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Urologic Complications of Cancer of the Uterine Cervix
THE JOURNAL OF UROLOGY
Vol. 68, No. 1, July 1952 Printed in U.S.A.
UROLOGIC COMPLICATIONS OF CANCER OF THE UTERINE CERVIX EDWARD W. BEACH
It is a clinical maxim that some degree of pelvic ureteral occlusion is inevitable in many women afflicted by cervical cancer and treated with radiation. The medical profession has assumed that the x-ray and radium are responsible for such ureteral strictures and other complications, but a careful study of the last 24 patients referred to me has caused me to doubt this. Exactly what role, if any, does radiotherapy play in the development of such ureteral stenosis? What is the role of neoplastic parametrial spread with its attendant pother of inflammation, in the etiology of such ureteral occlusion? Although every woman with cervical cancer is potentially a urologic patient, the experienced urologist is rarely intrigued by the actuality of urologic manifestations, because the latter usually have ominous import. More specifically, it is customary for the gynecologist to inaugurate and continue treatment of cervical cancer with no mind whatever paid the urinary tract. In fact, urologic talent is currently considered only a spare tire in the treatment ensemble and one reserved exclusively for a blowout. When such emergency occurs or the situation becomes desperate and vexatious urologic developments force belated consultation epitomized in those famous last words "For God's sake do something!" it is usually too late for anything but makeshift repair. Such malfeasance in management of cancer of the cervix uteri has, unfortunately, all but extinguish( c urologil: interest in the treatment of this disease. Moreover, many urologists have somehow acquired an impresc:on Jiat radiation therapy per se frequently causes stricture or atresia of uhe pelvic ureters. Theoretically and academically such a possibility is admissible, but the probability is remote and so is the incidence from a technical standpoint. Proof rests squarely on the proponent. Acceptance of the idea requires postmortem or factual evidence of which there is a remarkable dearth both in the literature and in my clinical experience. Ureteral stenosis of any degree is invariably accompanied by a palpable mass or increased denseness in the parametrium of the affected side or sides~whether neoplastic, inflammatory or organizing round-cell infiltration or some combination. A sound knowledge of cervical cancer with its infiltrative tendencies and concomitant inflammatory reaction plus a definitive understanding of radiotherapy seem the best antidote to such devil's wine. 1 It is almost axiomatic that the close anatomic relationship between the uterine cervix and the adjacent urinary tract paves the way for urinary repercussions if cancer of any extent exists in the cervix, usually by spread from the primary focus or by inflammation, but sometimes by radiation therapy with the bladder as a selective target. That cervical cancer deserves therefore a place on the top shelf of urologic interest is apparent in the following five facts: 0 1
Read at annual meeting, Western Section, American Urological Association, Sun Valley, Idaho, June 28, 1951. 1 Vinum daemonum. Essays of Francis Bacon. Essay on Truth. 178
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1) Cancer of the cervix comprises one of every four malignant tumors which afflict women. Breast cancer is first. 2) Sixty to eighty per cent of women so afflicted who succumb to this disease die of uremia contingent upon occlusion of the pelvic ureters. 2 3) Direct spread into the juxtaposed bladder or urethra is not uncommon. 4) Surgical attempts to control such cancer still impose considerable injury on the ureter. 5) Postradiation or factitial cystitis-an entity often difficult to diagnose and to treat-is rampant because radiation therapy for control of such cancer is at the present being used more and more. CANCER OF THE UTERINE CERVIX
This disease can exist in females of any age,3 but it is most common among women older than 35, particularly in the married and parous. 4 It seldom afflicts the spinster and is less common among Jewish women. 5 The big age group from a diagnostic standpoint is around 48 years. The vaginal portion of the cervix is covered by squamous epithelium with a sharp transition normally at the external os so that the endocervical canal is lined by a single layer of prismatic cells. Intrinsic glands therein have similar histologic architecture. These prismatic cells appear to constitute the nidus for so-called epidermoid cancer with its repertory of cellular morphology. 6 Given proper instigation (the role of epithelial instability, heredity, sex, physiologic age, endocrine imbalance, infection and trauma all have supporters) these prismatic cells appear to undergo metaplasia and to become arranged into sheets or stratified pavement epithelium devoid of glandular elements, not unlike the epithelium over the portio vaginalis. Notable exceptions are 1) true cervical adenocarcinoma 7 (rare-only 3 to 5 per cent of cases) and 2) adenoacanthoma8 with a relative admixture of both glandular and epithelial elements. Classification of epidermoid cancer based upon cellular morphology, a task for the pathologist, depends on the predominant cell type. Multiform variations 2 Cantril, Simeon T.: Radiation Therapy in the Management of Cancer of the Uterine Cervix. Springfield, Ill.: Charles C. Thomas, 1950, p. 23. 3 Ackerman, Lauren V. and Juan A. de! Regato: Cancer. Diagnosis, Treatment and Prognosis. St. Louis: The C. V. Mosby Co., 1947, pp. 852-854. Heckel, G. P.: Pediatrics 5: 924-929, 1950. 4 Maliphant, R. G.: Brit. Med. J., 1: 978-982, 1949. 5 Weir, P. and C. C. Little: J. Heredity, 25: 277-280, 1934. Weiner, I., Burke, L. and Goldberger, M.A.: Am. J. Obst. & Gynec. 61: 418-422, 1951. Healy, W. P., and Twombly, G. H.: Am. J. Roentgenol., 49: 522-523. 6 Regaud, C. and Gricouroff, G.: Bull. Assoc. fran9. p. l'etude du cancer, 22: 285-296, 1933. Regaud, C. Gricouroff, G., and Villela, E.: Bull. Assoc. fran9. p. l'etude du cancer 22: 668-677, 1933. 7 Baclesse, F. and Fernandez-Colmeiro, J.M.: Bull. Assoc. fran9. p. l'etude du cancer 30: 118-128, 1942. Ackerman, L. V. and de! Regato, J. A.: Cancer. Diagnosis, Treatment and prognosis. St. Louis: The C. V. Mosby Company, 1947, p. 859. (Incidence of 3.7 in 453 cases.) 8 Randall, C. L.: Adenocarcinoma of the Uterus. In: Progress in Gynecology, vol. 11. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1950, p. 490. Curtis, A.H. and Huffman, J. W.: A Textbook of Gynecology. Ed. 6, Philadelphia: W. B. Saunders Company, 1950, p. 338.
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are usually present. Martzloff9 divided this group into 1) the spinal cell typethe same as Broders' 10 grade 1 malignancy or "ripe" species, 2) the transition cell, or Broders' grade 2 malignancy still the "ripe" species and 3) the basal or fat spindle cell type-Broders' grade 3 and 4 malignancy-grade 3, the "middle ripe", and grade 4, "the unripe." In general, the anaplastic or dedifferentiated forms are most radiovulnerable, but they tend to spread early and they metastasize widely.
FIG. 1. Lymphatic drainage of uterus. Gross drawing: Large lymph channels. Longitudinal section: Microscopic endings of lymph system infiltrating walls of uterus. These may provide a means of metastasis.
Thanks to the pathologist's perspicacity, the nature of "noninvasive intraepithelial cancer" 11 of the cervix is now known. This condition has been called "basal cell hyperactivity", "carcinoma in situ, " 12 "beginnendes Karzinoma" 13 (by Schiller) and Bowen's disease. 14 It may antedate the frankly invasive clinical Martzloff, K. H.: Bull. Johns Hopkins Hosp., 34: 141-149, 184-194, 1923. Martzloff, K. H.: Bull. Johns Hopkins Hosp., 33: 221-222, 1922. Diseases of the cervix uteri. In: Practice of Surgery, by Lewis. Hagerstown, 1\!Id.: W. F. Prior Co., vol. 10, chap. 14, 1928. 10 Broders, A. C.: Minnesota Med. 8: 726-730, 1925. 11 Te Linde, Richard W. The relation of "intra-epithelial carcinoma" to invasive cancer of the cervix. In: Progress in gynecology. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1946, pp. 349-361. 12 Te Linde, Richard W. and Gerald A. Galvin: The present-day status of noninvasive cervical carcinoma. In: Progress in Gynecology, vol. 11. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1950, pp. 499-510. 13 Schiller, Walter: Arch. f. Gynak., 133: 211-283, 1928. 14 Bowen, John T.: J. Cutan. Dis., 30: 241-255, 1912. Also, J. Cutan. Dis. 33: 787-802, 1915. 9
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entity for an indeterminate period-possibly a decade or even more. 15 Unfortunately the gross appearance of the cervix does not betray the presence of such a lesion. Cervical cancer may spread in any direction by paracervical infiltration. Commonest is spread into the base of one or both broad ligaments. Extension upwards into endometrium or uterine wall is frequent (fig. 1). Distal infiltration of the portio vaginalis inclusive of the upper two thirds of the vagina is not rare. Later the lower third of the vagina may be invaded and this invasion is accompanied by inguinal adenopathy. Posterior extension toward the sacrum, rectum and sacral nerve roots may accrue and give rise to consonant subjective complaints.
Frn. 2. A, lymphatic system of pelvic organs. Uterus, its appendages and vagina are covered by a rich network of lymphatic vessels surrounding uterus and vagina. a and a', Lymph nodes at bifurcation of common iliac arteries. b and b', Lumbar glands in pre-aortic chain. c and c', Deep inguinal lymph nodes which may at times be involved by spread of carcinoma. (Through the courtesy of Cantril. 2 ) B, Schematic view of initial lymph node relays of lymphatic supply of cervix. gg. princ., Pre-ureteral chain (principal pathway). gg. hyp., Hypogastric chain (post-ureteral). gg. pro., Posterior chain leading to promontory. gg. bif., Less frequent route leading to bifurcation of internal iliac. (Through the courtesy of Cantril.2)
Lymphatic pathways are illustrated in figure 2. It is well to remember the dominant pre-ureteral trunk of lymphatic pathways into the broad ligaments which sponsors metastasis to pelvic glands from the obturator canal to the inferior iliosacral junction. The League of Nations Committee16 has adopted a workable classification based on extension proclivities: Stage 1 : Cancer confined entirely to the cervix. Stage 2: Parametrium invaded on one or both sides. Some uterine motility 15 Te Linde, Richard W. and Gerald A. Galvin: The present-day status of noninvasive cervical carcinoma. In: Progress in Gynecology. vol. 11. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1950, p. 506. 16 League of Nations, Health Organization, Cancer Commission: Report submitted by the Radiological Sub-Commission, Geneva, League of Nations Publications, 1929, 82 pp. Heyman, J.: Atlas illustrating the division of cancer of the uterine cervix into four stages. League of Nations Health Organization (Inquiry into the results of radiotherapy in cancer of the uterus). 1938, unnumbered pages.
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retained. Lesion spread into corpus uteri and upper portion of vagma. Stage 3: Infiltration extended through parametrium to pelvic wall-isolated masses palpable on pelvic wall. Lower third of vagina involved. Stage 4: Cancer involves bladder or rectum with spread outside the pelvis to other viscera. Because infection, cellulitis and inflammatory induration invariably accompany cancer spread, proper evaluation sometimes perplexes the most experienced. Diagnosis. Microscopic study of segregated scrapings from the cervix and uterus, using Papanicolaou or similar technique is sometimes helpful, but biopsy is essential. Cytologic and clinical study of the primary lesion and of extracervical spread conditions both treatment and prognosis. Symptoms vary. Abnormal or postmenopausal bleeding should arouse suspicion. Contemporary physicians must be mindful that abuse of estrogenic therapy during menopause 1s now common. Treatment. The field of therapy has laid somewhat fallow for the last few years. This may presage a bumper crop of new developments. In the surgical era all hope hinged upon the radical Wertheim17-the most formidable of all gynecological procedures-with a high mortality rate and a frightful bladder and ureteral morbidity especially in the hands of the inexperienced. The bladder suffers injury in about 17 per cent of cases; vesicovaginal fistulas occur in about 7 per cent. 18 Even in expert hands, the ureters are injured . in 7 to 10 per cent19 of cases; often the blood supply to the ureters is impaired and sloughing results. In 28 years of practice I have treated 14 such injuries, most of them resulting in ureterovaginal fistula, following the Wertheim procedure. ,Ve have the Wertheim operation to thank for much of what we know about cervical cancer-learned at the operating table and from pathologic specimens. The Martzloff modification20 is now more commonly used. Most clinics now take a dim view of surgical treatment alone, save in very early and selected instances. Granted that the lesion is "cancer in situ", what surgical procedure should be undertaken? Trachelectomy? Simple hysterectomy? Hysterectomy plus adnexectomy? The more radical Wertheim? Who knows? Anatomic studies of this entity have taught the necessity of removing an ample cuff of tissue about the limits of the portio vaginalis in these cases. 21 Many clinics in this country now depend solely upon x-ray and radium Wertheim, E.: Am. J. Obst., 66: 169-232, 1912. Bonney, V.: Am. J. Obst. & Gynec., 30: 815-830, 1935. Meigs, J. V.: Am. J. Obst. & Gynec., 49: 542-549, 1945. Meigs, J. V.: In: Progress in Gynecology, vol. 11. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1950, pp. 540-564. 18 Weibel, W.: Arch. f. Gyniik., 135: 1-57, 1928. Weibel, W.: Wein. Klin. Wchnschr., 38: 716-717, 1925. Wharton, L. R.: Gynecology. With a Section on Female Urology. Ed. 2, Philadelphia: W. B. Saunders Company, 1947, p. 501. 19 Wharton, Lawrence R.: Gynecology. With a Section on Female Urology. Ed. 2, Philadelphia: W. B. Saunders Company, 1947, p. 495. 20 Martzloff, Karl H.: Bull. Johns Hopkins Hosp., 34: 141-149; 184-194, 1923. 21 Foote, F. W., Jr. and Stewart, F. W.: Cancer 1: 431-440, 1948. 17
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to control cervical cancer. Those that have good radiotherapy departments put out an imposing array of statistics in support of their method. The gist of such statistical tables is that if treated early, possibly 8 of 10 cervical cancers may be controlled by radiotherapy and that later when one or both parametria are invaded, perhaps 1 of 3 may be so controlled, depending on the extent of invasion, the cellular morphology and who presents the statistics. It offers the additional advantage that the patient i's ambulatory throughout. Clearly radiotherapy is most favored in the current approach. However, because the metastatic lesions of some tumors are radiation-resistant, removal of the pelvic lymph glands on both sides is advocated after preliminary and intensive radiation. Taussig22 uses such a procedure, without hysterectomy, and Nathanson23 also uses it, with extraperitoneal exposure, in certain cases. Recently Meigs 24 has coupled the radical Wertheim operation with Taussig's gland resection in selected cases. While time has proved the value of radiation (in terms of 5 year control) there is as yet no unanimity as to dosage, modalities, application or sequence. Multifacets in the clinical picture stemming from the cellular morphology, conformation of the primary lesion, the presence of infection or cellulitis, the route and degree of extension, the pelvic pattern and the general condition of the patient all preclude standardized technique. Nor can radiation be used empirically or with a slide rule. Radiation must be tailored to the individual by the skilled radiologist in an effort to eradicate the cancer cells and yet preserve the integrity of normal surrounding tissues. The patients who are the subject of the discussion to follow underwent a high voltage ("soft ray") barrage through four skin portals (2A and 2P) using 8,000 to 10,000 r, and in suitable cases 3,000 to 4,000 r was given by vaginal cone. Radium element properly screened was used after the Stockholm25 technique, about 3,000 mg. hr. in the uterine corpus and 3,000 to 3,500 mg. hr. to the cervix and vaginal fornices. Alterations and modifications governed by the attendant circumstances were frequent. UROLOGIC COMPLICATIONS
The relevant clinical data from my 24 cases will be presented in the following general discussion of the urologic complications in radiation therapy of cancer of the cervix. The pelvic ureter. Figures 3 so 6 provide anatomic reconnoiterer. Of esoteric interest is the parametrial ureter which passes forward to the cervix and then Taussig, F. J.: Am. J. Obst. & Gynec., 45: 733-748, 1943. Leveuf, J. and Godard, H.: J. de chir. 43: 177-187, 1934. Nathanson, I. T.: Extra peritoneal iliac lymphadenectomy in the treatment of cancer of the cervix. In: Progress in Gynecology. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1946, pp. 388-394. 24 Meigs, Joe V.: Radical hysterectomy for cancer of the cervix with bilateral pelvic lymphadenectomy (the so-called Wertheim operation). In: Progress in Gynecology, vol. 11. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1950, p. 541. 25 Heyman, J., Reuterwall, 0., and Benner, S.: Acta radiol. 22: 11-98, 1941. Forssell, G.: Acta radiol., 28: 417-432, 1947. Forssell, G.: Hygeia, vol. 76, 1914. Forssell, G.: Fortschr. der a. d. Geb. d. Riintgenstrahlen, 25: 142-149, 1917. League of Nations, Health Organization, Cancer Commission: Report submitted by the Radiological Sub-Commission. Geneva, League of Nations Publications, 1929, 83 pp. Heyman, J.: 20: 85-91, 1947. 22
23
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downward and medially to the trigone. Of greatest urologic import is that ureteral segment where "water passes under a bridge" (ureter crossed by the uterine artery) which is almost opposite the internal os and about 1½cm. lateral to the cervix and that downward ureteral continuation ensheathed by the veins of the
FIG. 3. A, cross-section of female pelvis, showing basal structure of broad ligament, ligamentous supports of bladder and uterus, and fascial coats of pelvic organs. B, female pelvis, anterior view. Subperitoneal tissue of broad ligament, urinary bladder and uterus. Uterus is retracted from its normal anteverted position and peritoneum has been pulled back to show body of uterus, broad ligament and superior surface of bladder.
Fm. 4. Female pelvis, anterior superior view. Right ureter has been freed completely from its bed from 3 cm. below pelvic brim to trigone. Note proximity of parametria and pelvic lymph nodes to uterus. (Through courtesy of G. H. Twombly: Technique of radical hysterectomy for carcinoma of cervix. Cancer, 3: 975-991 [Nov.] 1950.)
vesicovaginal plexus which lies about 1 cm. above the lateral vaginal fornix. The most distal ureteral portion, about I½ cm. long, lying close to the vaginal wall, is also implicated by the cervical cancer. The terminal segment of pelvic ureter, some 7 to 8 cm. in length, is not only in close anatomic apposition to the cervix, but is also served by much the same lymph and blood vessels. Any morbid change in the cervix should therefore be
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reflected in some degree or have reciprocative amplification in the abutting ureter, conditioned by the character of the lesion, from initial hyperemia to compression or angulation of the duct because of parametrial extension. The commonest point of ureteral occlusion in parametrial spread is where the duct is crossed by the uterine artery (fig. 7); i.e. adjacent to the internal os and about 5 to 6 cm. up from the ureteral meatus. Twelve patients (all seen in the "supplicatory stage"-stages 3 and 4) had variable degree of occlusion at this point on one or both sides. In 5, nephrectomy was necessary because of unilateral
Frn. 5. Bilateral hydro-ureter due to obstruction arising from spread of cancer of cervix. (Through the courtesy of Cantril.2)
occlusion with sepsis and because great debilitation precluded other measures for relief. In another case with uremia, since only half a kidney remained, a quick ureterocutaneous groin fistula was established. In 3 other cases the vaginal or most distal ureteral segment was obstructed unilaterally. In 2, a stone was impacted in this pathologically narrowed portion and in another, ureteral occlusion was caused by neoplastic impingement near the anterior vaginal wall. In exact discernment of the presence and degree of ureteral occlusion, both retrograde (if possible) and excretory roentgenologic studies are necessary. The fact that a catheter can be passed up the ureter does not mean that the ureter is not partially occluded by segmental narrowing, extra-ureteric pressure or edema of the ureteral wall. It is quite common to thread a catheter through such an area of involvement initially and never again be successful in such endeavor.
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Indwelling catheters were poorly tolerated in these cases. Interval ureteral dilatations were not too helpful. The cause of ureteral occlusion in these cases was invariably a mass or some degree of induration in the base of the broad ligament-whether neoplastic or inflammatory or both, only clinical experience and observation could determine. In none of this limited group could radiotherapy be incriminated for the ureteral stenosis. In fact, in two cases partial bilateral ureteral occlusion and subjective symptoms were relieved considerably by a second course of radiation therapy.
FIG. 6. Early bilateral ureteral backpressure due to cancer of uterine cervix. Patient was a young woman. Conditions suitable for ureteral transplantation.
If the condition is advanced, seldom is reconstructive surgery advisable. Bilateral ureteral occlusion usually has dire prognostic connotation an~ hence nephrostomy or a shift of the ureter to the intestine or the contralateral structure has limited application from a practical standpoint in view of the psychology, general condition and life expectancy of such patients. The bladder. If cervical cancer spreads downward along the anterior vaginal wall, seldom does the bladder escape unscathed. Such extension-usually a forerunner of vesical involvement-can sometimes be palpated long before urinary symptoms are manifest. Excellent studies26 depicting cystoscopic changes and successive steps in the development of such bladder lesions which range from early trigonal asymmetry or distortion at the base through submucosal Aman-Jean, F.: Bull. Assoc. frarn;. p. l'etude du cancer 22: 556-589, 1933. Graves, Roger 0., Kickham, 0. J. E.and Nathanson, I. T.: Surg .. Obst. 63: 785-793, 1936. 26
,Ii;
Gynec.
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petechiasis and edema to actual nodule formation with ulceration and bleeding have been made and need no reiteration here. Among the 24 cases there were 2 vesicovaginal fistulae and 1 rectovesical fistula-obviously late and hopeless sequelae. Post-radiation cystitis: From the practical standpoint there are two typesan early and a late or delayed type. Much work has been done by Dean, 27 Colby28 and others 29 - 3o on this subject.
A.vesi.cal1s A.uterina\ __..-
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Fm. 7. Principal arteries and veins supplying organs of female pelvis. Uterine artery has been further exposed by partial removal of accompanying veins. All remaining structures still lie in positions they held prior to dissection. Note point at which ureter is crossed by uterine artery, common point of ureteral occlusion in cases in which parametrial spread has occurred.
The early type is a vasodilatation phenomenon and represents a specific response to radiation. It comes along 28 to 30 days astern of treatment. Subjective symptoms are rarely severe and usually clear quickly. If deep therapy alone is used, generalized cystitis is discovered with the cystoscope. If such reaction depends solely upon intracavitary use of radium element, areal distribution over the bladder base at certain points of maximal concentration is apparent cystoscopically. Every urologist who collaborates closely with the radiologist is familiar with such changes. The delayed type of factitional cystitis is signalized by its tardy appearance Dean, A. L. Jr.: J. A. M. A. 89: 1121-1123, 1927. Also J. Urol. 29: 559-570, 1933. Dean, A. L. Jr. and Slaughter, D. P.: J. Urol., 46: 917-924, 1941. 28 Colby, F. H.: New Eng. J. Med., 209: 231, 1933. 29 Everett, H. S.: Am. J. Obst. & Gynec. 38: 889-906, 1939. 30 Newell, Q. U. and Crossen, H. S.: Surg., Gynec. & Obst., 60: 763-768, 1935. 27
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after radiation. It seldom develops before a year has elapsed and may be delayed for as long as 10 to 12 years after radiotherapy. Average appearance time is given as 2½ years. This type of bladder lesion constitutes a trophic change predicated upon an obliterative endarteritis. It is characterized by sloughing of the bladder wall or trigone in variable degree. The slough may be so deep and extensive that a fistula forms. Subjective symptoms are often distressing and the healing of such a lesion is very slow. Usually the cervical canceris well controlled before these bladder lesions become apparent. There were 5 instances of delayed postradiation cystitis in my series. The youngest woman was 37 and the oldest 66 years of age. The earliest appearance of this trophic lesion was 17 months after radiation and the latest, 35 months thereafter. Each of these women had had at least 5,000 mg. hr. of intracavitary radium and none more than 6,200 mg. hr. These trophic bladder lesions were invariably multiple and comprised a number of moderate sized, shallow, irregular ulcers, usually retrotrigonal and toward the left lateral wall. These ulcers had a linear distribution, the edges were somewhat motheaten and the floor was covered with grayish yellow necrotic material. They were surrounded by an injected areola. Dysuria was prominent, especially frequency and burning. Hematuria was always an outstanding symptom. The cystoscopic appearance of such lesions is quite misleading and diagnosis necessitates careful cytological study of several biopsy specimens. It is most important to avoid subsequent radiation-if no cancer cells exist. Diagnosis is sometimes a problem even for the skilled pathologist in these instances, as the following case demonstrates: One of my patients had suffered a transitional cell cervical cancer which had been treated by radiation and 5,000 mg. hr. of intracavitary radium (well screened). This cancer was well controlled clinically. About 18 months after radiotherapy, a group of trophic bladder ulcers appeared, accompanied by the usual subjective and objective symptoms. A series of 3 or 4 biopsy specimens was obtained from the most suspicious areas. The pathologist, who had had 38 years of experience, stated that the lesion was a transitional cell bladder tumor with cellular morphology much like that of the cervical cancer which he had previously studied. Because of the p·atient's history, we were dubious and took several more biopsy specimens. Again the same pathological diagnosis. Meantime the patient grew restless and because of her urinary distress, enplaned for the Mayo Clinic. Dr. Edward N. Cook of the Clinic took 18 or 20 biopsy specimens before he could be certain that there were no cancer cells. Under his care the patient's symptoms were shortly relieved and the ulcers healed in approximately 6 months. The trophic ulcers I treated healed very slowly and usually required 6 to 10 months. Therapy, empirical or otherwise, did not seem to hasten healing. For the hyperacute cases of dysuria, continuous bladder irrigations with dilute silver solution (1: 3,000) was most helpful. Later, hydrostatic bladder dilatations followed by oily balsamic instillations gave some relief. In none of these cases did fistulae develop. The urethra. As the cervical cancer spreads downward along the anterior ·
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vaginal wall, in late stages, the urethra may be impinged upon by the neoplastic mass surrounding it or its wall may be invaded directly by the cancer. I had one such case; retention developed and catheterization was very difficult and painful because of the narrowed and compressed urethral lumen. A permanent cystostomy was made to relieve symptoms. Adjuvant treatment. Competent management of cervical cancer necessitates inquiry into theurologic status of these patients both initially and at appropriate intervals thereafter. If this is done and attention is thereby focused on the pelvic ureters before they become hopelessly fouled in this disease, the patient can be given much better care. For many of these unfortunate women, early ureterosigmoidostomy would be a blessing, if partial bilateral ureteral occlusion is worsening clinically. In another limited group, when the bladder is threatened by advancing spread of the cancer, but has not yet been involved, total cystectomy with uretero-intestinal transplantation might constitute a wise choice of treatment. Prevention of trophic bladder lesions is difficult in the absence of a reliable gauge for predetermining unusual individual susceptibility to radium, but better screening and more care in placement would help. SUMMARY
This article hopes to rekindle interest by stressing urologic repercussions in cervical cancer and to dispel some common fallacies by review of basic knowledge. It recalls certain factors pertinent to cervical cancer in its bearing on the adjacent urinary tract. It brings up the question whether radiotherapy per se induces ureteral stenosis in these cases and presents evidence that extension of the disease is the more likely cause. In these 12 cases of ureteral obstruction it was the only cause. It pleads for a preliminary and detailed urologic survey before any treatment of the cancer is begun so that early or unsuspected lesions of the urinary tract may be discovered and expeditiously cared for. It urges closer liason between the urologist, the gynecologist and the radiologist to the end of efficient management. The close anatomical relationship of the uterine cervix and the ureters obligates every urologist to actively crusade against current neglect of the urinary tract in the treatment of cancer of the cervix. Supplicatory consultations are too common and are a sad commentary on scientific management of this disease.
2900 L St., Sacramento 16, Calif.
Vol. 68, No. 1, July 1952 Printed in U.S.A.
UROLOGIC COMPLICATIONS OF CANCER OF THE UTERINE CERVIX EDWARD W. BEACH
It is a clinical maxim that some degree of pelvic ureteral occlusion is inevitable in many women afflicted by cervical cancer and treated with radiation. The medical profession has assumed that the x-ray and radium are responsible for such ureteral strictures and other complications, but a careful study of the last 24 patients referred to me has caused me to doubt this. Exactly what role, if any, does radiotherapy play in the development of such ureteral stenosis? What is the role of neoplastic parametrial spread with its attendant pother of inflammation, in the etiology of such ureteral occlusion? Although every woman with cervical cancer is potentially a urologic patient, the experienced urologist is rarely intrigued by the actuality of urologic manifestations, because the latter usually have ominous import. More specifically, it is customary for the gynecologist to inaugurate and continue treatment of cervical cancer with no mind whatever paid the urinary tract. In fact, urologic talent is currently considered only a spare tire in the treatment ensemble and one reserved exclusively for a blowout. When such emergency occurs or the situation becomes desperate and vexatious urologic developments force belated consultation epitomized in those famous last words "For God's sake do something!" it is usually too late for anything but makeshift repair. Such malfeasance in management of cancer of the cervix uteri has, unfortunately, all but extinguish( c urologil: interest in the treatment of this disease. Moreover, many urologists have somehow acquired an impresc:on Jiat radiation therapy per se frequently causes stricture or atresia of uhe pelvic ureters. Theoretically and academically such a possibility is admissible, but the probability is remote and so is the incidence from a technical standpoint. Proof rests squarely on the proponent. Acceptance of the idea requires postmortem or factual evidence of which there is a remarkable dearth both in the literature and in my clinical experience. Ureteral stenosis of any degree is invariably accompanied by a palpable mass or increased denseness in the parametrium of the affected side or sides~whether neoplastic, inflammatory or organizing round-cell infiltration or some combination. A sound knowledge of cervical cancer with its infiltrative tendencies and concomitant inflammatory reaction plus a definitive understanding of radiotherapy seem the best antidote to such devil's wine. 1 It is almost axiomatic that the close anatomic relationship between the uterine cervix and the adjacent urinary tract paves the way for urinary repercussions if cancer of any extent exists in the cervix, usually by spread from the primary focus or by inflammation, but sometimes by radiation therapy with the bladder as a selective target. That cervical cancer deserves therefore a place on the top shelf of urologic interest is apparent in the following five facts: 0 1
Read at annual meeting, Western Section, American Urological Association, Sun Valley, Idaho, June 28, 1951. 1 Vinum daemonum. Essays of Francis Bacon. Essay on Truth. 178
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1) Cancer of the cervix comprises one of every four malignant tumors which afflict women. Breast cancer is first. 2) Sixty to eighty per cent of women so afflicted who succumb to this disease die of uremia contingent upon occlusion of the pelvic ureters. 2 3) Direct spread into the juxtaposed bladder or urethra is not uncommon. 4) Surgical attempts to control such cancer still impose considerable injury on the ureter. 5) Postradiation or factitial cystitis-an entity often difficult to diagnose and to treat-is rampant because radiation therapy for control of such cancer is at the present being used more and more. CANCER OF THE UTERINE CERVIX
This disease can exist in females of any age,3 but it is most common among women older than 35, particularly in the married and parous. 4 It seldom afflicts the spinster and is less common among Jewish women. 5 The big age group from a diagnostic standpoint is around 48 years. The vaginal portion of the cervix is covered by squamous epithelium with a sharp transition normally at the external os so that the endocervical canal is lined by a single layer of prismatic cells. Intrinsic glands therein have similar histologic architecture. These prismatic cells appear to constitute the nidus for so-called epidermoid cancer with its repertory of cellular morphology. 6 Given proper instigation (the role of epithelial instability, heredity, sex, physiologic age, endocrine imbalance, infection and trauma all have supporters) these prismatic cells appear to undergo metaplasia and to become arranged into sheets or stratified pavement epithelium devoid of glandular elements, not unlike the epithelium over the portio vaginalis. Notable exceptions are 1) true cervical adenocarcinoma 7 (rare-only 3 to 5 per cent of cases) and 2) adenoacanthoma8 with a relative admixture of both glandular and epithelial elements. Classification of epidermoid cancer based upon cellular morphology, a task for the pathologist, depends on the predominant cell type. Multiform variations 2 Cantril, Simeon T.: Radiation Therapy in the Management of Cancer of the Uterine Cervix. Springfield, Ill.: Charles C. Thomas, 1950, p. 23. 3 Ackerman, Lauren V. and Juan A. de! Regato: Cancer. Diagnosis, Treatment and Prognosis. St. Louis: The C. V. Mosby Co., 1947, pp. 852-854. Heckel, G. P.: Pediatrics 5: 924-929, 1950. 4 Maliphant, R. G.: Brit. Med. J., 1: 978-982, 1949. 5 Weir, P. and C. C. Little: J. Heredity, 25: 277-280, 1934. Weiner, I., Burke, L. and Goldberger, M.A.: Am. J. Obst. & Gynec. 61: 418-422, 1951. Healy, W. P., and Twombly, G. H.: Am. J. Roentgenol., 49: 522-523. 6 Regaud, C. and Gricouroff, G.: Bull. Assoc. fran9. p. l'etude du cancer, 22: 285-296, 1933. Regaud, C. Gricouroff, G., and Villela, E.: Bull. Assoc. fran9. p. l'etude du cancer 22: 668-677, 1933. 7 Baclesse, F. and Fernandez-Colmeiro, J.M.: Bull. Assoc. fran9. p. l'etude du cancer 30: 118-128, 1942. Ackerman, L. V. and de! Regato, J. A.: Cancer. Diagnosis, Treatment and prognosis. St. Louis: The C. V. Mosby Company, 1947, p. 859. (Incidence of 3.7 in 453 cases.) 8 Randall, C. L.: Adenocarcinoma of the Uterus. In: Progress in Gynecology, vol. 11. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1950, p. 490. Curtis, A.H. and Huffman, J. W.: A Textbook of Gynecology. Ed. 6, Philadelphia: W. B. Saunders Company, 1950, p. 338.
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are usually present. Martzloff9 divided this group into 1) the spinal cell typethe same as Broders' 10 grade 1 malignancy or "ripe" species, 2) the transition cell, or Broders' grade 2 malignancy still the "ripe" species and 3) the basal or fat spindle cell type-Broders' grade 3 and 4 malignancy-grade 3, the "middle ripe", and grade 4, "the unripe." In general, the anaplastic or dedifferentiated forms are most radiovulnerable, but they tend to spread early and they metastasize widely.
FIG. 1. Lymphatic drainage of uterus. Gross drawing: Large lymph channels. Longitudinal section: Microscopic endings of lymph system infiltrating walls of uterus. These may provide a means of metastasis.
Thanks to the pathologist's perspicacity, the nature of "noninvasive intraepithelial cancer" 11 of the cervix is now known. This condition has been called "basal cell hyperactivity", "carcinoma in situ, " 12 "beginnendes Karzinoma" 13 (by Schiller) and Bowen's disease. 14 It may antedate the frankly invasive clinical Martzloff, K. H.: Bull. Johns Hopkins Hosp., 34: 141-149, 184-194, 1923. Martzloff, K. H.: Bull. Johns Hopkins Hosp., 33: 221-222, 1922. Diseases of the cervix uteri. In: Practice of Surgery, by Lewis. Hagerstown, 1\!Id.: W. F. Prior Co., vol. 10, chap. 14, 1928. 10 Broders, A. C.: Minnesota Med. 8: 726-730, 1925. 11 Te Linde, Richard W. The relation of "intra-epithelial carcinoma" to invasive cancer of the cervix. In: Progress in gynecology. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1946, pp. 349-361. 12 Te Linde, Richard W. and Gerald A. Galvin: The present-day status of noninvasive cervical carcinoma. In: Progress in Gynecology, vol. 11. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1950, pp. 499-510. 13 Schiller, Walter: Arch. f. Gynak., 133: 211-283, 1928. 14 Bowen, John T.: J. Cutan. Dis., 30: 241-255, 1912. Also, J. Cutan. Dis. 33: 787-802, 1915. 9
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entity for an indeterminate period-possibly a decade or even more. 15 Unfortunately the gross appearance of the cervix does not betray the presence of such a lesion. Cervical cancer may spread in any direction by paracervical infiltration. Commonest is spread into the base of one or both broad ligaments. Extension upwards into endometrium or uterine wall is frequent (fig. 1). Distal infiltration of the portio vaginalis inclusive of the upper two thirds of the vagina is not rare. Later the lower third of the vagina may be invaded and this invasion is accompanied by inguinal adenopathy. Posterior extension toward the sacrum, rectum and sacral nerve roots may accrue and give rise to consonant subjective complaints.
Frn. 2. A, lymphatic system of pelvic organs. Uterus, its appendages and vagina are covered by a rich network of lymphatic vessels surrounding uterus and vagina. a and a', Lymph nodes at bifurcation of common iliac arteries. b and b', Lumbar glands in pre-aortic chain. c and c', Deep inguinal lymph nodes which may at times be involved by spread of carcinoma. (Through the courtesy of Cantril. 2 ) B, Schematic view of initial lymph node relays of lymphatic supply of cervix. gg. princ., Pre-ureteral chain (principal pathway). gg. hyp., Hypogastric chain (post-ureteral). gg. pro., Posterior chain leading to promontory. gg. bif., Less frequent route leading to bifurcation of internal iliac. (Through the courtesy of Cantril.2)
Lymphatic pathways are illustrated in figure 2. It is well to remember the dominant pre-ureteral trunk of lymphatic pathways into the broad ligaments which sponsors metastasis to pelvic glands from the obturator canal to the inferior iliosacral junction. The League of Nations Committee16 has adopted a workable classification based on extension proclivities: Stage 1 : Cancer confined entirely to the cervix. Stage 2: Parametrium invaded on one or both sides. Some uterine motility 15 Te Linde, Richard W. and Gerald A. Galvin: The present-day status of noninvasive cervical carcinoma. In: Progress in Gynecology. vol. 11. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1950, p. 506. 16 League of Nations, Health Organization, Cancer Commission: Report submitted by the Radiological Sub-Commission, Geneva, League of Nations Publications, 1929, 82 pp. Heyman, J.: Atlas illustrating the division of cancer of the uterine cervix into four stages. League of Nations Health Organization (Inquiry into the results of radiotherapy in cancer of the uterus). 1938, unnumbered pages.
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retained. Lesion spread into corpus uteri and upper portion of vagma. Stage 3: Infiltration extended through parametrium to pelvic wall-isolated masses palpable on pelvic wall. Lower third of vagina involved. Stage 4: Cancer involves bladder or rectum with spread outside the pelvis to other viscera. Because infection, cellulitis and inflammatory induration invariably accompany cancer spread, proper evaluation sometimes perplexes the most experienced. Diagnosis. Microscopic study of segregated scrapings from the cervix and uterus, using Papanicolaou or similar technique is sometimes helpful, but biopsy is essential. Cytologic and clinical study of the primary lesion and of extracervical spread conditions both treatment and prognosis. Symptoms vary. Abnormal or postmenopausal bleeding should arouse suspicion. Contemporary physicians must be mindful that abuse of estrogenic therapy during menopause 1s now common. Treatment. The field of therapy has laid somewhat fallow for the last few years. This may presage a bumper crop of new developments. In the surgical era all hope hinged upon the radical Wertheim17-the most formidable of all gynecological procedures-with a high mortality rate and a frightful bladder and ureteral morbidity especially in the hands of the inexperienced. The bladder suffers injury in about 17 per cent of cases; vesicovaginal fistulas occur in about 7 per cent. 18 Even in expert hands, the ureters are injured . in 7 to 10 per cent19 of cases; often the blood supply to the ureters is impaired and sloughing results. In 28 years of practice I have treated 14 such injuries, most of them resulting in ureterovaginal fistula, following the Wertheim procedure. ,Ve have the Wertheim operation to thank for much of what we know about cervical cancer-learned at the operating table and from pathologic specimens. The Martzloff modification20 is now more commonly used. Most clinics now take a dim view of surgical treatment alone, save in very early and selected instances. Granted that the lesion is "cancer in situ", what surgical procedure should be undertaken? Trachelectomy? Simple hysterectomy? Hysterectomy plus adnexectomy? The more radical Wertheim? Who knows? Anatomic studies of this entity have taught the necessity of removing an ample cuff of tissue about the limits of the portio vaginalis in these cases. 21 Many clinics in this country now depend solely upon x-ray and radium Wertheim, E.: Am. J. Obst., 66: 169-232, 1912. Bonney, V.: Am. J. Obst. & Gynec., 30: 815-830, 1935. Meigs, J. V.: Am. J. Obst. & Gynec., 49: 542-549, 1945. Meigs, J. V.: In: Progress in Gynecology, vol. 11. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1950, pp. 540-564. 18 Weibel, W.: Arch. f. Gyniik., 135: 1-57, 1928. Weibel, W.: Wein. Klin. Wchnschr., 38: 716-717, 1925. Wharton, L. R.: Gynecology. With a Section on Female Urology. Ed. 2, Philadelphia: W. B. Saunders Company, 1947, p. 501. 19 Wharton, Lawrence R.: Gynecology. With a Section on Female Urology. Ed. 2, Philadelphia: W. B. Saunders Company, 1947, p. 495. 20 Martzloff, Karl H.: Bull. Johns Hopkins Hosp., 34: 141-149; 184-194, 1923. 21 Foote, F. W., Jr. and Stewart, F. W.: Cancer 1: 431-440, 1948. 17
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to control cervical cancer. Those that have good radiotherapy departments put out an imposing array of statistics in support of their method. The gist of such statistical tables is that if treated early, possibly 8 of 10 cervical cancers may be controlled by radiotherapy and that later when one or both parametria are invaded, perhaps 1 of 3 may be so controlled, depending on the extent of invasion, the cellular morphology and who presents the statistics. It offers the additional advantage that the patient i's ambulatory throughout. Clearly radiotherapy is most favored in the current approach. However, because the metastatic lesions of some tumors are radiation-resistant, removal of the pelvic lymph glands on both sides is advocated after preliminary and intensive radiation. Taussig22 uses such a procedure, without hysterectomy, and Nathanson23 also uses it, with extraperitoneal exposure, in certain cases. Recently Meigs 24 has coupled the radical Wertheim operation with Taussig's gland resection in selected cases. While time has proved the value of radiation (in terms of 5 year control) there is as yet no unanimity as to dosage, modalities, application or sequence. Multifacets in the clinical picture stemming from the cellular morphology, conformation of the primary lesion, the presence of infection or cellulitis, the route and degree of extension, the pelvic pattern and the general condition of the patient all preclude standardized technique. Nor can radiation be used empirically or with a slide rule. Radiation must be tailored to the individual by the skilled radiologist in an effort to eradicate the cancer cells and yet preserve the integrity of normal surrounding tissues. The patients who are the subject of the discussion to follow underwent a high voltage ("soft ray") barrage through four skin portals (2A and 2P) using 8,000 to 10,000 r, and in suitable cases 3,000 to 4,000 r was given by vaginal cone. Radium element properly screened was used after the Stockholm25 technique, about 3,000 mg. hr. in the uterine corpus and 3,000 to 3,500 mg. hr. to the cervix and vaginal fornices. Alterations and modifications governed by the attendant circumstances were frequent. UROLOGIC COMPLICATIONS
The relevant clinical data from my 24 cases will be presented in the following general discussion of the urologic complications in radiation therapy of cancer of the cervix. The pelvic ureter. Figures 3 so 6 provide anatomic reconnoiterer. Of esoteric interest is the parametrial ureter which passes forward to the cervix and then Taussig, F. J.: Am. J. Obst. & Gynec., 45: 733-748, 1943. Leveuf, J. and Godard, H.: J. de chir. 43: 177-187, 1934. Nathanson, I. T.: Extra peritoneal iliac lymphadenectomy in the treatment of cancer of the cervix. In: Progress in Gynecology. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1946, pp. 388-394. 24 Meigs, Joe V.: Radical hysterectomy for cancer of the cervix with bilateral pelvic lymphadenectomy (the so-called Wertheim operation). In: Progress in Gynecology, vol. 11. Ed. by Joe V. Meigs and Somers H. Sturgis. New York: Grune & Stratton, 1950, p. 541. 25 Heyman, J., Reuterwall, 0., and Benner, S.: Acta radiol. 22: 11-98, 1941. Forssell, G.: Acta radiol., 28: 417-432, 1947. Forssell, G.: Hygeia, vol. 76, 1914. Forssell, G.: Fortschr. der a. d. Geb. d. Riintgenstrahlen, 25: 142-149, 1917. League of Nations, Health Organization, Cancer Commission: Report submitted by the Radiological Sub-Commission. Geneva, League of Nations Publications, 1929, 83 pp. Heyman, J.: 20: 85-91, 1947. 22
23
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downward and medially to the trigone. Of greatest urologic import is that ureteral segment where "water passes under a bridge" (ureter crossed by the uterine artery) which is almost opposite the internal os and about 1½cm. lateral to the cervix and that downward ureteral continuation ensheathed by the veins of the
FIG. 3. A, cross-section of female pelvis, showing basal structure of broad ligament, ligamentous supports of bladder and uterus, and fascial coats of pelvic organs. B, female pelvis, anterior view. Subperitoneal tissue of broad ligament, urinary bladder and uterus. Uterus is retracted from its normal anteverted position and peritoneum has been pulled back to show body of uterus, broad ligament and superior surface of bladder.
Fm. 4. Female pelvis, anterior superior view. Right ureter has been freed completely from its bed from 3 cm. below pelvic brim to trigone. Note proximity of parametria and pelvic lymph nodes to uterus. (Through courtesy of G. H. Twombly: Technique of radical hysterectomy for carcinoma of cervix. Cancer, 3: 975-991 [Nov.] 1950.)
vesicovaginal plexus which lies about 1 cm. above the lateral vaginal fornix. The most distal ureteral portion, about I½ cm. long, lying close to the vaginal wall, is also implicated by the cervical cancer. The terminal segment of pelvic ureter, some 7 to 8 cm. in length, is not only in close anatomic apposition to the cervix, but is also served by much the same lymph and blood vessels. Any morbid change in the cervix should therefore be
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reflected in some degree or have reciprocative amplification in the abutting ureter, conditioned by the character of the lesion, from initial hyperemia to compression or angulation of the duct because of parametrial extension. The commonest point of ureteral occlusion in parametrial spread is where the duct is crossed by the uterine artery (fig. 7); i.e. adjacent to the internal os and about 5 to 6 cm. up from the ureteral meatus. Twelve patients (all seen in the "supplicatory stage"-stages 3 and 4) had variable degree of occlusion at this point on one or both sides. In 5, nephrectomy was necessary because of unilateral
Frn. 5. Bilateral hydro-ureter due to obstruction arising from spread of cancer of cervix. (Through the courtesy of Cantril.2)
occlusion with sepsis and because great debilitation precluded other measures for relief. In another case with uremia, since only half a kidney remained, a quick ureterocutaneous groin fistula was established. In 3 other cases the vaginal or most distal ureteral segment was obstructed unilaterally. In 2, a stone was impacted in this pathologically narrowed portion and in another, ureteral occlusion was caused by neoplastic impingement near the anterior vaginal wall. In exact discernment of the presence and degree of ureteral occlusion, both retrograde (if possible) and excretory roentgenologic studies are necessary. The fact that a catheter can be passed up the ureter does not mean that the ureter is not partially occluded by segmental narrowing, extra-ureteric pressure or edema of the ureteral wall. It is quite common to thread a catheter through such an area of involvement initially and never again be successful in such endeavor.
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Indwelling catheters were poorly tolerated in these cases. Interval ureteral dilatations were not too helpful. The cause of ureteral occlusion in these cases was invariably a mass or some degree of induration in the base of the broad ligament-whether neoplastic or inflammatory or both, only clinical experience and observation could determine. In none of this limited group could radiotherapy be incriminated for the ureteral stenosis. In fact, in two cases partial bilateral ureteral occlusion and subjective symptoms were relieved considerably by a second course of radiation therapy.
FIG. 6. Early bilateral ureteral backpressure due to cancer of uterine cervix. Patient was a young woman. Conditions suitable for ureteral transplantation.
If the condition is advanced, seldom is reconstructive surgery advisable. Bilateral ureteral occlusion usually has dire prognostic connotation an~ hence nephrostomy or a shift of the ureter to the intestine or the contralateral structure has limited application from a practical standpoint in view of the psychology, general condition and life expectancy of such patients. The bladder. If cervical cancer spreads downward along the anterior vaginal wall, seldom does the bladder escape unscathed. Such extension-usually a forerunner of vesical involvement-can sometimes be palpated long before urinary symptoms are manifest. Excellent studies26 depicting cystoscopic changes and successive steps in the development of such bladder lesions which range from early trigonal asymmetry or distortion at the base through submucosal Aman-Jean, F.: Bull. Assoc. frarn;. p. l'etude du cancer 22: 556-589, 1933. Graves, Roger 0., Kickham, 0. J. E.and Nathanson, I. T.: Surg .. Obst. 63: 785-793, 1936. 26
,Ii;
Gynec.
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petechiasis and edema to actual nodule formation with ulceration and bleeding have been made and need no reiteration here. Among the 24 cases there were 2 vesicovaginal fistulae and 1 rectovesical fistula-obviously late and hopeless sequelae. Post-radiation cystitis: From the practical standpoint there are two typesan early and a late or delayed type. Much work has been done by Dean, 27 Colby28 and others 29 - 3o on this subject.
A.vesi.cal1s A.uterina\ __..-
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Fm. 7. Principal arteries and veins supplying organs of female pelvis. Uterine artery has been further exposed by partial removal of accompanying veins. All remaining structures still lie in positions they held prior to dissection. Note point at which ureter is crossed by uterine artery, common point of ureteral occlusion in cases in which parametrial spread has occurred.
The early type is a vasodilatation phenomenon and represents a specific response to radiation. It comes along 28 to 30 days astern of treatment. Subjective symptoms are rarely severe and usually clear quickly. If deep therapy alone is used, generalized cystitis is discovered with the cystoscope. If such reaction depends solely upon intracavitary use of radium element, areal distribution over the bladder base at certain points of maximal concentration is apparent cystoscopically. Every urologist who collaborates closely with the radiologist is familiar with such changes. The delayed type of factitional cystitis is signalized by its tardy appearance Dean, A. L. Jr.: J. A. M. A. 89: 1121-1123, 1927. Also J. Urol. 29: 559-570, 1933. Dean, A. L. Jr. and Slaughter, D. P.: J. Urol., 46: 917-924, 1941. 28 Colby, F. H.: New Eng. J. Med., 209: 231, 1933. 29 Everett, H. S.: Am. J. Obst. & Gynec. 38: 889-906, 1939. 30 Newell, Q. U. and Crossen, H. S.: Surg., Gynec. & Obst., 60: 763-768, 1935. 27
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after radiation. It seldom develops before a year has elapsed and may be delayed for as long as 10 to 12 years after radiotherapy. Average appearance time is given as 2½ years. This type of bladder lesion constitutes a trophic change predicated upon an obliterative endarteritis. It is characterized by sloughing of the bladder wall or trigone in variable degree. The slough may be so deep and extensive that a fistula forms. Subjective symptoms are often distressing and the healing of such a lesion is very slow. Usually the cervical canceris well controlled before these bladder lesions become apparent. There were 5 instances of delayed postradiation cystitis in my series. The youngest woman was 37 and the oldest 66 years of age. The earliest appearance of this trophic lesion was 17 months after radiation and the latest, 35 months thereafter. Each of these women had had at least 5,000 mg. hr. of intracavitary radium and none more than 6,200 mg. hr. These trophic bladder lesions were invariably multiple and comprised a number of moderate sized, shallow, irregular ulcers, usually retrotrigonal and toward the left lateral wall. These ulcers had a linear distribution, the edges were somewhat motheaten and the floor was covered with grayish yellow necrotic material. They were surrounded by an injected areola. Dysuria was prominent, especially frequency and burning. Hematuria was always an outstanding symptom. The cystoscopic appearance of such lesions is quite misleading and diagnosis necessitates careful cytological study of several biopsy specimens. It is most important to avoid subsequent radiation-if no cancer cells exist. Diagnosis is sometimes a problem even for the skilled pathologist in these instances, as the following case demonstrates: One of my patients had suffered a transitional cell cervical cancer which had been treated by radiation and 5,000 mg. hr. of intracavitary radium (well screened). This cancer was well controlled clinically. About 18 months after radiotherapy, a group of trophic bladder ulcers appeared, accompanied by the usual subjective and objective symptoms. A series of 3 or 4 biopsy specimens was obtained from the most suspicious areas. The pathologist, who had had 38 years of experience, stated that the lesion was a transitional cell bladder tumor with cellular morphology much like that of the cervical cancer which he had previously studied. Because of the p·atient's history, we were dubious and took several more biopsy specimens. Again the same pathological diagnosis. Meantime the patient grew restless and because of her urinary distress, enplaned for the Mayo Clinic. Dr. Edward N. Cook of the Clinic took 18 or 20 biopsy specimens before he could be certain that there were no cancer cells. Under his care the patient's symptoms were shortly relieved and the ulcers healed in approximately 6 months. The trophic ulcers I treated healed very slowly and usually required 6 to 10 months. Therapy, empirical or otherwise, did not seem to hasten healing. For the hyperacute cases of dysuria, continuous bladder irrigations with dilute silver solution (1: 3,000) was most helpful. Later, hydrostatic bladder dilatations followed by oily balsamic instillations gave some relief. In none of these cases did fistulae develop. The urethra. As the cervical cancer spreads downward along the anterior ·
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vaginal wall, in late stages, the urethra may be impinged upon by the neoplastic mass surrounding it or its wall may be invaded directly by the cancer. I had one such case; retention developed and catheterization was very difficult and painful because of the narrowed and compressed urethral lumen. A permanent cystostomy was made to relieve symptoms. Adjuvant treatment. Competent management of cervical cancer necessitates inquiry into theurologic status of these patients both initially and at appropriate intervals thereafter. If this is done and attention is thereby focused on the pelvic ureters before they become hopelessly fouled in this disease, the patient can be given much better care. For many of these unfortunate women, early ureterosigmoidostomy would be a blessing, if partial bilateral ureteral occlusion is worsening clinically. In another limited group, when the bladder is threatened by advancing spread of the cancer, but has not yet been involved, total cystectomy with uretero-intestinal transplantation might constitute a wise choice of treatment. Prevention of trophic bladder lesions is difficult in the absence of a reliable gauge for predetermining unusual individual susceptibility to radium, but better screening and more care in placement would help. SUMMARY
This article hopes to rekindle interest by stressing urologic repercussions in cervical cancer and to dispel some common fallacies by review of basic knowledge. It recalls certain factors pertinent to cervical cancer in its bearing on the adjacent urinary tract. It brings up the question whether radiotherapy per se induces ureteral stenosis in these cases and presents evidence that extension of the disease is the more likely cause. In these 12 cases of ureteral obstruction it was the only cause. It pleads for a preliminary and detailed urologic survey before any treatment of the cancer is begun so that early or unsuspected lesions of the urinary tract may be discovered and expeditiously cared for. It urges closer liason between the urologist, the gynecologist and the radiologist to the end of efficient management. The close anatomical relationship of the uterine cervix and the ureters obligates every urologist to actively crusade against current neglect of the urinary tract in the treatment of cancer of the cervix. Supplicatory consultations are too common and are a sad commentary on scientific management of this disease.
2900 L St., Sacramento 16, Calif.