Post-Chemotherapy Tumor Residuals in Patients with Advanced Nonseminomatous Testicular Cancer. Is it Necessary to Resect All Residual Masses?

0022-5347/91/1452-0300$03.00/0 Vol. 145, 300-303, February 1991 Printed in U. S. A.

THE JOURNAL OF UROLOGY Copyright © 1991 by AMERICAN UROLOGICAL ASSOCIATION, INC.

POST-CHEMOTHERAPY TUMOR RESIDUALS IN PATIENTS WITH ADVANCED NONSEMINOMATOUS TESTICULAR CANCER. IS IT NECESSARY TO RESECT ALL RESIDUAL MASSES? HANNE LOTHERINGTON QVIST, SOPHIE D. FossA, SIGURD OUS, JOHAN H0IE, ANNA E. STENWIG AND KARL-ERIK GIERCKSKY From the Departments of Surgical Oncology, Medical Oncology and Radiotherapy, and Pathology, The Norwegian Radium Hospital, Oslo, Norway

ABSTRACT

A total of 15 patients with advanced nonseminomatous testicular cancer underwent 2 sequentia.l operations (4 in 1 patient) to remove residual masses after cisplatin-based combination chemotherapy. All patients had normal human chorionic gonadotropin and a-fetoprotein levels but persistent radiographic masses after chemotherapy. The operations included retroperitoneal lymph node dissection in 13 patients, thoracotomy in 15, hepatic resection in 3 and craniotomy in 1. Histological comparison of the specimens resected during post-chemotherapy operations 1 and 2 demonstrated different patterns in 7 of 15 patients. Of these 7 patients 4 had less favorable pathological features in the specimen removed during the second procedure. Residual malignant tumor or mature teratoma was found in at least 1 site in 12 of the 15 patients and only 3 had complete necrosis or fibrosis in both specimens examined. These data indicate the favorable impact of excising all post-chemotherapy tumor residuals in patients with advanced nonseminomatous testicular cancer. However, in patients with no teratomatous elements in the testicular tumor and complete necrosis or fibrosis in the initial post-chemotherapy operation specimen the probability of complete necrosis or fibrosis in remaining tumors appears to be high. KEY WORDS:

testis, carcinoma, testicular neoplasms, drug therapy

of the tumor as evidenced by abdominal and, in most cases, thoracic computerized tomography (CT). · All visible residual tumors were routinely removed, excising the larger tumor first. Retroperitoneal lymph node dissection was performed even when initially enlarged retroperitoneal lymph nodes had regained normal size after chemotherapy. Retroperitoneal lymph node dissection was performed in 13 patients, thoracotomy (12 lung resections and 3 removals of residuals in the mediastinum) in 13, hepatic resection in 3 and craniotomy in 1 (see table). All patients underwent at least 2 operations: 11 had retroperitoneal lymph node dissection plus thoracotomy, 1 had retroperitoneal lymph node dissection plus hepatic resection, 1 underwent 2 thoracotomies, 1 underwent hepatic resection plus craniotomy, and 1 underwent retroperitoneal lymph node dissection, hepatic resection and 2 thoracotomies. Histological classification of the primary tumor and the postchemotherapy operation specimens was performed according to the method of Collins and Pugh. 9 According to this classification several subgroups of nonseminomatous testicular tumors were identified: differentiated teratoma, intermediate malignant teratoma, trophoblastic malignant teratoma (all 3 types with teratomatous elements) and undifferentiated malignant teratoma (the only type without teratomatous elements). The histological response of the residual tumor to chemotherapy was classified as complete necrosis or fibrosis, mature teratoma or vital malignant tumor.

Cisplatin-based combination chemotherapy followed by resection of residual tumor is currently regarded as optimal treatment of advanced nonseminomatous testicular cancer. 1- 5 Retroperitoneal lymph node dissection and thoracotomy are the most commonly required procedures but a few patients require excision of tumor manifestations at other sites, such as the liver and brain. In some patients nothing but complete necrosis or fibrosis is found in all operative specimens, suggesting a possible over-treatment in these patients. This raises the question of whether complete necrosis or fibrosis can be predicted in patients when multiple operations are considered to reduce safely the number of surgical interventions. When the present treatment policy was launched in 1981 (Swedish-Norwegian testicular cancer project-SWENOTECA6 ) it was decided that "if a complete remission is not achieved after 4 cycles (of chemotherapy) every attempt must be made to resect the remaining tumor tissue" and that "retroperitoneal lymph node extirpation should be performed even if a clinical complete remission is achieved with chemotherapy alone." Patients with advanced nonseminomatous testicular cancer routinely have undergone sequential excisions of post-chemotherapy residual tumor at multiple sites. To determine the necessity for multiple operations the histological response of the residual tumors was compared. MATERIAL AND METHODS

From 1980 to 1989, 15 patients with advanced nonseminomatous testicular cancer (clinical stage III or IV according to the Royal Marsden Hospital classification system?) underwent 2 or more post-chemotherapy operations for removal of residual tumor (see table). At operation all patients had undergone at least 4 cycles of chemotherapy. Details of the chemotherapy regimen have been described previously. 8 They had attained normal levels of serum tumor markers (a-fetoprotein and human chorionic gonadotropin) but no or only partial remission Accepted for publication July 19, 1990.

RESULTS

The histological status of the primary testicular tumor and post-chemotherapy operative specimens for all patients is listed in the table. Of the 15 primary tumors 2 were classified as differentiated teratoma, 7 as intermediate malignant teratoma, 3 as trophoblastic malignant teratoma and 3 as undifferentiated malignant teratoma. Histological examination of specimens from the initial post-chemotherapy operation demonstrated complete necrosis or fibrosis in 6, while mature teratoma and malignant tumor were found in 8 and 1, respectively. The

300

Teratoma, differentiated Teratoma, differentiated Malignant teratoma, intermediate Malignant teratoma, intermediate Malignant teratoma, intermediate Malignant teratoma, intermediate Malignant teratoma, intermediate Malignant teratoma, intermediate Malignant teratoma, intermediate Malignant teratoma, trophoblastic Malignant teratoma, trophoblastic Malignant teratoma, trophoblastic Malignant teratoma, undifferentiated Malignant teratoma, undifferentiated Malignant teratoma, undifferentiated

2

4 5 6

7

8 9

10 11 12 13 14 15

IV IV III IV IV III IV IV IV IV IV

Metastasis Operations

Histology of Metastasis

Retroperitoneal lymphadenectomy, thoracotomy Retroperitoneal lymphadenectomy, thoracotomy Retroperitoneal lymphadenectomy, thoracotomy Thoracotomy, retroperitoneal lymphadenectomy Retroperitoneal lymphadenectomy, thoracotomy Retroperitoneal lymphadenectomy, thoracotomy Retroperitoneal lymphadenectomy, thoracotomy Retroperitoneal lymphadenectomy, thoracotomy Retroperitoneal lymphadenectomy, hepatotomy, thoracotomy x2 Thoracotomy X2

Mature teratoma, necrosis

Retroperitoneal lymphadenectomy, thoracotomy Hepatotomy, craniotomy

IV III

Thoracotomy, retroperitoneal lymphadenectomy Retroperitoneal lymphadenectomy, hepatotomy Retroperitoneal lymphadenectomy, thoracotomy

IV IV

mc9.ll.gnanlt tumor was taken from a . . neal 3) and a germ Such nongerm malignancies probably arise within teratomatous foci and are regarded as malignant transformations. 10 During post-chemotherapy 2 there was CO]mlJllet~e necrosis or fibrosis in 5 3 of which with necrosis or also in the specimen. Mature teratoma was found in 8 and malignant tumor in 2. The tumors were taken from the mediastinum 6) brain In the former case the constituted a minor component of the consisted of mature teratoma, and the free of tumor The latter of the brain metastases. Since necrosis or fibrosis both resected relnalnlng 12 all had tumor or mature teratoma in at least 1 site. Of these 5 teratoma both '·VV\r' ....... n than

Mature teratoma X2 Malignant tumor, mature teratoma Mature teratoma, necrosis Mature teratoma X2 Mature teratoma, malignant tumor Necrosis, mature teratoma Mature teratoma X2 Mature teratoma X4 Necrosis X2 Necrosis, mature teratoma Necrosis, malignant tumor Necrosis x2 Mature teratoma X2 Necrosis x2

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DISCUSSION

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sp4~clmE~ns and acteristics Residual ("~ at various anatomical sites: 2 3 8 of 12, m<:Hl~'nElnt tumor or mature teratoma was found among all types of testicular tumor, more tre~quently in tumors with teratomatous elements teratoma, intermediate malignant teratoma and trophoblastic malignant teratoma, 19 of 26 specimens) than in tumors without teratomatous elements (undifferentiated malignant teratoma, 2 of 6). In this context, it is noteworthy that both patients with undifferentiated malignant teratoma in the primary testicular tumor and complete necrosis or fibrosis at the initial operation repeated this benign histological type at the subsequent operation' whereas this was the case only for 1 of 4 patients with teratomatous elements in the primary'tumor. The operations were followed by 9 minor complications (pneumothorax in 2 patients, pneumonia in 4, atelectasis in 1, thrombosis in 1 and intra-abdominal abscess in 1). All patients VV\

......... ·v ...... ,"' ............. "' ... '"',

I, r .. 'Tr" ("1'Tr"1r-

status teratoma, or necrosis necrotic or fibrotic masses from removal. .JL.JL~A'"'''''' present removal seems to be since mature teratoma may have the for tumor recurrence/ 5 as also seen in 1 of our cases. of residual malignant tumor may have therapeutic value in some cases, or it assists in defining the optimal subsequent treatment strategy in others. We found residual malignant tumor or mature teratoma in two-thirds of all histological specimens and in 12 of the 15 patients. This result is higher than in most previous studies.2,5,13,14 The exact percentage of malignant tumor or mature teratoma may depend on the clinical stage of the disease, intensity of chemotherapy16 and indications for a post-chemov""'.J..

302

QVIST AND ASSOCIATES

therapy operation. Fossa et aI, who also included patients with less advanced disease (clinical stage lIb or more), only found malignant tumor or mature teratoma in approximately half of the specimens. 14 Although the risks related to a post-chemotherapy operation appear to be acceptable, as also demonstrated in our study, it is tempting to speculate whether the burden of surgical therapy could be decreased in selected patients. In regard to retroperitoneal lymph node dissection, an approach is to perform more limited nerve-sparing dissection techniques 17 with a minimal risk of dry ejaculation. As an alternative, certain residual masses may be left without surgical removal provided there is a high predicted probability of only necrotic or fibrotic content. Clinical research has focused on prognostic features possibly predictive of benign histological status in residual tumor. The CT appearance of the masses, that is the size, density and changes noted during the course of treatment, has been ruled insufficient to exclude the presence of residual malignancy or teratoma. 18,19 Whether magnetic resonance imaging of metastases can prove to correlate better with histological findings is presently under investigation. 20 Absence of teratomatous elements in the primary tumor histology (undifferentiated malignant teratoma) may represent a favorable prognostic feature,4, 14, 18 although this finding alone is not an adequate criterion, since approximately a fourth of such patients have been reported to have residual malignant tumor or mature teratoma in the resected tissue. 14 This is in agreement with our findings in which 1 of 4 patients with absence of teratomatous elements in the testicular tumor had mature teratoma in the residual masses. We compared the histological response of residual masses resected in sequential procedures to determine whether the histological status of the initial operative specimen may be predictive of that of the residual tumor resected during the subsequent procedure. In 7 of 15 patients the histological status of the initial operative specimen differed from that of the second specimen. A similar variable response to chemotherapy at different metastatic sites also has been reported previously.5 Possible explanations for such an observation stem from the generally accepted premise that neoplasms are composed of heterogeneous subpopulations that differ with regard to morphological type, biological activity, pattern of spread and therapeutic response. However, the contention that necrosis or fibrosis is found more often in the lung than in retroperitoneal metastases 5 could not be confirmed in our study. When correlating metastasis and primary tumor histological status, we found that 2 patients with absence of teratomatous elements in the primary tumor (undifferentiated malignant teratoma) and necrosis or fibrosis in the initial operative specimen repeated this benign histological finding in the subsequent operative specimen, whereas this was not the case for patients with teratomatous elements. Since the number of patients with undifferentiated malignant teratoma among our patients with clinical stages III and IV nonseminomatous testicular cancer was low, the significance of this observation remains to be verified. Even though the percentage of patients with necrosis or fibrosis in the residual mass appears to be elevated in certain subgroups with advanced nonseminomatous testicular cancer, we believe that the high frequency of residual cancer or mature teratoma demands surgical removal of all post-chemotherapy residual masses, since presently there is no precise method to define the nature of these masses before surgical removal.

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REFERENCES

EDITORIAL COMMENTS

1. Einhorn, L. H., Williams, S. D., Mandelbaum, I. and Donohue, J. P.: Surgical resection in disseminated testicular cancer following chemotherapeutic cytoreduction. Cancer, 48: 904, 1981. 2. Hendry, W. F., Goldstraw, P., Husband, J. E., Barrett, A., McElwain, T. J. and Peckham, M. J.: Elective delayed excision

The authors have raised an important question in the management of residual masses subsequent to chemotherapy for testicular cancer, that is whether all of these residual masses should be resected. Even though their numbers are relatively small, this carefully studied series of patients lends added credence to the necessity to resect residual