A clinicopathologic study of endometrial carcinomas with argyrophil cells

GYNECOLOGIC

ONCOLOGY

7, 223-232 (1979)

A Clinicopathologic

GAIKO UEDA,

Study of Endometrial with Argyrophil Cells

M.D., MASATO YAMASAKI, AND KEIICHI

Department

Carcinomas

M.D., MASAKI INOUE, M.D., M.D.

KURACHI,

qf Obstetrics and Gynecology,

Osaka University Osaka, Japan

Medical

School,

Received April 20, 1978 Of 41 endometrial carcinomas examined with Grimelius staining, 9 tumors were found to be composed predominantly or partially of argyrophil cells. They were 4 well-differentiated adenocarcinomas, 4 moderately differentiated adenocarcinomas, and 1 adenosquamous carcinoma. Argyrophil granules were found mainly in the apical portion and sometimes in the entire cytoplasm of glandular tumor cells in the well- and moderately differentiated adenocarcinomas. In the adenosquamous carcinoma, argyrophil granules were located in the squamous cells as well as in the grandular cells. The distribution of argyrophil granules was in parallel with that of secretory granules identified by electron microscopy. A clinicopathologic study of these 9 cases revealed that the patients with endometrial argyrophil cell carcinoma tended to be associated more frequently with obesity, hypertension, and diabetes mellitus than the patients with usual endometrial carcinoma.

Since the first discovery of an argyrophil cell adenocarcinoma of the endometrium [1,2], 9 additional such tumors have been found among 41 endometrial carcinomas examined [33. A clinicopathologic study of endometrial carcinomas with argyrophil cells based on these 9 cases is described in this paper. MATERIALS AND METHODS Formalin-fixed and paraffin-embedded sections of 41 endometrial carcinomas were examined with the Grimelius method [4] for argyrophil cells. Nine of them were found to have neoplastic argyrophil cells and submitted to a clinicopathologic study. Three argyrophil cell carcinomas were preliminarily studied by electron microscopy. Formalin-fixed tumor masses were cut into tiny pieces and refixed in 2.5% buffered glutaraldehyde after immersion in 0.2 M sodium cacodylate buffer. The tissues were then postfixed in 2% buffered osmium tetroxide, dehydrated in graded alcohols, and embedded in Epon. Ultrathin sections were stained with lead hydroxide and uranyl acetate for electron microscopy. RESULTS Clinical features. The clinical data of the nine endometrial carcinomas with argyrophil cells are summarized in Table 1. Case 8 was reported previously in 223 0090-8258/79/020223-10$01.00/O Ccnpyright @ 1979 by Academic Press, Inc. All rights of reproduction in any form reserved.

1

o/o

915

212

l/O

513

010

412

3/I

312

41

49

64

71

53

58

51

64

50

Age Grav/Para

Irregular

Menopause at age 54

Menopause at age 53 Irregular

Menopause at age 51 Regular

Menopause at age 51

Irregular

Regular

Menses

n.p.

n.p.

Diabetes mellitus Obesity and hypertension Hypertension

Hypertension

Obesity

Obesity

Obesity

Associated medical condition

Clinical

III

III

II

Ib

Ib

Ib

Ia

Ia

III

Clinical stage

STH, ADN

STH. ADN

Cobalt radiation STH, ADN, LN STH, ADN, LN STH, ADN

RH

RH

STH, ADN , LN

Treatment”

Metastasis to cervix Metastasis to 1. ovary ascites with malignant cells Metastasis to ovaries, cervix, Inn. inguinale

n,p,

n.p.

Metastasis to Inn. obturator -

Metastasis to 1. ovary cervix n.p.

Operative finding Histology

Goose egg size

Goose egg size Goose egg size Fist-size myoma Goose egg size

-

Fist-size myoma Goose egg size

G,

G,

G2

G,

G,

G2

G2

G

Fist-size Adeno(GJ myoma squamous

Gross

Pathological

ARGYROPHIL CELL CARCINOMA

Died, 3 months

Alive, 4 yrs Alive, 4 yrs Alive, 4 yrs Alive, 2 yrs

Lost

Alive, 10 yrs Lost

Alive, 11 yrs

Prognosis

B Abbreviations used: STH, simple total hysterectomy: ADN, adnexectomy; LN, lymphadnectomy; RH, radical hysterectomy with adnexectomy.

Case No.

TABLE

CLINICAL AND PATHOLOGICAL DATA OF THE PATIENTS WITH ENDOMETRIAL

ENDOMETRIAL

ARGYROPHIL

CELL CARCINOMA

225

FIG. I. A well-differentiated adenocarcinoma of the endometrium, showing papillary and tubular patterns. Hematoxylin-eosin, x40.

detail [2]. Such tumors were found at an incidence of 22%. The ages of these nine patients ranged from 41 to 71, with an average of 55.7, four patients (44%) being postmenopausal. Four patients (44%) were complicated with obesity, three (33%) with hypertension, and one (11%) with diabetes mellitus. Two patients (22%) were without any complications. On the other hand, the mean age of the remaining 32 patients with usual endometrial carcinomas was 55.6, and 22 patients (6%) were

FIG. 2. An adenosquamous carcinoma of the endometrium, showing tubular patterns, squamous components, and even keratinizing cells. Hematoxylin-eosin, x40.

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UEDA ET AL.

FIG. 3. Argyrophil granules are located mainly in the apical portion and sometimes in tht :e entire cytoplasm of tumor cells in well-differentiated adenocarcinoma. Grimelius stain, x40.

postmenopausal. Nine patients (28%) were complicated with obesity, and se:ven (22%) with hypertension, including two with both obesity and hypertensionn. No diabetes mellitus was found in these patients, and 18 patients (56%) were wiit1lout any complications. The clinical stage of the nine patients with endometri al argyrophil cell carcinoma ranged from I to III. Eight patients received surg:ical treatment and one irradiation. Six patients have been free from disease for 2 tc3 11

FIG. 4. A higher magnification of Fig. 3. Grimelius stain, x400.

ENDOMETRIAL

ARGYROPHIL

CELL CARCINOMA

227

FIG. 5. Location of argyrophil granules in the squamous components of an adenosquamous carcinoma. Grimelius stain. X 100.

years. One stage III patient was found by autopsy to have died of a fulminant hepatitis with only a small metastatic lesion in a para-aortic lymph node. Two stage I patients were lost to follow-up. Pathological features. Among eight patients treated by surgery, three were complicated with uterine myomas. Four tumors were histologically welldifferentiated adenocarcinomas (Fig. l), four were moderately differentiated

FIG. 6. A higher magnification of Fig. 5. Grimelius stain, x400.

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ET AL.

FIG. 7. Location of argyrophil granules in the glandular cells of an adenosquamous carcinoma. Grimelius stain, x 100.

adenocarcinomas, and one was an adenosquamous carcinoma (Fig. 2). Two welldifferentiated adenocarcinomas (Cases 8 and 9) and the adenosquamous carcinoma (Case 1) were composed predominantly, but others only partially, of argyrophil cells. In the well- and moderately differentiated adenocarcinomas, argyrophil granules were found mainly in the apical portion and sometimes in the entire cytoplasm of the tumor cells (Figs. 3 and 4). In the adenosquamous car-

FIG. 8.

A higher magnification of Fig. 7. Grimelius stain, x400.

ENDOMETRIAL

ARGYROPHIL

CELL

CARCINOMA

229

cinema, argyrophif granules were located in the squamous components (Figs. 5 and 6) as well as in the glandular tumor cells (Figs. 7 and 8). Electron micr-oscopy. The ultrastructures of tumor cells were more or less damaged due to the fixation in regular 10% formafin solution. However, the small spherical secretory granules in the cytoplasm were generally well preserved. They measured 150 to 350 nm in diameter and some of them were of a core type. In parallel with the distribution of argyrophif granules, they were located mainly in the apical portion and sometimes in the entire cytoplasm of the glandular tumor cells (Figs. 9 and 10). They were also present in the tumor cells showing a sheet-like arrangement (Fig. 11). DISCUSSION

Argyrophif cell adenocarcinoma of the endometrium was thought rare at first [1,2], but then was found to develop quite frequently [3]. Since the tumors were

only partially examined by routine histology, there remains the possibility that the real incidence may be higher than discovered. Histological focalization of argyrophif granules in the apical portion of glandular tumor cells seemed to be characteristic of the endometriaf adenocarcinomas. However, some glandular cells of the adenocarcinomas as well as many squamous cells of the adenosquamous carcinoma contained argyrophif granules in the entire cytoplasm. Such a distribution of argyrophil granules was also confirmed by the preliminary electron microscopic study. The histogenesis of this kind of tumor is presently open to question, but the following possibilities are postulated. First, the tumors may be derived from APUD cells which are yet to be detected in the normal endometrium [5]. APUD cells are characterized not only by functional properties productive of a variety of pofypeptide hormones, but also by morphological and cytochemicaf similarities, and are considered to form a third (endocrine) division of the nervous system [6]. Various cells are now described as APUD cells and related to hormone production by their tumors. Second, the cell hybridization theory 171may be applied to the histogenesis of these tumors; that is, the endometrial cancer cells may be hybridized with APUD cells. Third, the development of the tumors may be explained by the derepression of genetic code occurring during carcinogenesis, because the tumors occur at a disproportionate frequency notwithstanding that argyrophif cells have not been found in normal endometrium. The hormonal function of endometriaf carcinomas with argyrophif cells has not been well documented, although parathyroid hormone was detected in one undifferentiated endometriaf carcinoma [81. Recently, we have found the focalization of cafcitonin in neopfastic argyrophif cells by an immunoperoxidase method with anti-human cafcitonin [9]. On the other hand, endometriaf carcinomas are well known to be often complicated with obesity, hypertension, and diabetes meffitus [IO,1 I]. This has long been ascribed to a basic abnormality in the endocrine systems of the patients. Therefore, it is interesting to study the relationship between argyrophil cells of endometriaf carcinomas and associated medical conditions. The present study revealed that the patients with endometrial argyrophil cell carcinoma tended to be associated more frequently with obesity, hyperten-

230

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FIG. 9. Spherical secretory granules are located in the apical portion of the glandular tumor cells. Electron micrograph, x4600.

FIG. 10. Many secretory granules are present in the cytoplasm as well as in the apical portion of tumor cells. Electron micrography, x 15,400.

ENDOMETRIAL

ARGYROPHIL

CELL

CARCINOMA

231

FIG. 11. A few secretory granules are scattered in the cytoplasm of tumor cells showing a sheet-like arrangement in an adenosquamous carcinoma. Electron micrograph. x4700.

sion, and diabetes mellitus than those with usual endometrial carcinoma. This is also supported by the fact that calcitonin is located in the tumor cells, which suggests the possibility of other polypeptide hormone production related directly to the above-stated complications, because the production of calcitonin is intimately associated with that of parathyroid hormone [12], (Ysubunit of the glycoprotein hormones [ 131,and ACTH and /I-MSH [ 141in various tumors. This trend, however, remains to be solidified by more elaborate studies. REFERENCES 1. Ueda, G., Sato, Y., Yamasaki, M., Inoue, M., Hiramatsu, K., Kurachi, K., Takeda, S., Yamamoto, T., and Goi, S. Argyrophil cell adenocarcinoma of the endometrium, Acfa Obster. Gynaecol. Japan. 29, 1167-1168 (1977). 2. Ueda, G., Sate, Y., Yamasaki, M., Inoue, M., Hiramatsu, K., Tanaka, Y., Kurachi, K., Kobayashi, Y., Takeda, S., Yamamoto, T., and Goi, S. Argyrophil cell adenocarcinoma of the endometrium, Gynecol. Oncol. 6, 467-473 (1978). 3. Ueda, G., Sato, Y., Yamasaki, M., Inoue, M., Hiramatsu, K., Tanaka, Y., Kurachi, K., Takeda, S., Yamamoto, T., and Goi, S. Argyrophil cell adenocarcinomas in the female genital tracts, Acta Obstet.

Gynaecol.

Japon.

30, 397-398 (1978).

4. Grimelius, L. Silver nitrate stain for alpha 2 cells in human pancreatic islets, Actu Sm. Med. Upsala. 73, 243-270 (1968). 5. Fox, H., Kazzaz, B., and Langley, F. A. Argyrophil and argentaffin cells in the female genital tract and ovarian mutinous cysts, J. Pathol. Bacterial. 88, 479-488 (1964). 6. Pearse, A. G. E., and Takor Takor, T. Neuroendocrine embryology and the APUD concept, C/in. Endocrinol.

(SuppI.) 5, 229s-244s (1976).

7. Warner, T. F. C. S. Cell hybridisation in the genesis of ectopic hormone-secreting tumours, Lancer 1, 1259-1260 (1974).

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8. Sasano, N. Ectopic hormone producing tumors,J. Clin. Sci. 11, 1002-1008 (1975) (in Japanese). 9. Ueda, G., Yamasaki, M., Inoue, M., Sato, Y., Hiramatsu, K., Tanaka, Y., and Kurachi, K. Calcitonin-producing endometrial carcinomas demonstrated by immunohistology, Acta Obstet. Gynecol. Jupon. 30, 1365-1366 (1978). 10. Lucas, W. Causal relationships between endocrine-metabolic variables in patients with endometrial carcinoma, Obstet. Gynecol. Surv. 29, 507-528 (1974). 11. Demopoulos, R. I. Carcinoma of the endometrium, in Pnrho/ogv of the female genitul tract (A. Blaustein, Ed.), Springer-Verlag, New York, pp. 278-298 (1977). 12. Coombes, R. C., Ward, M. K., Greenberg, P. B., Hillyard, C. J., Tulloch, B. R., Morrison, R., and Joplin, G. F. Calcium metabolism in cancer. Studies using calcium isotopes and immunoassays for parathyroid hormone and calcitonin, Cancer 38, 2111-2120 (1976). 13. Rosen, S. W., and Weintraub, B. D. Ectopic production of the isolated alpha subunit of the glycoprotein hormones. A quantitative marker in certain cases of cancer, N. Engl. J. Med. 290, 1441-1447 (1974). 14. Adachi, 1. Human calcitonin in plasma and tissues. II. Calcitonin in tumor tissues, J. Japan. Sot. Intern. Med. 66, 648-654 (1977) (in Japanese).