AMERICAN JOURNAL OF CLINICAL PATHOLOGY Editorial
Transformation of Seminoma to Yolk Sac Tumor
The possibility that seminoma cells can transform into yolk sac tumor cells should be analyzed in two contexts. One is histogenetic and calls for evaluation of this possible transformation in the framework of available information derived from experimental models of germ cell tumors, and of current cytogenetic models of the pathogenesis of adult testicular germ cell tumors. The other context of this analysis relates to the clinical and therapeutic implications of such transformation. Experimentally, germ cell tumors have been produced by different procedures. Transplantation of germinal ridges from 12.5-day-old male fetuses under the testis capsule of adult syngeneic recipients results in the development of teratomas in a high percentage of cases.2 Similarly, teratomas, teratocarcinomas, and yolk sac tumors can be produced by ectopically transplanting early embryos under the capsule of the testis3 or kidney. 45 Yolk sac tumors can be obtained easily by conversion of teratocarcinoma cells to a modified ascites form.3 Embryonal carcinoma-derived mouse yolk sac tumors may appear by spontaneous differentiation6 or by retinoic acid-induced differentiation.7 Teratomas, teratocarcinomas, yolk sac tumors, and trophoblastic cells can be derived from the yolk sac in rats, in the absence of germ cells when the
Human seminoma cells transplanted into nude mice developed morphologic and functional features of yolk sac tumor. 13 The apparent maturation of metastases of germ cell tumors after chemotherapy, which appears to represent selection of less chemosensitive and more mature elements, and the finding of nonseminomatous elements in the metastases in patients with apparently pure primary seminomas, are well known clinical examples of transformation. 1214 It is therefore evident that just as the embryonal cells of the blastocyst are multipotential", ejUraembryonal cells, and even germ cell tumors, may, under appropriate conditions, display evidence of differentiation or "transformation" into different cell lines. It appears that a fertilized egg has several (probably six) 463
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
fetuses are removed from the uterus and the visceral yolk sac is pulled through the incision and left outside the uterus.8-9 The importance of the environment on pluripotential germ cells and epigenetic factors that regulate their phenotype is illustrated dramatically by the fate of teratocarcinoma cells. When cells from a teratocarcinoma cell line that had been grown for 8 years were implanted subcutaneously in a syngeneic recipient, a large tumor developed and killed the host. When cells from the same cell line were microinjected into blastocysts of another strain, these cells failed to display their malignant potential and participated in the normal development along with embryonic cells of the blastocyst. Strain-specific markers revealed a substantial contribution of tumor-lineage normal cells in tissues of the tumor-free, healthy animals.10 One of these mosaic males (dubbed Terry Tom) had all his normal germ line progeny derived from the tumor strain; due to the fortuitous XX composition of the blastocyst, the normal female gametes could not develop in a phenotypic male." Furthermore, the descendants of mosaic mice with teratocarcinoma-derived germ cells had no abnormalities, despite production of a large number of progeny, as is common in mice.12 However, if an excessive number of teratocarcinoma cells were injected into the blastocyst, they failed to respond to regulatory signals from the normal embryonic cells and remained tumorigenic, resulting in mice with no tumor-lineage cells in their normal tissues, but rather with a teratocarcinoma composed entirely of tumor cell strain.12
For this issue of the American Journal of Clinical Pathology, Drs. Czaja and Ulbright have written an article entitled "Evidence for the Transformation of Seminoma of Yolk Sac Tumor, with Histogenetic Considerations" (pages 468-477). The authors prospectively identified 30 germ cell tumors of testicular origin, possibly displaying differentiation of seminoma into yolk sac tumor elements. After reexamination, 10 of them, thought to demonstrate areas of potential seminoma-yolk sac tumor transformation, were selected. Focal presence of yolk sac tumor elements within lobules of seminoma was regarded as evidence of transformation, and was observed in six cases. In two cases, the spatial distribution of these two components, close apposition, rather than encasement of foci of yolk sac tumor within lobules of seminoma, was regarded as inconclusive evidence of transformation. The last two cases were interpreted as pure seminomas with microcystic foci; the latter changes, described by Damjanov1 can be misleading. Evidence of yolk sac differentiation was supported by reactivity of these foci for cytokeratin and alpha-fetoprotein.
464
AMERICAN JOURNAL OF CLINICAL PATHOLOGY Editorial
As line-specific differentiation genes are identified in the future, their role in the transformations observed in vitro and in vivo will become relevant and complement morphologic and immunohistochemical comparisons of the human embryo and germ cell tumors. 15 Stage-specific embryonic antigens are potential tools for the study of these master genes.16 The hypothesis of transformation of seminoma to yolk sac tumor suggested by Czaja and Ulbright finds support in cytogenetic studies by de Jong and colleagues17; their article on the pathogenesis of adult testicular germ cell tumors is an excellent review of cytogenetic data on this topic. From a therapeutic perspective, the possibility of transformation of seminoma to yolk sac tumor raises an important dilemma: because both tumors are treated differently and have different prognoses, should these cases be treated as pure seminomas or as combined germ cell tumors? Czaja and Ulbright tell us that "in addition to the foci of yolk sac tumor that occurred within lobules of seminoma, several of these cases contained separate yolk sac tumor areas." Furthermore, according to Table 1, some cases also had embryonal carcinoma and teratomatous components. Therefore, it is not surprising that all of their patients received protocols directed at germ cell tumors with nonseminomatous components. In the
study of Srigley and coworkers,18 4 of 47 patients with microscopically pure seminoma had ultrastructural evidence of epithelial differentiation that was regarded as early carcinomatous transformation. These patients were treated successfully as seminomas. It is possible that if the areas of transformation are only ultrastructural, the tumor may behave, and could be treated, as a seminoma. However, not enough information is available about the biologic behavior of tumors with only "ultrastructural transformation," and delineation of clinical guidelines will have to await further experience with similar cases. Tumors that consist of seminoma, in which foci of yolk sac or embryonal carcinomatous differentiation can be recognized, should be regarded as combined tumors and treated accordingly. How common is the transformation of seminoma to yolk sac tumor? There is little data to answer this question; we are not told how many cases were examined by Czaja and Ulbright from which 30 cases possibly displaying this transformation were chosen. Clinically significant cases of ultrastructural transformation must be uncommon because most patients with pure seminoma respond adequately to seminoma protocols. It would be desirable to look for ultrastructural evidence of such transformation in cases of seminoma that fail to respond to standard protocols. J. CARLOS MANIVEL,
M.D.
Department of Laboratory Medicine and Pathology Division of Surgical Pathology University of Minnesota Health Center Minneapolis, Minnesota
REFERENCES 1. Damjanov I, Niejadlik DC, Rabuffo JV, Donadio JA. Cribriform and sclerosing seminoma devoid of lymphoid infiltrates. Arch Pathol Lab Med 1980;104:527-530. 2. Stevens LC. Experimental production of testicular teratomas in mice. Proc Natl Acad Sci 1964;52:654-661. 3. Stevens LC. The development of transplantable teratocarcinomas from intratesticular grafts of pre- and postimplantation mouse embryos. Developmental Biology 1970;21:364-382. 4. Damjanov I, Solter D, Belicza M, Skreb N. Teratomas obtained through extrauterine growth of seven-day mouse embryos. J Nat Cancer Inst 1971 ;46:471 -480. 5. Damjanov I, Solter D. Yolk sac carcinoma grown from mouse egg cylinder. Arch Pathol 1973;95:182-184. 6. Sherman MI, Miller RA. F9 embryonal carcinoma cells can differentiate into endoderm-like cells. Developmental Biology 1978;63: 27-34. 7. Strickland S, Mahadavi V. The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell 1978;15:393-403. 8. Sobis H, Vandeputte M. Yolk sac-derived malignant tumors develop in the absence of germ cells. Oncodevelopmental Biology and Medicine 1983;4:415-422. 9. Sobis H, Hove VL, Vandeputte M. Trophoblastic and mesenchymal
A.J.C.P. • April 1992
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
"sets" of genes, each of which must be activated sequentially or alternatively to produce the various cell lines, including the blastocyst, yolk sac, trophoblast, embryonic epiblast (future somatic cells), gonocytes, and maturing gonocytes. When one "set" of genes is expressed by one cell, other "sets" are suppressed, but may be derepressed under appropriate conditions. Similar "sets" of genes and their possible expression, suppression, and derepression appears to be available to germ cell neoplasms, in such a way that when each of these sets of genes is expressed by a given tumor cell, the resulting phenotype will be that of embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, seminoma, and spermatocytic seminoma, respectively. With the possible exception of spermatocytic seminoma, descendants of other tumor germ cell types are able to "switch" to a different "set" of genes, resulting in combined tumors, or the presence in metastases of phenotypes not present in the primary tumor. The paper by Czaja and Ulbright in this issue provides evidence that germ tumor cells expressing a gonocyte set of genes and the phenotype of a seminoma may switch to a yolk sac set of genes with the expected phenotypic changes. However, the evidence for these sets of genes and their "on and ofF" switching during embryogenesis and spermatogenesis and in germ cell neoplasms is circumstantial and indirect.
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
465
Editorial
10. 11. 12. 13. 14.
structures in rat yolk sac carcinoma. Intl J Cancer 1982;29:181— 186. Mintz B. Gene expression in neoplasia and differentiation. Harvey Lecture 1975;71:193-246. Cronmiller C, Mintz B. Karyotypic normalcy and quasi-normalcy of developmentally totipotent mouse teratocarcinoma cells. Developmental Biology 1978;67:465-477. Mintz B, Fleischman RA. Teratocarcinomas and other neoplasms as developmental defects in gene expression. Adv Cancer Res 1981;34:211-278. Raghavan D, Heyderman E, Monaghan P, et al. Hypothesis: When is a seminoma not a seminoma? J Clin Pathol 1981;34:123-128. Bredael JJ, Vugrin D, Whitmore WF Jr. Autopsy findings in 154
15. 16. 17. 18.
patients with germ cell tumors of the testis. Cancer 1982;50:548551. Jacobsen GK. Histogenetic considerations concerning germ cell tumours. Virchows Arch (Pathol Anat) 1986;408:509-525. Solter D, Damjanov I. Teratocarcinoma and the expression of oncodevelopmental genes. Methods Cancer Res 1979;18:277-332. de Jong BD, Oosterhuis JW, Castedo SMMJ, et al. Pathogenesis of adult testicular germ cell tumors. Cancer Genet Cytogenet 1990;48:143-167. Srigley JR, Mackay B, Toto P, Ayala A. The ultrastructure and histogenesis of male germ neoplasia with emphasis on seminoma with early carcinomatous features. Ultrastructural Pathol 1988; 12: 67-86.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
Vol. 97 • No. 4
Transformation of Seminoma to Yolk Sac Tumor
The possibility that seminoma cells can transform into yolk sac tumor cells should be analyzed in two contexts. One is histogenetic and calls for evaluation of this possible transformation in the framework of available information derived from experimental models of germ cell tumors, and of current cytogenetic models of the pathogenesis of adult testicular germ cell tumors. The other context of this analysis relates to the clinical and therapeutic implications of such transformation. Experimentally, germ cell tumors have been produced by different procedures. Transplantation of germinal ridges from 12.5-day-old male fetuses under the testis capsule of adult syngeneic recipients results in the development of teratomas in a high percentage of cases.2 Similarly, teratomas, teratocarcinomas, and yolk sac tumors can be produced by ectopically transplanting early embryos under the capsule of the testis3 or kidney. 45 Yolk sac tumors can be obtained easily by conversion of teratocarcinoma cells to a modified ascites form.3 Embryonal carcinoma-derived mouse yolk sac tumors may appear by spontaneous differentiation6 or by retinoic acid-induced differentiation.7 Teratomas, teratocarcinomas, yolk sac tumors, and trophoblastic cells can be derived from the yolk sac in rats, in the absence of germ cells when the
Human seminoma cells transplanted into nude mice developed morphologic and functional features of yolk sac tumor. 13 The apparent maturation of metastases of germ cell tumors after chemotherapy, which appears to represent selection of less chemosensitive and more mature elements, and the finding of nonseminomatous elements in the metastases in patients with apparently pure primary seminomas, are well known clinical examples of transformation. 1214 It is therefore evident that just as the embryonal cells of the blastocyst are multipotential", ejUraembryonal cells, and even germ cell tumors, may, under appropriate conditions, display evidence of differentiation or "transformation" into different cell lines. It appears that a fertilized egg has several (probably six) 463
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
fetuses are removed from the uterus and the visceral yolk sac is pulled through the incision and left outside the uterus.8-9 The importance of the environment on pluripotential germ cells and epigenetic factors that regulate their phenotype is illustrated dramatically by the fate of teratocarcinoma cells. When cells from a teratocarcinoma cell line that had been grown for 8 years were implanted subcutaneously in a syngeneic recipient, a large tumor developed and killed the host. When cells from the same cell line were microinjected into blastocysts of another strain, these cells failed to display their malignant potential and participated in the normal development along with embryonic cells of the blastocyst. Strain-specific markers revealed a substantial contribution of tumor-lineage normal cells in tissues of the tumor-free, healthy animals.10 One of these mosaic males (dubbed Terry Tom) had all his normal germ line progeny derived from the tumor strain; due to the fortuitous XX composition of the blastocyst, the normal female gametes could not develop in a phenotypic male." Furthermore, the descendants of mosaic mice with teratocarcinoma-derived germ cells had no abnormalities, despite production of a large number of progeny, as is common in mice.12 However, if an excessive number of teratocarcinoma cells were injected into the blastocyst, they failed to respond to regulatory signals from the normal embryonic cells and remained tumorigenic, resulting in mice with no tumor-lineage cells in their normal tissues, but rather with a teratocarcinoma composed entirely of tumor cell strain.12
For this issue of the American Journal of Clinical Pathology, Drs. Czaja and Ulbright have written an article entitled "Evidence for the Transformation of Seminoma of Yolk Sac Tumor, with Histogenetic Considerations" (pages 468-477). The authors prospectively identified 30 germ cell tumors of testicular origin, possibly displaying differentiation of seminoma into yolk sac tumor elements. After reexamination, 10 of them, thought to demonstrate areas of potential seminoma-yolk sac tumor transformation, were selected. Focal presence of yolk sac tumor elements within lobules of seminoma was regarded as evidence of transformation, and was observed in six cases. In two cases, the spatial distribution of these two components, close apposition, rather than encasement of foci of yolk sac tumor within lobules of seminoma, was regarded as inconclusive evidence of transformation. The last two cases were interpreted as pure seminomas with microcystic foci; the latter changes, described by Damjanov1 can be misleading. Evidence of yolk sac differentiation was supported by reactivity of these foci for cytokeratin and alpha-fetoprotein.
464
AMERICAN JOURNAL OF CLINICAL PATHOLOGY Editorial
As line-specific differentiation genes are identified in the future, their role in the transformations observed in vitro and in vivo will become relevant and complement morphologic and immunohistochemical comparisons of the human embryo and germ cell tumors. 15 Stage-specific embryonic antigens are potential tools for the study of these master genes.16 The hypothesis of transformation of seminoma to yolk sac tumor suggested by Czaja and Ulbright finds support in cytogenetic studies by de Jong and colleagues17; their article on the pathogenesis of adult testicular germ cell tumors is an excellent review of cytogenetic data on this topic. From a therapeutic perspective, the possibility of transformation of seminoma to yolk sac tumor raises an important dilemma: because both tumors are treated differently and have different prognoses, should these cases be treated as pure seminomas or as combined germ cell tumors? Czaja and Ulbright tell us that "in addition to the foci of yolk sac tumor that occurred within lobules of seminoma, several of these cases contained separate yolk sac tumor areas." Furthermore, according to Table 1, some cases also had embryonal carcinoma and teratomatous components. Therefore, it is not surprising that all of their patients received protocols directed at germ cell tumors with nonseminomatous components. In the
study of Srigley and coworkers,18 4 of 47 patients with microscopically pure seminoma had ultrastructural evidence of epithelial differentiation that was regarded as early carcinomatous transformation. These patients were treated successfully as seminomas. It is possible that if the areas of transformation are only ultrastructural, the tumor may behave, and could be treated, as a seminoma. However, not enough information is available about the biologic behavior of tumors with only "ultrastructural transformation," and delineation of clinical guidelines will have to await further experience with similar cases. Tumors that consist of seminoma, in which foci of yolk sac or embryonal carcinomatous differentiation can be recognized, should be regarded as combined tumors and treated accordingly. How common is the transformation of seminoma to yolk sac tumor? There is little data to answer this question; we are not told how many cases were examined by Czaja and Ulbright from which 30 cases possibly displaying this transformation were chosen. Clinically significant cases of ultrastructural transformation must be uncommon because most patients with pure seminoma respond adequately to seminoma protocols. It would be desirable to look for ultrastructural evidence of such transformation in cases of seminoma that fail to respond to standard protocols. J. CARLOS MANIVEL,
M.D.
Department of Laboratory Medicine and Pathology Division of Surgical Pathology University of Minnesota Health Center Minneapolis, Minnesota
REFERENCES 1. Damjanov I, Niejadlik DC, Rabuffo JV, Donadio JA. Cribriform and sclerosing seminoma devoid of lymphoid infiltrates. Arch Pathol Lab Med 1980;104:527-530. 2. Stevens LC. Experimental production of testicular teratomas in mice. Proc Natl Acad Sci 1964;52:654-661. 3. Stevens LC. The development of transplantable teratocarcinomas from intratesticular grafts of pre- and postimplantation mouse embryos. Developmental Biology 1970;21:364-382. 4. Damjanov I, Solter D, Belicza M, Skreb N. Teratomas obtained through extrauterine growth of seven-day mouse embryos. J Nat Cancer Inst 1971 ;46:471 -480. 5. Damjanov I, Solter D. Yolk sac carcinoma grown from mouse egg cylinder. Arch Pathol 1973;95:182-184. 6. Sherman MI, Miller RA. F9 embryonal carcinoma cells can differentiate into endoderm-like cells. Developmental Biology 1978;63: 27-34. 7. Strickland S, Mahadavi V. The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell 1978;15:393-403. 8. Sobis H, Vandeputte M. Yolk sac-derived malignant tumors develop in the absence of germ cells. Oncodevelopmental Biology and Medicine 1983;4:415-422. 9. Sobis H, Hove VL, Vandeputte M. Trophoblastic and mesenchymal
A.J.C.P. • April 1992
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
"sets" of genes, each of which must be activated sequentially or alternatively to produce the various cell lines, including the blastocyst, yolk sac, trophoblast, embryonic epiblast (future somatic cells), gonocytes, and maturing gonocytes. When one "set" of genes is expressed by one cell, other "sets" are suppressed, but may be derepressed under appropriate conditions. Similar "sets" of genes and their possible expression, suppression, and derepression appears to be available to germ cell neoplasms, in such a way that when each of these sets of genes is expressed by a given tumor cell, the resulting phenotype will be that of embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, seminoma, and spermatocytic seminoma, respectively. With the possible exception of spermatocytic seminoma, descendants of other tumor germ cell types are able to "switch" to a different "set" of genes, resulting in combined tumors, or the presence in metastases of phenotypes not present in the primary tumor. The paper by Czaja and Ulbright in this issue provides evidence that germ tumor cells expressing a gonocyte set of genes and the phenotype of a seminoma may switch to a yolk sac set of genes with the expected phenotypic changes. However, the evidence for these sets of genes and their "on and ofF" switching during embryogenesis and spermatogenesis and in germ cell neoplasms is circumstantial and indirect.
AMERICAN JOURNAL OF CLINICAL PATHOLOGY
465
Editorial
10. 11. 12. 13. 14.
structures in rat yolk sac carcinoma. Intl J Cancer 1982;29:181— 186. Mintz B. Gene expression in neoplasia and differentiation. Harvey Lecture 1975;71:193-246. Cronmiller C, Mintz B. Karyotypic normalcy and quasi-normalcy of developmentally totipotent mouse teratocarcinoma cells. Developmental Biology 1978;67:465-477. Mintz B, Fleischman RA. Teratocarcinomas and other neoplasms as developmental defects in gene expression. Adv Cancer Res 1981;34:211-278. Raghavan D, Heyderman E, Monaghan P, et al. Hypothesis: When is a seminoma not a seminoma? J Clin Pathol 1981;34:123-128. Bredael JJ, Vugrin D, Whitmore WF Jr. Autopsy findings in 154
15. 16. 17. 18.
patients with germ cell tumors of the testis. Cancer 1982;50:548551. Jacobsen GK. Histogenetic considerations concerning germ cell tumours. Virchows Arch (Pathol Anat) 1986;408:509-525. Solter D, Damjanov I. Teratocarcinoma and the expression of oncodevelopmental genes. Methods Cancer Res 1979;18:277-332. de Jong BD, Oosterhuis JW, Castedo SMMJ, et al. Pathogenesis of adult testicular germ cell tumors. Cancer Genet Cytogenet 1990;48:143-167. Srigley JR, Mackay B, Toto P, Ayala A. The ultrastructure and histogenesis of male germ neoplasia with emphasis on seminoma with early carcinomatous features. Ultrastructural Pathol 1988; 12: 67-86.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 6, 2016
Vol. 97 • No. 4
