- Email: [email protected]
Appendiceal decidual reaction in pregnancy
Appendiceal decidual reaction in pregnancy L.
G.
TEDESCHI,
G.
C.
BOTTA,
Boston,
M.D. M.D.
Massachusetts
T H I s investigation has been provoked by the accidental observation of a vermiform appendix, removed incidentally at the time of cesarean section, which revealed an alteration at the serosal surface for which no gross explanation could be found. The alteration consisted of yellowish red raised nodules, varying in size from 0.1 to 0.3 cm. in the largest dimension, scattered throughout the serosal surface of the organ, including the mesoappendix. The microscopic sections revealed that these nodules consisted of masses of submesothelial decidual cells. This observation aroused our curiosity as to the frequency and the extent with which a decidual reaction takes place in the appendix during pregnancy; whether or not such a reaction is capable of eliciting symptoms that may stimulate acute appendicitis; and whether it possesses some kind of relationship with appendiceal endometriosis. In 1905, Hirschberg’ reported appendiceal decidual reaction in a woman operated upon for tubal pregnancy. Hofbauer,2 in a communication on decidual formation on the peritoneal surface of the gravid uterus, remarks, without further specification, that a few elements of decidua can be found in the mesenteriolum of the appendix. Recently recorded in the German literature3 is a case of “periappendicitis decidualis,” with symptoms of acute appendicitis. As far as we could determine, the only data available on
the frequency of the phenomenon are those of Israel and Roitman,4 who, in an editorial on prophylactic appendectomy in the course of gynecologic surgery, mention decidua-like cells in the serosa in 2 out of 50 appendices removed at cesarean section, namely 4 per cent of the cases. The earliest demonstration of decidual cells appearing outside of the endometrium in the course of pregnancy was made by Walker5 in 1887. He reported the occurrence of an ectopic decidual reaction in the pelvic peritoneum observed with a tubal pregnancy. This finding was confirmed in the peritoneal surface of the gravid uterus of an eclamptic patient by Pels-Leusden6 in 1895. A study by Schmor17 in 1897 indicates the occurrence of decidual reaction in pregnancy in the cul-de-sac and in the ovaries. By 1906 enough observations had been recorded to authorize Taussig* to introduce the term “ectopic decidual reaction” for the occurrence of decidual cells outside the endometrium during the course of pregnancy. GeipelQ, lo reported the occurrence of a decidual reaction in the peritoneal surface of the diaphragm, the splenic capsule, as well as in the pelvic lymph nodes. More recently, Israel and associatesll found evidence of a decidual reaction in the ovary in 80 per cent of their cases. A comparable evaluation of cervical biopsies obtained during pregnancy by McGee and SlateI” disclosed an incidence of decidual reaction in 20 per cent of their cases. Unique are the findings of decidual cells in the lung of a 26-year-old woman who died
From the Defiartment of Pathology, Massachusetts Memorial Hos#itals, Boston, Massachusetts, and the Department of Laboratories and Research, Framingham Union Hospital, Framingham, Massachusetts
631
632
Tedeschi
and
Botta
:
Fig. 1. Diffuse compact submesothelial decidual reaction of appendix. Note the cellular pleomorphism and at one point transition from flattened to low cuboidal cells of the mesotheiial lining (2 l-year-old, gravida i. para 0, first trimester, tubal pregnancy). (Hematoxylin and eosin. x180; reduced I/3.)
Fig. 2. Diffuse
loose type of submesothelial decidual reaction in the appendix of a 30year-old gravida iii, para i, third trimester of pregnancy (cesarean section). (Hematoxylin and eosin. x320; reduced ‘/3.)
4 months after delivery’” and cidual cells in the renal pelvisI Materials
and
that
of de-
methods
The present stludy is based on an evaluation of 90 appendices obtained from women during gestation. The material was contributed from the files of several hospitals in the Boston area: 24 cases each from the Boston Lying-in Hospital and Framingham Union Hospital, 20 from the Free Hospital for Women, 18 from the Massachusetts
Memorial Hospitals, and 4 from Boston City Hospital. In 21 of these cases, the appendectomy had been performed in connection with signs and symptoms of acute appendicitis. The specimens in this category pertained to women in various periods of gestation, from the first to the third trimester of pregnancy. In 41 additional cases, the appendices had been removed during operation for tubal pregnancy (first trimester). In one case the appendix was removed in the course of an
Volume Number
84 5
Appendiceal
decidual
reaction
in pregnancy
633
Fig.
3. Circumscribed submesothelial nodules of decidual cells in the appendix of a 26year-old gravida ii, para i, in the third trimester (cesarean section). (Hematoxylin and eosin. x320; reduced y3.)
Fig. 4. Appendiceal
endometrial implants with associated diffuse compact decidual reaction in a 29-year-old gravida i, para 0. Eighth week of gestation. (Hematoxylin and eosin. x 120 ; reduced v3. )
exploratory laparotomy for a ruptured hemorrhagic cyst (first trimester), and, in the remaining 27 cases, prophylactic appendectomy was performed at the time of cesarean section, at or near term. Two to three sections of each appendix were taken from different portions of the organ and examined. All cases were evaluated with sections stained with hematoxylin and eosin. In 5 of the most recent cases, PAS stain and stains for reticulum fibers were also applied.
An appendix was considered positive for decidual cells in the presence of large cells, from 20 to 30 p in the largest dimension, with pale, faintly basophilic, granulated cytoplasm, and a large nucleus with finely distributed chromatin. A fuchsinophilic intercellular matrix condensed around the cells in the PAS stained sections, as well as a marked argyrophilic intercellular network in the reticulumstained sections, were considered as additional diagnostic features.
634
Tedeschi
and
Botta
In 2 appendices, one obtained at the first trimester (tubal pregnancy) and the other at term (cesarean section), stains for glycogen and for fat (Sudan IV) were also carried out. Results Presence of ectopic decidua was found in 15 of the 90 appendices examined, namely, in 16.6 per cent of the cases. In one case, as mentioned in the introduction, a 31-yearold gravida iii, para ii, patient submitted to cesarean section, the finding was of such dimensions as to have given rise to a grossly detectable appendiceal alteration. In the remaining 14 cases, ectopic decidua was disclosed at the microscopic study of the sections. Of these 15 positive cases, 4 were in women in the first trimester of pregnancy, 10 at term or close to term, and one 4 days after delivery. The microscopic patterns of decidual reaction in our series mimicked very closely those noted in the ovary by Israel and associates.” They can be categorized in the following three main types: (a) diffuse compact decidual reaction, (b) diffuse loose decidual reaction, and (c) nodular decidual reaction. In the diffuse compact type (Fig. 1)) the cells lay in sheets beneath the mesothelial lining. However, they lacked the mosaic arrangement and cellular homogeneity of the latter. They frequently showed pronounced pleomorphism, including polygonal, spindleshaped, ovoid, and ameba-like cells provided with cytoplasmic processes. Multinucleated giant cells with occasional vacuoles in the cytoplasm were also noted. Presence of glycogen could be demonstrated in one of two . . appendices m which this determination was possible (first trimester). Neither of these 2 appendices revealed the presence of fats in the decidual cells in the sections stained by Sudan IV method. In the diffuse loose type of reaction (Fig. 2) the cells, whether isolated or in groups, rested in a loose matrix, which in the PAS stained sections showed prominent fuchsino-
September 1, 1962 Am. J. Obst. & Gynec.
philic pericellular condensation. In these areas of loose texture, the cells were also frequently enveloped by a network of argyrophilic fibers. The cellular pleomorphism was even more marked than in the cases which displayed compact decidual reaction. In the nodular type (Fig. 3)) the decidualike cells occurred in patches, both above and below the mesothelial lining. They varied in size from a mere cluster of 5 to 10 cells to tubercle-like nodules of 20 to 50 cells, particularly numerous in the proximity of the walls of minute blood capillaries. In all three types of reactions, the mesothelial lining was well preserved. Although it did not seem to participate in the formation of the decidua, the mesothelial cells in swollen and low some areas appeared cuboidal rather than flattened. Except for 2 cases in which ectopic decidua was seen in association with acute appendicitis, there was no evidence of a coexistent inflammatory reaction in any of the remaining cases. In 5 of the 15 cases in which a decidual reaction was noted, an exploratory laparotomy had been performed for symptoms of abdominal distress. In 3 cases, the preoperative diagnosis was appendicitis, in another, pelvic thrombophlebitis, and, in still another, no tentative diagnosis was made. A correlation of the clinical manifestations and of the pathologic findings in our series indicate that ectopic decidua, per se, in the absence of associated alterations, is not likely to give rise to signs and symptoms of abdominal distress. In the 5 cases of ectopic decidua in which the patient was operated on, the symptoms were explained by the finding of a gangrenous appendicitis in one case; in 2 other cases, by appendiceal endometriosis; and in another case by an acute appendicitis with associated carcinoid tumor. In one instance only, in which the exploratory laparotomy failed to reveal the cause of the abdominal distress, the possibility can be entertained that the appendiceal decidual reaction could have played a role in causing the abdominal distress that led to operation.
Volume Number
84 5
Comment The developmental potentialities of the subcelomic mesenchyme provide the explanation for the formation of ectopic decidua in the appendix. The cells, transformed into decidual cells, are stromal elements with the same embryonic origin of the cells from which the endometrial stroma develops. Thus, ectopic decidual formation presupposes the persistence in the subcelomic mesenchyme of the adult of undifferentiated stromal cells. Possible transitional stages from stem cells to decidual cells have been traced by Hofbauer2 in the omentum. Similar transitional patterns have been noted in the appendices of our series. The cell primarily involved in the process appeared to be a small spindle-shaped cell resembling a fibroblast, and its transformation into decidual cells took place through a progressive increase in the amount of cytoplasm and enlargement of the nucleus. Our observations are in agreement with Mallory’s statementI’ that the decidual cell is an offspring of the fibroblast. Evidence in support of this view has recently been provided by Stuermer and Stein’s demonstration16 that endometrium grown in vitro displays the structure of fibroblastic tissue in ordinary media, whereas when serum from umbilical cord is added to the medium it displays an epithelioid pattern, giving rise to sheets of decidua-like cells. Although, in the appendices of our series, the mesothelial lining did not seem to participate in the formation of decidua, in individual cases it showed evidence of proliferative activity with tendency to stratification and swelling of individual cells. Embryology gives support to the view that pelvic peritoneum, germinal epithelium, and uterine epithelium are all derivatives of the celomic epithelium. These genetic relationships can be used in explanation of the formation of endometrial glands in 2 of our cases, as well as of the mesothelial metaplastic change noted in several of the appendices in our series of cases. Decidual transformation constantlv takes
Appendiceal
decidual
reaction
in pregnancy
635
place in the endometrium in the course of pregnancy. Inasmuch as a similar reaction can potentially occur, but actually does not, as a rule, in other organs which likewise originate from the mesenchyme of the urogenital ridge, the nature of the factor or factors which are responsible for the occurrence of ectopic decidua are still open to speculation. All evidence points to the endocrine effects of progesterone as a mediating factor in decidual formation. Speert17 has evaluated, in the endometrial decidua of ectopic gestation, the hormonal influence of pregnancy, disassociated from the chemical action of the trophoblast. Formation of decidua may also take place in the absence of pregnancyl’* 22; decidua menstrualis is an example.23p 24 Wallart,25> 26 at the postmortem examination of 7 postmenopausal women, 5 of whom were over 70 years of age, noted decidua cells both at the surface of the ovary and within corpora albicantia. Aschheim and Zondek’s demonstrationz7 has shown decidua formation in the uterine mucosa of virgin rodents submitted to repeated transplantation of anterior hypephyseal substance. Hisaw and Velardoz8 have demonstrated that progesterone is more effective in forming decidua in the ovariectomized and adrenalectomized rat, and that ACTH inhibits the action of progesterone by way of the adrenal cortex. An experiment by Rigler and Rosenkram? in pseudopregnant animals indicates that the spleen plays a role in the development of decidua. Deciduomas have been induced in the experimental animal by intravenous and intraperitoneal injections of histamine and histamine releasers; on the contrary, antihistamines were seen to suppress the phenomenon 30-33 McKeowen and Zuckerman34 have produced endometrial progestational changes, in one instance accompanied by the formation of decidua, in rats injected with testosterone. Leathem and Craftss5 have
636
Tedeschi
and
September 1, 1962 Am. J. Ohst. & Gym.
Botta
shown
endometrial progestational changes in adrenalectomized cats that were spayed, submitted to desoxycorticosterone acetate treatment. This indicates that progesterone is not the only steroid hormone able to produce progestational changes. Hormonal effects are inherently systemic in nature; also, it is the potential propert) of the subcelomic mesenchyme to form decidua. Since ectopic decidua does not constantly take place under suitable hormonal stimulation, the occasionality of the finding leads to the search for trigger mechanisms. WelleP has stressed the point that the sites of ectopic decidua reaction correspond to the regions where endometriosis is most commonly found. Meye? has pointed out that the decidual response is most likely to take place at the sites of pre-existing inflammation, particularly those associated with formation of adhesions. In support of this view, Ober and associateP mention the occurrence of ectopic decidua during pregnancy in laparotomy and hysterectomy scars and in association with extrinsic and intrinsic endometriosis. The same investigators, in a series of 16 ovarian deciduomas in nonpregnant women, found coexistent endometriosis in 5 cases and paraovarian adhesions in 14. In 9 of these cases, the patient had been previously submitted to radiation therapy. Experimental evidence adds strength to the concept that local irritation can be a mediating factor. The synergistic action of progesterone and local trauma has been shown by Loeb3* in the uterus of guinea pigs. This has been confirmed by Unterberger’s experiment.39 Similarly, Goldstein and Tatelbaum’” have succeeded in eliciting deciduomas in guinea pigs, both in the endometrium and beneath the uterine serosa, at the point of incisional trauma, following administration of autologous lutein extracts. In Lacassagne and his co-workers’ experiment,“l radiation
injury proved to be instrumental in the occurrence of uterine deciduomas. Associated conditions, possibly implied as intermediate factors in the formation of decidua, were found in only 4 of our 15 cases: acute gangrenous appendicitis in one case, endometriosis in 2 others, and a carcinoid tumor and acute appendicitis in the fourth. In the remaining 11 cases, all the women were young and healthy. This necessarily brings into consideration the possible role of ontogenic factors. The failure of the subcelomic mesenchyme to transform into decidua, or its ability to do so under suitable hormonal stimulation, might actually rest on the disappearance or on the persistence of the potential properties that are inherent to the tissue involved. Summary
A series of 90 appendices removed during various stages of gestation were analyzed for the presence of ectopic decidual reaction. Fifteen showed the presence of submesothelial decidual cells, namely 16.6 per cent. In one case, the reaction was so pronounced as to have given rise to grossly detectable alterations. In the remaining cases, the finding was discovered on routine microscopic examination. Four of the cases of decidual reaction were associated with other findings; endometriosis in 2, acute gangrenous appendix in one, and acute appendicitis and a carcinoid tumor in another. The clinical significance of decidual formation in the vermiform appendix, as well as the pathogenesis and mechanisms operating in its formation, are discussed. We wish to express our appreciation to Dr. John M. Craig for having placed at our disposal the cast material from the files of the Boston Lying-in Hospital and the Free Hospital for Women and to Dr. Benjamin Tenney, Jr., for having consented for us to include in our series the cases from the Boston City Hospital.
REFERENCES 1.
Hirschberg, 1904.
A.:
Arch.
f. Gynsk.
74: 620,
‘-’3
Hofbauer, 603.
1929.
J.: AM. J.
OBST.
&
GYNEC. 17:
Volume Number
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
84 5
Kovacs, K., and Jakobovits, A.: Zentralbl. f. Gynlk. 75: 1987, 1953. Israel, S. L., and Roitman, H. B.: Obst. & Gynec. 10: 102, 1957. Walker. A.: Virchows Arch. f. oath. Anat. 107: 72, 1887. Pels-Leusden: Quoted by Hofbauer, J. : AM. J. OBST. & GY~EC. 17: 603, 1929. Schmorl. Cl. G.: Monatschr. f. Geburtsh. u. GynLk. 5: 46, 1897. Taussig, F. J.: Surg. Gynec. & Obst. 2: 292, 1906. Geipel, P.: Arch. f. Gynlk. 106: 177, 1916. Geipel, P.: Arch. f. GynPk. 131: 650, 1927. Israel, S. L., Bubenstone, A., and Meranze, D. R.: Obst. & Gynec. 3: 399, 1954. McGee, W. B., and Slate, T. A.: California Med. 82: 306, 1955. Park, W. W.: J. Path. & Bact. 67: 563, 1954. Bettinger, H. F.: J. Path. & Bact. 59: 686, 1947. Mallory, F. B.: Quoted by Hofbauer, J.: AM. J, OBST. & GYNEC. 17: 603, 1929. Stuermer, V. M., and Stein, R. J.: AM. J. OBST. & GYNEC. 60: 1332. 1950. Speert, H.: AM. J. OBST. h GYNBC. 76: 491, 1958. TeLinde, R. W., and Henriksen, E.: Am. J. OBST. & GYNEC. 39: 733, 1940. Bassis, M.: AM. J. OBST. & GYNEC. 72: 1029, 1956. Ober, W. B., Grady, H. G., and Schoenbucher, A. K.: Am. J. Path. 33: 199, 1957. Wagner: Quoted by Hofbauer, J.: AM. J. OBST. Sr GYNEG. 17: 603, 1929. Greenblatt, R. B., and Krafka, J.: Arch. Path. 31: 634, 1941.
Appendiceal
23. 24. 25. 26. 27. 28. 29. 30.
31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.
decidual
reaction
in pregnancy
637
Abraham, E. G.: Zentralbl. f. Gynak. 56: 464, 1932. Reinhart, H. L.: Am. J. Clin. Path. 5: 365, 1935. Wallart, J.: Gynec. & Obst. 33: 134, 1936. Wallart, J.: Arch. f. Gynak. 163: 50, 1937. Zondek and Aschheim: Quoted by Hofbauer, J.: AM. J. OBST. & GYNEC. 17: 603, 1929. Hisaw, F. L., and Velardo, J. T.: Proc. Sot. Exper. Biol. & Med. 89: 253, 1955. Rigler, R., and Rosenkranz, W.: Wien. klin. Wchnschr.. 69: 445, 1957. Shelesnvak. M. C.: In Pincus. Greaorv. editor: ‘Recent Progress in Hormone Rese&ch: New York, 1957, Academic Press, Inc., vol. 13, p. 269. Shelesnyak, M. C.: Bull. Sot. roy. belge Gyntc. et Obst. 27: 521, 1958. Kraicer, P., and Shelesnyak, M. C.: J. Endocrinol. 17: 324, 1958. Shelesnvak. M. C.: Mem. Sot. Endocrinol. 6: 84, 1958. ’ McKeowen, T., and Zuckerman. S.: Proc. Roy. Sot., London 124: 362, 1937: Leathem. 1. H.. and Crafts. R. C.: Anat. Rec. 76:‘90, 1946. Weller, C. V.: Am. J. Path. 11: 287, 1935. Meyer, R.: Ztschr. f. Geburtsh. u. Gyn~k. 74: 250. 1913. Loeb, L.: J. A. M. A. 50: 1897, 1908. Unterberger, F.: Monatschr. f. Geburtsh. u. GynIk. 55: 116, 1921. Goldstein, L. A., and Tatelbaum, A. J.: Am. J. Physiol. 91: 14, 1929. Lacassagne, A., Fehr, A., and Nyka, W.: Compt. rend. Sot. biol. 121: 385, 1936. Framingham Framingham,
Union Hospital Massachusetts
G.
TEDESCHI,
G.
C.
BOTTA,
Boston,
M.D. M.D.
Massachusetts
T H I s investigation has been provoked by the accidental observation of a vermiform appendix, removed incidentally at the time of cesarean section, which revealed an alteration at the serosal surface for which no gross explanation could be found. The alteration consisted of yellowish red raised nodules, varying in size from 0.1 to 0.3 cm. in the largest dimension, scattered throughout the serosal surface of the organ, including the mesoappendix. The microscopic sections revealed that these nodules consisted of masses of submesothelial decidual cells. This observation aroused our curiosity as to the frequency and the extent with which a decidual reaction takes place in the appendix during pregnancy; whether or not such a reaction is capable of eliciting symptoms that may stimulate acute appendicitis; and whether it possesses some kind of relationship with appendiceal endometriosis. In 1905, Hirschberg’ reported appendiceal decidual reaction in a woman operated upon for tubal pregnancy. Hofbauer,2 in a communication on decidual formation on the peritoneal surface of the gravid uterus, remarks, without further specification, that a few elements of decidua can be found in the mesenteriolum of the appendix. Recently recorded in the German literature3 is a case of “periappendicitis decidualis,” with symptoms of acute appendicitis. As far as we could determine, the only data available on
the frequency of the phenomenon are those of Israel and Roitman,4 who, in an editorial on prophylactic appendectomy in the course of gynecologic surgery, mention decidua-like cells in the serosa in 2 out of 50 appendices removed at cesarean section, namely 4 per cent of the cases. The earliest demonstration of decidual cells appearing outside of the endometrium in the course of pregnancy was made by Walker5 in 1887. He reported the occurrence of an ectopic decidual reaction in the pelvic peritoneum observed with a tubal pregnancy. This finding was confirmed in the peritoneal surface of the gravid uterus of an eclamptic patient by Pels-Leusden6 in 1895. A study by Schmor17 in 1897 indicates the occurrence of decidual reaction in pregnancy in the cul-de-sac and in the ovaries. By 1906 enough observations had been recorded to authorize Taussig* to introduce the term “ectopic decidual reaction” for the occurrence of decidual cells outside the endometrium during the course of pregnancy. GeipelQ, lo reported the occurrence of a decidual reaction in the peritoneal surface of the diaphragm, the splenic capsule, as well as in the pelvic lymph nodes. More recently, Israel and associatesll found evidence of a decidual reaction in the ovary in 80 per cent of their cases. A comparable evaluation of cervical biopsies obtained during pregnancy by McGee and SlateI” disclosed an incidence of decidual reaction in 20 per cent of their cases. Unique are the findings of decidual cells in the lung of a 26-year-old woman who died
From the Defiartment of Pathology, Massachusetts Memorial Hos#itals, Boston, Massachusetts, and the Department of Laboratories and Research, Framingham Union Hospital, Framingham, Massachusetts
631
632
Tedeschi
and
Botta
:
Fig. 1. Diffuse compact submesothelial decidual reaction of appendix. Note the cellular pleomorphism and at one point transition from flattened to low cuboidal cells of the mesotheiial lining (2 l-year-old, gravida i. para 0, first trimester, tubal pregnancy). (Hematoxylin and eosin. x180; reduced I/3.)
Fig. 2. Diffuse
loose type of submesothelial decidual reaction in the appendix of a 30year-old gravida iii, para i, third trimester of pregnancy (cesarean section). (Hematoxylin and eosin. x320; reduced ‘/3.)
4 months after delivery’” and cidual cells in the renal pelvisI Materials
and
that
of de-
methods
The present stludy is based on an evaluation of 90 appendices obtained from women during gestation. The material was contributed from the files of several hospitals in the Boston area: 24 cases each from the Boston Lying-in Hospital and Framingham Union Hospital, 20 from the Free Hospital for Women, 18 from the Massachusetts
Memorial Hospitals, and 4 from Boston City Hospital. In 21 of these cases, the appendectomy had been performed in connection with signs and symptoms of acute appendicitis. The specimens in this category pertained to women in various periods of gestation, from the first to the third trimester of pregnancy. In 41 additional cases, the appendices had been removed during operation for tubal pregnancy (first trimester). In one case the appendix was removed in the course of an
Volume Number
84 5
Appendiceal
decidual
reaction
in pregnancy
633
Fig.
3. Circumscribed submesothelial nodules of decidual cells in the appendix of a 26year-old gravida ii, para i, in the third trimester (cesarean section). (Hematoxylin and eosin. x320; reduced y3.)
Fig. 4. Appendiceal
endometrial implants with associated diffuse compact decidual reaction in a 29-year-old gravida i, para 0. Eighth week of gestation. (Hematoxylin and eosin. x 120 ; reduced v3. )
exploratory laparotomy for a ruptured hemorrhagic cyst (first trimester), and, in the remaining 27 cases, prophylactic appendectomy was performed at the time of cesarean section, at or near term. Two to three sections of each appendix were taken from different portions of the organ and examined. All cases were evaluated with sections stained with hematoxylin and eosin. In 5 of the most recent cases, PAS stain and stains for reticulum fibers were also applied.
An appendix was considered positive for decidual cells in the presence of large cells, from 20 to 30 p in the largest dimension, with pale, faintly basophilic, granulated cytoplasm, and a large nucleus with finely distributed chromatin. A fuchsinophilic intercellular matrix condensed around the cells in the PAS stained sections, as well as a marked argyrophilic intercellular network in the reticulumstained sections, were considered as additional diagnostic features.
634
Tedeschi
and
Botta
In 2 appendices, one obtained at the first trimester (tubal pregnancy) and the other at term (cesarean section), stains for glycogen and for fat (Sudan IV) were also carried out. Results Presence of ectopic decidua was found in 15 of the 90 appendices examined, namely, in 16.6 per cent of the cases. In one case, as mentioned in the introduction, a 31-yearold gravida iii, para ii, patient submitted to cesarean section, the finding was of such dimensions as to have given rise to a grossly detectable appendiceal alteration. In the remaining 14 cases, ectopic decidua was disclosed at the microscopic study of the sections. Of these 15 positive cases, 4 were in women in the first trimester of pregnancy, 10 at term or close to term, and one 4 days after delivery. The microscopic patterns of decidual reaction in our series mimicked very closely those noted in the ovary by Israel and associates.” They can be categorized in the following three main types: (a) diffuse compact decidual reaction, (b) diffuse loose decidual reaction, and (c) nodular decidual reaction. In the diffuse compact type (Fig. 1)) the cells lay in sheets beneath the mesothelial lining. However, they lacked the mosaic arrangement and cellular homogeneity of the latter. They frequently showed pronounced pleomorphism, including polygonal, spindleshaped, ovoid, and ameba-like cells provided with cytoplasmic processes. Multinucleated giant cells with occasional vacuoles in the cytoplasm were also noted. Presence of glycogen could be demonstrated in one of two . . appendices m which this determination was possible (first trimester). Neither of these 2 appendices revealed the presence of fats in the decidual cells in the sections stained by Sudan IV method. In the diffuse loose type of reaction (Fig. 2) the cells, whether isolated or in groups, rested in a loose matrix, which in the PAS stained sections showed prominent fuchsino-
September 1, 1962 Am. J. Obst. & Gynec.
philic pericellular condensation. In these areas of loose texture, the cells were also frequently enveloped by a network of argyrophilic fibers. The cellular pleomorphism was even more marked than in the cases which displayed compact decidual reaction. In the nodular type (Fig. 3)) the decidualike cells occurred in patches, both above and below the mesothelial lining. They varied in size from a mere cluster of 5 to 10 cells to tubercle-like nodules of 20 to 50 cells, particularly numerous in the proximity of the walls of minute blood capillaries. In all three types of reactions, the mesothelial lining was well preserved. Although it did not seem to participate in the formation of the decidua, the mesothelial cells in swollen and low some areas appeared cuboidal rather than flattened. Except for 2 cases in which ectopic decidua was seen in association with acute appendicitis, there was no evidence of a coexistent inflammatory reaction in any of the remaining cases. In 5 of the 15 cases in which a decidual reaction was noted, an exploratory laparotomy had been performed for symptoms of abdominal distress. In 3 cases, the preoperative diagnosis was appendicitis, in another, pelvic thrombophlebitis, and, in still another, no tentative diagnosis was made. A correlation of the clinical manifestations and of the pathologic findings in our series indicate that ectopic decidua, per se, in the absence of associated alterations, is not likely to give rise to signs and symptoms of abdominal distress. In the 5 cases of ectopic decidua in which the patient was operated on, the symptoms were explained by the finding of a gangrenous appendicitis in one case; in 2 other cases, by appendiceal endometriosis; and in another case by an acute appendicitis with associated carcinoid tumor. In one instance only, in which the exploratory laparotomy failed to reveal the cause of the abdominal distress, the possibility can be entertained that the appendiceal decidual reaction could have played a role in causing the abdominal distress that led to operation.
Volume Number
84 5
Comment The developmental potentialities of the subcelomic mesenchyme provide the explanation for the formation of ectopic decidua in the appendix. The cells, transformed into decidual cells, are stromal elements with the same embryonic origin of the cells from which the endometrial stroma develops. Thus, ectopic decidual formation presupposes the persistence in the subcelomic mesenchyme of the adult of undifferentiated stromal cells. Possible transitional stages from stem cells to decidual cells have been traced by Hofbauer2 in the omentum. Similar transitional patterns have been noted in the appendices of our series. The cell primarily involved in the process appeared to be a small spindle-shaped cell resembling a fibroblast, and its transformation into decidual cells took place through a progressive increase in the amount of cytoplasm and enlargement of the nucleus. Our observations are in agreement with Mallory’s statementI’ that the decidual cell is an offspring of the fibroblast. Evidence in support of this view has recently been provided by Stuermer and Stein’s demonstration16 that endometrium grown in vitro displays the structure of fibroblastic tissue in ordinary media, whereas when serum from umbilical cord is added to the medium it displays an epithelioid pattern, giving rise to sheets of decidua-like cells. Although, in the appendices of our series, the mesothelial lining did not seem to participate in the formation of decidua, in individual cases it showed evidence of proliferative activity with tendency to stratification and swelling of individual cells. Embryology gives support to the view that pelvic peritoneum, germinal epithelium, and uterine epithelium are all derivatives of the celomic epithelium. These genetic relationships can be used in explanation of the formation of endometrial glands in 2 of our cases, as well as of the mesothelial metaplastic change noted in several of the appendices in our series of cases. Decidual transformation constantlv takes
Appendiceal
decidual
reaction
in pregnancy
635
place in the endometrium in the course of pregnancy. Inasmuch as a similar reaction can potentially occur, but actually does not, as a rule, in other organs which likewise originate from the mesenchyme of the urogenital ridge, the nature of the factor or factors which are responsible for the occurrence of ectopic decidua are still open to speculation. All evidence points to the endocrine effects of progesterone as a mediating factor in decidual formation. Speert17 has evaluated, in the endometrial decidua of ectopic gestation, the hormonal influence of pregnancy, disassociated from the chemical action of the trophoblast. Formation of decidua may also take place in the absence of pregnancyl’* 22; decidua menstrualis is an example.23p 24 Wallart,25> 26 at the postmortem examination of 7 postmenopausal women, 5 of whom were over 70 years of age, noted decidua cells both at the surface of the ovary and within corpora albicantia. Aschheim and Zondek’s demonstrationz7 has shown decidua formation in the uterine mucosa of virgin rodents submitted to repeated transplantation of anterior hypephyseal substance. Hisaw and Velardoz8 have demonstrated that progesterone is more effective in forming decidua in the ovariectomized and adrenalectomized rat, and that ACTH inhibits the action of progesterone by way of the adrenal cortex. An experiment by Rigler and Rosenkram? in pseudopregnant animals indicates that the spleen plays a role in the development of decidua. Deciduomas have been induced in the experimental animal by intravenous and intraperitoneal injections of histamine and histamine releasers; on the contrary, antihistamines were seen to suppress the phenomenon 30-33 McKeowen and Zuckerman34 have produced endometrial progestational changes, in one instance accompanied by the formation of decidua, in rats injected with testosterone. Leathem and Craftss5 have
636
Tedeschi
and
September 1, 1962 Am. J. Ohst. & Gym.
Botta
shown
endometrial progestational changes in adrenalectomized cats that were spayed, submitted to desoxycorticosterone acetate treatment. This indicates that progesterone is not the only steroid hormone able to produce progestational changes. Hormonal effects are inherently systemic in nature; also, it is the potential propert) of the subcelomic mesenchyme to form decidua. Since ectopic decidua does not constantly take place under suitable hormonal stimulation, the occasionality of the finding leads to the search for trigger mechanisms. WelleP has stressed the point that the sites of ectopic decidua reaction correspond to the regions where endometriosis is most commonly found. Meye? has pointed out that the decidual response is most likely to take place at the sites of pre-existing inflammation, particularly those associated with formation of adhesions. In support of this view, Ober and associateP mention the occurrence of ectopic decidua during pregnancy in laparotomy and hysterectomy scars and in association with extrinsic and intrinsic endometriosis. The same investigators, in a series of 16 ovarian deciduomas in nonpregnant women, found coexistent endometriosis in 5 cases and paraovarian adhesions in 14. In 9 of these cases, the patient had been previously submitted to radiation therapy. Experimental evidence adds strength to the concept that local irritation can be a mediating factor. The synergistic action of progesterone and local trauma has been shown by Loeb3* in the uterus of guinea pigs. This has been confirmed by Unterberger’s experiment.39 Similarly, Goldstein and Tatelbaum’” have succeeded in eliciting deciduomas in guinea pigs, both in the endometrium and beneath the uterine serosa, at the point of incisional trauma, following administration of autologous lutein extracts. In Lacassagne and his co-workers’ experiment,“l radiation
injury proved to be instrumental in the occurrence of uterine deciduomas. Associated conditions, possibly implied as intermediate factors in the formation of decidua, were found in only 4 of our 15 cases: acute gangrenous appendicitis in one case, endometriosis in 2 others, and a carcinoid tumor and acute appendicitis in the fourth. In the remaining 11 cases, all the women were young and healthy. This necessarily brings into consideration the possible role of ontogenic factors. The failure of the subcelomic mesenchyme to transform into decidua, or its ability to do so under suitable hormonal stimulation, might actually rest on the disappearance or on the persistence of the potential properties that are inherent to the tissue involved. Summary
A series of 90 appendices removed during various stages of gestation were analyzed for the presence of ectopic decidual reaction. Fifteen showed the presence of submesothelial decidual cells, namely 16.6 per cent. In one case, the reaction was so pronounced as to have given rise to grossly detectable alterations. In the remaining cases, the finding was discovered on routine microscopic examination. Four of the cases of decidual reaction were associated with other findings; endometriosis in 2, acute gangrenous appendix in one, and acute appendicitis and a carcinoid tumor in another. The clinical significance of decidual formation in the vermiform appendix, as well as the pathogenesis and mechanisms operating in its formation, are discussed. We wish to express our appreciation to Dr. John M. Craig for having placed at our disposal the cast material from the files of the Boston Lying-in Hospital and the Free Hospital for Women and to Dr. Benjamin Tenney, Jr., for having consented for us to include in our series the cases from the Boston City Hospital.
REFERENCES 1.
Hirschberg, 1904.
A.:
Arch.
f. Gynsk.
74: 620,
‘-’3
Hofbauer, 603.
1929.
J.: AM. J.
OBST.
&
GYNEC. 17:
Volume Number
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
84 5
Kovacs, K., and Jakobovits, A.: Zentralbl. f. Gynlk. 75: 1987, 1953. Israel, S. L., and Roitman, H. B.: Obst. & Gynec. 10: 102, 1957. Walker. A.: Virchows Arch. f. oath. Anat. 107: 72, 1887. Pels-Leusden: Quoted by Hofbauer, J. : AM. J. OBST. & GY~EC. 17: 603, 1929. Schmorl. Cl. G.: Monatschr. f. Geburtsh. u. GynLk. 5: 46, 1897. Taussig, F. J.: Surg. Gynec. & Obst. 2: 292, 1906. Geipel, P.: Arch. f. Gynlk. 106: 177, 1916. Geipel, P.: Arch. f. GynPk. 131: 650, 1927. Israel, S. L., Bubenstone, A., and Meranze, D. R.: Obst. & Gynec. 3: 399, 1954. McGee, W. B., and Slate, T. A.: California Med. 82: 306, 1955. Park, W. W.: J. Path. & Bact. 67: 563, 1954. Bettinger, H. F.: J. Path. & Bact. 59: 686, 1947. Mallory, F. B.: Quoted by Hofbauer, J.: AM. J, OBST. & GYNEC. 17: 603, 1929. Stuermer, V. M., and Stein, R. J.: AM. J. OBST. & GYNEC. 60: 1332. 1950. Speert, H.: AM. J. OBST. h GYNBC. 76: 491, 1958. TeLinde, R. W., and Henriksen, E.: Am. J. OBST. & GYNEC. 39: 733, 1940. Bassis, M.: AM. J. OBST. & GYNEC. 72: 1029, 1956. Ober, W. B., Grady, H. G., and Schoenbucher, A. K.: Am. J. Path. 33: 199, 1957. Wagner: Quoted by Hofbauer, J.: AM. J. OBST. Sr GYNEG. 17: 603, 1929. Greenblatt, R. B., and Krafka, J.: Arch. Path. 31: 634, 1941.
Appendiceal
23. 24. 25. 26. 27. 28. 29. 30.
31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.
decidual
reaction
in pregnancy
637
Abraham, E. G.: Zentralbl. f. Gynak. 56: 464, 1932. Reinhart, H. L.: Am. J. Clin. Path. 5: 365, 1935. Wallart, J.: Gynec. & Obst. 33: 134, 1936. Wallart, J.: Arch. f. Gynak. 163: 50, 1937. Zondek and Aschheim: Quoted by Hofbauer, J.: AM. J. OBST. & GYNEC. 17: 603, 1929. Hisaw, F. L., and Velardo, J. T.: Proc. Sot. Exper. Biol. & Med. 89: 253, 1955. Rigler, R., and Rosenkranz, W.: Wien. klin. Wchnschr.. 69: 445, 1957. Shelesnvak. M. C.: In Pincus. Greaorv. editor: ‘Recent Progress in Hormone Rese&ch: New York, 1957, Academic Press, Inc., vol. 13, p. 269. Shelesnyak, M. C.: Bull. Sot. roy. belge Gyntc. et Obst. 27: 521, 1958. Kraicer, P., and Shelesnyak, M. C.: J. Endocrinol. 17: 324, 1958. Shelesnvak. M. C.: Mem. Sot. Endocrinol. 6: 84, 1958. ’ McKeowen, T., and Zuckerman. S.: Proc. Roy. Sot., London 124: 362, 1937: Leathem. 1. H.. and Crafts. R. C.: Anat. Rec. 76:‘90, 1946. Weller, C. V.: Am. J. Path. 11: 287, 1935. Meyer, R.: Ztschr. f. Geburtsh. u. Gyn~k. 74: 250. 1913. Loeb, L.: J. A. M. A. 50: 1897, 1908. Unterberger, F.: Monatschr. f. Geburtsh. u. GynIk. 55: 116, 1921. Goldstein, L. A., and Tatelbaum, A. J.: Am. J. Physiol. 91: 14, 1929. Lacassagne, A., Fehr, A., and Nyka, W.: Compt. rend. Sot. biol. 121: 385, 1936. Framingham Framingham,
Union Hospital Massachusetts