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Aetiology and histopathology of endometrial hyperplasia and carcinoma
Current Obstetrics & Gynaecology (1997)7, 2-7
© 1996Pearson ProfessionalLtd
Mini-symposium: Carcinoma in corpus uteri
Aetiology and histopathology of endometrial hyperplasia and carcinoma
M. C. Anderson and S. J. Robboy Endometrial hyperplasias and many endometrial carcinomas are the result of over-stimulation of the endometrium by oestrogens. Hyperplasias are classified as simple, complex or atypical, the t e r m s 'simple' and 'complex' referring to the glandular architectural pattern as assessed under low magnification and 'atypical' taking account of nuclear features under high power. Atypical hyperplasia may be difficult to distinguish from well-differentiated adenocarcinoma. The c o m m o n e s t type of adenocarcinoma, the typical endometrioid carcinoma, needs to be distinguished from the less frequently encountered serous and clear cell carcinomas because o f the much worse prognosis associated with the latter two types of tumour. Squamous elements may be found in endometrial carcinomas; the importance o f this finding and the value of assessing the malignancy of the s q u a m o u s c o m p o n e n t is controversial.
ENDOMETRIAL HYPERPLASIA
The endometrial hyperplasias are a heterogeneous group of proliferative disorders that cover a wide range, from an appearance that is little different from the late proliferative phase of a normal cycle to a complex pattern that may be difficult to distinguish from carcinoma. The hallmark of hyperplasia is an increased amount of glandular tissue relative to stroma, with concomitant architectural and sometimes cytological changes as outlined below. Only a minority of patients with hyperplasia develop carcinoma and many studies have in the past tried to subclassify hyperplasias in an attempt to identify those patients at highest risk of progression. No uniform system was widely adopted, and by the late 1970s there existed a confusing array of overlapping terms such as 'adenomatous hyperplasia', 'atypical hyperplasia', 'atypical adenomatous hyperplasia', and M. C. AndersonFRCOG, FRCPath, Department of Pathology,
Queen's MedicalCentre, Nottingham NG7 2UH, UK, S. J. RobboyMD, Department of Pathology,Duke University Medical Centre, Durham NC, USA. Correspondence to: M. C. A.
'carcinoma-in-situ' which were used differently by different authors. The International Society of Gynecological Pathologists (ISGP) and the World Health Organization (WHO) recently proposed a standardized classification scheme in which architectural and cytological features are independently evaluated. 1 The architecture is classified as either simple or complex, and the cytological features as atypical or not atypical. In its simplest form, the classification is as follows: • Simple hyperplasia • Complex hyperplasia • Atypical hyperplasia.
THE AETIOLOGY OF ENDOMETRIAL HYPERPLASIA
Endometrial hyperplasia is the result of excessive stimulation by oestrogens, although this association is somewhat clearer for simple hyperplasia than it is for complex and atypical hyperplasia. Simple hyperplasia includes lesions formerly termed cystic hyperplasia and mild adenomatous hyperplasia and is best
Aetiology and histopathology of endometrial hyperplasia and carcinoma thought of as an exaggeration of proliferative activity that merges with disordered proliferation. During the first half of the menstrual cycle, oestrogens stimulate proliferative activity of both glands and stroma, with mitotic activity in both elements. In the normal cycle, the effect of progesterone on the endometrium is to stimulate secretory activity and, at the same time, to inhibit proliferative activity, even though oestrogen secretion continues throughout the secretory phase. If ovulation occurs late or not at all, oestrogen remains unopposed and proliferation continues. This gives rise initially to disordered proliferation that may progress to simple hyperplasia after a period of time. In this way, simple hyperplasia is clearly no more than continued proliferation, a progression of the same process that occurs during the first half of the normal cycle. Disordered proliferation and simple hyperplasia may thus be regarded as the normal response of a normal endometrium to prolonged and unopposed oestrogen stimulation. The histological distinction between simple hyperplasia and disordered proliferation is not clear-cut and opinions vary about the differential diagnosis. Although disordered proliferation and simple hyperplasia are most frequent in women who are perimenopausal or just after the menopause, marked examples of disordered proliferation and sometimes simple hyperplasia may occur in teenagers, who have started menstruating but have not yet begun to ovulate. It is not unusual to find an endometrium that shows widespread changes of simple hyperplasia with superadded areas of complex and atypical hyperplasia. It is arguable whether the latter develops from the former but it seems plausible to suggest that endometrial glands that have been constantly stimulated by oestrogens for some time may alter their response and eventually proliferate in an architecturally and cytologically atypical fashion. An alternative explanation could be that simple, complex and atypical hyperplasia develop concurrently, the differences being the result of a variation in response by the endometrium from one area to another, both the result of stimulation by oestrogen. As the hyperplasias have the same aetiology as endometrial carcinoma, the factors discussed in the section on the aetiology of endometrial carcinoma apply equally to hyperplasia.
HISTOPATHOLOGY OF ENDOMETRIAL HYPERPLASIA Simple hyperplasia In simple hyperplasia, the glandular volume relative to stroma is increased, but the glands are minimally crowded. In comparison to normal proliferative endometrium, the glands lose their regular orientation towards the surface and become more randomly orientated. The gland size varies from small and round to cystically dilated and slightly irregular in outline
3
Fig. 1. Simplehyperplasia.The glands are generallyround or oval and vary in size, somebeing distended. Stromais abundant. (Haematoxylin& eosin; x 40) (Fig. 1). The glands are usually lined by a proliferativetype epithelium. A small percentage of hyperplasias of all types can show secretory changes, typically in the form of well-developed subnuclear and supranuclear vacuoles, but decidualized stroma is absent unless the woman is taking hormones containing progestagens or happens to have just recently ovulated. In many examples of simple hyperplasia, the stroma is abundant with little or no apparent glandular crowding. Occasional outpouchings or serrated gland borders can be seen in moderation, but if extensive must be called complex hyperpiasia. Cellular atypia is unusual but a mild degree of nuclear enlargement may be present. Simple hyperplasia is characteristically diffuse in distribution throughout the endometrium, because the whole functioning endometrium responds similarly to the hormonal stimulus.
Complex and atypical hyperplasia Whereas simple hyperplasia represents the normal response of a normal endometrium to excessive stimulation, complex and atypical hyperplasias appear to be the result of an abnormal response.
Complex hyperplasia."is defined as having more closely opposed glands with markedly irregular and serrated glandular outlines, the stroma usually contributing little, if at all, to the hyperplastic process (Fig. 2). The glands are often virtually back-to-back, a description that indicates glands with minimal intervening stroma. Although complex hyperplasia may be described as having back-to-back glands, it is important to realize that, in complex hyperplasia at least, a thin rim of stroma must separate the glands. The complete absence of stroma is pathognomonic for the diagnosis of adenocarcinoma. Gland outpouchings and 'buds' are frequent. Stratification of glandular cell nuclei is usually present, but lacks diagnostic significance; stratification can be seen in any hyperplasia. Examples previously termed moderate or severe 'adenomatous hyperplasia' fall largely into this category.
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Current Obstetrics & Gynaecology
Fig. 2. Complexhyperplasia.The glands are irregular in outline and are crowded.Although there is still a little stroma betweenthe glands, so that they are not back-to-back, the stroma is markedly reduced in amount. (Haematoxylin& eosin; x 40)
Fig. 3. Atypicalhyperplasia.The glands show generallysimilar architectural featuresto the complexhyperplasiaillustratedin Fig. 2. At a higher power,however,the nuclear abnormalities that warrant the diagnosis of atypicalhyperplasiaare apparent. The nuclei vary in size and many are enlarged, with clumping of chromatin and prominent nucleoli. (Haematoxylin& eosin; x 100)
Atypical hyperplasia: is defined by the presence of cytologic atypia. This concept has been the most controversial and the most difficult to apply in a reproducible fashion in clinical material. There is general agreement, however, that the definition includes increased nuclear size, nuclear rounding, clearing and clumping of chromatin, loss of nuclear polarity, and the presence of prominent nucleoli (Fig. 3). Another useful feature is the presence of abundant and densely eosinophilic cytoplasm. Mitotic activity is not a criterion for atypia, and does not help to distinguish atypical from non-atypical hyperplasias; many however disagree with the statement and consider mitoses an adverse sign. Glandular stratification is a criterion used by some even though the one study specifically addressing this point failed to demonstrate prognostic significance for this feature. This is an important difference, since many highly stratified lesions, which previously would have been designated as 'severe adenomatous hyperplasia', are now classified as complex hyperplasia without atypia when stratification is omitted as a criterion of atypicality. Many pathologists are uncomfortable in discounting the significance of such lesions. Complex and atypical hyperplasia are usually focal in distribution.
symptoms in women. Since 1975, numerous case control studies covering many thousands of patients have examined the relation between endometrial cancer and oestrogen use. Despite criticisms of many aspects of these investigations, it is apparent that the relative risk of developing endometrial carcinoma in women taking unopposed oestrogens is in the order of 6:1. 2 The figure is roughly similar whether the oestrogens are taken continuously or cyclically. The additional administration of progestogens for several days of each month reduces the risk of hyperplasia from about 13% to virtually zero, also thereby eliminating the risk of carcinoma. The anti-oestrogen tamoxifen is widely used as an adjuvant therapy for women with breast cancer. Tamoxifen is a nonsteroidal compound that acts by competing with oestrogen for oestrogen receptors. In women of childbearing age it therefore has an antioestrogenic effect but in women after the menopause who are hypo-oestrogenic, it has a weak oestrogenic effect. Several recent studies have shown that tamoxifen administration is associated with a 2 4 times increased risk of endometrial carcinoma, as well as being associated with other endometrial changes, particularly polyps containing a variety of types of metaplastic epithelium. 3,4 The carcinomas are mainly of early stage and low grade. Endogenous oestrogen as a factor in the aetiology of endometrial carcinoma has been known for many years in that it has been believed that a woman who develops endometrial carcinoma is likely to have a number of constitutional stigmata. Late menopause and low parity are both factors that appear to relate to an increase in overall oestrogen exposure and an association with infertility has been linked to anovulation. Obesity, hypertension and diabetes have frequently been quoted as risk factors for endometrial carcinoma as well as uncommon pathological sources of endogenous oestrogen, such as thecoma and granulosa cell tumour. The exact role that obesity plays in the development of endometrial carcinoma is far from clear and
E N D O M E T R I A L CARCINOMA
Aetiology of endometrial carcinoma The overriding stimulus behind the development of both endometrial hyperplasia and endometrial carcinoma is the effect of oestrogens, both endogenous and exogenous. From 1940 and for the next three decades, the incidence of endometrial cancer in the US was fairly constant; a notable rise in the number of cancer registrations then occurred in the years 1969 to 1973. This rise in the incidence of the disease coincided with a four-fold increase in the use of oestrogens for the alleviation of perimenopausal and postmenopausal
Aetiology and histopathology of endometrial hyperplasia and carcinoma appears to be quite complicated. The association in women past the menopause is commonly explained in terms of increased aromatisation of androgens to oestrogens in adipose tissue. It has been claimed that from one-third to three-quarters of patients with endometrial carcinoma are hypertensive. However, the association between endometrial carcinoma and hypertension may be another representation of the relationship with obesity. Certainly, although the association still persists, its strength decreases when the figures for the relationship between endometrial carcinoma and hypertension are corrected for obesity. It is further apparent that the risk factors for the development of endometrial carcinoma are additive. 5 This means that a woman who is obese and nulliparous is put at even higher risk if she is given unopposed oestrogen hormone replacement therapy. All the epidemiological, histological and behavioural information that is available about endometrial carcinoma suggests that there are two distinct forms of the disease, one that occurs in younger, perimenopausal women and is oestrogen-related, as described above, and another, more virulent form that occurs in older women who lack the above 'constitutional' factors and whose tumour is not related to oestrogens. 6 The patients in the former group have a longer history, lower grade tumours, less myometrial invasion, low potential for lymphatic spread, high sensitivity to progestagens, an association with carcinoma of the ovary, breast and colon and a generally favourable prognosis. In contrast, the latter group of patients have a short history, a higher grade of tumour, deeper myometrial invasion, a higher risk of lymphatic spread, low sensitivity to progestagen, no other associated tumours and a poorer prognosis. Furthermore, the former were more likely to also have hyperplasia in the residual endometrium, whereas the latter patients had atrophic endometrium. The 5-year survival for the two types were 86% and 59% respectively and the 10-year survivals were 76% and 55%.
The pathology of endometrial carcinoma Several histological subtypes of carcinoma occur in the endometrium. The current ISGP/WHO classification scheme is: • Endometrioid: Typical (60% of total) With squamous differentiation (adenoacanthoma and adenosquamous carcinoma) (25% of total) Secretory Ciliated • Serous papillary adenocarcinoma • Clear cell adenocarcinoma • Mucinous adenocarcinoma • Squamous cell carcinoma • Undifferentiated carcinoma • Mixed carcinoma (containing more than 10% of a second pattern).
5
Fig. 4. Endometriatadenocarcinoma- typicalendometrioid type. This is a well differentiatedexample(Grade 1) with no solid growth. The glands are crowdedwith a back-to-back appearance in places. This tumour has invaded the myometrium and a band of myometriumruns diagonallyacross the centre of the illustration. The epithelial cells showmarked loss of polarity and nuclear atypia. (Haematoxylin& eosin; x 100)
Around 60% of tumours are pure endometrioid; the others are less common. Excluding the tumours with a squamous component, which account for another 25% of cases, serous and clear cell tumours are the next most common. All other subtypes are relatively rare and will not be described further. As mucinous and pure squamous carcinomas are common in the cervix, a cervical origin must be excluded before it is concluded that a mucinous or squamous tumour has originated in the endometrium. Mixed carcinomas are not infrequent, and while the prognostic significance of such minor components of higher grade is not known, abundant anectodal evidence suggests that even small such components are associated with a more aggressive behaviour. Any serous or clear cell component is significant and should be reported.
Endometrioid carcinoma Endometrioid carcinoma (Fig. 4) has a glandular pattern generally resembling that of the normal proliferative phase endometrium, although often showing extreme complexity of the glands and a cribriform pattern. Multilayering of the epithelial cells is nearly always seen. The individual epithelial cells are larger than would be expected in the proliferative phase. Compared with the normal endometrium, the carcinoma cells have more rounded nuclei, clumped chromatin and prominent nucleoli. Mitotic figures are usually present but they may be scanty in the best differentiated examples. It is these well differentiated examples of endometrioid adenocarcinoma that are the most difficult to distinguish from the more severe forms of atypical hyperplasia. When the tumour has a papillary, villoglandular pattern, it must be distinguished from serous and clear cell papillary carcinomas, which are generally more aggressive. The endometrial stromal cells may also show abnormalities in the presence of a carcinoma. As many as 20%
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Current Obstetrics & Gynaecology
of cases contain stromal histiocytes that are laden with lipid but there is no correlation between the presence of these cells and the grade of the tumour or the survival of the patient. This change is simply a reactive response to tumour cells that have died. About one-third of patients with endometrial carcinoma also have areas of hyperplasia in the endometrium, a finding that may have an influence on prognosis, as described above. Endometrioid adenocarcinomas are graded according to the proportion of tumour that continues to form glands to that which has a solid growth pattern. Grade 1 tumours have 5% or less solid tumour, Grade 2 tumours 6-50% and Grade 3 tumours more than 50%. If there is marked nuclear atypia that is inappropriately abnormal for the architectural grade, the overall grade is raised by one. In our experience, this is rare and is a subjective evaluation. Adenocarcinoma with squamous differentiation
Approximately 25% of endometrial adenocarcinomas display focal squamous differentiation. In the late 1960s a distinction was made between tumours where the squamous component was well or poorly differentiated. The former were called 'adenoacanthoma' and the latter 'adenosquamous carcinoma'. Numerous studies have confirmed the significantly better prognosis associated with adenoacanthoma and endometrioid carcinoma without squamous differentiation (about 90% survival at 5 years) as compared to the adenosquamous carcinoma (65%). While the well differentiated component is often reported as being 'benign' or even as 'squamous metaplasia', it should be recognized that the squamous component is nonetheless neoplastic, as shown by cases where distant metastases contain the highly differentiated squamous elements. Plaguing most studies is the poor reproducibility in the current classification of these tumours. Usable criteria are needed for the recognition of squamous differentiation, so that a solid focus of adenocarcinoma in an endometrioid carcinoma will not be mistaken as squamous differentiation. Usable criteria are also needed to distinguish among the various degrees of squamous differentiation, that is, distinguishing between adenoacanthoma and adenosquamous carcinoma. Indeed, in large studies where the glandular and squamous components were graded independently, differentiation of the squamous component was shown to closely parallel that of the glandular component. Thus, the prognosis can be predicted by the glandular grade alone. The utility of the terms adenoacanthoma and adenosquamous carcinoma is that they are short, and reflect tumours where both the glandular and squamous components are well or poorly differentiated, respectively. In other words, adenoacanthoma usually has a low-grade glandular component, while adenosquamous carcinoma usually has a highgrade glandular component. The glandular
component is much easier to grade in a reproducible fashion. Grading of the glandular component is also superior in predicting lymph node metastases and 5-year survival. Furthermore, proportional hazard models indicate that the grade of the squamous component is not an independent prognostic variable. 7 As a result of comparative studies and the difficulties in classifying lesions as adenoacanthoma or adenosquamous carcinoma, the ISGP/WHO recommends that the term 'adenocarcinoma with squamous differentiation' be used in place of 'adenoacanthoma' and 'adenosquamous carcinoma'. Grading is to be based solely on the glandular component. We believe that if the term adenosquamous carcinoma is used, it should be reserved for those tumours in which the squamous component shows unequivocal cytological malignancy, mitotic activity or destructive stromal infiltration, 8 whereas adenoacanthoma should be reserved where the squamous component is uniformly well differentiated throughout, in small nests, and without mitotic activity or destructive stromal infiltration. Serous adenocarcinoma
Serous carcinomas have been recognized for many years in the endometrium but it has only been in the past decade that their very aggressive nature has been appreciated. 9 Compared with patients who have endometrioid carcinomas, those with serous tumours are on average 4 to 10 years older, have a very low incidence of oestrogen use, and lack previous or concurrent hyperplasia. The tumour's most striking feature is its aggressive behaviour; up to 75% of patients have Stage 3-4 disease at surgery and over half have metastases in lymph nodes. Not surprisingly, a disproportionately large fraction of relapses of endometrial carcinomas are in patients with serous tumours. Even minimal myometrial invasion is frequently associated with widespread disease, possibly reflecting spread via tubal reflux and subsequent peritoneal carcinomatosis. Histologically, serous tumours in the endometrium are identical to the more common ovarian serous carcinomas. They have a complex, branching papillary appearance with usually broad, thick fibrovascular cores, but occasionally thin to delicate cores. The papillae are covered by a stratified epithelium with a prominent and very characteristic tufting or budding pattern, with many groups of detached cells lying free between papillae. The nuclei are usually high grade, with marked pleomorphism and large macronucleoli along with occasional bizarre giant nuclei. Psammoma bodies are found in about one-third of cases. A high percentage of cases exhibit striking vascular invasion and deep myometrial penetration. Serous endometrial carcinomas also have a higher incidence of cervical and lower uterine segment involvement.9 The overall prognosis of patients with serous carcinomas is poor, as low as 14% 10 year survival; fewer than half of patients with Stage I tumour survive long-term.
Aetiology and histopathology o f endometrial hyperpiasia and carcinoma
Clear cell adenocarcinoma Clear cell carcinomas occur in the vagina, cervix and ovary as well as the endometrium and the histological appearances are the same at all four sites. Clear cell carcinomas comprise from 3 to 6% o f carcinomas of the endometrium. The histological appearances are striking and unmistakable both because of the variety of patterns presented and the characteristic nature o f the patterns themselves, which are: papillary, glandular, solid and tubulocystic. Most clear cell carcinomas have a mixture o f at least two o f these patterns. The epithelial cells forming the lining of the cysts in the tubulocystic areas frequently contain very little cytoplasm, so that the enlarged and pleomorphic nuclei appear to protrude into the lumina, presenting a 'hobnail' appearance. However, the most prominent diagnostic feature o f the clear cell carcinoma is the clearness of the cytoplasm in m a n y o f the cells (although not necessarily the majority); there is nothing in the cytoplasm that stains with haematoxylin and eosin. The glycogen that is present is leached out during normal fixation and processing. Mucin, if present, is found only in the lumina o f the glands formed by the clear cells. N o n e is intracytoplasmic. Nuclear pleomorphism is usually marked and the tumours are o f a high nuclear grade, with frequent mitotic figures. Architectural grading is difficult, because the t u m o u r is not structurally related
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to a normal tissue that it can be compared with. Clear cell carcinoma o f the endometrium occurs at an older age than endometrioid carcinoma and is associated with a poorer prognosis. REFERENCES 1. Scully RE, Bonfiglio TA, Kurman R J, Silverberg SG, Wilkinson EJ. Histological typing of female genital tract tumours. World Health Organization International Histological Classification of Tumours. Berlin: Springer-Verlag, 1994 2. Anderson MC, Butler EB, Chamberlain, G.V.E Oestrogen replacement and endometrial cancer. A statement by the British GynaecologicalCancer Group. Lancet 1981; 1: 1359-1360 3. Assikis VJ, Jordan VC. A realistic assessment of the association between tamoxifen and endometrial cancer. Endocr-Rel Cancer 1995; 2:235~41 4. Ismail SM. Pathology of endometrium treated with tamoxifen. J Clin Pathol 1994;47:827-833 5. Davies JL, Rosenhein NB, Antunes CMF, Stolley PDA. A review of the risk factors for endometrial carcinoma. Obstet Gynecol Surv 1981; 36:107-111 6. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983; 15:10-17 7. Zaino R J, Kurman R, Herbold D, et al. The significanceof squamous differentiation in endometrial carcinoma:data from a Gynecolo~c OncologyGroup study. Cancer 1991;68:2293-2302 8. Silverberg SG, Kurman RJ. Turnouts of the uterine corpus and gestational trophoblastic disease. Washington: Armed Forces Institute of Pathology, 1992 9. Longacre TA, Kempson RL, Hendrickson MR. Endometrial hyperplasia, metaplasia and carcinoma. In: Fox H, Wells M (eds). Haines and Taylor Obstetrical and Gynaecological Pathology. 4th ed. Edinburgh: Churchill Livingstone, 1995; 421 510
© 1996Pearson ProfessionalLtd
Mini-symposium: Carcinoma in corpus uteri
Aetiology and histopathology of endometrial hyperplasia and carcinoma
M. C. Anderson and S. J. Robboy Endometrial hyperplasias and many endometrial carcinomas are the result of over-stimulation of the endometrium by oestrogens. Hyperplasias are classified as simple, complex or atypical, the t e r m s 'simple' and 'complex' referring to the glandular architectural pattern as assessed under low magnification and 'atypical' taking account of nuclear features under high power. Atypical hyperplasia may be difficult to distinguish from well-differentiated adenocarcinoma. The c o m m o n e s t type of adenocarcinoma, the typical endometrioid carcinoma, needs to be distinguished from the less frequently encountered serous and clear cell carcinomas because o f the much worse prognosis associated with the latter two types of tumour. Squamous elements may be found in endometrial carcinomas; the importance o f this finding and the value of assessing the malignancy of the s q u a m o u s c o m p o n e n t is controversial.
ENDOMETRIAL HYPERPLASIA
The endometrial hyperplasias are a heterogeneous group of proliferative disorders that cover a wide range, from an appearance that is little different from the late proliferative phase of a normal cycle to a complex pattern that may be difficult to distinguish from carcinoma. The hallmark of hyperplasia is an increased amount of glandular tissue relative to stroma, with concomitant architectural and sometimes cytological changes as outlined below. Only a minority of patients with hyperplasia develop carcinoma and many studies have in the past tried to subclassify hyperplasias in an attempt to identify those patients at highest risk of progression. No uniform system was widely adopted, and by the late 1970s there existed a confusing array of overlapping terms such as 'adenomatous hyperplasia', 'atypical hyperplasia', 'atypical adenomatous hyperplasia', and M. C. AndersonFRCOG, FRCPath, Department of Pathology,
Queen's MedicalCentre, Nottingham NG7 2UH, UK, S. J. RobboyMD, Department of Pathology,Duke University Medical Centre, Durham NC, USA. Correspondence to: M. C. A.
'carcinoma-in-situ' which were used differently by different authors. The International Society of Gynecological Pathologists (ISGP) and the World Health Organization (WHO) recently proposed a standardized classification scheme in which architectural and cytological features are independently evaluated. 1 The architecture is classified as either simple or complex, and the cytological features as atypical or not atypical. In its simplest form, the classification is as follows: • Simple hyperplasia • Complex hyperplasia • Atypical hyperplasia.
THE AETIOLOGY OF ENDOMETRIAL HYPERPLASIA
Endometrial hyperplasia is the result of excessive stimulation by oestrogens, although this association is somewhat clearer for simple hyperplasia than it is for complex and atypical hyperplasia. Simple hyperplasia includes lesions formerly termed cystic hyperplasia and mild adenomatous hyperplasia and is best
Aetiology and histopathology of endometrial hyperplasia and carcinoma thought of as an exaggeration of proliferative activity that merges with disordered proliferation. During the first half of the menstrual cycle, oestrogens stimulate proliferative activity of both glands and stroma, with mitotic activity in both elements. In the normal cycle, the effect of progesterone on the endometrium is to stimulate secretory activity and, at the same time, to inhibit proliferative activity, even though oestrogen secretion continues throughout the secretory phase. If ovulation occurs late or not at all, oestrogen remains unopposed and proliferation continues. This gives rise initially to disordered proliferation that may progress to simple hyperplasia after a period of time. In this way, simple hyperplasia is clearly no more than continued proliferation, a progression of the same process that occurs during the first half of the normal cycle. Disordered proliferation and simple hyperplasia may thus be regarded as the normal response of a normal endometrium to prolonged and unopposed oestrogen stimulation. The histological distinction between simple hyperplasia and disordered proliferation is not clear-cut and opinions vary about the differential diagnosis. Although disordered proliferation and simple hyperplasia are most frequent in women who are perimenopausal or just after the menopause, marked examples of disordered proliferation and sometimes simple hyperplasia may occur in teenagers, who have started menstruating but have not yet begun to ovulate. It is not unusual to find an endometrium that shows widespread changes of simple hyperplasia with superadded areas of complex and atypical hyperplasia. It is arguable whether the latter develops from the former but it seems plausible to suggest that endometrial glands that have been constantly stimulated by oestrogens for some time may alter their response and eventually proliferate in an architecturally and cytologically atypical fashion. An alternative explanation could be that simple, complex and atypical hyperplasia develop concurrently, the differences being the result of a variation in response by the endometrium from one area to another, both the result of stimulation by oestrogen. As the hyperplasias have the same aetiology as endometrial carcinoma, the factors discussed in the section on the aetiology of endometrial carcinoma apply equally to hyperplasia.
HISTOPATHOLOGY OF ENDOMETRIAL HYPERPLASIA Simple hyperplasia In simple hyperplasia, the glandular volume relative to stroma is increased, but the glands are minimally crowded. In comparison to normal proliferative endometrium, the glands lose their regular orientation towards the surface and become more randomly orientated. The gland size varies from small and round to cystically dilated and slightly irregular in outline
3
Fig. 1. Simplehyperplasia.The glands are generallyround or oval and vary in size, somebeing distended. Stromais abundant. (Haematoxylin& eosin; x 40) (Fig. 1). The glands are usually lined by a proliferativetype epithelium. A small percentage of hyperplasias of all types can show secretory changes, typically in the form of well-developed subnuclear and supranuclear vacuoles, but decidualized stroma is absent unless the woman is taking hormones containing progestagens or happens to have just recently ovulated. In many examples of simple hyperplasia, the stroma is abundant with little or no apparent glandular crowding. Occasional outpouchings or serrated gland borders can be seen in moderation, but if extensive must be called complex hyperpiasia. Cellular atypia is unusual but a mild degree of nuclear enlargement may be present. Simple hyperplasia is characteristically diffuse in distribution throughout the endometrium, because the whole functioning endometrium responds similarly to the hormonal stimulus.
Complex and atypical hyperplasia Whereas simple hyperplasia represents the normal response of a normal endometrium to excessive stimulation, complex and atypical hyperplasias appear to be the result of an abnormal response.
Complex hyperplasia."is defined as having more closely opposed glands with markedly irregular and serrated glandular outlines, the stroma usually contributing little, if at all, to the hyperplastic process (Fig. 2). The glands are often virtually back-to-back, a description that indicates glands with minimal intervening stroma. Although complex hyperplasia may be described as having back-to-back glands, it is important to realize that, in complex hyperplasia at least, a thin rim of stroma must separate the glands. The complete absence of stroma is pathognomonic for the diagnosis of adenocarcinoma. Gland outpouchings and 'buds' are frequent. Stratification of glandular cell nuclei is usually present, but lacks diagnostic significance; stratification can be seen in any hyperplasia. Examples previously termed moderate or severe 'adenomatous hyperplasia' fall largely into this category.
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Current Obstetrics & Gynaecology
Fig. 2. Complexhyperplasia.The glands are irregular in outline and are crowded.Although there is still a little stroma betweenthe glands, so that they are not back-to-back, the stroma is markedly reduced in amount. (Haematoxylin& eosin; x 40)
Fig. 3. Atypicalhyperplasia.The glands show generallysimilar architectural featuresto the complexhyperplasiaillustratedin Fig. 2. At a higher power,however,the nuclear abnormalities that warrant the diagnosis of atypicalhyperplasiaare apparent. The nuclei vary in size and many are enlarged, with clumping of chromatin and prominent nucleoli. (Haematoxylin& eosin; x 100)
Atypical hyperplasia: is defined by the presence of cytologic atypia. This concept has been the most controversial and the most difficult to apply in a reproducible fashion in clinical material. There is general agreement, however, that the definition includes increased nuclear size, nuclear rounding, clearing and clumping of chromatin, loss of nuclear polarity, and the presence of prominent nucleoli (Fig. 3). Another useful feature is the presence of abundant and densely eosinophilic cytoplasm. Mitotic activity is not a criterion for atypia, and does not help to distinguish atypical from non-atypical hyperplasias; many however disagree with the statement and consider mitoses an adverse sign. Glandular stratification is a criterion used by some even though the one study specifically addressing this point failed to demonstrate prognostic significance for this feature. This is an important difference, since many highly stratified lesions, which previously would have been designated as 'severe adenomatous hyperplasia', are now classified as complex hyperplasia without atypia when stratification is omitted as a criterion of atypicality. Many pathologists are uncomfortable in discounting the significance of such lesions. Complex and atypical hyperplasia are usually focal in distribution.
symptoms in women. Since 1975, numerous case control studies covering many thousands of patients have examined the relation between endometrial cancer and oestrogen use. Despite criticisms of many aspects of these investigations, it is apparent that the relative risk of developing endometrial carcinoma in women taking unopposed oestrogens is in the order of 6:1. 2 The figure is roughly similar whether the oestrogens are taken continuously or cyclically. The additional administration of progestogens for several days of each month reduces the risk of hyperplasia from about 13% to virtually zero, also thereby eliminating the risk of carcinoma. The anti-oestrogen tamoxifen is widely used as an adjuvant therapy for women with breast cancer. Tamoxifen is a nonsteroidal compound that acts by competing with oestrogen for oestrogen receptors. In women of childbearing age it therefore has an antioestrogenic effect but in women after the menopause who are hypo-oestrogenic, it has a weak oestrogenic effect. Several recent studies have shown that tamoxifen administration is associated with a 2 4 times increased risk of endometrial carcinoma, as well as being associated with other endometrial changes, particularly polyps containing a variety of types of metaplastic epithelium. 3,4 The carcinomas are mainly of early stage and low grade. Endogenous oestrogen as a factor in the aetiology of endometrial carcinoma has been known for many years in that it has been believed that a woman who develops endometrial carcinoma is likely to have a number of constitutional stigmata. Late menopause and low parity are both factors that appear to relate to an increase in overall oestrogen exposure and an association with infertility has been linked to anovulation. Obesity, hypertension and diabetes have frequently been quoted as risk factors for endometrial carcinoma as well as uncommon pathological sources of endogenous oestrogen, such as thecoma and granulosa cell tumour. The exact role that obesity plays in the development of endometrial carcinoma is far from clear and
E N D O M E T R I A L CARCINOMA
Aetiology of endometrial carcinoma The overriding stimulus behind the development of both endometrial hyperplasia and endometrial carcinoma is the effect of oestrogens, both endogenous and exogenous. From 1940 and for the next three decades, the incidence of endometrial cancer in the US was fairly constant; a notable rise in the number of cancer registrations then occurred in the years 1969 to 1973. This rise in the incidence of the disease coincided with a four-fold increase in the use of oestrogens for the alleviation of perimenopausal and postmenopausal
Aetiology and histopathology of endometrial hyperplasia and carcinoma appears to be quite complicated. The association in women past the menopause is commonly explained in terms of increased aromatisation of androgens to oestrogens in adipose tissue. It has been claimed that from one-third to three-quarters of patients with endometrial carcinoma are hypertensive. However, the association between endometrial carcinoma and hypertension may be another representation of the relationship with obesity. Certainly, although the association still persists, its strength decreases when the figures for the relationship between endometrial carcinoma and hypertension are corrected for obesity. It is further apparent that the risk factors for the development of endometrial carcinoma are additive. 5 This means that a woman who is obese and nulliparous is put at even higher risk if she is given unopposed oestrogen hormone replacement therapy. All the epidemiological, histological and behavioural information that is available about endometrial carcinoma suggests that there are two distinct forms of the disease, one that occurs in younger, perimenopausal women and is oestrogen-related, as described above, and another, more virulent form that occurs in older women who lack the above 'constitutional' factors and whose tumour is not related to oestrogens. 6 The patients in the former group have a longer history, lower grade tumours, less myometrial invasion, low potential for lymphatic spread, high sensitivity to progestagens, an association with carcinoma of the ovary, breast and colon and a generally favourable prognosis. In contrast, the latter group of patients have a short history, a higher grade of tumour, deeper myometrial invasion, a higher risk of lymphatic spread, low sensitivity to progestagen, no other associated tumours and a poorer prognosis. Furthermore, the former were more likely to also have hyperplasia in the residual endometrium, whereas the latter patients had atrophic endometrium. The 5-year survival for the two types were 86% and 59% respectively and the 10-year survivals were 76% and 55%.
The pathology of endometrial carcinoma Several histological subtypes of carcinoma occur in the endometrium. The current ISGP/WHO classification scheme is: • Endometrioid: Typical (60% of total) With squamous differentiation (adenoacanthoma and adenosquamous carcinoma) (25% of total) Secretory Ciliated • Serous papillary adenocarcinoma • Clear cell adenocarcinoma • Mucinous adenocarcinoma • Squamous cell carcinoma • Undifferentiated carcinoma • Mixed carcinoma (containing more than 10% of a second pattern).
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Fig. 4. Endometriatadenocarcinoma- typicalendometrioid type. This is a well differentiatedexample(Grade 1) with no solid growth. The glands are crowdedwith a back-to-back appearance in places. This tumour has invaded the myometrium and a band of myometriumruns diagonallyacross the centre of the illustration. The epithelial cells showmarked loss of polarity and nuclear atypia. (Haematoxylin& eosin; x 100)
Around 60% of tumours are pure endometrioid; the others are less common. Excluding the tumours with a squamous component, which account for another 25% of cases, serous and clear cell tumours are the next most common. All other subtypes are relatively rare and will not be described further. As mucinous and pure squamous carcinomas are common in the cervix, a cervical origin must be excluded before it is concluded that a mucinous or squamous tumour has originated in the endometrium. Mixed carcinomas are not infrequent, and while the prognostic significance of such minor components of higher grade is not known, abundant anectodal evidence suggests that even small such components are associated with a more aggressive behaviour. Any serous or clear cell component is significant and should be reported.
Endometrioid carcinoma Endometrioid carcinoma (Fig. 4) has a glandular pattern generally resembling that of the normal proliferative phase endometrium, although often showing extreme complexity of the glands and a cribriform pattern. Multilayering of the epithelial cells is nearly always seen. The individual epithelial cells are larger than would be expected in the proliferative phase. Compared with the normal endometrium, the carcinoma cells have more rounded nuclei, clumped chromatin and prominent nucleoli. Mitotic figures are usually present but they may be scanty in the best differentiated examples. It is these well differentiated examples of endometrioid adenocarcinoma that are the most difficult to distinguish from the more severe forms of atypical hyperplasia. When the tumour has a papillary, villoglandular pattern, it must be distinguished from serous and clear cell papillary carcinomas, which are generally more aggressive. The endometrial stromal cells may also show abnormalities in the presence of a carcinoma. As many as 20%
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Current Obstetrics & Gynaecology
of cases contain stromal histiocytes that are laden with lipid but there is no correlation between the presence of these cells and the grade of the tumour or the survival of the patient. This change is simply a reactive response to tumour cells that have died. About one-third of patients with endometrial carcinoma also have areas of hyperplasia in the endometrium, a finding that may have an influence on prognosis, as described above. Endometrioid adenocarcinomas are graded according to the proportion of tumour that continues to form glands to that which has a solid growth pattern. Grade 1 tumours have 5% or less solid tumour, Grade 2 tumours 6-50% and Grade 3 tumours more than 50%. If there is marked nuclear atypia that is inappropriately abnormal for the architectural grade, the overall grade is raised by one. In our experience, this is rare and is a subjective evaluation. Adenocarcinoma with squamous differentiation
Approximately 25% of endometrial adenocarcinomas display focal squamous differentiation. In the late 1960s a distinction was made between tumours where the squamous component was well or poorly differentiated. The former were called 'adenoacanthoma' and the latter 'adenosquamous carcinoma'. Numerous studies have confirmed the significantly better prognosis associated with adenoacanthoma and endometrioid carcinoma without squamous differentiation (about 90% survival at 5 years) as compared to the adenosquamous carcinoma (65%). While the well differentiated component is often reported as being 'benign' or even as 'squamous metaplasia', it should be recognized that the squamous component is nonetheless neoplastic, as shown by cases where distant metastases contain the highly differentiated squamous elements. Plaguing most studies is the poor reproducibility in the current classification of these tumours. Usable criteria are needed for the recognition of squamous differentiation, so that a solid focus of adenocarcinoma in an endometrioid carcinoma will not be mistaken as squamous differentiation. Usable criteria are also needed to distinguish among the various degrees of squamous differentiation, that is, distinguishing between adenoacanthoma and adenosquamous carcinoma. Indeed, in large studies where the glandular and squamous components were graded independently, differentiation of the squamous component was shown to closely parallel that of the glandular component. Thus, the prognosis can be predicted by the glandular grade alone. The utility of the terms adenoacanthoma and adenosquamous carcinoma is that they are short, and reflect tumours where both the glandular and squamous components are well or poorly differentiated, respectively. In other words, adenoacanthoma usually has a low-grade glandular component, while adenosquamous carcinoma usually has a highgrade glandular component. The glandular
component is much easier to grade in a reproducible fashion. Grading of the glandular component is also superior in predicting lymph node metastases and 5-year survival. Furthermore, proportional hazard models indicate that the grade of the squamous component is not an independent prognostic variable. 7 As a result of comparative studies and the difficulties in classifying lesions as adenoacanthoma or adenosquamous carcinoma, the ISGP/WHO recommends that the term 'adenocarcinoma with squamous differentiation' be used in place of 'adenoacanthoma' and 'adenosquamous carcinoma'. Grading is to be based solely on the glandular component. We believe that if the term adenosquamous carcinoma is used, it should be reserved for those tumours in which the squamous component shows unequivocal cytological malignancy, mitotic activity or destructive stromal infiltration, 8 whereas adenoacanthoma should be reserved where the squamous component is uniformly well differentiated throughout, in small nests, and without mitotic activity or destructive stromal infiltration. Serous adenocarcinoma
Serous carcinomas have been recognized for many years in the endometrium but it has only been in the past decade that their very aggressive nature has been appreciated. 9 Compared with patients who have endometrioid carcinomas, those with serous tumours are on average 4 to 10 years older, have a very low incidence of oestrogen use, and lack previous or concurrent hyperplasia. The tumour's most striking feature is its aggressive behaviour; up to 75% of patients have Stage 3-4 disease at surgery and over half have metastases in lymph nodes. Not surprisingly, a disproportionately large fraction of relapses of endometrial carcinomas are in patients with serous tumours. Even minimal myometrial invasion is frequently associated with widespread disease, possibly reflecting spread via tubal reflux and subsequent peritoneal carcinomatosis. Histologically, serous tumours in the endometrium are identical to the more common ovarian serous carcinomas. They have a complex, branching papillary appearance with usually broad, thick fibrovascular cores, but occasionally thin to delicate cores. The papillae are covered by a stratified epithelium with a prominent and very characteristic tufting or budding pattern, with many groups of detached cells lying free between papillae. The nuclei are usually high grade, with marked pleomorphism and large macronucleoli along with occasional bizarre giant nuclei. Psammoma bodies are found in about one-third of cases. A high percentage of cases exhibit striking vascular invasion and deep myometrial penetration. Serous endometrial carcinomas also have a higher incidence of cervical and lower uterine segment involvement.9 The overall prognosis of patients with serous carcinomas is poor, as low as 14% 10 year survival; fewer than half of patients with Stage I tumour survive long-term.
Aetiology and histopathology o f endometrial hyperpiasia and carcinoma
Clear cell adenocarcinoma Clear cell carcinomas occur in the vagina, cervix and ovary as well as the endometrium and the histological appearances are the same at all four sites. Clear cell carcinomas comprise from 3 to 6% o f carcinomas of the endometrium. The histological appearances are striking and unmistakable both because of the variety of patterns presented and the characteristic nature o f the patterns themselves, which are: papillary, glandular, solid and tubulocystic. Most clear cell carcinomas have a mixture o f at least two o f these patterns. The epithelial cells forming the lining of the cysts in the tubulocystic areas frequently contain very little cytoplasm, so that the enlarged and pleomorphic nuclei appear to protrude into the lumina, presenting a 'hobnail' appearance. However, the most prominent diagnostic feature o f the clear cell carcinoma is the clearness of the cytoplasm in m a n y o f the cells (although not necessarily the majority); there is nothing in the cytoplasm that stains with haematoxylin and eosin. The glycogen that is present is leached out during normal fixation and processing. Mucin, if present, is found only in the lumina o f the glands formed by the clear cells. N o n e is intracytoplasmic. Nuclear pleomorphism is usually marked and the tumours are o f a high nuclear grade, with frequent mitotic figures. Architectural grading is difficult, because the t u m o u r is not structurally related
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to a normal tissue that it can be compared with. Clear cell carcinoma o f the endometrium occurs at an older age than endometrioid carcinoma and is associated with a poorer prognosis. REFERENCES 1. Scully RE, Bonfiglio TA, Kurman R J, Silverberg SG, Wilkinson EJ. Histological typing of female genital tract tumours. World Health Organization International Histological Classification of Tumours. Berlin: Springer-Verlag, 1994 2. Anderson MC, Butler EB, Chamberlain, G.V.E Oestrogen replacement and endometrial cancer. A statement by the British GynaecologicalCancer Group. Lancet 1981; 1: 1359-1360 3. Assikis VJ, Jordan VC. A realistic assessment of the association between tamoxifen and endometrial cancer. Endocr-Rel Cancer 1995; 2:235~41 4. Ismail SM. Pathology of endometrium treated with tamoxifen. J Clin Pathol 1994;47:827-833 5. Davies JL, Rosenhein NB, Antunes CMF, Stolley PDA. A review of the risk factors for endometrial carcinoma. Obstet Gynecol Surv 1981; 36:107-111 6. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983; 15:10-17 7. Zaino R J, Kurman R, Herbold D, et al. The significanceof squamous differentiation in endometrial carcinoma:data from a Gynecolo~c OncologyGroup study. Cancer 1991;68:2293-2302 8. Silverberg SG, Kurman RJ. Turnouts of the uterine corpus and gestational trophoblastic disease. Washington: Armed Forces Institute of Pathology, 1992 9. Longacre TA, Kempson RL, Hendrickson MR. Endometrial hyperplasia, metaplasia and carcinoma. In: Fox H, Wells M (eds). Haines and Taylor Obstetrical and Gynaecological Pathology. 4th ed. Edinburgh: Churchill Livingstone, 1995; 421 510