TESTIS TUMORS: REVIEW OF 125 CASES AT THE CLEVELAND ROBERT HOWARD
E. LEFEVRE, S. LEVIN,
LYNN H. BANOWSKY,
CLINIC M.D.
M.D. M.D.
BRUCE
H. STEWART,
M.D.
RALPH A. STRAFFON,
M.D.
CLARENCE
B. HEWITT,
M.D.
From the Departments of Urology and Pathology, The Cleveland Clinic Foundation and The Cleveland Clinic Educational Foundation, Cleveland, Ohio
ABSTRACT - One hundred twenty-jive cases of testicular tumor are reviewed. The prognostic significance of clinical features, certain laboratory test results, and histologic type are evaluated, and treatment results are presented. The most important prognostic clinical feature is the presence or absence of clinically evident metastases. The urinary gonadotropin levels are useful prognostically, but the intravenous pyelogram and lymphangiogram are statistically unreliable. The presence of tumor in retroperitoneal lymph nodes infEuenced survival only in the patients with embryonal carcinoma. Tumor type injluenced survival more than any other pathologic factor. Vascular invasion, local extension, and Leydig cell hyperplasia did not correlate with tumor behavior in germinal neoplasms. Patients with clinical Stage IA or IB teratocarcinoma had an 85 per cent survival rate with a wide variety of treatment.
Although testis tumors constitute only 1 per cent of all malignant growths in males, they present a therapeutic challenge to urologists. l This afIliction of young people makes satisfactory therapy as well as accurate prognosis important. There are five different types of primary malignant germinal testis tumors, but different classifications and terminology make comparisons of therapy difficult.2*3 Each of the three fundamental therapeutic approaches of surgery, radiation therapy, and chemotherapy has its own staunch advocates, and the most advantageous combination of therapy is a problem that has been discussed extensively. 4-7 Three basic diagnostic examinations, intravenous pyelography, lymphangiography, and urinary gonadotropin levels have varying degrees of prognostic significance.‘-” The prognostic significance of clinically evident metastases, retroperitoneal lymph nodes containing neoplasm, and histologic changes such as vascular invasion, local extension, and microfoci of choriocarcinoma merit collection of additional data.
588
Material and Methods One hundred sixty-six cases of testicular tumors treated at the Cleveland Clinic from 1950 through 1970 were reviewed. One hundred twenty-five patients had sufficient clinical, laboratory, therapeutic, and pathologic data to be included in this retrospective study. All patients had at least a three-year follow-up. Tumors were classified according to the nomenclature modified from that used by the American Testicular Tumor Registry at the Armed Forces Institute of Pathology. All available histologic sections were reviewed by one pathologist (H.L.) and one urologist (R.L.). Tumors having one element were classified in the appropriate category. Neoplasms with focal areas of seminoma were classified only according to their predominant neoplastic component. Tumors having teratoma and embryonal carcinoma were classified as teratocarcinoma. In the germinal neoplasms four histopathologic characteristics, vascular invasion, local extension,
UROLOGY
/ NOVEMBER
1975 / VOLUME
VI, NUMBER 5
interstitial cell hyperplasia, and presence of focal choriocarcinoma, were investigated to determine their prognostic value. Focal choriocarcinoma was diagnosed only when cytotrophoblastic and syncytial trophoblastic cells were present in juxtaposition. The finding of isolated syncytrophoblastic giant cells was not considered to be diagnostic of choriocarcinoma. In addition, all germinal tumors were staged according to the classification used at Walter Reed General Hospital. l1 All intravenous pyelograms and lymphangiograms were reviewed with one radiologist, and the results were correlated with surgical findings. Lymph nodes were interpreted as positive on lymphangiographic study if more than one third of any individual node was not visualized.
TABLE
I. Classijication and age distribution of
patients with testis tumor Type Germinal Seminoma Embryonal Teratocarcinoma Teratoma Choriocarcinoma Nongerminal Leydig Gonadal stromal Miscellaneous TOTALS
Number
Per Cent
Median Age (Years)
34 28 44 4 2
27.2 22.5 35.2 3.2 1.6
38.0 30.6 31.2 32.0 28.0
2 1 10
1.6 0.8 d 80
37.0 16.0 63.6
125
100
/ NOVEMBER1975
TABLE II. Presenting sign and symptoms of
testicular tumors
Various methods were used to determine urinary gonadotropin levels. Urinary gonadotropins were measured by the Aschheim-Zondek bioassay and the gravindex immunoassay, with results recorded as either elevated or not elevated. A twenty-four-hour quantitative urinary gonadotropin test described by Gorbman12 was also used and levels above 105 mouse units per twenty-four hours were recorded as elevated. Treatment varied with the type of tumor. Patients with seminoma received 3,000 r tumor dose for three weeks to the para-aortic and ipsilateral pelvic lymph nodes when there was no evidence of metastases. A similar dose was delivered via additional portals to the mediastinum and bilateral supraclavicular regions when either the clinical examination, lymphangiogram, or chest x-ray showed evidence of possible spread, Patients with metastatic seminoma received
UROLOGY
10 mg. of chlorambucil orally for ten days, repeated every two months. Most patients with teratoma, embryonal carcinoma, and teratocarcinoma who were not overwhelmed by extensive metastatic tumor, underwent bilateral retroperitoneal lymph node dissection performed through a midline incision. Technique of exposure and limits of dissection were as described by Mallis and Patton. l3 Irradiation was not given prior to retroperitoneal lymph node dissection. Most patients with embryonal carcinoma or teratocarcinoma who were considered inoperable or who had retroperitoneal involvement received 4,000 to 5,000 r postoperatively through the para-aortic and iliac portals. Similar doses were delivered to any other involved areas. Most patients with tumor present
/ VOLUMEVI,
NUMBER5
Symptom
Number
Per Cent
Painless swelling Pain Hardness Weight loss Heaviness Abdominal mass or pain Back pain Cough Decreased size Supraclavicular adenopathy Gynecomastia
100 72 32 20
80.0 57.0 25.6 20.8
12
9.0
7 6 2 1 7 7
5.6 4.8 1.6 0.8 5.6 5.6
in retroperitoneal lymph nodes or other evidence of metastases who received actinomycin had a dosage schedule of 3 to 5 mg. actinomycin in a five-day course every month until there was evidence of regression, and then every two months for two years. Some patients received actinomycin prophylactically in the previously described dosage every two to three months for two years. Results The number and percentage of each tumor type and the median age of occurrence are listed in Table I. Distribution of tumor types is not significantly different from other series, 14-17and the age distribution is as expected, with the mean age for patients with seminoma being almost a decade older th an patients with teratoma, teratocarcinoma, and embryonal carcinoma,
589
The miscellaneous group of tumors includes 2 lymphosarcomas, 2 reticulum cell sarcomas, 2 1 chronic granulocytic leukemia, plasmacytomas, and 3 secondary adenocarcinomas. Testicular swelling was the initial complaint in 8 of these 10 patients. Of the 18 patients over fifty years of age, 9 or 50 per cent were in this group of tumors of nontesticular origin. Table II summarizes the significant clinical findings. Swelling was the most common presenting complaint. Eight per cent of tumors were asymptomatic with a mass discovered on routine physical examination; 4.8 per cent occurred in cryptorchid testes; trauma was associated in 7.2 per cent; and the right side was involved more than the left (55.2 to 48.8 per cent). Clinically evident metastases were defined as the presence of a palpable abdominal mass, palpable supraclavicular lymph nodes, or roentgenographic evidence of lung or bone lesions. Only 1 of 30 patients (3 per cent) with clinical metastases survived, whereas 84 of 95 patients (88 per cent) without clinical metastases survived. Intravenous pyelograms were considered positive for retroperitoneal tumor if there was hydronephrosis of renal or ureteral displacement. Sixty-one patients had both an intravenous pyelogram and retroperitoneal lymph node dissection. Of 28 patients with metastatic neoplasm in lymph nodes, results of intravenous pyelograms were normal i .18and abnormal in 10. This represents a false & egative incidence of 64 per cent. Of 33 patients with no neoplasm in retroperitoneal lymph nodes, 5 of 33 had abnormalities detected in the intravenous pyelogram. This represents a false positive incidence of 15 per cent. Twenty patients had both lymphangiograms and lymph node dissection: results were false positive in 7; false negative in 5; equivocal or nondiagnostic in 3; and gave a positive correlap < 0.001 64%
UGT NONELEVATED
Relationship of deaths to urinary gonadolevels (UGT) in patients with germinal neo-
FIGURES.
tropin plasm.
590
UGT ELEVATED
tion with findings on retroperitoneal node dissection in 5. These were useful in diagnosing retroperitoneal node involvement in only 25 per cent of the cases. Urinary gonadotropin levels were measured in 71 patients. Figure 1 relates mortality rate to gonadotropin levels. Of the patients with elevated urinary gonadotropins, 64 per cent (16 of 25) died; only 17 per cent (6 of 36) with nonelevated urinary gonadotropins died. The histologic presence of focal choriocarcinoma per se histologically in germinal neoplasms is not a poor prognostic sign. Figure 2 relates the presence of focal choriocarcinoma to both urinary gonadotropin levels and.mortality. Only 1 of 7 patients who had histologic choriocarcinoma but negative urinary gonadotropins died. In contrast, 9 of 11 patients (82 per cent) who had both histologic choriocarcinoma and positive urinary gonadotropins died. Further histopathologic evaluation revealed no reliable correlation between survival and vascular invasion, local extension, or interstitial cell hyperplasia. Of the patients in whom both vascular invasion and local extension was demonstrated, 50 per cent survived more than three years. Fifty per cent of those patients who had clinically evident metastases at the time of admission and subsequently died did not have demonstrable vascular invasion. The presence of positive (Stage IB) or negative (Stage IA) retroperitoneal lymph nodes in patients without initial clinically evident metastases was related to treatment and survival. No difference was noted in the teratocarcinoma group in which over-all survival with negative nodes was 14 of 16 and with positive nodes was 7 of 8. In the patients with embryonal carcinoma, over-all survival with negative lymph nodes was 100 per cent (3 of 3) and with positive nodes was only 57 per cent (4 of 7). Treatment results are considered according to tumor type. Of 34 patients with seminoma, 28 (82 per cent) survived more than three years without evidence of persistent tumor. Of the 6 patients who died, all had evidence of metastases at the time of initial presentation, while none of the survivors had evidence of metastases on the initial examination. The 4 patients with teratoma were all treated with bilateral lymph node dissection, all had negative lymph nodes, none received chemotherapy or irradiation, and all are alive without evidence of recurrence of tumor three years after surgery.
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/ NOVEMBER1975
/ VOLUMEVI,
NUMBER5
100
83%
75 50 16%
25
NO CHORIO
NO CHORIO FOCAL CHORIO NONELEVATED UGT
FOCAL CHORIO ELEVATED UGT
Relationship qf deaths to urinary gonadotropin (UGT) and microfocus of chorioFIGURE 2. carcinoma in patients u&k testis tumor. In patients who had embryonal carcinoma the over-all survival rate was 11 of 27 (41 per cent). Of the 17 patients who died, 11 presented with metastases. Only 2 of 12 patients survived who presented initially with clinical metastases. Nine of 15 (60 per cent) of the patients who had no evidence of metastases at the initial examination survived. In this small group there was better survival rate in patients with lymph node dissection (7 of 10) compared with patients who did not undergo lymph node dissection (2 of 5).
There were 2 cases of pure choriocarcinoma. One patient was moribund at the time of hospital admission and died a few days later. The second patient had a bilateral lymph node dissection which was positive for choriocarcinoma. He received actinomycin therapy and died fifty-five months after the original diagnosis was made. Table III is a composite of all modes of therapy related to survival in patients with teratocarcinoma and embryonal carcinoma. The over-all survival rate of patients with teratocarcinoma was 29 of 44 (66 per cent). Of the 15 patients who with clinical evidence of died, 10 presented metastases and none of those who presented with metastases survived (0 of 10). Of 34 who had no evidence of metastases at the initial examination, 29 (85 per cent) survived. In this group of patients with teratocarcinoma who had no clinical evidence of metastases at the time of initial examination, there was no significant difference in survival in those who had radiation therapy alone (5 of 5), lymph node dissection alone (8 of 8), or combination therapy of lymph node dissection with radiation (2 of 3), with chemotherapy (11 of 13),and with both radiation and chemotherapy (2 of 3). TABLE III. -No Tumor Type and Stage
_____
Teratocarcinoma Stage lA, 1B Stage II, III Embryonal carcinoma Stage lA, 1B Stage II, III KEY: O=orchiectomy;
UROLOGY /
0
Comment The extent of tumor spread at the time of presentation and the type of tumor are the two most significant factors in predicting the survival of a patient with a germinal neoplasm of the testis. A three-year survival rate of 88 per cent occurred in those patients who presented without initial evidence of clinical metastases. Only 1 of 30 patients survived in that group with clinically evident metastases. Patients with certain tumor types survive longer than patients with other types. Seminomas
Modes of therapy
Node Dissection-
-Node
O+R
O+C
... ...
5/5 Q/2
..
l/2
818
213
o/4
0.3
...
...
...
l/3 o/2
... o/2
l/2 l/5
l/l
214
. ..
Rcradiation;
NOVEMBER 1975 /
O+C+R
C=chemotherapy.
0
O+R
.
Dissection-_, O+C
O+C+R
11/13 . .
213 O/l
212 l/2
213 O/l
Numbers in parentheses indicate
VOLUME VI, NUMBER 5
Over-all Survival
2;;;
E)
1
29144 (66)
percentages.
591
generally have a favorable prognosis, more than 95 per cent three-year survival in some studies. Patients with teratomas have an excellent chance for cure. The patient with pure choriocarcinoma is the most difficult to manage, often presenting severely ill, with pulmonary metastases. Patients with a Stage IA or IB teratocarcinoma have a better chance of survival (85 per cent) than patients with Stage IA and IB embryonal carcinoma (60 per cent). In this series which covers twenty years, no patient who survived more than three years without evidence of recurrence has died because of the testicular neoplasm. In 3 patients, a neoplasm has developed in the opposite testis at two, eight, and nine years after their initial tumor was removed. All have been treated successfully for the second tumor. The development of tumor in the other testis in 3 of 115 primary germinal tumors emphasizes the need for regular periodic physical examination for an indefinite period. Of the 3 diagnostic studies, the urinary gonadotropins have the most predictive value in regard to the prognosis of the patient. Our figures of 64 per cent mortality in those patients with elevated urinary gonadotropins compared with 17 per cent in those with nonelevated urinary gonadotropins matches the figures of 63 per cent and 18 per cent, respectively, found by Wilson and Woodhead,” and further emphasizes the significance of this test.13 The presence of elevated levels of chorionic gonadotropin should have even greater predictive value than the gonadotropins cited here which are a combination of chorionic and pituitary gonadotropin. Although the intravenous pyelogram is not accurate in predicting retroperitoneal lymph node involvement, it is essential to outline the renal anatomy, since occasionally a nephrectomy is necessary to complete adequate lymph node dissection. Lymphangiographic study has been considered by others to be necessary in the evaluation of patients, both pre- and postoperatively.g Because lymphangiography was helpful in the diagnosis of retroperitoneal node involvement in only 25 per cent of our cases, and because postdissection roentgenograms at the time of surgery have never required modification of the already completed bilateral lymph node dissection, they are no longer done routinely at the Cleveland Clinic in patients with embryonal carcinoma or with teratocarcinoma. In our institution the radio-
592
therapists perform lymphangiographic studies with seminomas to determine the extent of their radiation portals, and will irradiate the mediastinum and both supraclavicular regions if there appears to be para-aortic involvement. Patients with seminoma had a favorable response to a tumor dose of 3,000 r, and the survival rate is comparable to other series. In Stage IA and IB teratocarcinoma no difference in survival was noted in patients who received radiation alone, bilateral retroperitoneal node dissection alone, or bilateral node dissection with adjunctive radiation or chemotherapy or both. In addition, negative or positive nodes (Stage IA and Stage IB) had no influence on survival - 7 of 8 (87.5 per cent) versus 14of 16 (87.5 per cent). The number of patients with embryonal carcinoma is too small for the results of treatment to be statistically valid. However, results were better with bilateral retroperitoneal lymph node dissection and orchiectomy (7 of 10 survivals) than with orchiectomy alone (2 of 5 survivals). Careful pathologic evaluation of the tumors is essential. Sixteen cases were reclassified in our series. Two cases originally classified as choriocarcinoma were interpreted as teratocarcinoma; 4 teratomas were interpreted as teratocarcinomas; 5 embryonal carcinomas were reclassified as 4 teratocarcinomas and 1 seminoma; and 5 teratocarcinomas were interpreted as 4 embryonal carcinomas and 1 seminoma. Fortunately, this did not influence therapy except that 1 patient with seminoma with an original interpretation of teratocarcinoma had a lymph node dissection. The histopathologic finding of focal choriocarcinoma if associated with the presence of an elevated urinary gonadotropin level offers a poor prognosis. Other histopathologic findings of local extension, vascular invasion, or Leydig cell hyperplasia showed no significant correlation with survival. Summary One hundred twenty-five cases of testicular tumor are reviewed. The prognostic significance of clinical features, laboratory tests, and histologic type are evaluated, and treatment results are presented. The most important prognostic clinical feature is the presence or absence of clinically evident metastases. Of patients without clinical metastases, 88 per cent survived, while only 3 per cent of patients with clinical metastases survived. Of the common diagnostic and prognostic laboratory
UROLOGY
/ NOVEMBER
1975 / VOLUME
VI, NUMBER 5
tests, the urinary gonadotropins are extremely useful. The intravenous pyelogram and lymphangiogram are of limited usefulness and are statistically unreliable. The presence of positive lymph nodes influenced survival in patients with embryonal carcinoma, but made no difference in the teratocarcinoma group. The histopathologic characteristics of vascular invasion, local extension, and Leydig cell hyperplasia did not correlate with tumor behavior. Focal choriocarcinoma only when correlated with positive urinary gonadotropin levels had predictive significance. The histologic type of germinal tumor is important in predicting survival. Seminomas had an over-all 83 per cent survival with orchiectomy and radiation. There was no mortality in 4 patients with teratoma who had orchiectomy and lymph node dissection. Both patients with pure choriocarcinoma died. Patients with Stage IA or IB teratocarcinoma had an 85 per cent survival rate with node dissection alone, radiation alone, or a combination of lymph node dissection and chemotherapy. Patients with Stage IA or IB embryonal carcinoma had a 60 per cent survival rate. Regardless of any predictive ability, aggressive therapy of isolated tumor metastases combining surgical, radiation, and chemotherapy has proved successful in several cases that initially appeared to be hopeless. The Cleveland Clinic Foundation Cleveland, Ohio 44106 (DR. BANOWSKY) References 1. CAMPBELL, M. F., and HARRISON, J. H.: Urology, 3rd ed., Philadelphia, W. B. Saunders Company, 1970, p. 1211.
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/
NOVEMBER 1975 /
VOLUME VI, NUMBER 5
2. DIXON, F. J., and MOORE, R. A.: Tumors of the male of Pathology sex organs, in Armed Forces Institute Atlas of Tumor Pathology, Section 8, part 311, and 32, Washington, D.C., pp. 48-127. 3. COLLINS, D. H., and PUGH, R. C. B.: Classification and frequency of testicular tumors, Br. J. Ural. 36: 1 (1964). 4. RUBIN, P.: Cancer of the urogenital tract: testicular tumors, J.A.M.A. 213: 89 (1970). 5. GOLBEY, R. B.: The place of chemotherapy in the treatment of testicular tumors, ibid. 213: 101 (1970). 6. STAUBITZ, W. J., MAGOSS, I., GRACE, J. T., and SCHENK, W. C., III: Surgical management of testis tumors, J. Urol. 101: 350 (1969). 7. MAIER, J. G., and VAN BUSKIRK, K.: Treatment of testicular germ cell malignancies, J.A.M.A. 101: 97 (1970). 8. BUSCH, F. M., SAYECH, E. S., and CHENAULT, 0. W., in the manageJR. : Some uses of lymphangiography ment of testicular tumors, J. Urol. 93: 490 (1965). 9. WALLACE, S., and JINC, B. S.: Lymphangiography: diagnosis of nodal metastases from testicular malignancies, J.A.M.A. 213: 94 (1970). 10. WILSOX, J. M., and WOODHEAD, D. hf.: Prognostic and therapeutic implications of urinary gonadotropin levels in the management of testicular neoplasia, J. Urol. 108: 754 (1972). 11. MAIER, J. G., SULAK, M. H., and MITTEMEYER, B. T.: Seminoma of the testis: analysis of treatment success and failure, Am. J. Roentgenol. 102: 596 (1968). 12. GORRMAN, A.: Ultrafiltration of urine for collection and biological assay of excreted hypophyseal hormones, Endocrinology 37: 177 (1945). 13. MALLIS, N., and PATTON, J. F.: Transperitoneal bilateral lymphadenectomy in testis tumors, J. Urol. 80: 501 (1958). 14. ROBSON, C. J., BRUCE, A. W., and CHARBONNEAU, J.: Testicular tumors: a collective review from the Canadian academy of urological surgeons, ibid. 94: 440 (1965). 15. PATTON, J. F., and MALLIS, N. : Tumors of the testis, ibid. 81: 457 (1959). 16. FRIEDMAN, N. B., and MOORE, R. A.: Tumors of the testis: report of 922 cases, Mil. Surgeon. 99: 573 (1946). 17. PATTON, J. F., HEWITT, C. B., and MALLIS, N.: Diagnosis and treatment of tumors of the testis, J.A.M.A. 171: 2194 (1959).
593
E. LEFEVRE, S. LEVIN,
LYNN H. BANOWSKY,
CLINIC M.D.
M.D. M.D.
BRUCE
H. STEWART,
M.D.
RALPH A. STRAFFON,
M.D.
CLARENCE
B. HEWITT,
M.D.
From the Departments of Urology and Pathology, The Cleveland Clinic Foundation and The Cleveland Clinic Educational Foundation, Cleveland, Ohio
ABSTRACT - One hundred twenty-jive cases of testicular tumor are reviewed. The prognostic significance of clinical features, certain laboratory test results, and histologic type are evaluated, and treatment results are presented. The most important prognostic clinical feature is the presence or absence of clinically evident metastases. The urinary gonadotropin levels are useful prognostically, but the intravenous pyelogram and lymphangiogram are statistically unreliable. The presence of tumor in retroperitoneal lymph nodes infEuenced survival only in the patients with embryonal carcinoma. Tumor type injluenced survival more than any other pathologic factor. Vascular invasion, local extension, and Leydig cell hyperplasia did not correlate with tumor behavior in germinal neoplasms. Patients with clinical Stage IA or IB teratocarcinoma had an 85 per cent survival rate with a wide variety of treatment.
Although testis tumors constitute only 1 per cent of all malignant growths in males, they present a therapeutic challenge to urologists. l This afIliction of young people makes satisfactory therapy as well as accurate prognosis important. There are five different types of primary malignant germinal testis tumors, but different classifications and terminology make comparisons of therapy difficult.2*3 Each of the three fundamental therapeutic approaches of surgery, radiation therapy, and chemotherapy has its own staunch advocates, and the most advantageous combination of therapy is a problem that has been discussed extensively. 4-7 Three basic diagnostic examinations, intravenous pyelography, lymphangiography, and urinary gonadotropin levels have varying degrees of prognostic significance.‘-” The prognostic significance of clinically evident metastases, retroperitoneal lymph nodes containing neoplasm, and histologic changes such as vascular invasion, local extension, and microfoci of choriocarcinoma merit collection of additional data.
588
Material and Methods One hundred sixty-six cases of testicular tumors treated at the Cleveland Clinic from 1950 through 1970 were reviewed. One hundred twenty-five patients had sufficient clinical, laboratory, therapeutic, and pathologic data to be included in this retrospective study. All patients had at least a three-year follow-up. Tumors were classified according to the nomenclature modified from that used by the American Testicular Tumor Registry at the Armed Forces Institute of Pathology. All available histologic sections were reviewed by one pathologist (H.L.) and one urologist (R.L.). Tumors having one element were classified in the appropriate category. Neoplasms with focal areas of seminoma were classified only according to their predominant neoplastic component. Tumors having teratoma and embryonal carcinoma were classified as teratocarcinoma. In the germinal neoplasms four histopathologic characteristics, vascular invasion, local extension,
UROLOGY
/ NOVEMBER
1975 / VOLUME
VI, NUMBER 5
interstitial cell hyperplasia, and presence of focal choriocarcinoma, were investigated to determine their prognostic value. Focal choriocarcinoma was diagnosed only when cytotrophoblastic and syncytial trophoblastic cells were present in juxtaposition. The finding of isolated syncytrophoblastic giant cells was not considered to be diagnostic of choriocarcinoma. In addition, all germinal tumors were staged according to the classification used at Walter Reed General Hospital. l1 All intravenous pyelograms and lymphangiograms were reviewed with one radiologist, and the results were correlated with surgical findings. Lymph nodes were interpreted as positive on lymphangiographic study if more than one third of any individual node was not visualized.
TABLE
I. Classijication and age distribution of
patients with testis tumor Type Germinal Seminoma Embryonal Teratocarcinoma Teratoma Choriocarcinoma Nongerminal Leydig Gonadal stromal Miscellaneous TOTALS
Number
Per Cent
Median Age (Years)
34 28 44 4 2
27.2 22.5 35.2 3.2 1.6
38.0 30.6 31.2 32.0 28.0
2 1 10
1.6 0.8 d 80
37.0 16.0 63.6
125
100
/ NOVEMBER1975
TABLE II. Presenting sign and symptoms of
testicular tumors
Various methods were used to determine urinary gonadotropin levels. Urinary gonadotropins were measured by the Aschheim-Zondek bioassay and the gravindex immunoassay, with results recorded as either elevated or not elevated. A twenty-four-hour quantitative urinary gonadotropin test described by Gorbman12 was also used and levels above 105 mouse units per twenty-four hours were recorded as elevated. Treatment varied with the type of tumor. Patients with seminoma received 3,000 r tumor dose for three weeks to the para-aortic and ipsilateral pelvic lymph nodes when there was no evidence of metastases. A similar dose was delivered via additional portals to the mediastinum and bilateral supraclavicular regions when either the clinical examination, lymphangiogram, or chest x-ray showed evidence of possible spread, Patients with metastatic seminoma received
UROLOGY
10 mg. of chlorambucil orally for ten days, repeated every two months. Most patients with teratoma, embryonal carcinoma, and teratocarcinoma who were not overwhelmed by extensive metastatic tumor, underwent bilateral retroperitoneal lymph node dissection performed through a midline incision. Technique of exposure and limits of dissection were as described by Mallis and Patton. l3 Irradiation was not given prior to retroperitoneal lymph node dissection. Most patients with embryonal carcinoma or teratocarcinoma who were considered inoperable or who had retroperitoneal involvement received 4,000 to 5,000 r postoperatively through the para-aortic and iliac portals. Similar doses were delivered to any other involved areas. Most patients with tumor present
/ VOLUMEVI,
NUMBER5
Symptom
Number
Per Cent
Painless swelling Pain Hardness Weight loss Heaviness Abdominal mass or pain Back pain Cough Decreased size Supraclavicular adenopathy Gynecomastia
100 72 32 20
80.0 57.0 25.6 20.8
12
9.0
7 6 2 1 7 7
5.6 4.8 1.6 0.8 5.6 5.6
in retroperitoneal lymph nodes or other evidence of metastases who received actinomycin had a dosage schedule of 3 to 5 mg. actinomycin in a five-day course every month until there was evidence of regression, and then every two months for two years. Some patients received actinomycin prophylactically in the previously described dosage every two to three months for two years. Results The number and percentage of each tumor type and the median age of occurrence are listed in Table I. Distribution of tumor types is not significantly different from other series, 14-17and the age distribution is as expected, with the mean age for patients with seminoma being almost a decade older th an patients with teratoma, teratocarcinoma, and embryonal carcinoma,
589
The miscellaneous group of tumors includes 2 lymphosarcomas, 2 reticulum cell sarcomas, 2 1 chronic granulocytic leukemia, plasmacytomas, and 3 secondary adenocarcinomas. Testicular swelling was the initial complaint in 8 of these 10 patients. Of the 18 patients over fifty years of age, 9 or 50 per cent were in this group of tumors of nontesticular origin. Table II summarizes the significant clinical findings. Swelling was the most common presenting complaint. Eight per cent of tumors were asymptomatic with a mass discovered on routine physical examination; 4.8 per cent occurred in cryptorchid testes; trauma was associated in 7.2 per cent; and the right side was involved more than the left (55.2 to 48.8 per cent). Clinically evident metastases were defined as the presence of a palpable abdominal mass, palpable supraclavicular lymph nodes, or roentgenographic evidence of lung or bone lesions. Only 1 of 30 patients (3 per cent) with clinical metastases survived, whereas 84 of 95 patients (88 per cent) without clinical metastases survived. Intravenous pyelograms were considered positive for retroperitoneal tumor if there was hydronephrosis of renal or ureteral displacement. Sixty-one patients had both an intravenous pyelogram and retroperitoneal lymph node dissection. Of 28 patients with metastatic neoplasm in lymph nodes, results of intravenous pyelograms were normal i .18and abnormal in 10. This represents a false & egative incidence of 64 per cent. Of 33 patients with no neoplasm in retroperitoneal lymph nodes, 5 of 33 had abnormalities detected in the intravenous pyelogram. This represents a false positive incidence of 15 per cent. Twenty patients had both lymphangiograms and lymph node dissection: results were false positive in 7; false negative in 5; equivocal or nondiagnostic in 3; and gave a positive correlap < 0.001 64%
UGT NONELEVATED
Relationship of deaths to urinary gonadolevels (UGT) in patients with germinal neo-
FIGURES.
tropin plasm.
590
UGT ELEVATED
tion with findings on retroperitoneal node dissection in 5. These were useful in diagnosing retroperitoneal node involvement in only 25 per cent of the cases. Urinary gonadotropin levels were measured in 71 patients. Figure 1 relates mortality rate to gonadotropin levels. Of the patients with elevated urinary gonadotropins, 64 per cent (16 of 25) died; only 17 per cent (6 of 36) with nonelevated urinary gonadotropins died. The histologic presence of focal choriocarcinoma per se histologically in germinal neoplasms is not a poor prognostic sign. Figure 2 relates the presence of focal choriocarcinoma to both urinary gonadotropin levels and.mortality. Only 1 of 7 patients who had histologic choriocarcinoma but negative urinary gonadotropins died. In contrast, 9 of 11 patients (82 per cent) who had both histologic choriocarcinoma and positive urinary gonadotropins died. Further histopathologic evaluation revealed no reliable correlation between survival and vascular invasion, local extension, or interstitial cell hyperplasia. Of the patients in whom both vascular invasion and local extension was demonstrated, 50 per cent survived more than three years. Fifty per cent of those patients who had clinically evident metastases at the time of admission and subsequently died did not have demonstrable vascular invasion. The presence of positive (Stage IB) or negative (Stage IA) retroperitoneal lymph nodes in patients without initial clinically evident metastases was related to treatment and survival. No difference was noted in the teratocarcinoma group in which over-all survival with negative nodes was 14 of 16 and with positive nodes was 7 of 8. In the patients with embryonal carcinoma, over-all survival with negative lymph nodes was 100 per cent (3 of 3) and with positive nodes was only 57 per cent (4 of 7). Treatment results are considered according to tumor type. Of 34 patients with seminoma, 28 (82 per cent) survived more than three years without evidence of persistent tumor. Of the 6 patients who died, all had evidence of metastases at the time of initial presentation, while none of the survivors had evidence of metastases on the initial examination. The 4 patients with teratoma were all treated with bilateral lymph node dissection, all had negative lymph nodes, none received chemotherapy or irradiation, and all are alive without evidence of recurrence of tumor three years after surgery.
UROLOGY
/ NOVEMBER1975
/ VOLUMEVI,
NUMBER5
100
83%
75 50 16%
25
NO CHORIO
NO CHORIO FOCAL CHORIO NONELEVATED UGT
FOCAL CHORIO ELEVATED UGT
Relationship qf deaths to urinary gonadotropin (UGT) and microfocus of chorioFIGURE 2. carcinoma in patients u&k testis tumor. In patients who had embryonal carcinoma the over-all survival rate was 11 of 27 (41 per cent). Of the 17 patients who died, 11 presented with metastases. Only 2 of 12 patients survived who presented initially with clinical metastases. Nine of 15 (60 per cent) of the patients who had no evidence of metastases at the initial examination survived. In this small group there was better survival rate in patients with lymph node dissection (7 of 10) compared with patients who did not undergo lymph node dissection (2 of 5).
There were 2 cases of pure choriocarcinoma. One patient was moribund at the time of hospital admission and died a few days later. The second patient had a bilateral lymph node dissection which was positive for choriocarcinoma. He received actinomycin therapy and died fifty-five months after the original diagnosis was made. Table III is a composite of all modes of therapy related to survival in patients with teratocarcinoma and embryonal carcinoma. The over-all survival rate of patients with teratocarcinoma was 29 of 44 (66 per cent). Of the 15 patients who with clinical evidence of died, 10 presented metastases and none of those who presented with metastases survived (0 of 10). Of 34 who had no evidence of metastases at the initial examination, 29 (85 per cent) survived. In this group of patients with teratocarcinoma who had no clinical evidence of metastases at the time of initial examination, there was no significant difference in survival in those who had radiation therapy alone (5 of 5), lymph node dissection alone (8 of 8), or combination therapy of lymph node dissection with radiation (2 of 3), with chemotherapy (11 of 13),and with both radiation and chemotherapy (2 of 3). TABLE III. -No Tumor Type and Stage
_____
Teratocarcinoma Stage lA, 1B Stage II, III Embryonal carcinoma Stage lA, 1B Stage II, III KEY: O=orchiectomy;
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Comment The extent of tumor spread at the time of presentation and the type of tumor are the two most significant factors in predicting the survival of a patient with a germinal neoplasm of the testis. A three-year survival rate of 88 per cent occurred in those patients who presented without initial evidence of clinical metastases. Only 1 of 30 patients survived in that group with clinically evident metastases. Patients with certain tumor types survive longer than patients with other types. Seminomas
Modes of therapy
Node Dissection-
-Node
O+R
O+C
... ...
5/5 Q/2
..
l/2
818
213
o/4
0.3
...
...
...
l/3 o/2
... o/2
l/2 l/5
l/l
214
. ..
Rcradiation;
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O+C+R
C=chemotherapy.
0
O+R
.
Dissection-_, O+C
O+C+R
11/13 . .
213 O/l
212 l/2
213 O/l
Numbers in parentheses indicate
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Over-all Survival
2;;;
E)
1
29144 (66)
percentages.
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generally have a favorable prognosis, more than 95 per cent three-year survival in some studies. Patients with teratomas have an excellent chance for cure. The patient with pure choriocarcinoma is the most difficult to manage, often presenting severely ill, with pulmonary metastases. Patients with a Stage IA or IB teratocarcinoma have a better chance of survival (85 per cent) than patients with Stage IA and IB embryonal carcinoma (60 per cent). In this series which covers twenty years, no patient who survived more than three years without evidence of recurrence has died because of the testicular neoplasm. In 3 patients, a neoplasm has developed in the opposite testis at two, eight, and nine years after their initial tumor was removed. All have been treated successfully for the second tumor. The development of tumor in the other testis in 3 of 115 primary germinal tumors emphasizes the need for regular periodic physical examination for an indefinite period. Of the 3 diagnostic studies, the urinary gonadotropins have the most predictive value in regard to the prognosis of the patient. Our figures of 64 per cent mortality in those patients with elevated urinary gonadotropins compared with 17 per cent in those with nonelevated urinary gonadotropins matches the figures of 63 per cent and 18 per cent, respectively, found by Wilson and Woodhead,” and further emphasizes the significance of this test.13 The presence of elevated levels of chorionic gonadotropin should have even greater predictive value than the gonadotropins cited here which are a combination of chorionic and pituitary gonadotropin. Although the intravenous pyelogram is not accurate in predicting retroperitoneal lymph node involvement, it is essential to outline the renal anatomy, since occasionally a nephrectomy is necessary to complete adequate lymph node dissection. Lymphangiographic study has been considered by others to be necessary in the evaluation of patients, both pre- and postoperatively.g Because lymphangiography was helpful in the diagnosis of retroperitoneal node involvement in only 25 per cent of our cases, and because postdissection roentgenograms at the time of surgery have never required modification of the already completed bilateral lymph node dissection, they are no longer done routinely at the Cleveland Clinic in patients with embryonal carcinoma or with teratocarcinoma. In our institution the radio-
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therapists perform lymphangiographic studies with seminomas to determine the extent of their radiation portals, and will irradiate the mediastinum and both supraclavicular regions if there appears to be para-aortic involvement. Patients with seminoma had a favorable response to a tumor dose of 3,000 r, and the survival rate is comparable to other series. In Stage IA and IB teratocarcinoma no difference in survival was noted in patients who received radiation alone, bilateral retroperitoneal node dissection alone, or bilateral node dissection with adjunctive radiation or chemotherapy or both. In addition, negative or positive nodes (Stage IA and Stage IB) had no influence on survival - 7 of 8 (87.5 per cent) versus 14of 16 (87.5 per cent). The number of patients with embryonal carcinoma is too small for the results of treatment to be statistically valid. However, results were better with bilateral retroperitoneal lymph node dissection and orchiectomy (7 of 10 survivals) than with orchiectomy alone (2 of 5 survivals). Careful pathologic evaluation of the tumors is essential. Sixteen cases were reclassified in our series. Two cases originally classified as choriocarcinoma were interpreted as teratocarcinoma; 4 teratomas were interpreted as teratocarcinomas; 5 embryonal carcinomas were reclassified as 4 teratocarcinomas and 1 seminoma; and 5 teratocarcinomas were interpreted as 4 embryonal carcinomas and 1 seminoma. Fortunately, this did not influence therapy except that 1 patient with seminoma with an original interpretation of teratocarcinoma had a lymph node dissection. The histopathologic finding of focal choriocarcinoma if associated with the presence of an elevated urinary gonadotropin level offers a poor prognosis. Other histopathologic findings of local extension, vascular invasion, or Leydig cell hyperplasia showed no significant correlation with survival. Summary One hundred twenty-five cases of testicular tumor are reviewed. The prognostic significance of clinical features, laboratory tests, and histologic type are evaluated, and treatment results are presented. The most important prognostic clinical feature is the presence or absence of clinically evident metastases. Of patients without clinical metastases, 88 per cent survived, while only 3 per cent of patients with clinical metastases survived. Of the common diagnostic and prognostic laboratory
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tests, the urinary gonadotropins are extremely useful. The intravenous pyelogram and lymphangiogram are of limited usefulness and are statistically unreliable. The presence of positive lymph nodes influenced survival in patients with embryonal carcinoma, but made no difference in the teratocarcinoma group. The histopathologic characteristics of vascular invasion, local extension, and Leydig cell hyperplasia did not correlate with tumor behavior. Focal choriocarcinoma only when correlated with positive urinary gonadotropin levels had predictive significance. The histologic type of germinal tumor is important in predicting survival. Seminomas had an over-all 83 per cent survival with orchiectomy and radiation. There was no mortality in 4 patients with teratoma who had orchiectomy and lymph node dissection. Both patients with pure choriocarcinoma died. Patients with Stage IA or IB teratocarcinoma had an 85 per cent survival rate with node dissection alone, radiation alone, or a combination of lymph node dissection and chemotherapy. Patients with Stage IA or IB embryonal carcinoma had a 60 per cent survival rate. Regardless of any predictive ability, aggressive therapy of isolated tumor metastases combining surgical, radiation, and chemotherapy has proved successful in several cases that initially appeared to be hopeless. The Cleveland Clinic Foundation Cleveland, Ohio 44106 (DR. BANOWSKY) References 1. CAMPBELL, M. F., and HARRISON, J. H.: Urology, 3rd ed., Philadelphia, W. B. Saunders Company, 1970, p. 1211.
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2. DIXON, F. J., and MOORE, R. A.: Tumors of the male of Pathology sex organs, in Armed Forces Institute Atlas of Tumor Pathology, Section 8, part 311, and 32, Washington, D.C., pp. 48-127. 3. COLLINS, D. H., and PUGH, R. C. B.: Classification and frequency of testicular tumors, Br. J. Ural. 36: 1 (1964). 4. RUBIN, P.: Cancer of the urogenital tract: testicular tumors, J.A.M.A. 213: 89 (1970). 5. GOLBEY, R. B.: The place of chemotherapy in the treatment of testicular tumors, ibid. 213: 101 (1970). 6. STAUBITZ, W. J., MAGOSS, I., GRACE, J. T., and SCHENK, W. C., III: Surgical management of testis tumors, J. Urol. 101: 350 (1969). 7. MAIER, J. G., and VAN BUSKIRK, K.: Treatment of testicular germ cell malignancies, J.A.M.A. 101: 97 (1970). 8. BUSCH, F. M., SAYECH, E. S., and CHENAULT, 0. W., in the manageJR. : Some uses of lymphangiography ment of testicular tumors, J. Urol. 93: 490 (1965). 9. WALLACE, S., and JINC, B. S.: Lymphangiography: diagnosis of nodal metastases from testicular malignancies, J.A.M.A. 213: 94 (1970). 10. WILSOX, J. M., and WOODHEAD, D. hf.: Prognostic and therapeutic implications of urinary gonadotropin levels in the management of testicular neoplasia, J. Urol. 108: 754 (1972). 11. MAIER, J. G., SULAK, M. H., and MITTEMEYER, B. T.: Seminoma of the testis: analysis of treatment success and failure, Am. J. Roentgenol. 102: 596 (1968). 12. GORRMAN, A.: Ultrafiltration of urine for collection and biological assay of excreted hypophyseal hormones, Endocrinology 37: 177 (1945). 13. MALLIS, N., and PATTON, J. F.: Transperitoneal bilateral lymphadenectomy in testis tumors, J. Urol. 80: 501 (1958). 14. ROBSON, C. J., BRUCE, A. W., and CHARBONNEAU, J.: Testicular tumors: a collective review from the Canadian academy of urological surgeons, ibid. 94: 440 (1965). 15. PATTON, J. F., and MALLIS, N. : Tumors of the testis, ibid. 81: 457 (1959). 16. FRIEDMAN, N. B., and MOORE, R. A.: Tumors of the testis: report of 922 cases, Mil. Surgeon. 99: 573 (1946). 17. PATTON, J. F., HEWITT, C. B., and MALLIS, N.: Diagnosis and treatment of tumors of the testis, J.A.M.A. 171: 2194 (1959).
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