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Endometrial hyperplasia and carcinoma in-situ
GYNECOLOGIC
ONCOLOGY
2, 152-161 (1974)
Endometrial
Hyperplasia FRANK
and Carcinoma
VELLIOS,M.
in-Situ
D.
University of Texas Southwestern Medical Dallas, Texas 75235
School at Dallas
Received March 3,1974 Endometrial epithelial atypias which precede the development of adenocarcinema have been observed in endometria examined prior to the development of carcinoma, concommitantly in the endometrium of patients who elsewhere in the same specimen have areas of adenocarcinoma, and in some instances in actual transition from foci of such atypias to adenocarcinomas. The atypias can be categorized histologically as adenomatous hyperplasia, atypical hyperplasia, and carcinoma in situ. Cystic hyperplasia GF&lcnomatous polyp in some instances appear to antedate these precursor lesions. They are observed in about 10% of endomeial curettage specimens in a general hospital. They must be differentiated from o&r lesions not known to be precursors of carcinoma, including intraglandular morules, squamous metaplasia, tubal metaplasia, and cystic atrophy. The frequency of these lesions progressing to carcinoma has not been determined but has been estimated to be 10%. That these lesions are all reversible when normal menstrual cycles are established or by the use of progesterone or progestational agents is established.
The
of endometrial carcinoma [l] has spurred interest so that steps can be taken to eradicate them. In 1900, Cullen illustrated lesions which he considered precursors of carcinoma in endometrial tissue adjacent to invasive adenocarcinoma of the endometrium 121. Studies of these precursor lesions have been reported by Taylor [3], Novak and Yui [4], Hertig et ~2. [5-71, Novak and Rutledge [81, Speert [9], Copenhaver [lo], Gusberg and associates [ll-141, Buehl and associates [15], and Wentz [16,17]. Several types of lesions have been described, and these have been referred to as postmenopausal hyperplasia, or as a group, atypical hyperplasia. in
increasing
identifying
frequency
precursor
lesions
TYPES
OF LESIONS
Precursors of invasive endometrial carcinoma include adenomatous hyperplasia, atypical hyperplasia, and carcinoma in situ. Each of these lesions has a distinctive histologic appearance, but transitions between them are frequent. Endometrial polyp and cystic hyperplasia in some instances appear to antedate these precursor lesions. It is unfortunate that several of these lesions have been designated “hyperplasias” in that frequently only small amounts of endometrial tissue are present, but disorderly growth of the epithelium is present. These lesions are better designated “dysplasias,” comparable to lesions involving the uterine cervix. 152 Copyright All rights
@ 1974 by Academic Press, Inc. of reproduction in any form reserved.
ENDOMETRIAL
HYPEFWLASIA
AND
CARCINOMA
IN
SITU
153
Adenomatous polyps usually are recognized in curettage specimens as fragments of endometrium different than the remainder of the endometrial tissue. Polyps removed intact may be appreciated grossly and surface epithelium identified on three sides microscopically. Frequently ulceration is present. Usually some of the glands are dilated, and characteristically a fibrous stalk containing a large, thick-walled artery is present. This vessel is probably derived from the straight artery which supplies the basal zone of the endometrium. The adenomatous polyp is an overgrowth of the basal zone of the endometrium, and in some instances the superficial part of the polyp may continue to show functional changes. Abnormalities of all types, including the development of adenocarcinoma, may occur in these polyps. Cystic hyperplasia is characterized by an increase in the amount of endometrial tissue present. Frequently the cystic spaces may be recognized grossly in the tissue. Some of the glands become giant forms with debris and histiocytes in the lumina. They must be differentiated from the dilated glands of cystic atrophy (Fig. 1). The glands are lined by epithelium typical of the proliferative phase, but in some glands the epithelium is low columnar, cuboidal, or flat (Fig. 2). In addition to the epithelial changes, the stroma is increased in amount so that the dilated glands are not closely packed. The nuclei of the stromal cells are larger and mitoses more frequent than usual. Adenomatous hyperplasia [18] is characterized by outpouchings of bud-like projections into the supporting stroma (Fig. 3). Initially, these are connected with the parent gland as finger-like projections but they can become pinched off so that the buds with the parent gland form a small cluster of closely packed glands. The epithelium lining the glands is proliferative-phase type. The lesion is often multifocal. Atypical hyperplasia may be a stage in the progression from adenomatous hyperplasia. It is characterized by large glands or cysts usually closely packed with little intervening stroma. The lumina often contain dense eosinophilic coagulum. The epithelial cells are tall columnar type (Fig. 4). They frequently are enlarged, as is the size of their nuclei, but not as large as the nuclei of carcinoma in situ. Nucleoli are indistinct or absent. Papillary infoldings may be present but usually are not pronounced. Adenomatous and atypical hyperplasia frequently occur concommitantly in the same specimen. The histologic changes of carcinoma in situ [15] include loss of polarity of nuclei, piling up of epithelial cells, and intraglandular bridges, all occurring within gland lumina in the usual endometrial architecture. When the glands are crowded together with little interve.ning stroma, the likelihood of stromal invasion is high. Cellular changes include nuclear hyperchromatism and irregularity, clumping of nuclear chromatin, and frequently cytoplasmic eosinophilia (Fig. 5). The nuclei are usually large, about twice the diameter of nuclei of the proliferative phase (Figs. 5 and 6). The chromatin is often clumped on the nuclear membrane, resulting in nuclear clearing. Nucleoli are, apparent in some cells, b’ut usually they are small. Changes which may simulate these atypias include cystic atrophy, tubal metaplasia, intraglandular morules, and squamous metaplasia, and the AriasStella reaction of early pregnancy.
154
FRANK
VELLIOS
ENDOMETRIAL
HYPERPLASIA
AND
CARCINOMA
IN
SITU
155
156
FRANK
VELLIOS
ENDOMETFUAL
HYPERF’LASIA
AND CARCINOMA
IN SITU
157
158
FRANK
VELLIOS
ENDOMETRIAL
HYPERPLASIA
AND
CARCINOMA
IN
159
SITU
rr 0
160
FRANK
PREVALENCE
OF
VELLIOS
ENDOMETRIAL
ATYPIAS
The prevalence of precursor lesions of endometrial carcinoma has not been determined. The findings of a review of endometrial curettage specimens, obtained from 1212 patients, examined in the Surgical Pathology Laboratory of Parkland Memorial Hospital during the 4-yr period July 1, 1969, to June 30, 1973, is shown in Table I. Curettage specimens obtained from pregnancyrelated conditions were excluded from the tabulation. Two of the younger paENDOMETRIAL
TABLE I FINDINGS IN CURETTAGE
SPECIMENS Patient
Finding
by curettage
Proliferative phase Secretory phase Menstrual Benign (not otherwise classified) Progestational effect Acute inflammation byometd Acute or chronic inflammation Inactive or consistent with anovulation Atrophy or cystic atrophy Cystic hyperplasia Adenomatous hyperplasia Atypical hyperplasia Adenomatous and atypical hyperplasia CIS and adenomatous and/or atypical hyperplasia Focal adenocarcinoma with adenomatous and atypical hyperplasia Focal adenocarcinoma with CIS Adenomatous polyp Adenomatous polyp with CIS and/or adenomatous and atypical hyperplasia Adenomatous polyp with adenomatous and atypical hyperplasia Adenocarcinoma Adenoacanthoma Mixed adenosquamous carcinoma Papillary carcinoma Carcinosarcoma
s35
36-40
-
age (yr)
41-50
51-55
296 166 12 7
64 36 1 4
148 71 3 18
23 3
50
5
11
1
56+
Total 540 277 16 46
9
4
67 4
18
2
2
22
11
1
8
6
37
18 7 1 4
4 1 1 2
5 10 7 4 9
34 6 4 4 4
47 40 23 10 24
4
7
1
2
1
1
1
2
2
1
6
3
2 2
4 2
16 4
4
2
6
3
8 1 1
15 1 2
4 1 108
4 1 1212
1
593
125
306
80
ENDOMETRIAL
HYPERPLASIA
AND
CARCINOMA
IN
SITU
161
tients had clinical findings consistent with the Stein-Levi&al syndrome. In 10% of the specimens, the findings of cystic hyperplasia, adenomatous hyperplasia, atypical hyperplasia, or carcinoma in situ, or combinations of these changes, were observed. During the same period, 22 endometrial carcinomas and one carcinosarcoma were diagnosed by means of the curettage specimen, The incidence of progression of these lesions to invasive carcinoma is not known, but it has been estimated that 10% of the atypias may result in carcinoma. It has been established that some of these lesions may be reversed by establishing normal menstrual cycles or by administration of progestational agents to the patients [16,17,19,20]. Th e incidence of recurrence of the lesions after such reversal has not been determined. REFERENCES 1. CHRISTOPHERSON, W. M., MENDEZ, W. M., PARKER, J. E., LUNDEN, F. E., JR., AND AHUJA, E. M. Carcinoma of the endometrium: a study ofchanging rates over a 15-year period. Cancer 27, 1005, 1971. 2. CULLEN, T. S. Cancer of the uterus. Appleton New York, (1900). 3. TAYLOR, H. C., JR. Endometrial hyperplasia and carcinoma of the body of the uterus. Amer. J. Obstet. Gynecol. 23, 309 (1932). 4. NOVAK, E., AND YUI, E. Relation of endometrial hyperplasia to adenocarcinoma of the uterus. Amer. J. Obstet. Gynecol. 32,674 (1936). 5. HERTIG, A. T., AND SOMMERS, S. C. Genesis of endometrial carcinoma. I. Study of prior biopsies. Cancer 2,946 (1949). 6. HERTIG, A. T., SOMMERS, S. C., AND BENGLOFF, H. Genesis of endometrial carcinoma. III. Carcinoma in situ. Cancer 2, 964 (1949). 7. SOMMERS, S. C., HERTZ, A. T., AND BENGLOFF, H. Genesis of endometrial carcinoma. II. Cases I9 to 35 years old. Cancer 2,957 (1949). 8. NOVAK, E., AND RUTLEDGE, F. Atypical endometrial hyperplasia simulating adenocarcinema. Amer. J. Obstet. Gynecol. 55, 46 (1948). 9. SPEERT, H. The premalignant phase of endometrial carcinoma. Cancer 5,927 (1952). 10. COPENHAVER, E. H. Atypical endometrial hyperplasia. Obstet. Gynecol. 13, 264 (1959). 11. GUSBERG, S. B. Precursors of corpus carcinoma: estrogens and adenomatous hyperplasia. Amer. J. Obstet. Gynecol. 54,905 (1947). 12. GUSBERG, S. G., MOORE, D. B., AND MARTIN, F. Precursors of corpus cancer. II. A clinical and p: ‘hological study of adenomatous hyperplasia. Amer. J. Obstet. Gynecol. 68, 1472 (1954). 13. GUSBERG, S. B., AND HALL, R. E. Precursors of corpus cancer. III. The appearance of cancer of the endometrium in estrogenically conditioned patients. Obstet. Gynecol. 17,397 (1961). 14. GUSBERG, S. B., AND KAPLAN, A. L. Precursors of corpus cancer. IV. Adenomatous hyperplasia as stage 0 carcinoma of the endometrium. Amer. J. Obstet. Gynecol. 22,662 (1963). 15. BUEHL, I. A., VELLIOS, F., CARTER, J. E., AND HUBER, C. P. Carcinoma in situ of the endometrium. Amer. J. Clin. Puthol. 42,594 (1964). 16. WENTZ, W. B. Effect of a progestational agent on endometrial hyperplasia and endometrial cancer. Obstet. Gynecol. 24,370 (1964). 17. WENTZ, W. B. Treatment of persistent endometrial hyperplasia with progestins. Amer. J. Obstet. Gynecol. 96, 999 (1966). 18. GORE, H., AND HERTIG, A. T. Premalignant lesions of the endometrium. C&n. Obstet. Gynecol. 5, 1148 (1962). 19. KISTNER, R. W. Histological effects of progestins on hyperplasia and carcinoma in situ of the endometrium. Cancer 12, 1106 (1959). 20. KAUFMAN, R. H., ABBOTT, J. P., AND WALL, J. A. The endometrium before and after wedge resection of the ovaries in Stein-Lever&al syndrome. Amer. J. Obstet. Gynecol. 77, 1271 (1959).
ONCOLOGY
2, 152-161 (1974)
Endometrial
Hyperplasia FRANK
and Carcinoma
VELLIOS,M.
in-Situ
D.
University of Texas Southwestern Medical Dallas, Texas 75235
School at Dallas
Received March 3,1974 Endometrial epithelial atypias which precede the development of adenocarcinema have been observed in endometria examined prior to the development of carcinoma, concommitantly in the endometrium of patients who elsewhere in the same specimen have areas of adenocarcinoma, and in some instances in actual transition from foci of such atypias to adenocarcinomas. The atypias can be categorized histologically as adenomatous hyperplasia, atypical hyperplasia, and carcinoma in situ. Cystic hyperplasia GF&lcnomatous polyp in some instances appear to antedate these precursor lesions. They are observed in about 10% of endomeial curettage specimens in a general hospital. They must be differentiated from o&r lesions not known to be precursors of carcinoma, including intraglandular morules, squamous metaplasia, tubal metaplasia, and cystic atrophy. The frequency of these lesions progressing to carcinoma has not been determined but has been estimated to be 10%. That these lesions are all reversible when normal menstrual cycles are established or by the use of progesterone or progestational agents is established.
The
of endometrial carcinoma [l] has spurred interest so that steps can be taken to eradicate them. In 1900, Cullen illustrated lesions which he considered precursors of carcinoma in endometrial tissue adjacent to invasive adenocarcinoma of the endometrium 121. Studies of these precursor lesions have been reported by Taylor [3], Novak and Yui [4], Hertig et ~2. [5-71, Novak and Rutledge [81, Speert [9], Copenhaver [lo], Gusberg and associates [ll-141, Buehl and associates [15], and Wentz [16,17]. Several types of lesions have been described, and these have been referred to as postmenopausal hyperplasia, or as a group, atypical hyperplasia. in
increasing
identifying
frequency
precursor
lesions
TYPES
OF LESIONS
Precursors of invasive endometrial carcinoma include adenomatous hyperplasia, atypical hyperplasia, and carcinoma in situ. Each of these lesions has a distinctive histologic appearance, but transitions between them are frequent. Endometrial polyp and cystic hyperplasia in some instances appear to antedate these precursor lesions. It is unfortunate that several of these lesions have been designated “hyperplasias” in that frequently only small amounts of endometrial tissue are present, but disorderly growth of the epithelium is present. These lesions are better designated “dysplasias,” comparable to lesions involving the uterine cervix. 152 Copyright All rights
@ 1974 by Academic Press, Inc. of reproduction in any form reserved.
ENDOMETRIAL
HYPEFWLASIA
AND
CARCINOMA
IN
SITU
153
Adenomatous polyps usually are recognized in curettage specimens as fragments of endometrium different than the remainder of the endometrial tissue. Polyps removed intact may be appreciated grossly and surface epithelium identified on three sides microscopically. Frequently ulceration is present. Usually some of the glands are dilated, and characteristically a fibrous stalk containing a large, thick-walled artery is present. This vessel is probably derived from the straight artery which supplies the basal zone of the endometrium. The adenomatous polyp is an overgrowth of the basal zone of the endometrium, and in some instances the superficial part of the polyp may continue to show functional changes. Abnormalities of all types, including the development of adenocarcinoma, may occur in these polyps. Cystic hyperplasia is characterized by an increase in the amount of endometrial tissue present. Frequently the cystic spaces may be recognized grossly in the tissue. Some of the glands become giant forms with debris and histiocytes in the lumina. They must be differentiated from the dilated glands of cystic atrophy (Fig. 1). The glands are lined by epithelium typical of the proliferative phase, but in some glands the epithelium is low columnar, cuboidal, or flat (Fig. 2). In addition to the epithelial changes, the stroma is increased in amount so that the dilated glands are not closely packed. The nuclei of the stromal cells are larger and mitoses more frequent than usual. Adenomatous hyperplasia [18] is characterized by outpouchings of bud-like projections into the supporting stroma (Fig. 3). Initially, these are connected with the parent gland as finger-like projections but they can become pinched off so that the buds with the parent gland form a small cluster of closely packed glands. The epithelium lining the glands is proliferative-phase type. The lesion is often multifocal. Atypical hyperplasia may be a stage in the progression from adenomatous hyperplasia. It is characterized by large glands or cysts usually closely packed with little intervening stroma. The lumina often contain dense eosinophilic coagulum. The epithelial cells are tall columnar type (Fig. 4). They frequently are enlarged, as is the size of their nuclei, but not as large as the nuclei of carcinoma in situ. Nucleoli are indistinct or absent. Papillary infoldings may be present but usually are not pronounced. Adenomatous and atypical hyperplasia frequently occur concommitantly in the same specimen. The histologic changes of carcinoma in situ [15] include loss of polarity of nuclei, piling up of epithelial cells, and intraglandular bridges, all occurring within gland lumina in the usual endometrial architecture. When the glands are crowded together with little interve.ning stroma, the likelihood of stromal invasion is high. Cellular changes include nuclear hyperchromatism and irregularity, clumping of nuclear chromatin, and frequently cytoplasmic eosinophilia (Fig. 5). The nuclei are usually large, about twice the diameter of nuclei of the proliferative phase (Figs. 5 and 6). The chromatin is often clumped on the nuclear membrane, resulting in nuclear clearing. Nucleoli are, apparent in some cells, b’ut usually they are small. Changes which may simulate these atypias include cystic atrophy, tubal metaplasia, intraglandular morules, and squamous metaplasia, and the AriasStella reaction of early pregnancy.
154
FRANK
VELLIOS
ENDOMETRIAL
HYPERPLASIA
AND
CARCINOMA
IN
SITU
155
156
FRANK
VELLIOS
ENDOMETFUAL
HYPERF’LASIA
AND CARCINOMA
IN SITU
157
158
FRANK
VELLIOS
ENDOMETRIAL
HYPERPLASIA
AND
CARCINOMA
IN
159
SITU
rr 0
160
FRANK
PREVALENCE
OF
VELLIOS
ENDOMETRIAL
ATYPIAS
The prevalence of precursor lesions of endometrial carcinoma has not been determined. The findings of a review of endometrial curettage specimens, obtained from 1212 patients, examined in the Surgical Pathology Laboratory of Parkland Memorial Hospital during the 4-yr period July 1, 1969, to June 30, 1973, is shown in Table I. Curettage specimens obtained from pregnancyrelated conditions were excluded from the tabulation. Two of the younger paENDOMETRIAL
TABLE I FINDINGS IN CURETTAGE
SPECIMENS Patient
Finding
by curettage
Proliferative phase Secretory phase Menstrual Benign (not otherwise classified) Progestational effect Acute inflammation byometd Acute or chronic inflammation Inactive or consistent with anovulation Atrophy or cystic atrophy Cystic hyperplasia Adenomatous hyperplasia Atypical hyperplasia Adenomatous and atypical hyperplasia CIS and adenomatous and/or atypical hyperplasia Focal adenocarcinoma with adenomatous and atypical hyperplasia Focal adenocarcinoma with CIS Adenomatous polyp Adenomatous polyp with CIS and/or adenomatous and atypical hyperplasia Adenomatous polyp with adenomatous and atypical hyperplasia Adenocarcinoma Adenoacanthoma Mixed adenosquamous carcinoma Papillary carcinoma Carcinosarcoma
s35
36-40
-
age (yr)
41-50
51-55
296 166 12 7
64 36 1 4
148 71 3 18
23 3
50
5
11
1
56+
Total 540 277 16 46
9
4
67 4
18
2
2
22
11
1
8
6
37
18 7 1 4
4 1 1 2
5 10 7 4 9
34 6 4 4 4
47 40 23 10 24
4
7
1
2
1
1
1
2
2
1
6
3
2 2
4 2
16 4
4
2
6
3
8 1 1
15 1 2
4 1 108
4 1 1212
1
593
125
306
80
ENDOMETRIAL
HYPERPLASIA
AND
CARCINOMA
IN
SITU
161
tients had clinical findings consistent with the Stein-Levi&al syndrome. In 10% of the specimens, the findings of cystic hyperplasia, adenomatous hyperplasia, atypical hyperplasia, or carcinoma in situ, or combinations of these changes, were observed. During the same period, 22 endometrial carcinomas and one carcinosarcoma were diagnosed by means of the curettage specimen, The incidence of progression of these lesions to invasive carcinoma is not known, but it has been estimated that 10% of the atypias may result in carcinoma. It has been established that some of these lesions may be reversed by establishing normal menstrual cycles or by administration of progestational agents to the patients [16,17,19,20]. Th e incidence of recurrence of the lesions after such reversal has not been determined. REFERENCES 1. CHRISTOPHERSON, W. M., MENDEZ, W. M., PARKER, J. E., LUNDEN, F. E., JR., AND AHUJA, E. M. Carcinoma of the endometrium: a study ofchanging rates over a 15-year period. Cancer 27, 1005, 1971. 2. CULLEN, T. S. Cancer of the uterus. Appleton New York, (1900). 3. TAYLOR, H. C., JR. Endometrial hyperplasia and carcinoma of the body of the uterus. Amer. J. Obstet. Gynecol. 23, 309 (1932). 4. NOVAK, E., AND YUI, E. Relation of endometrial hyperplasia to adenocarcinoma of the uterus. Amer. J. Obstet. Gynecol. 32,674 (1936). 5. HERTIG, A. T., AND SOMMERS, S. C. Genesis of endometrial carcinoma. I. Study of prior biopsies. Cancer 2,946 (1949). 6. HERTIG, A. T., SOMMERS, S. C., AND BENGLOFF, H. Genesis of endometrial carcinoma. III. Carcinoma in situ. Cancer 2, 964 (1949). 7. SOMMERS, S. C., HERTZ, A. T., AND BENGLOFF, H. Genesis of endometrial carcinoma. II. Cases I9 to 35 years old. Cancer 2,957 (1949). 8. NOVAK, E., AND RUTLEDGE, F. Atypical endometrial hyperplasia simulating adenocarcinema. Amer. J. Obstet. Gynecol. 55, 46 (1948). 9. SPEERT, H. The premalignant phase of endometrial carcinoma. Cancer 5,927 (1952). 10. COPENHAVER, E. H. Atypical endometrial hyperplasia. Obstet. Gynecol. 13, 264 (1959). 11. GUSBERG, S. B. Precursors of corpus carcinoma: estrogens and adenomatous hyperplasia. Amer. J. Obstet. Gynecol. 54,905 (1947). 12. GUSBERG, S. G., MOORE, D. B., AND MARTIN, F. Precursors of corpus cancer. II. A clinical and p: ‘hological study of adenomatous hyperplasia. Amer. J. Obstet. Gynecol. 68, 1472 (1954). 13. GUSBERG, S. B., AND HALL, R. E. Precursors of corpus cancer. III. The appearance of cancer of the endometrium in estrogenically conditioned patients. Obstet. Gynecol. 17,397 (1961). 14. GUSBERG, S. B., AND KAPLAN, A. L. Precursors of corpus cancer. IV. Adenomatous hyperplasia as stage 0 carcinoma of the endometrium. Amer. J. Obstet. Gynecol. 22,662 (1963). 15. BUEHL, I. A., VELLIOS, F., CARTER, J. E., AND HUBER, C. P. Carcinoma in situ of the endometrium. Amer. J. Clin. Puthol. 42,594 (1964). 16. WENTZ, W. B. Effect of a progestational agent on endometrial hyperplasia and endometrial cancer. Obstet. Gynecol. 24,370 (1964). 17. WENTZ, W. B. Treatment of persistent endometrial hyperplasia with progestins. Amer. J. Obstet. Gynecol. 96, 999 (1966). 18. GORE, H., AND HERTIG, A. T. Premalignant lesions of the endometrium. C&n. Obstet. Gynecol. 5, 1148 (1962). 19. KISTNER, R. W. Histological effects of progestins on hyperplasia and carcinoma in situ of the endometrium. Cancer 12, 1106 (1959). 20. KAUFMAN, R. H., ABBOTT, J. P., AND WALL, J. A. The endometrium before and after wedge resection of the ovaries in Stein-Lever&al syndrome. Amer. J. Obstet. Gynecol. 77, 1271 (1959).