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Metastases from Tumors of the Testis
METASTASES FROM TUMORS OF THE TESTIS DAVID W. MACKENZIE AND MAX RATNER From the Departments of Urology, Royal Victoria Hospital and Jewish General Hospital, Montreal, Canada
Tumors of the testis are not commonly met with, yet the subject has been discussed very freely in the literature. There are few new growths of the body that have caused so much discussion and dispute as have the tumors of the testis. This disagreement has resulted from a difference of opinion regarding classification, pathogenesis, and treatment of these tumors. A vast literature has accumulated, but even today there is no unanimity of opinion. However, there has been a distinct advance in the knowledge of the subject, and it is hoped that the near future may bring even better harmony and co-operation between the opposing groups. Practically all new growths of the testis metastasize early and extensively, both by the lymphatics and blood stream. The extension usually takes place first by the way of lymphatics although haematogenous metastases may be encountered without clinical evidence of lymphatic involvement. The normal lymphatic drainage of the testis involves the spermatic and retroperitoneal glands, the latter situated along the aorta and inferior vena cava. There is undoubtedly further communication with the epigastric, mediastinal, and finally the left supraclavicular lymph nodes. This lymphatic supply has been definitely shown both anatomically and clinically. Enough data in cases of teratoma of the testis has accumulated to clearly demonstrate the ab.ave route of metastases, namely along the spermatic, retroperitoneal, epigastric, mediastinal, and finally the left supraclavicular lymph nodes. In 1910, Jamieson and Dobson, after extensive studies of the lymphatics of the testis, demonstrated that the arrangement of these lymphatics is such that the complete removal is exceedingly difficult and dangerous, if not impracticable. It is this anatomy of the lymphatic drainage that has convinced several surgeons of the futility of the radical operation for teratoma of the testis. These men claim that if a radical removal of the glands is undertaken, it should include the lymph nodes beyond the renal region as well, but that procedure is of course impossible. Blood stream metastases are also very common, and usually manifest 592
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themselves early in the course of the disease. The portal of entry is probably the pampiniform plexus of veins. Secondary growths have been reported in practically all organs and tissues of the body (figs. 1, 2, 3, 4 and 5). Thus they have been observed in the lung, pleura, liver, spleen, kidney, adrenal, brain, spinal cord, heart muscle, skull, spine, bony pelvis, and femur. The organs most commonly involved however, are the lungs, liver, and kidneys. Invasion of the spermatic and iliac veins by continuous growth has been observed, and occasionally the growth has extended even as far as the right side of the heart.
FIG. 1. Section of brain showing a metastatic growth in right cerebral hemisphere secondary to chorio-epithelioma of right testis.
Desjardins and his associates find the average time from the onset of symptoms to the demonstration of metastases, to be 2 years, and 4 months. Smith, Dresser, and Mintz, report the presence of metastases in untreated cases within a few months after onset of symptoms. Gordon-Taylor and Till found that the length of history as judged by the time the patient had noticed a testicular tumor before medical advice was sought varied from 2 weeks to 5 years. In our own series metastases made their appearance anywhere from two months to several
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years after onset of the testicular swelling. It is obvious that the above observations as to time are grossly inaccurate. This is due partly to the fact that a large number of patients are unable to give a correct history as to when the tumor in the scrotum was first noticed. Many of them overlook the testicular tumor for a long time, and their attention may actually be drawn to it either by a physician, or following an injury to the scrotum. One of our cases insisted that he had had the same sized swelling of the right testis since an injury at the age of 8 years. He was 43 years old on admission. Moreover, several cases are admitted to a hospital with neurological, pulmonary, or gastro-
FIG. 2. Photomicrograph ·of brain metastasis from chorio-epithelioma of right testis. Note Langhans' and syncytial cells.
intestinal symptoms due to metastases from a testicular tumor, and it is during a routine physical examination that a mass in the scrotum is first observed. It is apparent therefore that an accurate estimation of the period of time that elapses from the onset of the swelling in the scrotum to the appearance of metastases, is in a great majority of cases well nigh impossible to determine. It is indeed surprising, the number of men that have a growth of the testis without any knowledge of it. This is particularly true if the tumor is not large. It is important to emphasize at this point that a growth of the testis may be small. Moreover the size of the growth is in no way proportional to the degree of malignancy. We know of at least 3 cases of testicular tumor that proved
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to be very malignant, yet the actual size varied from that of a walnut to a small plum. We may also add that in a number of cases, testicular sensation was still present. This depends on whether or not there still remains some normal testicular tissue.
FIG. 3. Photograph of lung showing multiple metastases from an embryonal carcinoma of right testis.
When one realizes that a large percentage of patients with tumors of the testis first consult a physician or surgeon when metastases are
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already demonstrable, the urgent need for early recognition and treatment can be readily appreciated. Seventy-three per cent of the patients reported by Dean (1935) showed local recurrence or metastases on admission. Smith, Dresser and Mintz, report 31 per cent of their 100 patients with metastases prior to treatment. In our series of 29 patients, 15 had apparent local or distant metastases when first examined. There are other similar reports of high incidence. When one adds to
FIG. 4. Photograph of kidney showing multiple metastases from an embryonal carcinoma of right testis.
this group the number of cases who clinically have non-demonstrable metastases, the sum total must be quite high. Symptomatology. The symptoms of metastases from testicular tumors depend upon the site and size of the secondary growth. Involvement of the glands along the cord may give rise to a large and painful swelling. As the retroperitoneal glands enlarge a mass may be detected either below the umbilicus or in the epigastrium (fig. 11). Often this abdominal tumor grows to such a size as to cause pressure
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on adjacent organs with resulting nausea, vomiting, and even severe abdominal pain. Cases have been observed in whom the retroperitoneal glands have actually compressed the ureters on both sides causing anuria and subsequent uraemia and death. Other cases have been seen in whom one ureter only was compressed by the retroperitoneal metastases, causing destruction of the corresponding kidney. We have had examples of both types. In a number of instances the retroperitoneal tumor has obstructed the iliac veins causing oedema of the lower extremities (fig. 10). One of our
FIG. 5. Photograph showing metastases in spleen from embryonal carcinoma of right
testis.
cases had such a condition, and at autopsy it was found that the venous circulation of the right leg was impeded by enlarged metastatic glands. When the mediastinal glands are replaced by growth, pain in the chest, cough, and at times difficulty in breathing and swallowing ensue (fig. 8). The left supraclavicular glands are frequently involved, and they may cause pain and stiffness of the neck. As already indicated metastases through the blood stream probably result from the invasion of the pampiniform plexus by growth (figs. 6 and 7). We have observed metastases in the lungs, liver, kidney,
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spleen, adrenals, brain, dura, skull, chest wall, and even in the right ventricle of the heart (fig. 9). Patients with secondary growths of the lung usually complain of cough, expectoration, and very often pain. Cases
FIG. 6
FIG
7
6. Photograph of x-ray of a skull showing a rarefied area in right frontal region. This was due to metastatic growth secondary to teratoid tumor of right testis. FIG. 7. Photograph of x-ray of the same skull as figure 6 taken 4 months later. Note marked increase in size of rarefaction. FIG.
FIG. 7a. Photomicrograph of rarefied area of the skull seen in figures 6 and 7. Note preponderance of histoid elements, cartilage, fibrous tissue and muscle. This picture was identical with section from tumor of testis.
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have been reported with profuse pulmonary haemorrhage. Haematuria due to involvement of the kidneys is not an uncommon clinical finding.
Frc. 8
Frc. 9
FIG. 8. Photograph of x-ray of chest showing a metastatic growth of mediastinum secondary to embryonal teratoma of left testis. Frc. 9. Photograph of x-ray of chest showing large metastatic growth of right hmg secondary to embryonal carcinoma of right testis.
FIG. 10. Photograph of x-ray showing a. retroperitoneal metastatic growth pushing left kidnev and ureter outwards. Tbis mass was secondary to embryonal carcinoma of left testis.·
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Systemic symptoms occur frequently and are often noticed early in the course of the disease. There may be weakness, anorexia, loss of weight and anaemia. The onset of these symptoms suggests very strongly the presence of metastases. However, metastases may be present without obvious systemic symptoms. Recently we observed 2 cases with demonstrable retroperitoneal metastases. Both patients were well nourished and felt perfectly healthy. Their only complaint was a painless mass in the scrotum.
FIG. 11. Photograph of an x-ray after a barium drink. Note small intestines pushed over towards the right side by a large retroperitoneal metastatic growth which was secondary to an embryonal teratoma of left testis. ·
An interesting group of patients are those who are admitted to other departments than Urology, complaining of symptoms caused by metastases. In many instances the original tumor of the testis is overlooked, and it is only after a thorough examination that the true nature of the disease is established. At times the correct diagnosis is made at the autopsy table only. We have observed a small number of such cases, and we wish to mention 5 of them briefly. Case 1. E. M., aged 64 years, entered Medical Service August 30, 1926, complaining of a mass in the left upper quadrant of the abdomen. On further
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questioning it was elicited that the patient had a swelling and some pain in the right side of the scrotum. The mass in the scrotum was first noticed a. month prior to admission, and the mass in the abdomen was observed a short while after. Physical examination disclosed a large, firm, irregular tumor in the left upper quadrant of the abdomen, and a mass in the right groin. The growth in the right side of the scrotum was the size of an orange, firm, and did not transmit light. There were also a few small bilateral inguinal glands. Patient died 5 days after admission to the hospital. Autopsy disclosed embryonal carcinoma of the right testis with metastases to the retroperitoneal glands, inguinal glands, adrenals, and the right ventricle of the heart. This patient was admitted to the Medical Ward primarily because of the mass in the abdomen, and the possibility of a new growth of the stomach had been entertained. A tumor of the scrotum was not considered until after his admission to the hospital, when a provisional diagnosis of a new growth of the right testis with metastases was made. This was confirmed at autopsy. Case 2. H. 0., aged 38 years, was admitted to the Neurological Service on July 25, 1924, in coma. The history obtained was that there was cough and soreness of chest for 3 months, swelling of the right leg for 1 month, loss of function of the left arm for 2 months, and a mass in the right side of scrotum for 9 months. Weakness and loss of weight was noticed even prior to the onset of the scrotal swelling. During his stay in the hospital the patient had a number of typical attacks of Jacksonian epilepsy. Physical examination revealed (1) consolidation of the upper lobe of the right lung, and at the hilus of the left lung; (2) evidence of a lesion of the right cerebral hemisphere; (3) a mass the size of a chicken's egg in the right side of the scrotum. It was hard and nodular. A provisional diagnosis of a tumor of the right testis with metastases was made. The patient died the same day. An autopsy showed chorio-epithelioma of the right testis with metastases to the kidney, liver, spleen, lungs, chest wall, brain, and retroperitoneal glands.
There are a number of interesting features in this case. The patient was admitted to the Neurological Service because of coma, and it was only after a careful physical examination that the question of a malignant tumor of the right testis with metastases was considered. Furthermore, the primary growth and the metastases showed evidence of syncitial and Langhans layers of cells. Moreover there were signs that resembled pregnancy, namely enlarged and tender breasts and the
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presence of colostrum. The swelling of the right leg was due to pressure on the venous circulation by enlarged glands. The attacks of Jacksonian epilepsy and loss of function of the left arm were apparently caused by the large metastases to the right cerebral hemisphere. Case 3. P. M., aged 21 years, was admitted to the Surgical Service March 31, 1938, complaining of sharp pain in the left upper quadrant of the abdomen, nausea and vomiting. Physical examination revealed a mass in the left upper quadrant of the abdomen, and the question of a lesion of the stomach was seriously considered. A barium series was carried out, but the stomach was found to be normal as well as the remainder of the gastro-intestinal system. However, there was evidence of a retroperitoneal mass which was pushing the small bowel towards the right side. A surgical lesion of the left kidney was suspected. A urological examination disclosed the mass in the abdomen, but also a hard mass the size of a walnut in the left side of scrotum. This was considered as a possible teratoma of the testis, and the mass in the abdomen was probably retroperitoneal metastases. The patient was then transferred to the Urological Service where an orchidectomy was performed. The pathological report substantiated the original provisional diagnosis. The lesion was an embryonal teratoma with lymphoid stroma. He was given high voltage x-ray therapy and is still under treatment. The mass in the abdomen has decreased in size but yet remains quite large however. Case 4. R. N., aged 43 years, was examined in the Neuro-Surgical Department in July 1936, following an injury to the right frontal and parietal portion of the head. There was a haematoma present, and when it subsided the patient noticed for the first time a soft depressed area of the right frontal parietal region. X-ray examination revealed a rarefied area in the frontal bone. He returned in November of the same year, when another x-ray examination of the skull revealed a rapid increase in the size of the rarefied area. A physical examination also showed a mass in the right side of the scrotum, which according to the patient had been present since an injury at the age of 8 years. On further questioning it was ascertained that the mass had not increased in size in the last number of years. A urological consultation was requested, and a diagnosis of tumor of the right testis was made. Patient then had an orchidectomy. The anatomical diagnosis was: histoid teratoma with sarcomatous changes. An x-ray of the chest taken about this time showed a shadow on the right side suggestive of a metastasis. Patient was given five deep x-ray treatments and was then transferred back to Neuro-Surgery for further investigation of the skull. On November 28, 1936, a biopsy of the right frontoparietal area was performed. It was found that the dura was also invaded by this tumor mass. The histopathological study of this biopsy specimen was at first
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reported as a sarcoma, and the question arose whether this growth of the skull was primary and not connected with the tumor of the testis. Subsequent careful studies, however., revealed that the growth in the skull and the dura were metastatic, and secondary to the growth in the testis. The patient is now under observation, and x-ray treatment is being continued periodically. Obviously the tumor of the testis was present for a number of years.
It is reasonable to suppose therefore, that the growth was at first benign and then became malignant. Another interesting point is that metastases to the skull and dura from tumors of the testis are quite rare. Moreover this secondary growth was soft, pulsating and produced a definite depression in the right fronto-parietal region. Another striking feature is that an injury to the skull was responsible for the patient's admission to the hospital, and it is rational to assume that he might have carried on for a long time before consulting a physician if not for that accident. As it is he presented himself for treatment quite late in the course of the disease. Case 5. T. P., aged 46 years, was admitted to the Medical Service because of cough, difficulty in swallowing, and pain over the sternum which had been present for 8 months. He gave a history of having had his left testis removed 2 years prior to admission during a herniotomy. Physical examination including x-ray of chest revealed a large irregular mass in the mediastinum. There was also a large firm mass and several smaller ones in the left supraclavicular region. One of these tumors in the neck was removed and the pathological report was: metastatic growth from an embryonal teratoma, probably of the testis. Apparently this was the reason for the removal of the testis at the time of the hernia operation. He was given high voltage x-ray therapy but without beneficial results. He died 4 months later. Autopsy revealed metastases to mediastinum, adrenals, right kidney, retroperitoneal glands, and left supraclavicular lymph nodes.
Diagnosis. When a metastasis from a testicular tumor has reached a large size, it is usually not difficult to diagnose it. The great problem is to ascertain the presence of a secondary tumor when it is still small. It is an established fact that these metastases are present long before there is any clinical evidence of them. To detect them at an early date would undoubtedly aid in the prognosis and ultimate result. Since the discovery by Zondek in 1929 of Prolan A in the urine of a patient with a teratoma of the testis, there has accumulated a voluminous literature on the clinical evaluation of the excretion of this sex hormone as a diag-
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nostic aid in these tumors. Many workers have been quite enthusiastic, and apparently very successful in this work. According to Ferguson the test goes even further, and may be used to diagnose the exact histopathology of the tumor. In a recent article this same worker discussed the quantitative determination of prolan in detecting hidden testicular metastases. Patients who have had a tumor of the testis are frequently examined and a quantitative determination of the prolan in the urine is carried out. If there is present more than 400 mouse units per litre of the hormone, deep x-ray therapy is instituted at once. Moreover this same investigator claims that the biological response of the tumor to irradiation as measured quantitatively by the excretion of the prolan is of greater prognostic value than the anatomical description of its radioresistance or radiosensitivity. For example: if after irradiation of the growth there is no decrease in the amount of prolan A in the urine, then one is justified in assuming that the tumor is radioresistant. On the other hand if the amount of prolan in the urine decreases after high voltage x-ray therapy then the tumor is radiosensitive. We must admit that we have not been successful in the quantitative determinations of prolan A in our patients with testicular tumors. The quantities found were always small, and in 3 cases that we know of with generalized metastases due to an embryonal teratoma with lymphoid stroma, the amount found varied from 18 to 400 rat units per litre. This latter quantity is the largest amount that Dr. Browne, who is responsible for the biological assays, has been able to demonstrate. Moreover, in a number of other proven cases the biological assays were either negative or showed less than 20 rat units per litre. Similar failures to demonstrate the presence of prolan in the urine in cases with testicular tumors have been observed in other clinics. In a recent and extensive article Gordon-Taylor and Till mention 4 patients with testicular neoplasm who failed to give a positive reaction; 2 of whom showed definite abdominal metastases. It might be added that similar small amounts of hormone have been demonstrated in the urine of perfectly normal male individuals, castrates, and cases of orchitis. Owen and Cutler in addition found the presence of hormone in cases of increased intracranial pressure and in patients with cyst of the testis, and in granuloma. Our series is not a sufficiently large one from which to draw conclusions, yet we are of the opinion that a negative prolan reaction should not influence one to alter a previously formed clinical diagnosis of a
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testicular growth. If there is present a mass or nodule in the scrotum that clinically is considered a new growth of the testis, do not allow a negative prolan reaction to bias your opinion. Moreover too much reliance must not be placed on the hormone estimation to determine the presence or absence of metastases. Furthermore the prognosis of a tumor must not be determined only by the quantitative estimation of prolan following irradiation. It would be more accurate and logical to correlate the clinical picture and a careful histopathological diagnosis with the hormonal studies. A great advance has apparently been made with the discovery of this hormone in the urine of men with testicular tumors. It is sincerely hoped that with the recent advances of the biochemistry of prolan A, a more exact knowledge of this hormone will soon be available, and more exact methods of biological assay will be devised. Treatment. All workers are agreed that the most beneficial treatment of metastases in testicular tumors is high voltage x-ray therapy. It is almost miraculous to have a large mass in the abdomen or in the chest actually disappear after a few irradiation treatments (fig. 12). These are the radiosensitive tumors. The picture is not as bright when the tumor you are dealing with is radioresistant. Here the growth not only does not decrease in size, but may actually become larger in spite of the treatment (fig. 13). Until recently all types of metastases from tumors of the testis have been treated by the full erythema dose, which is very intensive radiation. It was found that the radiosensitive tumors yielded after 1 course of this treatment. On the other hand, the radioresistant growths would not respond to even 2 cycles of high voltage x-ray. Due to the fact that further therapy would cause severe radiation sickness (nausea, vomiting, anorexia, lo15s of weight and severe dehydration) more treatments could not be given. Lately these annoying complications have been eliminated by using the Coutard technique of treatment, which consists of giving smaller divided doses of irradiation over a longer period of time. This procedure has 2 distinct advantages; (1) it eliminates radiation sickness, and (2) increases the tolerance of the patient to x-ray therapy. Patients are now given small doses daily over a longer period of time, and the total dose delivered to each skin portal has been increased from 850 R to 4000 R in some cases. The Memorial Hospital reports good results with this form of radiation. We are also using the Coutard technique at the present time.
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Prognosis and results. At best the prognosis in tumors of the testis must be guarded, but the results generally have been better, thanks to the almost universal use of high voltage x-ray therapy. In 1931, we reported on 13 cases of tumors of the testis with 2 patients living and well; one 4 years, 11 months, and the other, 5 years, 4 months after operation. These patients are still living and well. Since then local or distant metastases at the time of admission. Of these, 9 are
FIG. 12. Photographs of x-rays showing value of high voltage irradiation in retroperitonea metastases. On left is pyelogram taken before high voltage x-ray therapy was given; and note kidney pushed laterally by retroperitoneal glands. Note also definite hydronephrosis. On right is pyelogram taken after high voltage x-ray therapy was given. Note kidney is nearer midline and dilatation of renal pelvis and calices definitely diminished. Clinically large mass, which was present before treatment, disappeared.
known to be alive, 4 with metastases and 5 without any clinical evidence of secondary invasion. Of the 5 well patients, one is alive for 5 years, and two for nearly 4 years, and two for less than 3 years, after their first admission to the hospital. The 5 year cure, and one of the 4 year survivals, both had clinical evidence of metastases on admission. The we have encountered 16 other cases, and nearly half of them showed former had a large abdominal mass which disappeared after high voltage
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x-ray therapy. He is seel!- periodically, and to date is perfectly well. Four patients are known to be dead, and 3 have not been traced. Summarizing on 29 cases, we have to date 3 patients alive and well for 5 years or more; 3 cases alive and well nearly four years; 2 cases alive and well for less than three years; 3 cases alive with metastases; 14 are dead, and 4 cannot be traced.
FIG. 13. Photograph of pyelogram from same patient as figure 12 taken 3 weeks after x-ray therapy was stopped. There is again definite dilatation of renal pelvis and calices. Note also that kidney has been pushed laterally. SUMMARY AND CONCLUSIONS
Tumors of the testis metastasize very early by way of the lymphatics and blood vessels. The lymphatic spread is along the glands of the spermatic cord, up along the retroperitoneal group, thence to the mediastinal, and finally to the supraclavicular region on the left side. Blood stream metastases probably result from the invasion of the pampiniform plexus of veins by the tumor. Metastases from tumors of the testis occur long before there is any clinical evidence of them. Many patients with testicular tumors consult a physician when metastases have already made their appearance. Several of these
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patients are admitted to departments other than urology complaining of symptoms caused by these unrecognized secondary growths. Patients should have a thorough examination of the genital organs when seen by a physician. Every nodule discovered should be carefully investigated. Every patient with a tumor of the testis must be examined periodically, at least 3 times yearly, and a very careful search made for metastases, including an x-ray examination of the chest. If a secondary growth is discovered immediate irradiation must be instituted. A quantitative estimation of prolan A in the urine should be determined in every case of suspected tumor of the testis, and periodically in every patient known to have had a testicular growth. A negative reaction, however, does not exclude the presence of a testicular growth or metastases. The prognosis of a case of testicular growth must be determined not only by the biological response of the tumor to irradiation, but also by the clinical picture, and by a careful histopathological study of the growth. Intensive irradiation should be given in all cases with metastases. If the tumor is radioresistant the use of prolonged irradiation with smaller doses, as developed by Coutard, is recommended. Since the use of high voltage x-ray therapy the prognosis and results of tumors of the testis, even those with metastases, have been better. REFERENCES BROWNE, J. S. L.: Personal communication. (Montreal, Canada.) DEAN, A. L.: Teratoid tumors of testis. J. A. M. A., 105: 1965, 1935. DESJARDINS, A. U., MORTON, S. A., AND SQUIRE, F. H.: Proc. Staff Meeting, Mayo Clinic, 4: 3, 1929. FERGUSON, R. S.: Clinical evaluation of quantitative excretion of Prolan A in teratoma testis. J. Urol., 31: 397, 1934. - - - : Studies in diagnosis and treatment of teratoma testis. Am. J. Roentgen. and Radium Therapy, 31: 356, 1934. - - - - : Selective irradiation in management of teratoma testis. J. Urol., 34: 458, 1935. GORDON-TAYLOR, G., AND TILL, ANTHONY S.: On malignant disease of testicle, with special reference to neoplasms of undescended organ. Brit. J. Urol., 10: 1, 1938. HINMAN, F.: Principles and Practice of Urology. 1935, W. B. Saunders Co., Philadelphia. - - - : Prognosis and treatment of tumors of testis. J. Urol., 34: 72, 1935. --~---, GrnsoN, T. E., AND KUTZMANN, A. A.: Radical operation for teratoma of testis and analysis of 79 cases. Surg., Gynec. and Obst., 37: 429, 1923. JAMESON, EDWIN: Personal communication. (Saranac Lake, N. Y.) - - - - AND DOBSON, J. F.: Lymphatics of testicle. Lancet, London, p. 493, 1910. MACKENZIE, D. W., AND RATNER, MAX: Tumors of testis. Brief series with special reference to pathology and clinical malignancy. Surg., Gynec. and Obst., 52: 336, 1931. OWEN, S. E., AND CUTLER, MAX: Comparison of prolan bioassays in teratoma and other conditions. Am. J. Med. Sci., 192: 61, 1936. SMITH, G. G., DRESSER, R., AND MINTZ, E. R.: Radiation treatment of tumors of testicle. J. Urol., 34: 462, 1935.
Tumors of the testis are not commonly met with, yet the subject has been discussed very freely in the literature. There are few new growths of the body that have caused so much discussion and dispute as have the tumors of the testis. This disagreement has resulted from a difference of opinion regarding classification, pathogenesis, and treatment of these tumors. A vast literature has accumulated, but even today there is no unanimity of opinion. However, there has been a distinct advance in the knowledge of the subject, and it is hoped that the near future may bring even better harmony and co-operation between the opposing groups. Practically all new growths of the testis metastasize early and extensively, both by the lymphatics and blood stream. The extension usually takes place first by the way of lymphatics although haematogenous metastases may be encountered without clinical evidence of lymphatic involvement. The normal lymphatic drainage of the testis involves the spermatic and retroperitoneal glands, the latter situated along the aorta and inferior vena cava. There is undoubtedly further communication with the epigastric, mediastinal, and finally the left supraclavicular lymph nodes. This lymphatic supply has been definitely shown both anatomically and clinically. Enough data in cases of teratoma of the testis has accumulated to clearly demonstrate the ab.ave route of metastases, namely along the spermatic, retroperitoneal, epigastric, mediastinal, and finally the left supraclavicular lymph nodes. In 1910, Jamieson and Dobson, after extensive studies of the lymphatics of the testis, demonstrated that the arrangement of these lymphatics is such that the complete removal is exceedingly difficult and dangerous, if not impracticable. It is this anatomy of the lymphatic drainage that has convinced several surgeons of the futility of the radical operation for teratoma of the testis. These men claim that if a radical removal of the glands is undertaken, it should include the lymph nodes beyond the renal region as well, but that procedure is of course impossible. Blood stream metastases are also very common, and usually manifest 592
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themselves early in the course of the disease. The portal of entry is probably the pampiniform plexus of veins. Secondary growths have been reported in practically all organs and tissues of the body (figs. 1, 2, 3, 4 and 5). Thus they have been observed in the lung, pleura, liver, spleen, kidney, adrenal, brain, spinal cord, heart muscle, skull, spine, bony pelvis, and femur. The organs most commonly involved however, are the lungs, liver, and kidneys. Invasion of the spermatic and iliac veins by continuous growth has been observed, and occasionally the growth has extended even as far as the right side of the heart.
FIG. 1. Section of brain showing a metastatic growth in right cerebral hemisphere secondary to chorio-epithelioma of right testis.
Desjardins and his associates find the average time from the onset of symptoms to the demonstration of metastases, to be 2 years, and 4 months. Smith, Dresser, and Mintz, report the presence of metastases in untreated cases within a few months after onset of symptoms. Gordon-Taylor and Till found that the length of history as judged by the time the patient had noticed a testicular tumor before medical advice was sought varied from 2 weeks to 5 years. In our own series metastases made their appearance anywhere from two months to several
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years after onset of the testicular swelling. It is obvious that the above observations as to time are grossly inaccurate. This is due partly to the fact that a large number of patients are unable to give a correct history as to when the tumor in the scrotum was first noticed. Many of them overlook the testicular tumor for a long time, and their attention may actually be drawn to it either by a physician, or following an injury to the scrotum. One of our cases insisted that he had had the same sized swelling of the right testis since an injury at the age of 8 years. He was 43 years old on admission. Moreover, several cases are admitted to a hospital with neurological, pulmonary, or gastro-
FIG. 2. Photomicrograph ·of brain metastasis from chorio-epithelioma of right testis. Note Langhans' and syncytial cells.
intestinal symptoms due to metastases from a testicular tumor, and it is during a routine physical examination that a mass in the scrotum is first observed. It is apparent therefore that an accurate estimation of the period of time that elapses from the onset of the swelling in the scrotum to the appearance of metastases, is in a great majority of cases well nigh impossible to determine. It is indeed surprising, the number of men that have a growth of the testis without any knowledge of it. This is particularly true if the tumor is not large. It is important to emphasize at this point that a growth of the testis may be small. Moreover the size of the growth is in no way proportional to the degree of malignancy. We know of at least 3 cases of testicular tumor that proved
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to be very malignant, yet the actual size varied from that of a walnut to a small plum. We may also add that in a number of cases, testicular sensation was still present. This depends on whether or not there still remains some normal testicular tissue.
FIG. 3. Photograph of lung showing multiple metastases from an embryonal carcinoma of right testis.
When one realizes that a large percentage of patients with tumors of the testis first consult a physician or surgeon when metastases are
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already demonstrable, the urgent need for early recognition and treatment can be readily appreciated. Seventy-three per cent of the patients reported by Dean (1935) showed local recurrence or metastases on admission. Smith, Dresser and Mintz, report 31 per cent of their 100 patients with metastases prior to treatment. In our series of 29 patients, 15 had apparent local or distant metastases when first examined. There are other similar reports of high incidence. When one adds to
FIG. 4. Photograph of kidney showing multiple metastases from an embryonal carcinoma of right testis.
this group the number of cases who clinically have non-demonstrable metastases, the sum total must be quite high. Symptomatology. The symptoms of metastases from testicular tumors depend upon the site and size of the secondary growth. Involvement of the glands along the cord may give rise to a large and painful swelling. As the retroperitoneal glands enlarge a mass may be detected either below the umbilicus or in the epigastrium (fig. 11). Often this abdominal tumor grows to such a size as to cause pressure
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on adjacent organs with resulting nausea, vomiting, and even severe abdominal pain. Cases have been observed in whom the retroperitoneal glands have actually compressed the ureters on both sides causing anuria and subsequent uraemia and death. Other cases have been seen in whom one ureter only was compressed by the retroperitoneal metastases, causing destruction of the corresponding kidney. We have had examples of both types. In a number of instances the retroperitoneal tumor has obstructed the iliac veins causing oedema of the lower extremities (fig. 10). One of our
FIG. 5. Photograph showing metastases in spleen from embryonal carcinoma of right
testis.
cases had such a condition, and at autopsy it was found that the venous circulation of the right leg was impeded by enlarged metastatic glands. When the mediastinal glands are replaced by growth, pain in the chest, cough, and at times difficulty in breathing and swallowing ensue (fig. 8). The left supraclavicular glands are frequently involved, and they may cause pain and stiffness of the neck. As already indicated metastases through the blood stream probably result from the invasion of the pampiniform plexus by growth (figs. 6 and 7). We have observed metastases in the lungs, liver, kidney,
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spleen, adrenals, brain, dura, skull, chest wall, and even in the right ventricle of the heart (fig. 9). Patients with secondary growths of the lung usually complain of cough, expectoration, and very often pain. Cases
FIG. 6
FIG
7
6. Photograph of x-ray of a skull showing a rarefied area in right frontal region. This was due to metastatic growth secondary to teratoid tumor of right testis. FIG. 7. Photograph of x-ray of the same skull as figure 6 taken 4 months later. Note marked increase in size of rarefaction. FIG.
FIG. 7a. Photomicrograph of rarefied area of the skull seen in figures 6 and 7. Note preponderance of histoid elements, cartilage, fibrous tissue and muscle. This picture was identical with section from tumor of testis.
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have been reported with profuse pulmonary haemorrhage. Haematuria due to involvement of the kidneys is not an uncommon clinical finding.
Frc. 8
Frc. 9
FIG. 8. Photograph of x-ray of chest showing a metastatic growth of mediastinum secondary to embryonal teratoma of left testis. Frc. 9. Photograph of x-ray of chest showing large metastatic growth of right hmg secondary to embryonal carcinoma of right testis.
FIG. 10. Photograph of x-ray showing a. retroperitoneal metastatic growth pushing left kidnev and ureter outwards. Tbis mass was secondary to embryonal carcinoma of left testis.·
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Systemic symptoms occur frequently and are often noticed early in the course of the disease. There may be weakness, anorexia, loss of weight and anaemia. The onset of these symptoms suggests very strongly the presence of metastases. However, metastases may be present without obvious systemic symptoms. Recently we observed 2 cases with demonstrable retroperitoneal metastases. Both patients were well nourished and felt perfectly healthy. Their only complaint was a painless mass in the scrotum.
FIG. 11. Photograph of an x-ray after a barium drink. Note small intestines pushed over towards the right side by a large retroperitoneal metastatic growth which was secondary to an embryonal teratoma of left testis. ·
An interesting group of patients are those who are admitted to other departments than Urology, complaining of symptoms caused by metastases. In many instances the original tumor of the testis is overlooked, and it is only after a thorough examination that the true nature of the disease is established. At times the correct diagnosis is made at the autopsy table only. We have observed a small number of such cases, and we wish to mention 5 of them briefly. Case 1. E. M., aged 64 years, entered Medical Service August 30, 1926, complaining of a mass in the left upper quadrant of the abdomen. On further
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questioning it was elicited that the patient had a swelling and some pain in the right side of the scrotum. The mass in the scrotum was first noticed a. month prior to admission, and the mass in the abdomen was observed a short while after. Physical examination disclosed a large, firm, irregular tumor in the left upper quadrant of the abdomen, and a mass in the right groin. The growth in the right side of the scrotum was the size of an orange, firm, and did not transmit light. There were also a few small bilateral inguinal glands. Patient died 5 days after admission to the hospital. Autopsy disclosed embryonal carcinoma of the right testis with metastases to the retroperitoneal glands, inguinal glands, adrenals, and the right ventricle of the heart. This patient was admitted to the Medical Ward primarily because of the mass in the abdomen, and the possibility of a new growth of the stomach had been entertained. A tumor of the scrotum was not considered until after his admission to the hospital, when a provisional diagnosis of a new growth of the right testis with metastases was made. This was confirmed at autopsy. Case 2. H. 0., aged 38 years, was admitted to the Neurological Service on July 25, 1924, in coma. The history obtained was that there was cough and soreness of chest for 3 months, swelling of the right leg for 1 month, loss of function of the left arm for 2 months, and a mass in the right side of scrotum for 9 months. Weakness and loss of weight was noticed even prior to the onset of the scrotal swelling. During his stay in the hospital the patient had a number of typical attacks of Jacksonian epilepsy. Physical examination revealed (1) consolidation of the upper lobe of the right lung, and at the hilus of the left lung; (2) evidence of a lesion of the right cerebral hemisphere; (3) a mass the size of a chicken's egg in the right side of the scrotum. It was hard and nodular. A provisional diagnosis of a tumor of the right testis with metastases was made. The patient died the same day. An autopsy showed chorio-epithelioma of the right testis with metastases to the kidney, liver, spleen, lungs, chest wall, brain, and retroperitoneal glands.
There are a number of interesting features in this case. The patient was admitted to the Neurological Service because of coma, and it was only after a careful physical examination that the question of a malignant tumor of the right testis with metastases was considered. Furthermore, the primary growth and the metastases showed evidence of syncitial and Langhans layers of cells. Moreover there were signs that resembled pregnancy, namely enlarged and tender breasts and the
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presence of colostrum. The swelling of the right leg was due to pressure on the venous circulation by enlarged glands. The attacks of Jacksonian epilepsy and loss of function of the left arm were apparently caused by the large metastases to the right cerebral hemisphere. Case 3. P. M., aged 21 years, was admitted to the Surgical Service March 31, 1938, complaining of sharp pain in the left upper quadrant of the abdomen, nausea and vomiting. Physical examination revealed a mass in the left upper quadrant of the abdomen, and the question of a lesion of the stomach was seriously considered. A barium series was carried out, but the stomach was found to be normal as well as the remainder of the gastro-intestinal system. However, there was evidence of a retroperitoneal mass which was pushing the small bowel towards the right side. A surgical lesion of the left kidney was suspected. A urological examination disclosed the mass in the abdomen, but also a hard mass the size of a walnut in the left side of scrotum. This was considered as a possible teratoma of the testis, and the mass in the abdomen was probably retroperitoneal metastases. The patient was then transferred to the Urological Service where an orchidectomy was performed. The pathological report substantiated the original provisional diagnosis. The lesion was an embryonal teratoma with lymphoid stroma. He was given high voltage x-ray therapy and is still under treatment. The mass in the abdomen has decreased in size but yet remains quite large however. Case 4. R. N., aged 43 years, was examined in the Neuro-Surgical Department in July 1936, following an injury to the right frontal and parietal portion of the head. There was a haematoma present, and when it subsided the patient noticed for the first time a soft depressed area of the right frontal parietal region. X-ray examination revealed a rarefied area in the frontal bone. He returned in November of the same year, when another x-ray examination of the skull revealed a rapid increase in the size of the rarefied area. A physical examination also showed a mass in the right side of the scrotum, which according to the patient had been present since an injury at the age of 8 years. On further questioning it was ascertained that the mass had not increased in size in the last number of years. A urological consultation was requested, and a diagnosis of tumor of the right testis was made. Patient then had an orchidectomy. The anatomical diagnosis was: histoid teratoma with sarcomatous changes. An x-ray of the chest taken about this time showed a shadow on the right side suggestive of a metastasis. Patient was given five deep x-ray treatments and was then transferred back to Neuro-Surgery for further investigation of the skull. On November 28, 1936, a biopsy of the right frontoparietal area was performed. It was found that the dura was also invaded by this tumor mass. The histopathological study of this biopsy specimen was at first
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reported as a sarcoma, and the question arose whether this growth of the skull was primary and not connected with the tumor of the testis. Subsequent careful studies, however., revealed that the growth in the skull and the dura were metastatic, and secondary to the growth in the testis. The patient is now under observation, and x-ray treatment is being continued periodically. Obviously the tumor of the testis was present for a number of years.
It is reasonable to suppose therefore, that the growth was at first benign and then became malignant. Another interesting point is that metastases to the skull and dura from tumors of the testis are quite rare. Moreover this secondary growth was soft, pulsating and produced a definite depression in the right fronto-parietal region. Another striking feature is that an injury to the skull was responsible for the patient's admission to the hospital, and it is rational to assume that he might have carried on for a long time before consulting a physician if not for that accident. As it is he presented himself for treatment quite late in the course of the disease. Case 5. T. P., aged 46 years, was admitted to the Medical Service because of cough, difficulty in swallowing, and pain over the sternum which had been present for 8 months. He gave a history of having had his left testis removed 2 years prior to admission during a herniotomy. Physical examination including x-ray of chest revealed a large irregular mass in the mediastinum. There was also a large firm mass and several smaller ones in the left supraclavicular region. One of these tumors in the neck was removed and the pathological report was: metastatic growth from an embryonal teratoma, probably of the testis. Apparently this was the reason for the removal of the testis at the time of the hernia operation. He was given high voltage x-ray therapy but without beneficial results. He died 4 months later. Autopsy revealed metastases to mediastinum, adrenals, right kidney, retroperitoneal glands, and left supraclavicular lymph nodes.
Diagnosis. When a metastasis from a testicular tumor has reached a large size, it is usually not difficult to diagnose it. The great problem is to ascertain the presence of a secondary tumor when it is still small. It is an established fact that these metastases are present long before there is any clinical evidence of them. To detect them at an early date would undoubtedly aid in the prognosis and ultimate result. Since the discovery by Zondek in 1929 of Prolan A in the urine of a patient with a teratoma of the testis, there has accumulated a voluminous literature on the clinical evaluation of the excretion of this sex hormone as a diag-
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nostic aid in these tumors. Many workers have been quite enthusiastic, and apparently very successful in this work. According to Ferguson the test goes even further, and may be used to diagnose the exact histopathology of the tumor. In a recent article this same worker discussed the quantitative determination of prolan in detecting hidden testicular metastases. Patients who have had a tumor of the testis are frequently examined and a quantitative determination of the prolan in the urine is carried out. If there is present more than 400 mouse units per litre of the hormone, deep x-ray therapy is instituted at once. Moreover this same investigator claims that the biological response of the tumor to irradiation as measured quantitatively by the excretion of the prolan is of greater prognostic value than the anatomical description of its radioresistance or radiosensitivity. For example: if after irradiation of the growth there is no decrease in the amount of prolan A in the urine, then one is justified in assuming that the tumor is radioresistant. On the other hand if the amount of prolan in the urine decreases after high voltage x-ray therapy then the tumor is radiosensitive. We must admit that we have not been successful in the quantitative determinations of prolan A in our patients with testicular tumors. The quantities found were always small, and in 3 cases that we know of with generalized metastases due to an embryonal teratoma with lymphoid stroma, the amount found varied from 18 to 400 rat units per litre. This latter quantity is the largest amount that Dr. Browne, who is responsible for the biological assays, has been able to demonstrate. Moreover, in a number of other proven cases the biological assays were either negative or showed less than 20 rat units per litre. Similar failures to demonstrate the presence of prolan in the urine in cases with testicular tumors have been observed in other clinics. In a recent and extensive article Gordon-Taylor and Till mention 4 patients with testicular neoplasm who failed to give a positive reaction; 2 of whom showed definite abdominal metastases. It might be added that similar small amounts of hormone have been demonstrated in the urine of perfectly normal male individuals, castrates, and cases of orchitis. Owen and Cutler in addition found the presence of hormone in cases of increased intracranial pressure and in patients with cyst of the testis, and in granuloma. Our series is not a sufficiently large one from which to draw conclusions, yet we are of the opinion that a negative prolan reaction should not influence one to alter a previously formed clinical diagnosis of a
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testicular growth. If there is present a mass or nodule in the scrotum that clinically is considered a new growth of the testis, do not allow a negative prolan reaction to bias your opinion. Moreover too much reliance must not be placed on the hormone estimation to determine the presence or absence of metastases. Furthermore the prognosis of a tumor must not be determined only by the quantitative estimation of prolan following irradiation. It would be more accurate and logical to correlate the clinical picture and a careful histopathological diagnosis with the hormonal studies. A great advance has apparently been made with the discovery of this hormone in the urine of men with testicular tumors. It is sincerely hoped that with the recent advances of the biochemistry of prolan A, a more exact knowledge of this hormone will soon be available, and more exact methods of biological assay will be devised. Treatment. All workers are agreed that the most beneficial treatment of metastases in testicular tumors is high voltage x-ray therapy. It is almost miraculous to have a large mass in the abdomen or in the chest actually disappear after a few irradiation treatments (fig. 12). These are the radiosensitive tumors. The picture is not as bright when the tumor you are dealing with is radioresistant. Here the growth not only does not decrease in size, but may actually become larger in spite of the treatment (fig. 13). Until recently all types of metastases from tumors of the testis have been treated by the full erythema dose, which is very intensive radiation. It was found that the radiosensitive tumors yielded after 1 course of this treatment. On the other hand, the radioresistant growths would not respond to even 2 cycles of high voltage x-ray. Due to the fact that further therapy would cause severe radiation sickness (nausea, vomiting, anorexia, lo15s of weight and severe dehydration) more treatments could not be given. Lately these annoying complications have been eliminated by using the Coutard technique of treatment, which consists of giving smaller divided doses of irradiation over a longer period of time. This procedure has 2 distinct advantages; (1) it eliminates radiation sickness, and (2) increases the tolerance of the patient to x-ray therapy. Patients are now given small doses daily over a longer period of time, and the total dose delivered to each skin portal has been increased from 850 R to 4000 R in some cases. The Memorial Hospital reports good results with this form of radiation. We are also using the Coutard technique at the present time.
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Prognosis and results. At best the prognosis in tumors of the testis must be guarded, but the results generally have been better, thanks to the almost universal use of high voltage x-ray therapy. In 1931, we reported on 13 cases of tumors of the testis with 2 patients living and well; one 4 years, 11 months, and the other, 5 years, 4 months after operation. These patients are still living and well. Since then local or distant metastases at the time of admission. Of these, 9 are
FIG. 12. Photographs of x-rays showing value of high voltage irradiation in retroperitonea metastases. On left is pyelogram taken before high voltage x-ray therapy was given; and note kidney pushed laterally by retroperitoneal glands. Note also definite hydronephrosis. On right is pyelogram taken after high voltage x-ray therapy was given. Note kidney is nearer midline and dilatation of renal pelvis and calices definitely diminished. Clinically large mass, which was present before treatment, disappeared.
known to be alive, 4 with metastases and 5 without any clinical evidence of secondary invasion. Of the 5 well patients, one is alive for 5 years, and two for nearly 4 years, and two for less than 3 years, after their first admission to the hospital. The 5 year cure, and one of the 4 year survivals, both had clinical evidence of metastases on admission. The we have encountered 16 other cases, and nearly half of them showed former had a large abdominal mass which disappeared after high voltage
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x-ray therapy. He is seel!- periodically, and to date is perfectly well. Four patients are known to be dead, and 3 have not been traced. Summarizing on 29 cases, we have to date 3 patients alive and well for 5 years or more; 3 cases alive and well nearly four years; 2 cases alive and well for less than three years; 3 cases alive with metastases; 14 are dead, and 4 cannot be traced.
FIG. 13. Photograph of pyelogram from same patient as figure 12 taken 3 weeks after x-ray therapy was stopped. There is again definite dilatation of renal pelvis and calices. Note also that kidney has been pushed laterally. SUMMARY AND CONCLUSIONS
Tumors of the testis metastasize very early by way of the lymphatics and blood vessels. The lymphatic spread is along the glands of the spermatic cord, up along the retroperitoneal group, thence to the mediastinal, and finally to the supraclavicular region on the left side. Blood stream metastases probably result from the invasion of the pampiniform plexus of veins by the tumor. Metastases from tumors of the testis occur long before there is any clinical evidence of them. Many patients with testicular tumors consult a physician when metastases have already made their appearance. Several of these
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patients are admitted to departments other than urology complaining of symptoms caused by these unrecognized secondary growths. Patients should have a thorough examination of the genital organs when seen by a physician. Every nodule discovered should be carefully investigated. Every patient with a tumor of the testis must be examined periodically, at least 3 times yearly, and a very careful search made for metastases, including an x-ray examination of the chest. If a secondary growth is discovered immediate irradiation must be instituted. A quantitative estimation of prolan A in the urine should be determined in every case of suspected tumor of the testis, and periodically in every patient known to have had a testicular growth. A negative reaction, however, does not exclude the presence of a testicular growth or metastases. The prognosis of a case of testicular growth must be determined not only by the biological response of the tumor to irradiation, but also by the clinical picture, and by a careful histopathological study of the growth. Intensive irradiation should be given in all cases with metastases. If the tumor is radioresistant the use of prolonged irradiation with smaller doses, as developed by Coutard, is recommended. Since the use of high voltage x-ray therapy the prognosis and results of tumors of the testis, even those with metastases, have been better. REFERENCES BROWNE, J. S. L.: Personal communication. (Montreal, Canada.) DEAN, A. L.: Teratoid tumors of testis. J. A. M. A., 105: 1965, 1935. DESJARDINS, A. U., MORTON, S. A., AND SQUIRE, F. H.: Proc. Staff Meeting, Mayo Clinic, 4: 3, 1929. FERGUSON, R. S.: Clinical evaluation of quantitative excretion of Prolan A in teratoma testis. J. Urol., 31: 397, 1934. - - - : Studies in diagnosis and treatment of teratoma testis. Am. J. Roentgen. and Radium Therapy, 31: 356, 1934. - - - - : Selective irradiation in management of teratoma testis. J. Urol., 34: 458, 1935. GORDON-TAYLOR, G., AND TILL, ANTHONY S.: On malignant disease of testicle, with special reference to neoplasms of undescended organ. Brit. J. Urol., 10: 1, 1938. HINMAN, F.: Principles and Practice of Urology. 1935, W. B. Saunders Co., Philadelphia. - - - : Prognosis and treatment of tumors of testis. J. Urol., 34: 72, 1935. --~---, GrnsoN, T. E., AND KUTZMANN, A. A.: Radical operation for teratoma of testis and analysis of 79 cases. Surg., Gynec. and Obst., 37: 429, 1923. JAMESON, EDWIN: Personal communication. (Saranac Lake, N. Y.) - - - - AND DOBSON, J. F.: Lymphatics of testicle. Lancet, London, p. 493, 1910. MACKENZIE, D. W., AND RATNER, MAX: Tumors of testis. Brief series with special reference to pathology and clinical malignancy. Surg., Gynec. and Obst., 52: 336, 1931. OWEN, S. E., AND CUTLER, MAX: Comparison of prolan bioassays in teratoma and other conditions. Am. J. Med. Sci., 192: 61, 1936. SMITH, G. G., DRESSER, R., AND MINTZ, E. R.: Radiation treatment of tumors of testicle. J. Urol., 34: 462, 1935.