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Endometrial carcinoma: The need to pursue a new path(ology)
GYNECOLOGIC
ONCOLOGY
45, 233-234 (1992)
EDITORIAL Endometrial Carcinoma: The Need to Pursue a New Path(ology) Endometrial carcinoma is the most common invasive gynecologic malignancy in the United States, with about 33,000 new cases diagnosed annually [l]. Fortunately, more than 80% are cured by surgery, reflecting frequent diagnosis at an early stage. Nevertheless, about 3000 women died of this tumor last year. Several strategies might be considered to reduce this number in the future, including the following: (1) identification and reduction of risk factors, (2) identification of precursor lesions and means to diagnose preinvasive tumors, (3) identification of women with tumors having a high probability of recurrence, and (4) identification of effective therapy for advanced disease. Where do we stand currently with respect to each of these areas of study? It has (1) IdentiJcation and reduction of risk factors. been hypothesized that there are two distinct clinicopathologic types of endometrial adenocarcinoma [2]. The majority of endometrial adenocarcinomas appear to be related to an endogenous or exogenous estrogen-induced proliferation of the endometrial glands. The addition of a progestin appears to be protective, and oral contraceptive users are at diminished risk compared to control populations. Most of the estrogen-associated tumors tend to be well differentiated, of low stage, steroid receptor rich, and associated with a good behavior. A second group of tumors, such as papillary serous and clear cell carcinomas, do not seem to be related to estrogenic stimulation of the endometrium and do have a distinctly worse prognosis. Unfortunately, risk factors for this second group remain undefined. (2) Ident$cation of precursor lesions and means to diagnose preinvasive lesions. A complete spectrum of his-
tologically defined lesions characterized by increasingly complex and disorganized growth has been identified in the endometrium, beginning with disordered proliferation and including hyperplasias with varying degrees of architectural and cytologic atypia, culminating in well-differentiated adenocarcinoma. The vast majority of these lesions are diploid by relatively crude estimation of DNA content. It is thus appealing to consider these morphologic alterations as reflecting a sequence of relatively subtle
genetic events including oncogene amplification or overexpression, or loss of suppressor genes, similar to the adenoma-carcinoma model of colonic carcinoma proposed by Fearon and Vogelstein [3]. Fortunately, the continued growth is often accompanied by noncyclic shedding and bleeding, which prompts the alert clinician to diagnose preinvasive lesions by biopsy or curettage. Unfortunately, not all carcinomas progress through this pathway, and once again, the types with the most aggressive behavior are usually not found in a setting of hyperplasia. (3) Ident$cation of women with tumors having a high probability of recurrence. There is no shortage of fea-
tures characterized either clinically or pathologically that have been associated with aggressive biologic behavior, including advanced stage, deep myometrial invasion, vascular invasion, papillary serous or clear cell histologic type, poor histologic differentiation, aneuploidy, absence of steroid receptors, and advanced age [4]. The significance of oncogene alterations, elaboration of growth factors, morphometric or immunohistochemical characteristics, and host immune response are currently under investigation or disputed. (4) Zdentijication of effective therapy for poor prognosis and advanced disease. Surgery is remarkably effective
therapy for the limited disease found in most women with endometrial carcinoma. However, the weakest link in this chain of strategies appears to be effective therapy which can produce long-term remission in women with metastatic tumors. Postoperative vaginal cuff or pelvic radiation therapy may reduce the risk of central recurrence, but chemotherapy and endocrine therapy have been of limited value for metastatic endometrial carcinomas, with low response rates (about 25%), which are usually of short duration (about 4-6 months) [4]. Having reviewed our strategies, the following question then comes to mind-of what value is it to identify patients with endometrial adenocarcinomas who are at high risk of recurrence, if we have no effective therapeutic response? I think that it is precisely because of our current inability to treat advanced disease that we need to concentrate our efforts on the first three strategies, including
233 OG90-8258192 $4.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
234
EDITORIAL
identification of the specific features that allow tumors to invade and metastasize. Ultimately, our future treatment may include a form of gene therapy, or be directed at inhibitors of growth factors or the enzymes that permit invasion of matrix. Ambros and Kurman [5], in this issue, present new information regarding features that may be associated with invasion or metastasis. They investigated women with endometrial adenocarcinomas usually considered to have a good prognosis (Stage I) and identified a subset at high risk of failure. Multivariate analysis indicated that the depth of myometrial invasion, DNA ploidy (determined by static image analysis), and a feature they describe as vascular invasion-associated change (VIAC) each significantly contributed to a model predicting survival. VIAC was defined as vascular invasion by tumor or myometrial perivascular lymphocytic infiltrates. To limit confounding variables they wisely limited the tumors to those of typical endometrial type and rigorously assesseddepth of invasion and vascular invasion, using immunohistochemistry when necessary. However, there are deficiencies in the study-their population, was small (N = 57) and perhaps atypical, with a relatively high proportion dead from disease (35%). It is unclear how reproducibly VIAC can be recognized by different pathologists. Most importantly, the study was designed to determine which, if any, of a group of proposed features might display prognostic significance (i.e., a learning set). A new criterion, VIAC, was identified in the learning set. Now, it will be necessary to confirm the significance of their observations in another population, which would constitute a test set. Finally, we are left with a questionwhy are infiltrates of lymphocytes around blood vessels of the myometrium important? Interestingly, the density of lymphoid infiltrates at the tumor-stromal interface has not been clearly related to the differentiation of the tu-
mors [6,7]. Are the perivascular lymphoid cells the sentinels marking the site of prior vascular permeation by tumor? Are these the lymphocytes that successfully aided the host by killing tumor, preventing metastasis? Are they the ones that failed to recognize neoplastic cells as aberrant? Or are they suppressor lymphocytes that helped to diminish the host response to tumor cells? We need to learn not only the pathologic characteristics associated with poor outcome, but also the functional changes that underlie them.
REFERENCES 1. American Cancer Society. Cancer statistics 1991, Cu 41, 1 (1991). 2. Bokhman, J. V. Two pathogenetic types of endometrial carcinoma,
Gynecul. Onco2. 15, 10 (1983). Fearon, E. R., and Vogelstein, B. A genetic model for colorectal 3. tumorigenesis, Cell 61, 759 (1990). 4. Park, R., Grigsby, P. W., Muss, H., and Norris, H. J. Corpus: Epithelial tumors, in Principles and practice of gynecologic oncology (W. Hoskins, C. Perez, and R. Young, Eds.), Lippincott, Philadelphia, pp. 663-693 (1992). 5. Ambros, R. A., and Kurman, R. J. Identification of patients with Stage I uterine endometrioid adenocarcinoma at high risk of recurrence by DNA ploidy, myometrial invasion, and vascular invasion, Gynecol.
Oncol., 45, 235-239.
6, Deligdisch, L. Morphologic correlates of host response in endometrial carcinoma, Am. J. Reprod. Immunol.
2, 54-57 (1982).
7, Silverberg, S. G., Sasano, N., and Yajima, A. Endometrial carcinoma in Miyagi Prefecture, Japan: Histopathologic analysis of a cancer registry-based series and comparison with cases in American women, Cancer 49, 150441510 (1982).
Richard J. Zaino, M.D. Department of Pathology Hershey Medical Center Penn State University
ONCOLOGY
45, 233-234 (1992)
EDITORIAL Endometrial Carcinoma: The Need to Pursue a New Path(ology) Endometrial carcinoma is the most common invasive gynecologic malignancy in the United States, with about 33,000 new cases diagnosed annually [l]. Fortunately, more than 80% are cured by surgery, reflecting frequent diagnosis at an early stage. Nevertheless, about 3000 women died of this tumor last year. Several strategies might be considered to reduce this number in the future, including the following: (1) identification and reduction of risk factors, (2) identification of precursor lesions and means to diagnose preinvasive tumors, (3) identification of women with tumors having a high probability of recurrence, and (4) identification of effective therapy for advanced disease. Where do we stand currently with respect to each of these areas of study? It has (1) IdentiJcation and reduction of risk factors. been hypothesized that there are two distinct clinicopathologic types of endometrial adenocarcinoma [2]. The majority of endometrial adenocarcinomas appear to be related to an endogenous or exogenous estrogen-induced proliferation of the endometrial glands. The addition of a progestin appears to be protective, and oral contraceptive users are at diminished risk compared to control populations. Most of the estrogen-associated tumors tend to be well differentiated, of low stage, steroid receptor rich, and associated with a good behavior. A second group of tumors, such as papillary serous and clear cell carcinomas, do not seem to be related to estrogenic stimulation of the endometrium and do have a distinctly worse prognosis. Unfortunately, risk factors for this second group remain undefined. (2) Ident$cation of precursor lesions and means to diagnose preinvasive lesions. A complete spectrum of his-
tologically defined lesions characterized by increasingly complex and disorganized growth has been identified in the endometrium, beginning with disordered proliferation and including hyperplasias with varying degrees of architectural and cytologic atypia, culminating in well-differentiated adenocarcinoma. The vast majority of these lesions are diploid by relatively crude estimation of DNA content. It is thus appealing to consider these morphologic alterations as reflecting a sequence of relatively subtle
genetic events including oncogene amplification or overexpression, or loss of suppressor genes, similar to the adenoma-carcinoma model of colonic carcinoma proposed by Fearon and Vogelstein [3]. Fortunately, the continued growth is often accompanied by noncyclic shedding and bleeding, which prompts the alert clinician to diagnose preinvasive lesions by biopsy or curettage. Unfortunately, not all carcinomas progress through this pathway, and once again, the types with the most aggressive behavior are usually not found in a setting of hyperplasia. (3) Ident$cation of women with tumors having a high probability of recurrence. There is no shortage of fea-
tures characterized either clinically or pathologically that have been associated with aggressive biologic behavior, including advanced stage, deep myometrial invasion, vascular invasion, papillary serous or clear cell histologic type, poor histologic differentiation, aneuploidy, absence of steroid receptors, and advanced age [4]. The significance of oncogene alterations, elaboration of growth factors, morphometric or immunohistochemical characteristics, and host immune response are currently under investigation or disputed. (4) Zdentijication of effective therapy for poor prognosis and advanced disease. Surgery is remarkably effective
therapy for the limited disease found in most women with endometrial carcinoma. However, the weakest link in this chain of strategies appears to be effective therapy which can produce long-term remission in women with metastatic tumors. Postoperative vaginal cuff or pelvic radiation therapy may reduce the risk of central recurrence, but chemotherapy and endocrine therapy have been of limited value for metastatic endometrial carcinomas, with low response rates (about 25%), which are usually of short duration (about 4-6 months) [4]. Having reviewed our strategies, the following question then comes to mind-of what value is it to identify patients with endometrial adenocarcinomas who are at high risk of recurrence, if we have no effective therapeutic response? I think that it is precisely because of our current inability to treat advanced disease that we need to concentrate our efforts on the first three strategies, including
233 OG90-8258192 $4.00 Copyright 0 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
234
EDITORIAL
identification of the specific features that allow tumors to invade and metastasize. Ultimately, our future treatment may include a form of gene therapy, or be directed at inhibitors of growth factors or the enzymes that permit invasion of matrix. Ambros and Kurman [5], in this issue, present new information regarding features that may be associated with invasion or metastasis. They investigated women with endometrial adenocarcinomas usually considered to have a good prognosis (Stage I) and identified a subset at high risk of failure. Multivariate analysis indicated that the depth of myometrial invasion, DNA ploidy (determined by static image analysis), and a feature they describe as vascular invasion-associated change (VIAC) each significantly contributed to a model predicting survival. VIAC was defined as vascular invasion by tumor or myometrial perivascular lymphocytic infiltrates. To limit confounding variables they wisely limited the tumors to those of typical endometrial type and rigorously assesseddepth of invasion and vascular invasion, using immunohistochemistry when necessary. However, there are deficiencies in the study-their population, was small (N = 57) and perhaps atypical, with a relatively high proportion dead from disease (35%). It is unclear how reproducibly VIAC can be recognized by different pathologists. Most importantly, the study was designed to determine which, if any, of a group of proposed features might display prognostic significance (i.e., a learning set). A new criterion, VIAC, was identified in the learning set. Now, it will be necessary to confirm the significance of their observations in another population, which would constitute a test set. Finally, we are left with a questionwhy are infiltrates of lymphocytes around blood vessels of the myometrium important? Interestingly, the density of lymphoid infiltrates at the tumor-stromal interface has not been clearly related to the differentiation of the tu-
mors [6,7]. Are the perivascular lymphoid cells the sentinels marking the site of prior vascular permeation by tumor? Are these the lymphocytes that successfully aided the host by killing tumor, preventing metastasis? Are they the ones that failed to recognize neoplastic cells as aberrant? Or are they suppressor lymphocytes that helped to diminish the host response to tumor cells? We need to learn not only the pathologic characteristics associated with poor outcome, but also the functional changes that underlie them.
REFERENCES 1. American Cancer Society. Cancer statistics 1991, Cu 41, 1 (1991). 2. Bokhman, J. V. Two pathogenetic types of endometrial carcinoma,
Gynecul. Onco2. 15, 10 (1983). Fearon, E. R., and Vogelstein, B. A genetic model for colorectal 3. tumorigenesis, Cell 61, 759 (1990). 4. Park, R., Grigsby, P. W., Muss, H., and Norris, H. J. Corpus: Epithelial tumors, in Principles and practice of gynecologic oncology (W. Hoskins, C. Perez, and R. Young, Eds.), Lippincott, Philadelphia, pp. 663-693 (1992). 5. Ambros, R. A., and Kurman, R. J. Identification of patients with Stage I uterine endometrioid adenocarcinoma at high risk of recurrence by DNA ploidy, myometrial invasion, and vascular invasion, Gynecol.
Oncol., 45, 235-239.
6, Deligdisch, L. Morphologic correlates of host response in endometrial carcinoma, Am. J. Reprod. Immunol.
2, 54-57 (1982).
7, Silverberg, S. G., Sasano, N., and Yajima, A. Endometrial carcinoma in Miyagi Prefecture, Japan: Histopathologic analysis of a cancer registry-based series and comparison with cases in American women, Cancer 49, 150441510 (1982).
Richard J. Zaino, M.D. Department of Pathology Hershey Medical Center Penn State University