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Adenocarcinoma of the endometrium following radiation therapy and associated with hilus cell hyperplasia
CURRENT OPINION Clinical problems
Adenocarcinoma of the endometrium following radiation therapy and associated with hilus cell hyperplasia
Case presentation
weight loss, anemia, anorexia, and a mass in the right side of the abdomen. She was admitted to Presbyterian Hospital where an adenocarcinoma of the cecum was resected and an ileotransverse colostomy was performed. The regional lymph nodes were free of tumor on microscopic examination, and no tumor implants were seen in the pelvis at exploration. She remained in good health until the present admission. In July, 1960, vaginal staining began, continuing to the time of admission and progressing to frank flowing without clots. She consulted her personal physician late in October and was admitted on Nov. 8, 1960. There were no other complaints on admission. Specifically, she denied hirsutism, change in voice, weight, or body build, alopecia, or acne. Physical examination was essentially negative. There were no stigmas of androg€1cnization. The breasts were small and atrophic, free from discharge or masses. Abdominal scars consistent with previous surgical procedures were present, and there was a zone of dry, scaly, somewhat pigmented skin over the suprapubic area. Pelvic examination revealed atrophic external genitals consistent with the patient's age. The introitus admitted two fingers tightly, and the vaginal mucosa
Richard Schuldenfrei, M.D. Department of Obstetrics and Gynecology Albert Einstein College of Medicine A 65-year-old white widow, gravida m, para i, was admitted to Sloane Hospital for Women on Nov. 8, 1960, because of painless vaginal bleeding of 5 months' duration. Menarche was at age 18; menstrual cycles were 24 days with flow 3 days. She had a normal term delivery in 1917 at 22 years and spontaneous abortions in 1923 and 1926, both treated by curettage. In 1932, at the age of 37, she developed hematuria and was treated at Bellevue Hospital with a clinical diagnosis of carcinoma of the bladder. She received 2,800 r air dose through four pelvic ports with a 200 kv. machine, giving an estimated midpelvic dose of 1,350 ± 200 r. Following this treatment menses ceased. Because of recurrent hematuria and passage of gravel, suprapubic cystostomy and curettage of the bladder was done 7 months later. Tissue removed at this time was diagnosed as "infected papilloma of bladder, with ulceration and calcareous encrustation." She remained asymptomatic for 16 years. In 1948 at the age of 53 she developed 1186
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was thin, shiny, and delicate. The cervix was clean and small. The uterus was small, anterior, and freely movable. There were no adnexal masses. Preoperative endocrine studies were not done. Exfoliative cytology was Class II with trichomonads; there was no cornification. Other laboratory studies were unrevealing. Dilatation and curettage was done 2 days after entry, and microscopic examination yielded a diagnosis of a welldifferentiated adenocarcinoma of the endometrium (Fig. 1). A total abdominal hysterectomy and bilateral salpingo-oophorectomy were done on November 16. She was discharged 10 days later after an uneventful postoperative course. Pelvic irradiation of 4,000 r to the midpelvis by the betatron was scheduled. Pathologic observations. Gross. The uterus was small and atrophic, weighing 60 grams. The exocervix and endocervix were normal. The endometrial cavity contained a fungating necrotic tumor arising from the right cornu. It measured 4 em. in average diameter and invaded the subjacent myometrium to a depth of 0.5 em. Elsewhere the myometrium averaged 1.2 em. in thickness. The Fallopian tubes were thin and atrophic. The right ovary measured 3 by 2 by 2 em., the left ovary 3.5 by 1.5 by 1.0 ern. Their external surfaces showed normal convolutions, and on section numerous corpora albicantia were seen. No remarkable features were seen in the hila. Microscopic. The endometrium was largely replaced by a well-differentiated overgrowth of neoplastic glands exhibiting the usual cellular features of malignancy. Mucus secretion was demonstrable by the HotchkissMcManus-PAS technique. Invasion of lymphatic and venous channels in the subjacent myometrium was readily demonstrable. In areas where neoplastic transformation had not occurred, the endometrium was a thin, atrophic mucosa with simple tubular glands embedded in a compact cellular stroma. The ovarian cortices were of normal postmenopausal cellularity with no follicular structures, and there were numerous corpora albicantia in the inner cortex and medulla.
Clinical problems
1187
Fig. 1. Uterine curettings reveal a well-differentiated adenocarcinoma. (Hematoxylin and eosin. xlOO.j
Fig. 2. Section of ovary showing an intracortical nest of polyhedral cells with abundant pale-staining cytoplasm. (Hematoxylin and eosin. x40.)
Fig. 3. Crystalloids of Reinke are seen clearly in a section overstained with eosin. (Hematoxylin and eosin. x600.)
1188
Clinical problems .~III.
Fig. 4. A delicate meshwork of argyrophilic fibers surrounds groups of the proliferated ovarian hilus cells. (Wild er's reticulum stain. x 220.)
An occasional nest of polyhedral cells was found in the cortex (Fig. 2). Such nests were indistinctly marginated, and the polyhedral cells were relatively small, arranged in a mosaic, and conforming in every particular to the cells seen in greater quantity in the region of the hilus. Occupying a great proportion of the hilar area in both ovaries, somewhat more extensive on the right than on the left, was a diffuse proliferation of large and small nests and cords of polyhedral cells scattered in and among the nerves and blood vessels of the area. Although the proliferation was multifocal and none of the clusters was grossly visible as a discrete mass, some of the larger aggregates approached tumefaction. The largest single cluster measured slightly less than 1 mm. in diameter. The constituent cells were polyhedral, measuring 30 to 40 p. in diameter, with a centrally placed, relatively unstructured nucleus, sharply defined cell margins, and an eosinophilic cytoplasm that was often abundant but sometimes foamy, even vacuolated. Yellow-brown lipochrome pigment was readily identified in sections counterstained lightly with eosin. Crystalloids of Reinke (Fig. 3) were easily identified in sections stained more heavily with eosin. They stained dark black with Heidenhain's iron hematoxylin and bright orange-red with Masson's trichrome stain. Delicate sinusoidal blood vessels and an inconspicuous collagenous fibrous network
:'\ovcmfwr , 1'161 Ob>t. & Gynrc .
J.
formed the stroma for these nests, and sections stained by Wilder's method for reticulum revealed delicate argyrophilic fibrils (Fig. 4 ) coursing around small groups of these cells. In a few fields typical nests of these polyhedral cells were seen in intimate association with nonmyelinated nerve fibers. The proliferated polyhedral cells were identified as ovarian hilus cells. Postoperative studies. In the absence of any overt indication, endocrine studies were not performed prior to operation. Following operation an x-ray film of the skull revealed a normal sella turcica. Urinary 17 -ketosteroid excretion was 5.2 mg. per 24 hours. Urinary gonadotropin ( FSH ) excretion was more than 50 and less than 100 M.U. per 24 hours. These values are normal in this laboratory for a postmenopausal woman. Problem: Would you discuss this problem particularly as it relates to hilus cell hyperplasia. Consultation Nikolas A. Janov ski, M.D. , and William B. Ober, M.D. , New York , N ew York Columbia University, College of Physicians and Surgeons Admittedly, it is often difficult to draw a precise distinction between a benign endocrine adenoma and diffuse hyperplasia; nevertheless, we have elected to interpret the hilus cell overgrowth as hyperplasia because it was bilateral and there was no discrete, macroscopic nodule, however small. Husslein1 has reported a case in which a discrete hilus cell tumor 4.5 by 3.5 mm. was found in one ovary of a 60-year-old woman who developed adenocarcinoma of the endometrium 25 years after x-ray castration for uterine myomas. Shaw and Dastur 2 have reported 4 cases in which readily detectible clusters of ovarian hilus cells were found in association with endometrial carcinoma .; one of their patients, a nullipara 57 years old, had been treated 9 years previously for uterine hemorrhage with 2,400 mg.hr. of radium. In a series of cases of endometrial adenocarcinoma they found ovarian hilus cells to
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be more prominent than in the controls. However, it is difficult to determine from their account whether there was a true hyperplasia of hilus cells or whether their observations merely represent the upper limits of a normal observation in the ovaries of a group of postmenopausal women. Significantly, there was no evidence of androgenization in any of the 4 cases they studied in detail, or in Husslein's case, or in the present case. Simard and Simard 3 describe the case of a 67 -year-old woman who developed enlargement and tenderness of the breasts concurrently with disappearance of hot flashes. The clitoris was also enlarged. The ovaries showed not only hyperplasia of hilus cell nests but foci of luteinization of cortical stroma. The endometrium showed cystic glandular hyperplasia. Symptoms regressed following hysterectomy and bilateral salpingo-oophorectomy. They referred to the hilus cells as sympathicotopic cells, and they did not recognize the luteinization as such; however, Scully 4 recognized the luteinization from their photomicrographs, and we concur in his interpretation. In his own case, Scully observed a 7 by 6 mm. nodule of hilus cells in one ovary and a 2 mm. nodule in the other ovary of a 73-year-old woman with adenocarcinoma of the endometrium. There was also patchy, focal luteinization of cortical stroma. The patient exhibited moderate facial hirsutism and the endometrial smear was well cornified. Two years after hysterectomy and bilateral salpingo-oophorectomy, hirsutism and cornification of exfoliated cells were still present. While hilus cells are occasionally detectible in the ovaries of newborn babies, infants, and children, they apparently increase with age, particularly after the menopause, and are identified more readily in sections of menopausal and postmenopausal women. Prominence of ovarian hilus cells have been observed in such diverse contexts as anencephaly, 5 pregnancy, 6 • 7 ovarian dysgenesis with and without masculinization, 8 • 9 and choriocarcinoma. 6 • 10 Sternberg and associates6 were able to produce bilateral hyper-
Clinical problems 1189
plasia of hilus cells in the ovaries of adult women following injection of large doses of chorionic gonadotropin. It is interesting to speculate that the hyperplasia of hilus cells in the case reported here may reflect the continuous unopposed stimulation by pituitary gonadotropins at postmenopausal levels over a period of 28 years following pelvic irradiation. However, the gonadotropin level was not very much elevated, and, despite the corroborative support of Husslein's case 1 and Case 3 of Shaw and Dastur, 2 hyperplasia of hilus cells can occur without antecedent pelvic irradiation and subsequent failure of pituitary suppression. The possible relationship of hilus cell proliferation to neurogenic stimuli is suggested by the report by Scully and Cohen 11 of a ganglioneuroma of the adrenal medulla which contained widely distributed hilus cells with crystalloids of Reinke. Such neuroendocrine relationships are reinforced by the common observation that hilus cells are often normally found in close topographic association with nonmyelinated nerve fibers. Androgenic effects of both tumor and hyperplasia of hilus cells has been reported and well documented by SternbergY MerrilP 3 has tabulated the reported cases of tumor of hilus cell origin. Apparently, in all 10 patients androgenic effects were present to some degree, and most of them showed remission of masculinization following surgical removal of the tumor, but the 17-ketosteroid level was rarely significantly elevated. One of these patients was pregnant, and one of us (W. B. 0.) has seen another example of hilus cell tumor of the ovary in pregnancy; it is difficult to reconcile the concept of "masculinization" with the presence of an intrauterine gestation. Clinical androgenization is less constant when there is hyperplasia of the hilus cells as distinguished from true tumor formation. It is possible that some of the reported instances of hyperplasia merely represent the upper limit of a normal cellular constituent; however, it is equally possible that hyperplasia need not be accompanied by parallel hyperfunction. In Scully's case 4 as well as in the case of Simard and Simard 3 there was both clinical and morphologic evi-
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dence of hyperestrogenism. It is tempting to assign the increased estrogen production to the patches of luteinized cortical stroma, but chemical proof is lacking in all the cases under discussion, and we must reserve judgment upon which cell elaborates which hormone (if any) until more direct evidence is at hand. There is some evidence that interstitial cells in the testis can elaborate estrogens. Herrmann and associates14 cited interstitial cell tumors with gynecomastia as a source of estrogens, and Maddock and Nelson 15 found increase in Leydig cells and elevated urinary estrogens in men treated with chorionic gonadotropin. Scully 16 has reported the case of a postmenopausal woman with polypoid cystic hyperplasia of the endometrium and early adenocarcinoma; one ovary contained a tumor composed of fasciculated spindle cells resembling a thecoma in which there were scattered clusters of hilus cells containing crystalloids and other nests of small epithelial cells consistent with either granulosa cells or Sertoli cells. The relationship of hilus cell hyperplasia to endometrial adenocarcinoma in this case, or in any other case, is entirely speculative. In the cases of true hilus cell tumor, one patient had normal menses and another was pregnant, but in the postmenopausal patients the endometrium, when reported, was atrophic, appropriate to the patients' age. This is in keeping with the observation by Greene 17 that about 85 per cent of endometrial adenocarcinomas arise in an atrophic, not a hyperplastic, endometrium. However, the implication inherent in Shaw and Dastur's original communication has been pursued by several observers. Sommers and Meissner 18 found 2 instances of hilus cell hyperplasia in 38 patients with endometrial cancer. Jackson and Dockerty19 described the ovary in relation to the Stein-Leventhal syndrome: 27 of their patients did not have endometrial neoplasm and were treated by ovariotomy and wedge resection; 16 of their patients had an associated endometrial adenocarcinoma and were treated by hysterectomy and bilateral salpingo-oophorectomy.
J.
Obst. & Gyn<·c.
They observed 5 instances of hilus cell hyperplasia in the 16 patients with endometrial adenocarcinoma, but warn that the two groups are not comparable because tissue from the ovarian hilus was not removed in those patients undergoing wedge resection. Sherman and Woolf 20 found hyperplasia of hilus cells in 81.9 per cent of 133 patients with endometrial adenocarcinoma, in 23 per cent of 52 patients with postmenopausal endometrial hyperplasia, and in only 5.9 per cent of 34 patients with normal atrophic postmenopausal endometrium. They correlated elevated LH levels with these observations, and in 31 of 31 patients ( 100 per cent) with adenocarcinoma of the endometrium the preoperative urinary LH level was elevated above normal, falling to normal levels in all patients after bilateral oophorectomy. Unfortunately, there was no preoperative indication for endocrine studies in this patient. However, at no time was there any clinical or morphologic evidence of excess estrogenic or androgenic activity. It remains to be demonstrated whether the doctrine of steroid interconversion can be applied to hilus cells, i.e .. whether cells which have the capacity to synthesize androgens can under appropriate conditions synthesize estrogens. The total of our knowledge of the hilus cell in this respect is that it is under the control of gonadotropic hormones, probably LH, to sorne extent, and that when neoplastic it can elaborate androgenic substances, albeit inconstantly. The relation of the hilus cell and its secretions to the pituitary-ovarian relationship and the effect of disturbances of this relationship upon endometrial carcinogenesis merit further investigation. This case falls into two other oncologic categories which may equally well bear upon carcinogenesis. It is an example of "multiple primary malignant neoplasm." 21 Even though there is no histopathologic documentation of the carcinoma of the bladder for which the patient received x-ray therapy, she did develop an adenocarcinoma of the cecum 16 years later and adenocarcinoma of the endometrium 28 years later. If one cares to speculate upon a constitutional "tumor diath-
Clinical problems
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esis," this case is as good as any. In fact, it is also a matter for conjecture that this patient may have had as a constitutional factor a greater than average complement of hilus cells as a young girl and that their presence in increased number may have been responsible for the delay of menarche until the age of 18 as well as for their ready postmenopausal overgrowth. Also, she presents an example of "malignant tumor of the uterus developing following pelvic irradiation." The statistical basis for the validity of this mode of carcinogenesis has been debated pro and con, 2 ~-~ 8 but in this case there is the added feature that the adenocarcinoma of the cecum, as well as the adenocarcinoma of the endometrium, might also be attributed to this background. If this hypothesis has any validity, the tumor (or tumors) would be a direct effect of ionizing irradiation and the hilus cell hyperplasia a secondary effect. At this juncture one might speculate that Beren-
REFERENCES
1. Husslein, H.:
Zentralbl. Gynak. 73: 1649,
1951. 2. Shaw, W., and Dastur, B.: Brit. M. J. 2: 4619, 1949. 3. Simard, L. C., and Simard, R.: Rev. canad. bioi. 3: 388, 1944. 4. Scully, R. E.: AM. J. 0BST. & GYNEC. 65: 1248, 1953. 5. Kohn, A.: Endokrinologie 1: 3, 1928. 6. Sternberg, W. H., Segaloff, A., and Gaskill, C. J.: J. Clin. Endocrinol. 13: 139, 1953. 7. Branon, D.: Am. J. Path. 3: 343, 1927. 8. Gordan, G. S., Overstreet, E. W., Traut, H. F., and Winch, G. A.: ]. Clin. Endocrinol. 15: 1, 1955. 9. Greenblatt, R. B., Carmona, N., and Higdon, L.: J. Clin. Endocrinol. 16: 235, 1956. 10. Ober, W. B.: Unpublished observations. 11. Scully, R. E., and Cohen, R. B.: Cancer 14: 421, 1961. 12. Sternberg, W. H.: Am. J. Path. 25: 493, 1949. 13. Merrill, J. A.: AM. J. 0BST. & GvNEC. 78: 1258, 1959. 14. Herrmann, W. L., Buckner, F., and Baskin, A.: ]. Clin. Endocrinol. 18: 834, 1958. 15. Maddock, W. 0., and Nelson, W. 0.: J. Clin. Endocrinol. 12: 985, 1952.
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blum's concept of cocarcinogenesis 29 might be applicable. If so, the ionizing radiation would serve as the initiating action and the hypothetical endocrine alteration would serve as the promoting action. Last, we must remember that in any given patient we do not know the cause of endometrial carcinoma. Indeed, the tumor need not arise from any one given set of pathogenetic circumstances. Adenocarcinoma of the endometrium may develop as the end point of a number of independent pathogenetic pathways. A number of possible mechanisms may, as in the present case, be found in the patient's history or in the pathologic observations. Whether such mechanisms operate independently or in concert is beyond conjecture. Indeed, it is even probable, in the light of present-day ignorance, that the tumor in the uterus arose independently of any of the factors mentioned in the above discussion.
16. Scully, R. E.: J. Clin. Endocrinol. 13: 1254, 1953. 17. Greene, R. R., Roddick, J. W., Jr., and Milligan, M.: Ann. New York Acad. Sc. 75: 586, 1959. 18. Sommers, S. C., and Meissner, W. A.: Cancer 10: 516, 1957. 19. Jackson, R. L., and Dockerty, M. B.: AM. J. 0BST. & GYNEC. 73: 161, 1957. 20. Sherman, A. I., and Woolf, R. B.: AM. J. 0BST. & GYNEC. 77: 233, 1959. 21. Moerte1, C. G., Dockerty, M. B., and Bagenstoss, A. H.: Cancer 14: 221, 1961. 22. Scheffey, L. C.: AM. J. OBsT. & (;YNEc. 44: 925, 1942. 23. Corscaden, J. A., Fertig, J. W., and Gusberg, S. B.: AM. J. 0BsT, & GvNEC. 51: I, 1946. 24. Speert, H., and Peightal, T. C.: AM. J. 0BST. & GYNEC. 57: 261, 1949. 25. Palmer, J. P., and Spratt, D. W.: AM. J. 0BST. & GYNEC. 72: 497, 1956. 26. Stander, R. W.: Obst. & Gynec. 10: 223, 1957. 27. Copeland, W. E., Nelson, P. K., and Payne, F. L.: AM. J. 0BsT. & GvNEC. 73: 615, 1957. 28. Hofmann, D., and Kunzler, E.: Med. Klin. 15: 68. 1960. 29. Berenblum, L: Cancer Res. 14: 471, 1954.
Adenocarcinoma of the endometrium following radiation therapy and associated with hilus cell hyperplasia
Case presentation
weight loss, anemia, anorexia, and a mass in the right side of the abdomen. She was admitted to Presbyterian Hospital where an adenocarcinoma of the cecum was resected and an ileotransverse colostomy was performed. The regional lymph nodes were free of tumor on microscopic examination, and no tumor implants were seen in the pelvis at exploration. She remained in good health until the present admission. In July, 1960, vaginal staining began, continuing to the time of admission and progressing to frank flowing without clots. She consulted her personal physician late in October and was admitted on Nov. 8, 1960. There were no other complaints on admission. Specifically, she denied hirsutism, change in voice, weight, or body build, alopecia, or acne. Physical examination was essentially negative. There were no stigmas of androg€1cnization. The breasts were small and atrophic, free from discharge or masses. Abdominal scars consistent with previous surgical procedures were present, and there was a zone of dry, scaly, somewhat pigmented skin over the suprapubic area. Pelvic examination revealed atrophic external genitals consistent with the patient's age. The introitus admitted two fingers tightly, and the vaginal mucosa
Richard Schuldenfrei, M.D. Department of Obstetrics and Gynecology Albert Einstein College of Medicine A 65-year-old white widow, gravida m, para i, was admitted to Sloane Hospital for Women on Nov. 8, 1960, because of painless vaginal bleeding of 5 months' duration. Menarche was at age 18; menstrual cycles were 24 days with flow 3 days. She had a normal term delivery in 1917 at 22 years and spontaneous abortions in 1923 and 1926, both treated by curettage. In 1932, at the age of 37, she developed hematuria and was treated at Bellevue Hospital with a clinical diagnosis of carcinoma of the bladder. She received 2,800 r air dose through four pelvic ports with a 200 kv. machine, giving an estimated midpelvic dose of 1,350 ± 200 r. Following this treatment menses ceased. Because of recurrent hematuria and passage of gravel, suprapubic cystostomy and curettage of the bladder was done 7 months later. Tissue removed at this time was diagnosed as "infected papilloma of bladder, with ulceration and calcareous encrustation." She remained asymptomatic for 16 years. In 1948 at the age of 53 she developed 1186
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was thin, shiny, and delicate. The cervix was clean and small. The uterus was small, anterior, and freely movable. There were no adnexal masses. Preoperative endocrine studies were not done. Exfoliative cytology was Class II with trichomonads; there was no cornification. Other laboratory studies were unrevealing. Dilatation and curettage was done 2 days after entry, and microscopic examination yielded a diagnosis of a welldifferentiated adenocarcinoma of the endometrium (Fig. 1). A total abdominal hysterectomy and bilateral salpingo-oophorectomy were done on November 16. She was discharged 10 days later after an uneventful postoperative course. Pelvic irradiation of 4,000 r to the midpelvis by the betatron was scheduled. Pathologic observations. Gross. The uterus was small and atrophic, weighing 60 grams. The exocervix and endocervix were normal. The endometrial cavity contained a fungating necrotic tumor arising from the right cornu. It measured 4 em. in average diameter and invaded the subjacent myometrium to a depth of 0.5 em. Elsewhere the myometrium averaged 1.2 em. in thickness. The Fallopian tubes were thin and atrophic. The right ovary measured 3 by 2 by 2 em., the left ovary 3.5 by 1.5 by 1.0 ern. Their external surfaces showed normal convolutions, and on section numerous corpora albicantia were seen. No remarkable features were seen in the hila. Microscopic. The endometrium was largely replaced by a well-differentiated overgrowth of neoplastic glands exhibiting the usual cellular features of malignancy. Mucus secretion was demonstrable by the HotchkissMcManus-PAS technique. Invasion of lymphatic and venous channels in the subjacent myometrium was readily demonstrable. In areas where neoplastic transformation had not occurred, the endometrium was a thin, atrophic mucosa with simple tubular glands embedded in a compact cellular stroma. The ovarian cortices were of normal postmenopausal cellularity with no follicular structures, and there were numerous corpora albicantia in the inner cortex and medulla.
Clinical problems
1187
Fig. 1. Uterine curettings reveal a well-differentiated adenocarcinoma. (Hematoxylin and eosin. xlOO.j
Fig. 2. Section of ovary showing an intracortical nest of polyhedral cells with abundant pale-staining cytoplasm. (Hematoxylin and eosin. x40.)
Fig. 3. Crystalloids of Reinke are seen clearly in a section overstained with eosin. (Hematoxylin and eosin. x600.)
1188
Clinical problems .~III.
Fig. 4. A delicate meshwork of argyrophilic fibers surrounds groups of the proliferated ovarian hilus cells. (Wild er's reticulum stain. x 220.)
An occasional nest of polyhedral cells was found in the cortex (Fig. 2). Such nests were indistinctly marginated, and the polyhedral cells were relatively small, arranged in a mosaic, and conforming in every particular to the cells seen in greater quantity in the region of the hilus. Occupying a great proportion of the hilar area in both ovaries, somewhat more extensive on the right than on the left, was a diffuse proliferation of large and small nests and cords of polyhedral cells scattered in and among the nerves and blood vessels of the area. Although the proliferation was multifocal and none of the clusters was grossly visible as a discrete mass, some of the larger aggregates approached tumefaction. The largest single cluster measured slightly less than 1 mm. in diameter. The constituent cells were polyhedral, measuring 30 to 40 p. in diameter, with a centrally placed, relatively unstructured nucleus, sharply defined cell margins, and an eosinophilic cytoplasm that was often abundant but sometimes foamy, even vacuolated. Yellow-brown lipochrome pigment was readily identified in sections counterstained lightly with eosin. Crystalloids of Reinke (Fig. 3) were easily identified in sections stained more heavily with eosin. They stained dark black with Heidenhain's iron hematoxylin and bright orange-red with Masson's trichrome stain. Delicate sinusoidal blood vessels and an inconspicuous collagenous fibrous network
:'\ovcmfwr , 1'161 Ob>t. & Gynrc .
J.
formed the stroma for these nests, and sections stained by Wilder's method for reticulum revealed delicate argyrophilic fibrils (Fig. 4 ) coursing around small groups of these cells. In a few fields typical nests of these polyhedral cells were seen in intimate association with nonmyelinated nerve fibers. The proliferated polyhedral cells were identified as ovarian hilus cells. Postoperative studies. In the absence of any overt indication, endocrine studies were not performed prior to operation. Following operation an x-ray film of the skull revealed a normal sella turcica. Urinary 17 -ketosteroid excretion was 5.2 mg. per 24 hours. Urinary gonadotropin ( FSH ) excretion was more than 50 and less than 100 M.U. per 24 hours. These values are normal in this laboratory for a postmenopausal woman. Problem: Would you discuss this problem particularly as it relates to hilus cell hyperplasia. Consultation Nikolas A. Janov ski, M.D. , and William B. Ober, M.D. , New York , N ew York Columbia University, College of Physicians and Surgeons Admittedly, it is often difficult to draw a precise distinction between a benign endocrine adenoma and diffuse hyperplasia; nevertheless, we have elected to interpret the hilus cell overgrowth as hyperplasia because it was bilateral and there was no discrete, macroscopic nodule, however small. Husslein1 has reported a case in which a discrete hilus cell tumor 4.5 by 3.5 mm. was found in one ovary of a 60-year-old woman who developed adenocarcinoma of the endometrium 25 years after x-ray castration for uterine myomas. Shaw and Dastur 2 have reported 4 cases in which readily detectible clusters of ovarian hilus cells were found in association with endometrial carcinoma .; one of their patients, a nullipara 57 years old, had been treated 9 years previously for uterine hemorrhage with 2,400 mg.hr. of radium. In a series of cases of endometrial adenocarcinoma they found ovarian hilus cells to
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be more prominent than in the controls. However, it is difficult to determine from their account whether there was a true hyperplasia of hilus cells or whether their observations merely represent the upper limits of a normal observation in the ovaries of a group of postmenopausal women. Significantly, there was no evidence of androgenization in any of the 4 cases they studied in detail, or in Husslein's case, or in the present case. Simard and Simard 3 describe the case of a 67 -year-old woman who developed enlargement and tenderness of the breasts concurrently with disappearance of hot flashes. The clitoris was also enlarged. The ovaries showed not only hyperplasia of hilus cell nests but foci of luteinization of cortical stroma. The endometrium showed cystic glandular hyperplasia. Symptoms regressed following hysterectomy and bilateral salpingo-oophorectomy. They referred to the hilus cells as sympathicotopic cells, and they did not recognize the luteinization as such; however, Scully 4 recognized the luteinization from their photomicrographs, and we concur in his interpretation. In his own case, Scully observed a 7 by 6 mm. nodule of hilus cells in one ovary and a 2 mm. nodule in the other ovary of a 73-year-old woman with adenocarcinoma of the endometrium. There was also patchy, focal luteinization of cortical stroma. The patient exhibited moderate facial hirsutism and the endometrial smear was well cornified. Two years after hysterectomy and bilateral salpingo-oophorectomy, hirsutism and cornification of exfoliated cells were still present. While hilus cells are occasionally detectible in the ovaries of newborn babies, infants, and children, they apparently increase with age, particularly after the menopause, and are identified more readily in sections of menopausal and postmenopausal women. Prominence of ovarian hilus cells have been observed in such diverse contexts as anencephaly, 5 pregnancy, 6 • 7 ovarian dysgenesis with and without masculinization, 8 • 9 and choriocarcinoma. 6 • 10 Sternberg and associates6 were able to produce bilateral hyper-
Clinical problems 1189
plasia of hilus cells in the ovaries of adult women following injection of large doses of chorionic gonadotropin. It is interesting to speculate that the hyperplasia of hilus cells in the case reported here may reflect the continuous unopposed stimulation by pituitary gonadotropins at postmenopausal levels over a period of 28 years following pelvic irradiation. However, the gonadotropin level was not very much elevated, and, despite the corroborative support of Husslein's case 1 and Case 3 of Shaw and Dastur, 2 hyperplasia of hilus cells can occur without antecedent pelvic irradiation and subsequent failure of pituitary suppression. The possible relationship of hilus cell proliferation to neurogenic stimuli is suggested by the report by Scully and Cohen 11 of a ganglioneuroma of the adrenal medulla which contained widely distributed hilus cells with crystalloids of Reinke. Such neuroendocrine relationships are reinforced by the common observation that hilus cells are often normally found in close topographic association with nonmyelinated nerve fibers. Androgenic effects of both tumor and hyperplasia of hilus cells has been reported and well documented by SternbergY MerrilP 3 has tabulated the reported cases of tumor of hilus cell origin. Apparently, in all 10 patients androgenic effects were present to some degree, and most of them showed remission of masculinization following surgical removal of the tumor, but the 17-ketosteroid level was rarely significantly elevated. One of these patients was pregnant, and one of us (W. B. 0.) has seen another example of hilus cell tumor of the ovary in pregnancy; it is difficult to reconcile the concept of "masculinization" with the presence of an intrauterine gestation. Clinical androgenization is less constant when there is hyperplasia of the hilus cells as distinguished from true tumor formation. It is possible that some of the reported instances of hyperplasia merely represent the upper limit of a normal cellular constituent; however, it is equally possible that hyperplasia need not be accompanied by parallel hyperfunction. In Scully's case 4 as well as in the case of Simard and Simard 3 there was both clinical and morphologic evi-
1190
Clinical problems
:-.lovembeJ, 1961 Am.
dence of hyperestrogenism. It is tempting to assign the increased estrogen production to the patches of luteinized cortical stroma, but chemical proof is lacking in all the cases under discussion, and we must reserve judgment upon which cell elaborates which hormone (if any) until more direct evidence is at hand. There is some evidence that interstitial cells in the testis can elaborate estrogens. Herrmann and associates14 cited interstitial cell tumors with gynecomastia as a source of estrogens, and Maddock and Nelson 15 found increase in Leydig cells and elevated urinary estrogens in men treated with chorionic gonadotropin. Scully 16 has reported the case of a postmenopausal woman with polypoid cystic hyperplasia of the endometrium and early adenocarcinoma; one ovary contained a tumor composed of fasciculated spindle cells resembling a thecoma in which there were scattered clusters of hilus cells containing crystalloids and other nests of small epithelial cells consistent with either granulosa cells or Sertoli cells. The relationship of hilus cell hyperplasia to endometrial adenocarcinoma in this case, or in any other case, is entirely speculative. In the cases of true hilus cell tumor, one patient had normal menses and another was pregnant, but in the postmenopausal patients the endometrium, when reported, was atrophic, appropriate to the patients' age. This is in keeping with the observation by Greene 17 that about 85 per cent of endometrial adenocarcinomas arise in an atrophic, not a hyperplastic, endometrium. However, the implication inherent in Shaw and Dastur's original communication has been pursued by several observers. Sommers and Meissner 18 found 2 instances of hilus cell hyperplasia in 38 patients with endometrial cancer. Jackson and Dockerty19 described the ovary in relation to the Stein-Leventhal syndrome: 27 of their patients did not have endometrial neoplasm and were treated by ovariotomy and wedge resection; 16 of their patients had an associated endometrial adenocarcinoma and were treated by hysterectomy and bilateral salpingo-oophorectomy.
J.
Obst. & Gyn<·c.
They observed 5 instances of hilus cell hyperplasia in the 16 patients with endometrial adenocarcinoma, but warn that the two groups are not comparable because tissue from the ovarian hilus was not removed in those patients undergoing wedge resection. Sherman and Woolf 20 found hyperplasia of hilus cells in 81.9 per cent of 133 patients with endometrial adenocarcinoma, in 23 per cent of 52 patients with postmenopausal endometrial hyperplasia, and in only 5.9 per cent of 34 patients with normal atrophic postmenopausal endometrium. They correlated elevated LH levels with these observations, and in 31 of 31 patients ( 100 per cent) with adenocarcinoma of the endometrium the preoperative urinary LH level was elevated above normal, falling to normal levels in all patients after bilateral oophorectomy. Unfortunately, there was no preoperative indication for endocrine studies in this patient. However, at no time was there any clinical or morphologic evidence of excess estrogenic or androgenic activity. It remains to be demonstrated whether the doctrine of steroid interconversion can be applied to hilus cells, i.e .. whether cells which have the capacity to synthesize androgens can under appropriate conditions synthesize estrogens. The total of our knowledge of the hilus cell in this respect is that it is under the control of gonadotropic hormones, probably LH, to sorne extent, and that when neoplastic it can elaborate androgenic substances, albeit inconstantly. The relation of the hilus cell and its secretions to the pituitary-ovarian relationship and the effect of disturbances of this relationship upon endometrial carcinogenesis merit further investigation. This case falls into two other oncologic categories which may equally well bear upon carcinogenesis. It is an example of "multiple primary malignant neoplasm." 21 Even though there is no histopathologic documentation of the carcinoma of the bladder for which the patient received x-ray therapy, she did develop an adenocarcinoma of the cecum 16 years later and adenocarcinoma of the endometrium 28 years later. If one cares to speculate upon a constitutional "tumor diath-
Clinical problems
Volume 82 Number 5
esis," this case is as good as any. In fact, it is also a matter for conjecture that this patient may have had as a constitutional factor a greater than average complement of hilus cells as a young girl and that their presence in increased number may have been responsible for the delay of menarche until the age of 18 as well as for their ready postmenopausal overgrowth. Also, she presents an example of "malignant tumor of the uterus developing following pelvic irradiation." The statistical basis for the validity of this mode of carcinogenesis has been debated pro and con, 2 ~-~ 8 but in this case there is the added feature that the adenocarcinoma of the cecum, as well as the adenocarcinoma of the endometrium, might also be attributed to this background. If this hypothesis has any validity, the tumor (or tumors) would be a direct effect of ionizing irradiation and the hilus cell hyperplasia a secondary effect. At this juncture one might speculate that Beren-
REFERENCES
1. Husslein, H.:
Zentralbl. Gynak. 73: 1649,
1951. 2. Shaw, W., and Dastur, B.: Brit. M. J. 2: 4619, 1949. 3. Simard, L. C., and Simard, R.: Rev. canad. bioi. 3: 388, 1944. 4. Scully, R. E.: AM. J. 0BST. & GYNEC. 65: 1248, 1953. 5. Kohn, A.: Endokrinologie 1: 3, 1928. 6. Sternberg, W. H., Segaloff, A., and Gaskill, C. J.: J. Clin. Endocrinol. 13: 139, 1953. 7. Branon, D.: Am. J. Path. 3: 343, 1927. 8. Gordan, G. S., Overstreet, E. W., Traut, H. F., and Winch, G. A.: ]. Clin. Endocrinol. 15: 1, 1955. 9. Greenblatt, R. B., Carmona, N., and Higdon, L.: J. Clin. Endocrinol. 16: 235, 1956. 10. Ober, W. B.: Unpublished observations. 11. Scully, R. E., and Cohen, R. B.: Cancer 14: 421, 1961. 12. Sternberg, W. H.: Am. J. Path. 25: 493, 1949. 13. Merrill, J. A.: AM. J. 0BST. & GvNEC. 78: 1258, 1959. 14. Herrmann, W. L., Buckner, F., and Baskin, A.: ]. Clin. Endocrinol. 18: 834, 1958. 15. Maddock, W. 0., and Nelson, W. 0.: J. Clin. Endocrinol. 12: 985, 1952.
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blum's concept of cocarcinogenesis 29 might be applicable. If so, the ionizing radiation would serve as the initiating action and the hypothetical endocrine alteration would serve as the promoting action. Last, we must remember that in any given patient we do not know the cause of endometrial carcinoma. Indeed, the tumor need not arise from any one given set of pathogenetic circumstances. Adenocarcinoma of the endometrium may develop as the end point of a number of independent pathogenetic pathways. A number of possible mechanisms may, as in the present case, be found in the patient's history or in the pathologic observations. Whether such mechanisms operate independently or in concert is beyond conjecture. Indeed, it is even probable, in the light of present-day ignorance, that the tumor in the uterus arose independently of any of the factors mentioned in the above discussion.
16. Scully, R. E.: J. Clin. Endocrinol. 13: 1254, 1953. 17. Greene, R. R., Roddick, J. W., Jr., and Milligan, M.: Ann. New York Acad. Sc. 75: 586, 1959. 18. Sommers, S. C., and Meissner, W. A.: Cancer 10: 516, 1957. 19. Jackson, R. L., and Dockerty, M. B.: AM. J. 0BST. & GYNEC. 73: 161, 1957. 20. Sherman, A. I., and Woolf, R. B.: AM. J. 0BST. & GYNEC. 77: 233, 1959. 21. Moerte1, C. G., Dockerty, M. B., and Bagenstoss, A. H.: Cancer 14: 221, 1961. 22. Scheffey, L. C.: AM. J. OBsT. & (;YNEc. 44: 925, 1942. 23. Corscaden, J. A., Fertig, J. W., and Gusberg, S. B.: AM. J. 0BsT, & GvNEC. 51: I, 1946. 24. Speert, H., and Peightal, T. C.: AM. J. 0BST. & GYNEC. 57: 261, 1949. 25. Palmer, J. P., and Spratt, D. W.: AM. J. 0BST. & GYNEC. 72: 497, 1956. 26. Stander, R. W.: Obst. & Gynec. 10: 223, 1957. 27. Copeland, W. E., Nelson, P. K., and Payne, F. L.: AM. J. 0BsT. & GvNEC. 73: 615, 1957. 28. Hofmann, D., and Kunzler, E.: Med. Klin. 15: 68. 1960. 29. Berenblum, L: Cancer Res. 14: 471, 1954.