CLINICAL
DILEMMA
IN MANAGEMENT
YOLK SAC TUMOR OF CHILDHOOD ARTHUR
M. SMITH,
RAGHUNATHA W. C. NEIL
OF
TESTIS
M.D.
N. RAO, M.D.
SHELOR,
M.D.
From the Section of Urology, and Department of Pathology, Medical College of Georgia, Augusta, Georgia, and the Southeast Alabama Medical Center, Dothan, Alabama
ABSTRACT -An “expectant” approach to management of yolk sac type testis tumors in two boys led to therapeutic failure. The rationale for such “nontherapy” in light of current knowledge is discussed. The need for more sophisticated tumor staging as well as improved chemotherapeutic approaches in treatment planning is suggested.
Yolk sac tumor of the prepubertal testis, also known by a variety of other names (Teilum tumor, endodermal sinus tumor, embryonal adenocarcinoma) is an uncommon pathologic entity. ‘s2 Generally, the physician initially treating the patient with such a lesion is unfamiliar with accumulated clinical experience concerning In addition, the dearth of insuch neoplasms. formation concerning the relatively small numbers of such patients who have been treated in a uniform manner with adequate follow-up, provides little guidance or confidence to the physician who must make the critical therapeutic decisions regarding his patient. The 2 cases described herein exemplify the dilemma facing the clinician called upon to treat this disease. Case Reports Case 1 An otherwise healthy eight and one-halfmonth-old boy in Greece was noted by his mother to have a left testicular mass. At nine months of age, an inguinal orchiectomy of the clinical 5 by 5-cm. mass led to a diagnosis of embryonal adenocarcinoma. He was brought to the United States for further evaluation. Physical examination, other than for his healing groin scar, was unremarkable. Results of complete
88
blood cell count (CBC), urinalysis, chest and skeletal x-ray films, sedimentation rate, and intravenous pyelogram (IVP) were negative. After multidisciplinary consultations, it was decided that neither retroperitoneal node dissection, irradiation nor chemotherapy was indicated at that time. It was recommended that the patient be followed closely and observed carefully for future evidence of disease, before instituting further therapy. He returned to Greece. His subsequent course was described in a letter from his physician: “At twelve and fourteen months of age, he was noted to be in good general condition without clinical findings. At seventeen months, he was pale, losing weight, and irritable. In his abdomen, masses of tumor were palpable more prominently in the region of the liver and spleen, The surgeon decided to operate upon him but was unable to do anything. He died at nineteen months of age.” Case 2 A two-year-old Caucasian boy was operated on for a clinical incarcerated inguinal hernia. At a distinctly abnormal 6.5 by 4-cm. surgery, testicular mass was excised with the spermatic cord at the internal inguinal ring. Infantile embryo& carcinoma was diagnosed. IVP and chest x-ray film were normal. After multidisciplinary consultation, it was elected to initiate a
UROLOGY
/ JULY1979 / VOLUMEXIV,
NUMBER1
schedule of monthly examinations and chest roentgenograms. Eight months postoperatively, the patient was hospitalized for failure to eat and upper gastrointestinal complaints. On physical examination a 10 by 6-cm. right abdominal mass was noted. Since the IVP showed a right retroperitoneal mass and the chest film revealed two metastatic lesions in the left upper lung field with widening of the mid-mediastinum, he was started on a regimen of vinblastine, bleomycin, and cis-platinum. Although he had an initial dramatic objective response, his longterm status is as yet indeterminate. Pathology The two tumors studied share common features (Figs. 1 and 2). Both are predominantly made up of anastomosing strands of cells forming labyrinthine patterns. The cells are of vari-
ous shapes: cuboidal, columnar, flat, and elongated spindle cells. The nuclei show variations in size and shape and are occasionally nucleolated. The labyrinthine spaces vary in size and are either occasionally cystic, containing basophilic mucoid material, or are empty. Eosinophilic hyaline globules, that vary in size, are seen in the spaces and also in the epithelial cells lining the spaces. Occasionally the tumor cells are arranged around blood vessels that are lined only by a layer of endothelial cells on a basement membrane. In longitudinal sections these appear elongated and papillary and in cross sections are of glomeruloid shape, projecting into cystic spaces lined by tumor cells. The tumor from Case 1 is somewhat more cellular with islands of polygonal cells and also contains ductular structures lined by columnar cells with a brush border (Fig. 1). The glomeruloid structures, the labyrinthine pattern formed by the anastomosing arrangement, and the hyaline globules that characterize these two tumors would place them in the category of tumors referred to as Teilum tumor (also known as endodermal sinus tumor, embryonal adenocarcinoma, and embryonal adenocarcinema of infancy). Comment
FIGURE
1.
Case
1. Eosinophilic
lying free in spaces. (Hematoxylin magnification
hyaline globules and eosin, original
X 400.)
Viewing these cases several years retrospectively, both patients might have benefited from more exacting initial diagnostic staging utilizing serum alpha fetoprotein as a clinical marker (possibly even beta subunit of human chorionic gonadotropin, but this has not yet been of proved value here), computerized
FIGURE 2. Case 2. (A) Labyrinthine pattern formed of channels lined by epithelial cells; in center left, is of labyrinthine channels and two glomeruloid structures. glomeruloid structure. (B) High magnafkation x 120 and X 360, respectively.) (Hematoxylin and eosin, original magnifkations
UROLOGY
/ JULY1979
/ VOLUMEXIV,
NUMBER1
89
transaxial tomography of the abdomen, and possibly chest tomography, both with sedation if required. (The value of the latter two tomographic techniques in the age group in question is not fully defined and not necessarily enthusiastically supported by all members of the radiologic community.) The decision to omit retroperitoneal node dissection in both cases was based on a lack of conviction concerning the value of the procedure in this clinical setting. Previously published opinion has suggested that clinical staging of this neoplasm reliably reflects pathologic staging. 2 Indeed, several larger series have shown that of those patients clinically staged as having tumors localized in the testis, retroperitoneal node dissection usually produced negative nodes. 2-4 This tumor has always been believed to have a propensity toward primarily hematogenous dissemination. Consequently, retroperitoneal lymphatic spread in the absence of such bloodborne spread (commonly detected via pulmonary metastasis) was most unusual. Stated otherwise, retroperitoneal metastases rarely antedate pulmonary metastases. Hence, considering the unlikelihood of retroperitoneal lymphatic metastases where clinical findings suggest clinical localization ofthe tumor to the testis, there exists a reasonable question concerning the value of retroperitoneal lymphadenectomy or for that matter, prophylactic retroperitoneal irradiation. 5 The stated increase in survival when retroperitoneal lymphadenectomy has been performed, despite the finding of negative nodes, not only defies logic, but also is hampered by the relatively small number of cases used to support such data and the fact that a representative proportion of these patients received other adjunctive modalities.* In addition, the potential for skeletal growth disturbances from radiation given prophylactically, without evidence of retroperitoneal disease in this age group, may be significant. Permanent neutralization of bone marrow reserve, potentially limiting subsequent chemotherapy attempts, is another factor to be weighed in the balance. In the 2 aforementioned cases, chemotherapy was not immediately instituted because of a lack of any agents of proved long-term effectiveness in this disease, general reticence to administer any agents in an adjunctive fashion in this age group in the absence of proved extragonadal disease, lack of evidence that chemotherapy given prophylactically was any more effective
90
than that administered after neoplastic secondaries became clinically apparent, and distinct concern for the long-term effects on the patient of any chemotherapy, especially when no confirmatory evidence of spread was at hand. The major risk assumed while waiting to see whether or not any metastasis manifested clinically, however, was that during the time interval involved, the tumor burden might become excessive, rendering any rescue attempts more difficult. (Anecdotal experiences in this setting with pulmonary irradiation, wedge resections of pulmonary nodules, and rescue chemotherapy with empirically chosen agents are few in number and provide no great break-throughs.) In addition, at this important juncture, the local physician, into whose hands the follow-up care is often placed, may be ill equipped to make any rapid critical management judgments even if patient compliance with assiduous follow-up is adhered to. This inevitably leads to some delay, with consequent patient inanition and increasing tumor presence. Conclusions As further experience with the agents vinblastine, bleomycin, and cis-platinum in children is accumulated, there may be a greater willingness to employ these agents earlier (as was the experience with actinomycin-D and vincristine in the treatment of nephroblastoma).g The demonstrable antineoplastic effectiveness of these three agents, even upon retroperitoneal disease in adults with metastatic testis neoplasms, may further obviate the visceral inclination of the treating physicians to employ empirical retroperitoneal lymphadenectomy and/or irradiation in children with yolk sac testis tumors. Emphasis on improved clinical staging may potentially enable better selection of those patients requiring earlier chemotherapy. As with the 2 cases described, however, in the absence of widely available techniques for sophisticated culling out of patients at highest risk, it would appear that due consideration must be given toward disregarding the potential future longterm sequelae of chemotherapy and perhaps treating the children aggressively and earlier. Given our present state of knowledge, this may be the only means for providing these children with a reasonable chance for survival. The initial expectant management philosophy employed in the 2 cases presented herein was obviously unsuccessful.
UROLOGY
/ JULY 1979
/ VOLUME
XIV,
NUMBER
1
Section of Urology Medical College of Georgia Augusta, Georgia 30901 (DR. SMITH) ACKNOWLEDGMENT: To Dr. Joachim Wigger, Division of Developmental Pathology, Columbia University College of Physicians and Surgeons, for his help in preparation of some of the case material. References 1. Huntington R, et al: Germinal tumors exhibiting the endodermal sinus pattern of Teilum in young children, Cancer 16: 34 (1963). 2. Young PG, Mount BM, Foote FW, and Whitmore WF: EmbryonaI adenocarcinoma in the prepubertal testis, ibid. 26:
UROLOGY
/
JULY 1979
/
VOLUME
XIV, NUMBER
1
1065 (1970). of testicular neoplasms 3. Hopkins TB, et al: The management in children, J. Urol. 120: 96 (1978). 4. Gangai MP: Testicular neoplasms in an infant, Cancer 22: 658 (1968). 5. Houser R, Izant R, and Persky L: Testicular tumors in children, Am. J. Surg. 110: 876 (1965). 6. Sabio H, Burgert EO, Jr, Farrow GM, and Kelahs PP: Embryonal carcinoma of the testis in childhood, Cancer 34: 2118 (1974). 7. Smith JP: Testicular tumors in infants and children, Urology 2: 353 (1973). 8. TefR M. Vawter GF. and Mitus A: Radiotheraneutic management of testicular neoplasms in children, Radiology 88: 457 (1967). 9. Ghavimi F, Helson L, Rosen G, and Wollner N: VAB III combination chemotherapy in childhood malignancies, Proc. Am. Assoc. Cancer Res. 18: 324 (1977).
91
DILEMMA
IN MANAGEMENT
YOLK SAC TUMOR OF CHILDHOOD ARTHUR
M. SMITH,
RAGHUNATHA W. C. NEIL
OF
TESTIS
M.D.
N. RAO, M.D.
SHELOR,
M.D.
From the Section of Urology, and Department of Pathology, Medical College of Georgia, Augusta, Georgia, and the Southeast Alabama Medical Center, Dothan, Alabama
ABSTRACT -An “expectant” approach to management of yolk sac type testis tumors in two boys led to therapeutic failure. The rationale for such “nontherapy” in light of current knowledge is discussed. The need for more sophisticated tumor staging as well as improved chemotherapeutic approaches in treatment planning is suggested.
Yolk sac tumor of the prepubertal testis, also known by a variety of other names (Teilum tumor, endodermal sinus tumor, embryonal adenocarcinoma) is an uncommon pathologic entity. ‘s2 Generally, the physician initially treating the patient with such a lesion is unfamiliar with accumulated clinical experience concerning In addition, the dearth of insuch neoplasms. formation concerning the relatively small numbers of such patients who have been treated in a uniform manner with adequate follow-up, provides little guidance or confidence to the physician who must make the critical therapeutic decisions regarding his patient. The 2 cases described herein exemplify the dilemma facing the clinician called upon to treat this disease. Case Reports Case 1 An otherwise healthy eight and one-halfmonth-old boy in Greece was noted by his mother to have a left testicular mass. At nine months of age, an inguinal orchiectomy of the clinical 5 by 5-cm. mass led to a diagnosis of embryonal adenocarcinoma. He was brought to the United States for further evaluation. Physical examination, other than for his healing groin scar, was unremarkable. Results of complete
88
blood cell count (CBC), urinalysis, chest and skeletal x-ray films, sedimentation rate, and intravenous pyelogram (IVP) were negative. After multidisciplinary consultations, it was decided that neither retroperitoneal node dissection, irradiation nor chemotherapy was indicated at that time. It was recommended that the patient be followed closely and observed carefully for future evidence of disease, before instituting further therapy. He returned to Greece. His subsequent course was described in a letter from his physician: “At twelve and fourteen months of age, he was noted to be in good general condition without clinical findings. At seventeen months, he was pale, losing weight, and irritable. In his abdomen, masses of tumor were palpable more prominently in the region of the liver and spleen, The surgeon decided to operate upon him but was unable to do anything. He died at nineteen months of age.” Case 2 A two-year-old Caucasian boy was operated on for a clinical incarcerated inguinal hernia. At a distinctly abnormal 6.5 by 4-cm. surgery, testicular mass was excised with the spermatic cord at the internal inguinal ring. Infantile embryo& carcinoma was diagnosed. IVP and chest x-ray film were normal. After multidisciplinary consultation, it was elected to initiate a
UROLOGY
/ JULY1979 / VOLUMEXIV,
NUMBER1
schedule of monthly examinations and chest roentgenograms. Eight months postoperatively, the patient was hospitalized for failure to eat and upper gastrointestinal complaints. On physical examination a 10 by 6-cm. right abdominal mass was noted. Since the IVP showed a right retroperitoneal mass and the chest film revealed two metastatic lesions in the left upper lung field with widening of the mid-mediastinum, he was started on a regimen of vinblastine, bleomycin, and cis-platinum. Although he had an initial dramatic objective response, his longterm status is as yet indeterminate. Pathology The two tumors studied share common features (Figs. 1 and 2). Both are predominantly made up of anastomosing strands of cells forming labyrinthine patterns. The cells are of vari-
ous shapes: cuboidal, columnar, flat, and elongated spindle cells. The nuclei show variations in size and shape and are occasionally nucleolated. The labyrinthine spaces vary in size and are either occasionally cystic, containing basophilic mucoid material, or are empty. Eosinophilic hyaline globules, that vary in size, are seen in the spaces and also in the epithelial cells lining the spaces. Occasionally the tumor cells are arranged around blood vessels that are lined only by a layer of endothelial cells on a basement membrane. In longitudinal sections these appear elongated and papillary and in cross sections are of glomeruloid shape, projecting into cystic spaces lined by tumor cells. The tumor from Case 1 is somewhat more cellular with islands of polygonal cells and also contains ductular structures lined by columnar cells with a brush border (Fig. 1). The glomeruloid structures, the labyrinthine pattern formed by the anastomosing arrangement, and the hyaline globules that characterize these two tumors would place them in the category of tumors referred to as Teilum tumor (also known as endodermal sinus tumor, embryonal adenocarcinoma, and embryonal adenocarcinema of infancy). Comment
FIGURE
1.
Case
1. Eosinophilic
lying free in spaces. (Hematoxylin magnification
hyaline globules and eosin, original
X 400.)
Viewing these cases several years retrospectively, both patients might have benefited from more exacting initial diagnostic staging utilizing serum alpha fetoprotein as a clinical marker (possibly even beta subunit of human chorionic gonadotropin, but this has not yet been of proved value here), computerized
FIGURE 2. Case 2. (A) Labyrinthine pattern formed of channels lined by epithelial cells; in center left, is of labyrinthine channels and two glomeruloid structures. glomeruloid structure. (B) High magnafkation x 120 and X 360, respectively.) (Hematoxylin and eosin, original magnifkations
UROLOGY
/ JULY1979
/ VOLUMEXIV,
NUMBER1
89
transaxial tomography of the abdomen, and possibly chest tomography, both with sedation if required. (The value of the latter two tomographic techniques in the age group in question is not fully defined and not necessarily enthusiastically supported by all members of the radiologic community.) The decision to omit retroperitoneal node dissection in both cases was based on a lack of conviction concerning the value of the procedure in this clinical setting. Previously published opinion has suggested that clinical staging of this neoplasm reliably reflects pathologic staging. 2 Indeed, several larger series have shown that of those patients clinically staged as having tumors localized in the testis, retroperitoneal node dissection usually produced negative nodes. 2-4 This tumor has always been believed to have a propensity toward primarily hematogenous dissemination. Consequently, retroperitoneal lymphatic spread in the absence of such bloodborne spread (commonly detected via pulmonary metastasis) was most unusual. Stated otherwise, retroperitoneal metastases rarely antedate pulmonary metastases. Hence, considering the unlikelihood of retroperitoneal lymphatic metastases where clinical findings suggest clinical localization ofthe tumor to the testis, there exists a reasonable question concerning the value of retroperitoneal lymphadenectomy or for that matter, prophylactic retroperitoneal irradiation. 5 The stated increase in survival when retroperitoneal lymphadenectomy has been performed, despite the finding of negative nodes, not only defies logic, but also is hampered by the relatively small number of cases used to support such data and the fact that a representative proportion of these patients received other adjunctive modalities.* In addition, the potential for skeletal growth disturbances from radiation given prophylactically, without evidence of retroperitoneal disease in this age group, may be significant. Permanent neutralization of bone marrow reserve, potentially limiting subsequent chemotherapy attempts, is another factor to be weighed in the balance. In the 2 aforementioned cases, chemotherapy was not immediately instituted because of a lack of any agents of proved long-term effectiveness in this disease, general reticence to administer any agents in an adjunctive fashion in this age group in the absence of proved extragonadal disease, lack of evidence that chemotherapy given prophylactically was any more effective
90
than that administered after neoplastic secondaries became clinically apparent, and distinct concern for the long-term effects on the patient of any chemotherapy, especially when no confirmatory evidence of spread was at hand. The major risk assumed while waiting to see whether or not any metastasis manifested clinically, however, was that during the time interval involved, the tumor burden might become excessive, rendering any rescue attempts more difficult. (Anecdotal experiences in this setting with pulmonary irradiation, wedge resections of pulmonary nodules, and rescue chemotherapy with empirically chosen agents are few in number and provide no great break-throughs.) In addition, at this important juncture, the local physician, into whose hands the follow-up care is often placed, may be ill equipped to make any rapid critical management judgments even if patient compliance with assiduous follow-up is adhered to. This inevitably leads to some delay, with consequent patient inanition and increasing tumor presence. Conclusions As further experience with the agents vinblastine, bleomycin, and cis-platinum in children is accumulated, there may be a greater willingness to employ these agents earlier (as was the experience with actinomycin-D and vincristine in the treatment of nephroblastoma).g The demonstrable antineoplastic effectiveness of these three agents, even upon retroperitoneal disease in adults with metastatic testis neoplasms, may further obviate the visceral inclination of the treating physicians to employ empirical retroperitoneal lymphadenectomy and/or irradiation in children with yolk sac testis tumors. Emphasis on improved clinical staging may potentially enable better selection of those patients requiring earlier chemotherapy. As with the 2 cases described, however, in the absence of widely available techniques for sophisticated culling out of patients at highest risk, it would appear that due consideration must be given toward disregarding the potential future longterm sequelae of chemotherapy and perhaps treating the children aggressively and earlier. Given our present state of knowledge, this may be the only means for providing these children with a reasonable chance for survival. The initial expectant management philosophy employed in the 2 cases presented herein was obviously unsuccessful.
UROLOGY
/ JULY 1979
/ VOLUME
XIV,
NUMBER
1
Section of Urology Medical College of Georgia Augusta, Georgia 30901 (DR. SMITH) ACKNOWLEDGMENT: To Dr. Joachim Wigger, Division of Developmental Pathology, Columbia University College of Physicians and Surgeons, for his help in preparation of some of the case material. References 1. Huntington R, et al: Germinal tumors exhibiting the endodermal sinus pattern of Teilum in young children, Cancer 16: 34 (1963). 2. Young PG, Mount BM, Foote FW, and Whitmore WF: EmbryonaI adenocarcinoma in the prepubertal testis, ibid. 26:
UROLOGY
/
JULY 1979
/
VOLUME
XIV, NUMBER
1
1065 (1970). of testicular neoplasms 3. Hopkins TB, et al: The management in children, J. Urol. 120: 96 (1978). 4. Gangai MP: Testicular neoplasms in an infant, Cancer 22: 658 (1968). 5. Houser R, Izant R, and Persky L: Testicular tumors in children, Am. J. Surg. 110: 876 (1965). 6. Sabio H, Burgert EO, Jr, Farrow GM, and Kelahs PP: Embryonal carcinoma of the testis in childhood, Cancer 34: 2118 (1974). 7. Smith JP: Testicular tumors in infants and children, Urology 2: 353 (1973). 8. TefR M. Vawter GF. and Mitus A: Radiotheraneutic management of testicular neoplasms in children, Radiology 88: 457 (1967). 9. Ghavimi F, Helson L, Rosen G, and Wollner N: VAB III combination chemotherapy in childhood malignancies, Proc. Am. Assoc. Cancer Res. 18: 324 (1977).
91
