ages cannot be too strongly emphasized. All solid ovarian tumors should be regarded as potentially malignant. 4. The establishment of a diagnosis of ovarian malignancy or potential' ovarian malignancy will depend on the detection of ovarian cancer and the papillary cystadenoma at the time of operation in the majority of cases. When a solid ovarian tumor is encountered at operation, careful inspection and palpation of both ovaries and adjacent structures must be made. Following the removal of such a tumor, it should be sectioned immediately and histologic examination made at once if there is any suspicion of cancer. 5. When the diagnosis of cancer of the ovary is established at operation, as radical an approach to this form of malignancy must be made as to cancer in any other region of the body. Both tubes and ovaries, uterus and cervix and, when indicated, adjacent structures such as the omentum must be removed. 6. In the removal of ovarian tumors, the importance of the avoidance of spilling of the contents, and the careful search for implants and metastases in the abdominal cavity must be appreciated. 7. Intensive deep radiation therapy should be given to these patients postoperatively. 8. With the establishment of an early diagnosis of carcinoma of the ovary, with radical removal of these tumors and with the use of deep radiation therapy, the end results should be reasonably good and the five-year survival rate approach that of carcinoma of the breast and carcinoma of the colon and rectum. REFERENCES 1. Bernstein, P.: Tumors of the ovary. A study of 1101 cases of operations for ovarian tumor. Am. J. Obst. & Gynec., 82:1023-1039 (Dec.) 1936. 2. Curtis, A. H.: Textbook of gynecology. Ed. 4, Philadelphia, W. B. Saunders Co., 1943, p. 362. 3. Curtis, A. H. (ref. 2), p. 360. 4. Curtis, A. H. (ref. 2), p. 371. 5. Ewing, J.: Neoplastic diseases. Ed. 3, Philadelphia, W. B. Saunders Co., 1942. 6. Golay, E.: Deformation particuliere de l'uterus dans un cas de carcinome de l'ovaire droit.-Atrophie de l'ovaire gauche.-Absence des regles. Bull. Soc. Anat. d. Par., 51:258, 1876.
690
NEIL W. SWINTON, CHARLES R. YANCEY
7. Meigs, J.: Cancer of the ovary. Surg., Gynec. & Obst., 71:44-53 (July) 1940. 8. Meyer, R.: Quoted by Novak: Gynecological and obstetrical pathology. Philadelphia, W. B. Saunders Co., 1940. 9. Miller, J.: Weibliche Geschlechtsorgane. III. Teil. Die Krankheiten des Eierstockes. Henke and Lubarsch's Handb.d.spez.path.Anat.u.Histol., vol. 7, 1937. 10. Novak, E: Tumors of the ovary. Davis' Obstetrics and Gynecology. Hagerstown, Md., W. F. Prior, Inc., vol. 2, chap. 15, 1944. 11. Pemberton, F. A.: Carcinoma 6f the ovary. Am. J. Obst. & Gynec., 40:751-763 (Nov.) 1940. 12. Pfannenstiel, H. J.: trber die Pseudomuzine der zystischen Ovariengeschwiilste. Beitrage zur Lehre vom Paralbumin und zur pathologischen Anatomie der Ovarientumoren. Arch.f.Gynak., 38:407, 1890. 13. Selye, H.: Encyclopedia of Endocrinology. Sect. IV. Ovary, vol. vii, Ovarian tumors. Montreal, Richardson, Bond and Wright, 1946. 14. Te Linde, R. W.: Operative gynecology. Philadelphia, J. B. Lippincott Co., 1946, p. 577.
W.
SWINTON AND CHARLES
R.
YANCEY
MALIGNANT tumors of the ovary comprise approximately 4 per cent9 of malignant disease found in women. Eighty-nine patients wit!l ovarian malignancy have been seen at the clinic during the past fifteen years. A review of these cases at this time reveals that frequentl~ a diagnosis of cancer was not made before operation and even at operation in certain cases the presence of malignancy was not suspected. In an attempt to make earlier diagnoses of ovarian malignant disease, obtain data on potentially malignant ovarian tumors, further information on the detection of malignant change in these tumors aJ the time of operation and to determine the type of treatment indicated when ovarian cancer is encountered, we have reviewed the 64 cases of ovarian cancer in which we have complete data at this time and also have reviewed the recent literature on the subject.
TABLE 1 INCIDENCE OF VARIOUS TUMORS IN (After Bernsteinl )
1101
CASES
Follicle cysts ........................................ Dennoid cysts ....................................... Serous papillary cystadenocarcinomas ................... Corpus luteum cysts .................................. Pseudomucinous papillary cystadenomas ................. Endometriosis of the ovary ............................ Serous papillary cystadenomas .........................
Per cent . 36 . 16 . 14 . 11 6 . 4 . 3 .
In a collected series of 160,324 admissions to gynecologic clinics, an incidence of ovarian tumors of 2.8 per cent was found. IS Table 1 represents a typical distribution in a reported series of 1101 ovarian tumors of various types. 1 Approximately 15 per cent of these tumors were malignant, of which 50 per cent were bilateral. Considering ovarian tumors of all types, it was found that they are most commonly observed in women between 30 and 40 years of age. 1 In a survey of 2,083 cases of ovarian cancer reported, however, the average age was estimated to be between 49 and 52 years. 9 Cases of malignant disease of the ovary have been reported in children and in patients over 80. In our series the youngest was 5 years old and the oldest 77 years. It is not the purpose in this report to review in detail the vari(lli's classifications of ovarian tumors which have been presented or to go into detail on the histology of the various types of ovarian tumors. 681
682
NEIL W. SWINTON, CHARLES R. YANCEY
TABLE 2 CLASSIFICATION OF OVARIAN TuMoRS ACCORDING TO NOVAK1o
Benign Tumors 1. Cystic a. Non-neoplastic Follicle cysts Lutein cysts Corpus luteum cysts (including corpus albicans cysts) Theca lutein cysts Germinal inclusion cysts Endometrial cysts b. Neoplastic Cystadenoma Pseudomucinous simple papillary Serous simple papillary Dermoid 2. Solid a. Papilloma, fibroma-adenoma, fibroma, fibromyoma, angioma, lymphangioma, chondroma, osteoma b. Brenner tumors c. Adrenal tumors (masculinovoblastoma) Malignant Tumors 1. Carcinoma
2.
3. 4. 5.
a. Primary solid carcinoma Adenocarcinoma Nonpapillary Papillary Medullary carcinoma Carcinoma simplex Scirrhous carcinoma Alveolar carcinoma Plexiform carcinoma Mesonephroma (not clearly established as yet) Embryonic or dysontogenetic Granulosa-ceIl carcinoma (often cystic) Arrhenoblastoma Dysgerminoma (seminoma) Chorionepithelioma b. Cystic carcinoma Pseudomucinous cystadenocarcinoma Serous papillary cystadenocarcinoma Epidermoid carcinoma arising in dermoid cyst Secondary or Metastatic Carcinoma a. Adenocarcinoma, simple b. Krukenberg tumor c. Epidermoid carcinoma d. Chorionepithelioma e. Hypernephroma Teratoma (including struma ovarii) Sarcoma (round-cell, spindle-cell, mixed-cell) Melanoma
CANCER OF THE OVARY
683
Ewing 5 has stated that "ovarian tumors present a wider scope of structure, greater individual variation and a more complex embryologic and histogenic basis than those of any other organ .. For these reasons they have escaped satisfactory classification. In a substantial proportion of ovarian tumors as they actually occur, the diagnosis is largely a matter of arbitrary decision on the part of the observer." In spite of the many different classifications of ovarian tumors that have been presented, however, it is important to classify such tumors in some manner for purposes of discussion. The classification of Novak, 10 using the benign or malignant nature of the tumor as the most important criterion, has seemed the most practical to us. This classification of ovarian tumors is presented in Table ~. CYSTIC BENIGN TUMORS OF THE OVARY
The non-neoplastic tumors, which comprise the common cystic tumors of the ovary, are not related to the subject of malignancy except in the differential diagnosis, and will not be reviewed. The neoplastic group, the cystadenomas and the dermoids, however, have a definite relation to ovarian malignancy and, for a clear understanding of many of the problems connected with the diagnosis and treatment of ovarian cancer, must be thoroughly understood. Cystadenomas may be classified as either serous or pseudomucinous. The pseudomucinous cystadenomas may attain enormous size and in general are larger than the serous variety. Characteristically, they contain a thick, pseudomucinous fluid. They usually consist of large, rounded, cystic compartments of varying thicknesses. The large majority of tumors of this type are of the simple variety and not directly related to the development of malignancy. Approximately 10 per cent are of the papillary variety,2 which is much more important from the standpoint of malignant degeneration. MeyerS believes that approximately 5 per cent of these pseudomucinous cysts may become malignant. Of particular importance in this type of tumor is the pseudo'myxoma peritonei resulting from rupture of tumors of this type. Rupture of these tumors is followed by the implantation of pseudomucinous epithelium throughout the peritoneal cavity. They may penetrate the liver and other organs and set up various sources of secreting cells. Although these tumors are not truly malignant and are slow to develop, this complication invariably results in an eventually fatal outcome. Serous cystadenomas occur slightly less frequently than the pseudomucinous, may attain a large size but in general are smaller than the pseudomucinous variety. They characteristically contain a strawcolored fluid except when discolored by hemorrhage. The cysts are usually multilocular but may be made up of only a few large compartments. A much higher percentage of cystadenomas of this type may show papillary excrescences on the exterior of the cyst wall and,
684
NEIL W. SWINTON, CHARLES R. YANCEY
even more common, in the interior of the tumor. Of particular importance in the consideration of malignancy are those tumors showing a papillomatous growth, and Curtis 3 emphasized that every tumor of the ovary with a papillomatous growth upon the outer surface must be regarded as a malignant tumor, irrespective of its histologic characteristics. Curtis further stated that a benign papillary growth confined within a heavy capsule is relatively harmless; when the tumor has but a thin capsule, when there has, been leakage of the cyst contents from tapping or following rupture or, most importantly, when there are papillomatous growths on the surface, the prognosis is more serious. When papillary growths are fQund on the surface of these tumors, peritoneal implants occur in at least 25 per cent of the cases. Even though these implants may regress following removal of the primary lesion, ultimate death is the usual eventuality. Furthermore, the histologic differentiation between the papillary cystadenoma and cystadenocarcinoma frequently is very difficult and at times impossible. It may thus be seen from this discussion of the cystadenomas that a large percentage of these tumors making up the papillomatous variety must be considered as definite premalignant tumors. Thus, an early diagnosis of the cystadenomas and their treatment constitute a very important aspect of our attack on ovarian cancer. The differential diagnosis of minute cystomas from simple retention cysts is primarily an academic one and of no particular significance. When tumors attain any appreciable size, however, the detection of a papillomatous growth is very important. These latter tumors are usually of greater weight than the simple cysts. There is more of a tendency to fix~tion and they have' a nodular, firm surface. Nodules in the cul-de-sac are suggestive of a papillary growth. Although ascites may be found with the simple cyst variety, usually the presence of ascites indicates a more serious prognosis. It is unfortunately common that many of the cystadenomas do not cause early symptoms; however, disturbances of menstruation are frequent although sterility is rare. Pain in the pelvis and sensations of weight and pressure may occur. On physical examination, cystic ovarian tumors usually are found anterior to the uterus, which is an important differential point in diagnosing inflammatory cysts. The latter are usually lateral and posterior to the fundus. It must be remembered that the boggy, painless swelling of a tubal pregnancy may also be commonly found anterior to the uterus. The surface of a cystadenoma is usually lobulated and the tumor firm. A twisted ovarian pedicle is common with cystadenoma and is more frequent with the pseudomucinous type. It must be carefully remembered, however, that there are no preoperative criteria which will establish a definite diagnosis of the cystadenomatous group of benign ovarian tumors. Final diagnosis
CANCER OF THE OVARY
685
must await the intra-abdominal examination of the tumor by the surgeon and usually a histologic examination of the tumor by a pathologist. All patients with an ovarian cystic tumor 7 cm. or more in diameter should be carefully observed. A thin-walled, soft cyst will usually prove not to be a cystadenoma and may vary in size on repeated examinations or actually disappear. The persistence of the tumor, its firmness, induration, nodules, heaviness, pain, increase in size and demonstrable ascites are indications for exploration and probable removal. In discussing the treatment of the cystadenomas, the prevention of any spilling of the tumor content is to be particularly emphasized because of the danger of implants. The tapping of cysts is to be avoided whenever possible. Dermoid cysts occur frequently, comprising, according to Curtis,4 approximately 10 per cent of all ovarian tumors. They are the most common tumor found in children, sarcoma being the next most frequent. They may attain considerable size, develop slowly and are usually not found until adult life. The usual contents of dermoids found elsewhere, hair and teeth and other epithelial structures, are common. Torsion of the pedicle occurs frequently; associated ascites is rare. The importance of bowel perforation as a result of the extension or perforation of the dermoid ovarian cyst has been mentioned in the literature. These tumors may develop malignancy, although malignant degeneration probably does not occur in over 1 or 2 per cent of tumors· of this type. 14 Dermoid tumors frequently are bilateral and when such tumors are found, careful inspection of the opposite ovary must be made as the tumor in the adjacent ovary may be very small and frequently not detected unless a careful search is made. In such instances bilateral oophorectomy is indicated. DIAGNOSIS OF CANCER OF THE OVARY
The age incidence in the group of 64 cases of carcinoma of the ovary reported in this series is presented in Table 3. In this group of patients, 15 or 24 per cent had never married. Twenty-nine patients, or 45 per cent, had borne an average of three children. Twenty, or 31 per cent, were married but had never been pregnant. Unfortunately, and it has been generally recognized, there is no early characteristic symptomatology of carcinoma of the ovary. In our series of cases, 26 patients, or 40 per cent, came to the clinic for examination because of an abdominal enlargement and a feeling of a lump in the lower abdomen. This is the usual first sign of an ovarian tumor. This enlargement may be associated with a feeling of heaviness and pressure in the pelvis and occasionally with pain. Two patients particularly mentioned associated pain. Fifteen patients, or 23 per cent, came primarily because of pain or distress in the lower ab-
686
NEIL W. SWINTON, CHARLES R. YANCEY
domen without recognized abdominal enlargement. Eleven presented varying gynecologic complaints. Of the latter group, the most common were menorrhagia and metrorrhagia. Ten or 15 per cent were detected on routine pelvic examination (Table 4). Amenorrhea may occur.6 In the literature, hyperplasia of the mammary gland, even accompanied by lactation, virilization and various other endocrine changes have been described. 12 It is recognized that fertility is TABLE 3 ACE INCIDENCE
Age Group Number 5- 30 ........................ 4 31-40 ........................ 7 41-50 ........................ 21 51- 60 ........................ 18 Over 60 ........................ 14' Total .... , .... .... ......... 64 Average, 50.0 years
Per Cent 6.2 10.9 32.6 28.1 21.8
definitely decreased in the presence of ovarian carcinoma, and one of our patients came to the clinic primarily because of sterility. The symptoms caused by metastasis of ovarian tumors are common and deserve no special emphasis. Ascites is frequent. Hydrothorax is frequently noted. Anemia, fever and emaciation are usually found only in the late stages of the disease. In establishing the diagnosis of carcinoma of the ovary, it is to be remembered that malignant tumors are usually lateral to or behind TABLE 4 CHlEF COMPLAINT
Number Abdominal pain ....................... 15 Abdominal enlargement ................ 26 Pain and enlargement .................. 2 Incidentally discovered on routine pelvic examinaton ......................... 10 Various gynecologic complaints (menorrhagia, metrorrhagia, sterility) ......... 11 Total .......................... 64
Per Cent 23 40 3
15
17
the uterus, whereas simple cysts and tubal pregnancies are found anterior to the uterus. The malignant growth is firm and nodular, and any solid ovarian tumor should be considered as potentially malignant. Induration, fixation and the pJ;esence of bilateral tumors should suggest malignancy. Induration and nodules in the cul-de-sac are common. Of particular significance is bleeding after the menopause in patients in whom curettage has ruled out the presence of malignant disease in the uterus. Frequently, these tumors are small, but careful
CANCER OF THE OVARY
687
and repeated examinations of the ovary must be made with the possibility of a neoplasm in the ovary considered. The presence of ascites, hydrothorax and other signs suggestive of ovarian metastases must be borne in mind. In the differential diagnosis, particularly in bilateral tumors, the possibility of metastatic Krukenberg's tumors from the gastrointestinal tract must be remembered. The differentiation from diverticulitis and carcinoma of the sigmoid for masses in the left pelvis must be ruled out. Peritoneoscopy may be of assistance in establishing the diagnosis. In many of these cases, however, particularly in the benign but definitely premalignant papillary cystadenomas, the diagnosis will be made only at operation. A careful and complete abdominal exploration must, of course, first be made, the presence of ascites, the presence of peritoneal, omental or other implants or metastases noted, both ovaries must be inspected, and it must be remembered that 50 per cent of malignant tumors occur in both ovaries. Before the ovary is removed, all abdominal contents should be carefully walled off to avoid the danger from spilling of cystic content. All ovarian tumors following removal should be sectioned in the operating room by an assistant and the contents of the tumor noted. When there is any question of malignancy, histologic examination by means of a frozen section by a competent pathologist should be made immediately. It is only in this way in many of these patients that a diagnosis will be made and radical surgery carried out when indicated. TREATMENT
The treatment of the benign papillary cystadenoma is excision. Even during the child-bearing period when the tumors are bilateral, careful consideration must be given to the bilateral removal of these definitely premalignant tumors. When malignancy can be established, radical surgery must be carried out as in any other type of malignant disease. The operation should consist of a radical resection of the tumor; when necessary, isolation of the ureter, removal of both the fundus and cervix, and because of the high incidence of bilateral ovarian cancer, removal of both ovaries is included. Pemberton l l has emphasized the importance of routine resection of the omentum in these patients because of the high incidence of omental metastases. This custom has not been followed in our series but certainly merits careful consideration when the procedure does not add an undue risk to the patient. The types of operation carried out in our series are tabulated in Table 5. It is to be noted that in several of these cases, the radical type of operation which we now believe essential was not carried out. In the majority of instances this was because histologic examination of the tumor was not made at the time of operation and the presence of a definite ovarian malignancy was not demonstrated.
688
NEIL W. SWINTON, CHARLES R. YANCEY
The majority of observers advise the use of deep radiation therapy in addition to surgery in the treatment of these cases. TABLE 5 TYPES OF OPERATIONS IN GROUP
I
Dead or RecurNo Recurrence rence at Last Examination (5 Years) 4 Unilateral oophorectomy ................... 1 8 Bilateral oophorectomy ..................... 0 Supravaginal hysterectomy and bilateral oophorec7 tomy ................................ Complete hysterectomy and bilateral oophorec2t tomy .................................. 1 5 Exploratory laparotomy .................... 0 <> Six of these were done in the presence of demonstrable peritoneal implants. t Done in the presence of demonstrable peritoneal implants.
It has been our policy following operation for cancer of the ovary to give patients deep radiation therapy; 2000 r is given through each of two portals anteriorly and two portals posteriorly. The entire pelvis is covered. Forty-one of our patients received radiation therapy. TABLE 6 RESULTS
Group I (Operated on prior to March 1942) No Recurrence (5 Years) Number .......... 9 Per cent .......... 14
Known Dead or No Recent Recurrence Follow-up 27 9 42 14
Total
45
Group II (Operated on Mter March 1942) No Recurrence after 1 Yr. 2 Yrs. 3 Yrs. 4 Yrs. 6 2 Number 3 Per cent .......... · 9
Known Dead or No Recent Recurrence Follow-up Total 19 4 7 6 10
Various end-result studies have been reported in the literature, recording five-year survival rates varying from 14 to 32 per cent. 7 ,11 The end results in our series ~re reported in Table 6. Of 45 patients operated on' prior to 1942, 9 have survived without evidence of recurrence for five or more years. This is an incidence of 14 per cent.
CANCER OF THE OVARY
689
SUMMARY AND CONCLUSIONS
1. Characteristically, ovarian cancer does not cause early symptoms. An abdominal enlargement, lower abdominal pain and disturbances of menstruation are the common symptoms noted. 2. The importance of the premalignant, benign neoplastic ovarian tumors, . that is the papillary cystadenomas, must be appreciated and the tumors removed when found. Unfortunately, the papillary cystadenomas also do not present characteristic early symptoms. 3. Because of the absence of early symptoms in carcinoma of the ovary and the potentially malignant ovarian tumors, the importance of routine pelvic examinations in women during the child-bearing and postmenopausal ages cannot be too strongly emphasized. All solid ovarian tumors should be regarded as potentially malignant. 4. The establishment of a diagnosis of ovarian malignancy or potential' ovarian malignancy will depend on the detection of ovarian cancer and the papillary cystadenoma at the time of operation in the majority of cases. When a solid ovarian tumor is encountered at operation, careful inspection and palpation of both ovaries and adjacent structures must be made. Following the removal of such a tumor, it should be sectioned immediately and histologic examination made at once if there is any suspicion of cancer. 5. When the diagnosis of cancer of the ovary is established at operation, as radical an approach to this form of malignancy must be made as to cancer in any other region of the body. Both tubes and ovaries, uterus and cervix and, when indicated, adjacent structures such as the omentum must be removed. 6. In the removal of ovarian tumors, the importance of the avoidance of spilling of the contents, and the careful search for implants and metastases in the abdominal cavity must be appreciated. 7. Intensive deep radiation therapy should be given to these patients postoperatively. 8. With the establishment of an early diagnosis of carcinoma of the ovary, with radical removal of these tumors and with the use of deep radiation therapy, the end results should be reasonably good and the five-year survival rate approach that of carcinoma of the breast and carcinoma of the colon and rectum. REFERENCES 1. Bernstein, P.: Tumors of the ovary. A study of 1101 cases of operations for ovarian tumor. Am. J. Obst. & Gynec., 82:1023-1039 (Dec.) 1936. 2. Curtis, A. H.: Textbook of gynecology. Ed. 4, Philadelphia, W. B. Saunders Co., 1943, p. 362. 3. Curtis, A. H. (ref. 2), p. 360. 4. Curtis, A. H. (ref. 2), p. 371. 5. Ewing, J.: Neoplastic diseases. Ed. 3, Philadelphia, W. B. Saunders Co., 1942. 6. Golay, E.: Deformation particuliere de l'uterus dans un cas de carcinome de l'ovaire droit.-Atrophie de l'ovaire gauche.-Absence des regles. Bull. Soc. Anat. d. Par., 51:258, 1876.
690
NEIL W. SWINTON, CHARLES R. YANCEY
7. Meigs, J.: Cancer of the ovary. Surg., Gynec. & Obst., 71:44-53 (July) 1940. 8. Meyer, R.: Quoted by Novak: Gynecological and obstetrical pathology. Philadelphia, W. B. Saunders Co., 1940. 9. Miller, J.: Weibliche Geschlechtsorgane. III. Teil. Die Krankheiten des Eierstockes. Henke and Lubarsch's Handb.d.spez.path.Anat.u.Histol., vol. 7, 1937. 10. Novak, E: Tumors of the ovary. Davis' Obstetrics and Gynecology. Hagerstown, Md., W. F. Prior, Inc., vol. 2, chap. 15, 1944. 11. Pemberton, F. A.: Carcinoma 6f the ovary. Am. J. Obst. & Gynec., 40:751-763 (Nov.) 1940. 12. Pfannenstiel, H. J.: trber die Pseudomuzine der zystischen Ovariengeschwiilste. Beitrage zur Lehre vom Paralbumin und zur pathologischen Anatomie der Ovarientumoren. Arch.f.Gynak., 38:407, 1890. 13. Selye, H.: Encyclopedia of Endocrinology. Sect. IV. Ovary, vol. vii, Ovarian tumors. Montreal, Richardson, Bond and Wright, 1946. 14. Te Linde, R. W.: Operative gynecology. Philadelphia, J. B. Lippincott Co., 1946, p. 577.