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Arias-stella phenomenon in spontaneous and therapeutic abortion
Arias-Stella phenomenon
in spontaneous and
therapeutic abortion STEVEN
G.
Richmond,
SILVERBERG,
M.D.
Virginia
Endometrium from 100 abortions was examined histologically for euidence of the Arias-Stella phenomenon. This reaction was present in 73.9 per cent of spontaneous (predominantly incomplete) abortions and 81.3 per cent of therapeutic abortions, not a significant dieerence. This high incidence of the Arias-Stella phenomenon in therapeutic abortions is offered as a rebuttal to the suggestion that it appears only when there is disturbance of trophoblastic tissue, as in spontaneous abortion and ectopic Pregnancy. Both the present study and other publications which are reviewed suggest that the Arias-Stella phenomenon is an exaggerated proliferative and secretory response to elevated hormonal levels, rather than an involutional and regressive sequel to fetal death.
I N 1 9 5 4, I N A classic reference in the annals of descriptive histopathology, AriasStellal described the endometrial changes that have subsequently come to bear his name. He studied 182 cases of uterine abortion, 26 cases of hydatidiform mole, 14 cases of chorionepithelioma, 4 cases of syncytial endometritis, and a solitary case of ectopic pregnancy and observed similar endometrial alterations in some cases of each of these conditions. These consisted of marked secretory and proliferative activity (often within the same gland), piling up of cells within gland lumina to form syncytiaf masses, very tall cells containing voluminous vacuolated, foamy cytoplasm, and hypertrophic, hyperchromatic nuclei showing marked variation in shape, often including “bizarre” and “monstrous” forms. Arias-Stellale3 thought that these changes represented an active proliferative and secretory response to hormones secreted by (or From the Division of Surgical Medical College of Virginia. Received 1971.
for
publication
Ac;;pted
for publication
in the presence of) trophoblastic tissue, but other authors? have suggested that they were involutional and regressive in nature. Although most studies of the Arias-Stella phenomenon have emphasized its diagnostic significance in cases of ectopic pregnancy, others*. g have commented on its frequency in intra- as well as extra-uterine implantations, while still otherslo have claimed that it is extremely rare in both uterine abortions and ectopic pregnancies. A recent publications has suggested that it appears “. . . only when there is disturbance of trophoblastic tissue, as is the case in intrauterine incomplete abortion and when bleeding begins in the Fallopian tube in tubal pregnancy.” These authors commented that they had never seen the Arias-Stella reaction in any of a “large number” of therapeutic abortions, in accidental complete abortions, or in postmortem material from women dying during pregnancy. Since we have recently begun to see pathologic material from a large number of therapeutic abortions at the Medical College of Virginia, we had the opportunity to undertake a prospective study of the incidence of Arias-Stella phenomenon in this material and to compare its frequency with
Pathology,
October November
22, 11,
777
778
March Am. J. Obstet.
Silverberg
Fig. 1. The Arias-Stella phenomenon in a curettage specimen from a 16-year-old white girl, 10 weeks pregnant. Note masses of clear cells piling up into the gland lumen, with considerable nuclear enlargement, hyperchromatism, and irregularity. (Hematoxylin and eosin. Original magnification
x325.) that in spontaneous abortions. Materials
and
complete
15, 1972 Gynecol.
Fig. 2. The Arias-Stella phenomenon in a hysterectomy specimen from a 33-year-old black woman, 15 weeks pregnant. Changes are somewhat less marked than those seen in Fig. 1, but large clear cells and hyperchromatic, atypical nuclei are clearly evident. Note surrounding decidual reaction. (Hematoxylin and eosin. Original magnification X300.)
and incomplete among which were massively enlarged and misshapen, bizarre forms (Figs. 1 and 2).
methods
Endometrial tissue was examined histologically in material from 100 consecutive abortions in which sufficient endometrium was available for study. Cases in which the material consisted solely of fetal and/or placental tissue were automatically excluded, as were cases in which microscopic examination of endometrium revealed fewer than 25 glands. All specimens were examined by the pathologist without prior knowledge of whether the abortion was spontaneous or therapeutic. The Arias-Stella phenomenon was recorded as being present or absent, the sole criterion for its presence being at least a single endometrial gland lined by enlarged cells with voluminous “clear” cytoplasm and containing large, hyperchromatic nuclei,
Results Of the 100 cases examined, 23 represented spontaneous abortions of intrauterine pregnancies, the great majority of which were incomplete. The patients ranged in age from 13 to 36 years; and in recorded duration of pregnancy (by date of last menstrual period), from 2 to 16 weeks. Eight patients were white, and 15 were black. The Arias-Stella phenomenon was recognized in 17 of these 23 cases, an incidence of 73.9 per cent. Seventy-five cases involved therapeutic abortions, of which there were 26 hysterectomies of gravid uteri and 49 lesser procedures (curettages and saline injections). These patients ranged from 14 to 40 years of age and from 4 to 18 weeks pregnant. A
Volume Number
112 6
notable difference from the previous group was that 51 patients were white and only 24 were black. Among this entire group of therapeutic abortions, 61 of 75 cases (81.3 per cent) showed the Arias-Stella phenomenon, There was no significant difference between the incidence of this reaction in the hysterectomy specimens, where more endometrium was available for study (22 of 26 cases or 84.6 per cent), and its frequency in the curettage and saline injection specimens (39 of 49 cases or 79.6 per cent). However, only representative sections from the hysterectomy specimens were subjected to microscopic examination. Two cases of tubal pregnancy were also seen in which endometrium was avaiIable for examination, and the Arias-Stella phenomenon was present in both. Comment The over-all incidence of the Arias-Stella phenomenon in the present series of cases is exactly 80 per cent (80 of 100 cases). This is quite similar to the figure of 70 per cent (43 of 61 cases) among “intrauterine abortions” (presumably spontaneous) reported by Lloyd and Fienberg’ and of 68 per cent (34 of 50 cases) among incomplete abortions in the series of Pildes and Wheeler.g The true incidence may well be 100 per cent, but this can be established only by examining the entire endometrial lining from a large series of gravid uteri, which has not yet been attempted. On the other hand, in one of the largest series in the literature, Roach, Guderian, and BrewerlO failed to identify the Arias-Stella phenomenon in any of 225 abortions (also presumably spontaneous, with an average duration of pregnancy of 7 weeks) but found it in 44.8 per cent of term pregnancies delivered by cesarean section and in 24 to 28 per cent of cases of hydatidiform mole, choriocarcinoma, and syncytial endometritis. The great majority of reported studies of the Arias-Stella phenomenon have emphasized its significance in the diagnosis of rctopic pregnancy, when the trophoblastic tissue is not accessible to the curet. In a recent literature review of the Arias-Stella phe-
Arias-Stella
phenomenon
in abortion
779
nomenon in ectopic pregnancy,4 its incidence in reported series was found to vary from 2.9 to 100 per cent, with a combined fi‘gure for all series of 49.5 per cent. The only reports of which we are aware that have specifically commented on the Arias-Stella reaction in therapeutic abortion are those of Beswick and Gregory” and of Wagner and Richart.l’ As mentioned above, the former authors stated that they had never seen the reaction except when there was “disturbance of trophoblastic tissue,” as in spontaneous abortion and ectopic pregnancy. The latter authors, on the other hand, studied nuclear deoxyribonucleic acid (DNA) content in endometria from 5 women with Arias-Stella changes, all of whom had undergone therapeutic abortion. The exact nature of the Arias-Stella phenomenon and its pathogenesis have remained obscure in the 17 years since its initial characterization, although most authors have bclieved it to be a secretory response of some sort, mediated by the hormonal environment of pregnancy. Arias-Stella’ originally suggested that the alterations might be the resuIt of stimulation by chorionic and estrogenic hormones and subsequently was able to provoke similar changes in the endometria of normal rats treated with chorionic gonadotropin and estrogen and of castrated rats treated with estrogen and progesterone.?, 3 These early studies established that pregnancy is not an absolute requirement for the development of these changes, and tbtly havr since been reported in several series of nonpregnant patients. Thus, Bernhardt, Bruns, and DroseJ noted them in 9 of 10 women who had received clomiphene during the preceding menstrual cycle, and Cianci and Russo7 found them in 2.15 per cent of endometrial biopsies from a large series of nongravid patients (particularly those in the puerperium and in postmenopausal women who had received radiation therapy). Although the radiation-induced c.hanges may not be mediated by high hormonal leve.ls (and may not be entirely comparable histologically to classical Arias-Stella changes, either), all of the other situations in which
780 Silverberg
the Arias-Stella phenomenon occurs are ones in which the hormonal environment varies from that of the normal menstrual cycle. Wagner and Richart, I1 studying endometrial gland cells from 5 patients with the AriasStella reaction by Feulgen microspectrocytophotometry, noted that the nuclear DNA values were characteristically polyploid (i.e., multiples of the normal diploid DNA content). They further commented that endometrial polyploidy is not seen during the normal menstrual cycle but is known to occur in pregnant women and in nonpregnant women receiving chorionic gonadotropins. The question of whether Arias-Stella changes are proliferative and secretory or involutional and regressive has been argued in the literature but seems to be settled in favor of the former mechanism at the present time. Lloyd and Fienberg* have been the principal proponents of the involutional theory. On the basis of nucelar pyknosis and infolding, absence of mitotic activity, and lack of evidence of fetal viability in their material (ectopic pregnancies and intrauterine abortions seen before 1963, the latter
REFERENCES
1. Arias-Stella, J.: Arch. Pathol. 58: 112, 1954. 2. AriasStella, J.: Arch. Pathol. 60: 49, 1955. 3. Arias-Stella, J.: Arch. Pathol. 60: 59, 1955. 4. Bernhardt, R. N., Bruns, P. D., and Drose, V. E.: Obstet. Gynecol. 28: 849, 1966. 5. Beswick, I. P., and Gregory, M. M.: J. Obstet. Gynaecol. Br. Commonw. 78: 143, 1971. 6. de BNX, J., and Ancla, M.: AM. J. OBSTET. GYNECOL. 89: 661, 1964.
March Am. .I. Obstet.
15, 1972 Gynecol.
thus presumably all spontaneous), they stated that, “, . . we believe that the A-S reaction is produced after death of the fetus and early degeneration of villi with consequent fall in hormonal levels,” and is “. . . essentially a regressive secretory phase phenomenon.“8 However, the presence of the Arias-Stella reaction in term pregnancies9 and material from therapeutic abortions (Wagner and RicharP and the present series) indicates that fetal death is not a prerequisite for these endometrial changes. The polyploidy noted by Wagner and RicharP indicates that these are actively dividing rather than dying cells, since polyploidy apparently results from a failure of cytokinesis following mitotic division, with the resulting 2 nuclei becoming arranged on the same spindle during the subsequent mitotic division.ll Finally, an ultrastructural study by de Brux and AnclaG has shown evidence of excessive secretory activity in the clear cells and of very active protein metabolism in the other cells of Arias-Stella glands, thus also militating against an involutional phenomenon.
7. 8. 9. 10.
11.
Cianci, S., and Russo, 3.: Clin. Ginekol. 11: 3, 196% . Lloyd, H. E. D., and Fienberg, R.: Am. J. Clin. Pathol. 43: 428. 1965. Pildes, R. B., and Wheeler, J. D.: AM. J. OBSTET. GYNECOL. 73: 79, 1957. Roach, W. R., Guderian, A. M., and Brewer, J. I.: AM. J. OBSTET. GYNECOL. 79: 680, 1960. Wagner, D., and Richart, R. M.: Arch. Pathol. 85: 475, 1968.
in spontaneous and
therapeutic abortion STEVEN
G.
Richmond,
SILVERBERG,
M.D.
Virginia
Endometrium from 100 abortions was examined histologically for euidence of the Arias-Stella phenomenon. This reaction was present in 73.9 per cent of spontaneous (predominantly incomplete) abortions and 81.3 per cent of therapeutic abortions, not a significant dieerence. This high incidence of the Arias-Stella phenomenon in therapeutic abortions is offered as a rebuttal to the suggestion that it appears only when there is disturbance of trophoblastic tissue, as in spontaneous abortion and ectopic Pregnancy. Both the present study and other publications which are reviewed suggest that the Arias-Stella phenomenon is an exaggerated proliferative and secretory response to elevated hormonal levels, rather than an involutional and regressive sequel to fetal death.
I N 1 9 5 4, I N A classic reference in the annals of descriptive histopathology, AriasStellal described the endometrial changes that have subsequently come to bear his name. He studied 182 cases of uterine abortion, 26 cases of hydatidiform mole, 14 cases of chorionepithelioma, 4 cases of syncytial endometritis, and a solitary case of ectopic pregnancy and observed similar endometrial alterations in some cases of each of these conditions. These consisted of marked secretory and proliferative activity (often within the same gland), piling up of cells within gland lumina to form syncytiaf masses, very tall cells containing voluminous vacuolated, foamy cytoplasm, and hypertrophic, hyperchromatic nuclei showing marked variation in shape, often including “bizarre” and “monstrous” forms. Arias-Stellale3 thought that these changes represented an active proliferative and secretory response to hormones secreted by (or From the Division of Surgical Medical College of Virginia. Received 1971.
for
publication
Ac;;pted
for publication
in the presence of) trophoblastic tissue, but other authors? have suggested that they were involutional and regressive in nature. Although most studies of the Arias-Stella phenomenon have emphasized its diagnostic significance in cases of ectopic pregnancy, others*. g have commented on its frequency in intra- as well as extra-uterine implantations, while still otherslo have claimed that it is extremely rare in both uterine abortions and ectopic pregnancies. A recent publications has suggested that it appears “. . . only when there is disturbance of trophoblastic tissue, as is the case in intrauterine incomplete abortion and when bleeding begins in the Fallopian tube in tubal pregnancy.” These authors commented that they had never seen the Arias-Stella reaction in any of a “large number” of therapeutic abortions, in accidental complete abortions, or in postmortem material from women dying during pregnancy. Since we have recently begun to see pathologic material from a large number of therapeutic abortions at the Medical College of Virginia, we had the opportunity to undertake a prospective study of the incidence of Arias-Stella phenomenon in this material and to compare its frequency with
Pathology,
October November
22, 11,
777
778
March Am. J. Obstet.
Silverberg
Fig. 1. The Arias-Stella phenomenon in a curettage specimen from a 16-year-old white girl, 10 weeks pregnant. Note masses of clear cells piling up into the gland lumen, with considerable nuclear enlargement, hyperchromatism, and irregularity. (Hematoxylin and eosin. Original magnification
x325.) that in spontaneous abortions. Materials
and
complete
15, 1972 Gynecol.
Fig. 2. The Arias-Stella phenomenon in a hysterectomy specimen from a 33-year-old black woman, 15 weeks pregnant. Changes are somewhat less marked than those seen in Fig. 1, but large clear cells and hyperchromatic, atypical nuclei are clearly evident. Note surrounding decidual reaction. (Hematoxylin and eosin. Original magnification X300.)
and incomplete among which were massively enlarged and misshapen, bizarre forms (Figs. 1 and 2).
methods
Endometrial tissue was examined histologically in material from 100 consecutive abortions in which sufficient endometrium was available for study. Cases in which the material consisted solely of fetal and/or placental tissue were automatically excluded, as were cases in which microscopic examination of endometrium revealed fewer than 25 glands. All specimens were examined by the pathologist without prior knowledge of whether the abortion was spontaneous or therapeutic. The Arias-Stella phenomenon was recorded as being present or absent, the sole criterion for its presence being at least a single endometrial gland lined by enlarged cells with voluminous “clear” cytoplasm and containing large, hyperchromatic nuclei,
Results Of the 100 cases examined, 23 represented spontaneous abortions of intrauterine pregnancies, the great majority of which were incomplete. The patients ranged in age from 13 to 36 years; and in recorded duration of pregnancy (by date of last menstrual period), from 2 to 16 weeks. Eight patients were white, and 15 were black. The Arias-Stella phenomenon was recognized in 17 of these 23 cases, an incidence of 73.9 per cent. Seventy-five cases involved therapeutic abortions, of which there were 26 hysterectomies of gravid uteri and 49 lesser procedures (curettages and saline injections). These patients ranged from 14 to 40 years of age and from 4 to 18 weeks pregnant. A
Volume Number
112 6
notable difference from the previous group was that 51 patients were white and only 24 were black. Among this entire group of therapeutic abortions, 61 of 75 cases (81.3 per cent) showed the Arias-Stella phenomenon, There was no significant difference between the incidence of this reaction in the hysterectomy specimens, where more endometrium was available for study (22 of 26 cases or 84.6 per cent), and its frequency in the curettage and saline injection specimens (39 of 49 cases or 79.6 per cent). However, only representative sections from the hysterectomy specimens were subjected to microscopic examination. Two cases of tubal pregnancy were also seen in which endometrium was avaiIable for examination, and the Arias-Stella phenomenon was present in both. Comment The over-all incidence of the Arias-Stella phenomenon in the present series of cases is exactly 80 per cent (80 of 100 cases). This is quite similar to the figure of 70 per cent (43 of 61 cases) among “intrauterine abortions” (presumably spontaneous) reported by Lloyd and Fienberg’ and of 68 per cent (34 of 50 cases) among incomplete abortions in the series of Pildes and Wheeler.g The true incidence may well be 100 per cent, but this can be established only by examining the entire endometrial lining from a large series of gravid uteri, which has not yet been attempted. On the other hand, in one of the largest series in the literature, Roach, Guderian, and BrewerlO failed to identify the Arias-Stella phenomenon in any of 225 abortions (also presumably spontaneous, with an average duration of pregnancy of 7 weeks) but found it in 44.8 per cent of term pregnancies delivered by cesarean section and in 24 to 28 per cent of cases of hydatidiform mole, choriocarcinoma, and syncytial endometritis. The great majority of reported studies of the Arias-Stella phenomenon have emphasized its significance in the diagnosis of rctopic pregnancy, when the trophoblastic tissue is not accessible to the curet. In a recent literature review of the Arias-Stella phe-
Arias-Stella
phenomenon
in abortion
779
nomenon in ectopic pregnancy,4 its incidence in reported series was found to vary from 2.9 to 100 per cent, with a combined fi‘gure for all series of 49.5 per cent. The only reports of which we are aware that have specifically commented on the Arias-Stella reaction in therapeutic abortion are those of Beswick and Gregory” and of Wagner and Richart.l’ As mentioned above, the former authors stated that they had never seen the reaction except when there was “disturbance of trophoblastic tissue,” as in spontaneous abortion and ectopic pregnancy. The latter authors, on the other hand, studied nuclear deoxyribonucleic acid (DNA) content in endometria from 5 women with Arias-Stella changes, all of whom had undergone therapeutic abortion. The exact nature of the Arias-Stella phenomenon and its pathogenesis have remained obscure in the 17 years since its initial characterization, although most authors have bclieved it to be a secretory response of some sort, mediated by the hormonal environment of pregnancy. Arias-Stella’ originally suggested that the alterations might be the resuIt of stimulation by chorionic and estrogenic hormones and subsequently was able to provoke similar changes in the endometria of normal rats treated with chorionic gonadotropin and estrogen and of castrated rats treated with estrogen and progesterone.?, 3 These early studies established that pregnancy is not an absolute requirement for the development of these changes, and tbtly havr since been reported in several series of nonpregnant patients. Thus, Bernhardt, Bruns, and DroseJ noted them in 9 of 10 women who had received clomiphene during the preceding menstrual cycle, and Cianci and Russo7 found them in 2.15 per cent of endometrial biopsies from a large series of nongravid patients (particularly those in the puerperium and in postmenopausal women who had received radiation therapy). Although the radiation-induced c.hanges may not be mediated by high hormonal leve.ls (and may not be entirely comparable histologically to classical Arias-Stella changes, either), all of the other situations in which
780 Silverberg
the Arias-Stella phenomenon occurs are ones in which the hormonal environment varies from that of the normal menstrual cycle. Wagner and Richart, I1 studying endometrial gland cells from 5 patients with the AriasStella reaction by Feulgen microspectrocytophotometry, noted that the nuclear DNA values were characteristically polyploid (i.e., multiples of the normal diploid DNA content). They further commented that endometrial polyploidy is not seen during the normal menstrual cycle but is known to occur in pregnant women and in nonpregnant women receiving chorionic gonadotropins. The question of whether Arias-Stella changes are proliferative and secretory or involutional and regressive has been argued in the literature but seems to be settled in favor of the former mechanism at the present time. Lloyd and Fienberg* have been the principal proponents of the involutional theory. On the basis of nucelar pyknosis and infolding, absence of mitotic activity, and lack of evidence of fetal viability in their material (ectopic pregnancies and intrauterine abortions seen before 1963, the latter
REFERENCES
1. Arias-Stella, J.: Arch. Pathol. 58: 112, 1954. 2. AriasStella, J.: Arch. Pathol. 60: 49, 1955. 3. Arias-Stella, J.: Arch. Pathol. 60: 59, 1955. 4. Bernhardt, R. N., Bruns, P. D., and Drose, V. E.: Obstet. Gynecol. 28: 849, 1966. 5. Beswick, I. P., and Gregory, M. M.: J. Obstet. Gynaecol. Br. Commonw. 78: 143, 1971. 6. de BNX, J., and Ancla, M.: AM. J. OBSTET. GYNECOL. 89: 661, 1964.
March Am. .I. Obstet.
15, 1972 Gynecol.
thus presumably all spontaneous), they stated that, “, . . we believe that the A-S reaction is produced after death of the fetus and early degeneration of villi with consequent fall in hormonal levels,” and is “. . . essentially a regressive secretory phase phenomenon.“8 However, the presence of the Arias-Stella reaction in term pregnancies9 and material from therapeutic abortions (Wagner and RicharP and the present series) indicates that fetal death is not a prerequisite for these endometrial changes. The polyploidy noted by Wagner and RicharP indicates that these are actively dividing rather than dying cells, since polyploidy apparently results from a failure of cytokinesis following mitotic division, with the resulting 2 nuclei becoming arranged on the same spindle during the subsequent mitotic division.ll Finally, an ultrastructural study by de Brux and AnclaG has shown evidence of excessive secretory activity in the clear cells and of very active protein metabolism in the other cells of Arias-Stella glands, thus also militating against an involutional phenomenon.
7. 8. 9. 10.
11.
Cianci, S., and Russo, 3.: Clin. Ginekol. 11: 3, 196% . Lloyd, H. E. D., and Fienberg, R.: Am. J. Clin. Pathol. 43: 428. 1965. Pildes, R. B., and Wheeler, J. D.: AM. J. OBSTET. GYNECOL. 73: 79, 1957. Roach, W. R., Guderian, A. M., and Brewer, J. I.: AM. J. OBSTET. GYNECOL. 79: 680, 1960. Wagner, D., and Richart, R. M.: Arch. Pathol. 85: 475, 1968.