AJCP / Original Article
High Prevalence of Atypical Hyperplasia in the Endometrium of Patients With Epithelial Ovarian Cancer Marjanka J. J. M. Mingels, MD,1 Rina Masadah, MD, PhD,2,3 Yvette P. Geels, MD,1 Irene Otte-Höller,2 Ineke M. de Kievit, MD, PhD,4 Jeroen A. W. M. van der Laak, PhD,2 Maaike A. P. C. van Ham, MD, PhD,1 Johan Bulten, MD, PhD,2 and Leon F. A. G. Massuger, MD, PhD1 From the Departments of 1Obstetrics and Gynecology and 2Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 3Department of Pathology, Hasanuddin University, Makassar, Indonesia; and 4 Department of Pathology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands. Key Words: Epithelial ovarian cancer; Atypical hyperplasia; Endometrial intraepithelial carcinoma; Endometrium Am J Clin Pathol August 2014;142:213-221 DOI: 10.1309/AJCPTGJOPXUW6RVO
ABSTRACT Objectives: The aim of the present study is to determine the prevalence of endometrial premalignancies in women diagnosed with epithelial ovarian cancer (EOC). Methods: Endometrial and ovarian specimens of 186 patients with EOC were retrospectively selected using the nationwide pathology network and registry, and sections were comprehensively reviewed: 136 (73%) serous, 19 (10%) endometrioid, 15 (8%) mucinous, seven (4%) clear cell, and nine (5%) undifferentiated. Immunohistochemical phenotypes were compared for patients with serous EOC with concurrent endometrial pathology. Results: In 31%, endometrial (pre)malignancy was found: carcinoma in 3%, endometrial intraepithelial carcinoma (EIC) in 4%, and atypical hyperplasia in 24%. Atypical hyperplasia was found in 47% of endometrioid EOCs but in 7% to 33% of other subtypes. Body mass index was higher concurrent to atypical hyperplasia (P = .001). Serous EOC and EIC immunophenotypes were comparable, whereas atypical hyperplasia was expressed differently. Conclusions: Apart from synchronous endometrial carcinoma, endometrial premalignancies should be taken into account when determining optimal treatment for women diagnosed with EOC.
© American Society for Clinical Pathology
Epithelial ovarian cancer (EOC) is a highly aggressive and rapidly progressive tumor. Surgical management of EOC includes primary debulking or interval debulking after neoadjuvant chemotherapy. All international guidelines recommend a hysterectomy in these women to accomplish complete debulking, since the serosa of the uterus is one of the most frequent sites of peritoneal spread, and complete debulking surgery is associated with improved overall survival.1,2 Another justification to perform routine hysterectomy in patients with EOC includes the presence of a double primary carcinoma in the endometrium in 10% of endometrioid ovarian carcinomas and in 2% to 5% of serous, clear cell, and mucinous carcinomas.3-5 Knowledge of the prevalence of synchronous endometrial premalignancies in these women is nevertheless poor. In studies reporting on EOC and concurrent endometrial carcinomas, no additional information is given on the prevalence of endometrial premalignancies. One study investigated a small cohort of extraovarian carcinomas and reported endometrial hyperplasia in 13% of cases, in addition to synchronous endometrial carcinoma in 6%.1 The few studies analyzing the endometrium in general (asymptomatic) populations reported a much lower prevalence of endometrial lesions, with hyperplasia found in 1% to 2%, atypical hyperplasia in 1%, and carcinoma in 0.5%.6-10 The aim of this study was to extensively review the endometrium of a large cohort of patients with EOC to assess the prevalence of endometrial pathology in these women. Correlations were analyzed between endometrial lesions and clinical risk factors that are known to influence endometrial proliferation. Furthermore, immunohistochemical expression patterns of the most common type of
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ovarian carcinomas, serous ovarian carcinomas, and concurrent endometrial lesions were analyzed.
Materials and Methods Patient and Samples All patients surgically treated for EOC in the Radboud University Nijmegen Medical Centre (RUNMC) from April 1996 through December 2010 were selected. The search term ovarian carcinoma was entered in the Dutch nationwide network and registry of histopathology and cytopathology (PALGA), yielding 311 patients satisfying these constraints. In total, 108 patients were excluded because hysterectomy was not performed at the RUNMC; in 34 patients, hysterectomy already had been performed for benign reasons or at primary incomplete debulking in another institution, and in 48 patients, the uterus remained in situ because of an inability to achieve complete debulking or uterus preservation. Twentysix patients visited our institution only for a second opinion on treatment management and revision of pathologic diagnosis. For the remaining 203 patients, all available H&E-stained endometrial and ovarian sections were retrieved from the pathology archive of the RUNMC. Embedding of endometrial tissue was performed according to routine protocol. Seventeen patients had to be excluded because not all sections were available for review. Therefore, the final study population contained 186 patients with EOC: 136 (73%) women diagnosed with serous carcinoma, 19 (10%) with endometrioid carcinoma, 15 (8%) with mucinous carcinoma, seven (4%) with clear cell carcinoma, and nine (5%) with undifferentiated carcinoma. Medical records and surgical and pathology reports were retrieved to determine pertinent clinical and pathologic data. Data obtained included age, menopausal state, BRCA mutation status, International Federation of Gynecology and Obstetrics (FIGO) stage, and treatment management. Patients were staged in accordance with the FIGO surgical staging adopted in 1988.11 Conditions that are able to cause unopposed estrogen stimulation were retrieved from medical records: late menopause, high body mass index (BMI; by peripheral conversion of androstenedione to estrogen in adipose tissue of obese women), or an estrogen-producing tumor. On behalf of the research ethics committee of the RUNMC, the study was carried out in accordance with the applicable rules concerning the review of research ethics committees and informed consent. Histopathology All ovarian and endometrial sections were reviewed by two pathologists with extensive experience in gynecopathology. In case of a discrepancy in diagnosis, consensus was 214 214
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reached between both pathologists. The following endometrial entities were scored in the endometrium: normal endometrium, hyperplasia, atypical hyperplasia, endometrial intraepithelial carcinoma (EIC), and invasive carcinoma ❚Image 1❚. A classification scheme developed by Kurman et al12 and adapted by the World Health Organization was used to interpret endometrial hyperplasia with or without atypia. For the identification of EIC, previously published criteria were used that define EIC morphologically as the replacement of endometrial surface epithelium and glands, without myometrial or stromal invasion, by malignant cells that are identical to serous carcinoma cells.12-14 Immunohistochemical Analysis Immunohistochemical stainings were performed on sections from formalin-fixed, paraffin-embedded samples in which endometrial atypical hyperplasia or EIC was identified in patients diagnosed with serous EOC. A representative sample of the ovarian carcinoma was added in each case. Sections of 5 µm were sliced and incubated with monoclonal antibodies against p53 (dilution 1:250, clone DO-7; Neomarkers, Fremont, CA), WT1 monoclonal antibody (dilution 1:20, clone 49, NCL-L-WT1-562; Leica Biosystems, Newcastle Upon Tyne, UK), Ki-67 (dilution 1:100, clone MIB-1; DAKO, Glostrup, Denmark), estrogen receptor (ER) (dilution 1:100, clone SP-1; Thermo Scientific, Fremont, CA), progesterone receptor (PR) (dilution 1:500, clone PgR636; DAKO), and p16 (dilution 1:500, clone 16PO4; Neomarkers). Antigen retrieval was processed according to the manufacturers’ guidelines, and antigen-antibody complexes were localized using the standard streptavidin-biotin technique (Vector Laboratories, Burlingame, CA) with diaminobenzidine as chromogen. Normal endometrial tissue was used as a control in each case, and a positive control was included in each batch of staining. Immunohistochemical stainings were interpreted by two authors (J.B. and M.J.J.M.M.). Expression of nuclear staining for p53, p16, and WT1 was scored as the percentage of positive stained tumor cells and classified as follows: 1% to 50%, 51% to 75%, more than 75%, or complete absence of expression. Intense expression of p53 in more than 75% of tumor cells or complete absence of expression was considered strongly correlated with the presence of a TP53 mutation.15 Expression of nuclear staining for Ki-67, ER, and PR was scored as the percentage of positive stained cells and classified as follows: less than 5% (–, negative), 5% to 20% (+, weak), more than 20% to 50% (++, moderate), and more than 50% (+++, strong). Membranous and/or cytoplasmic expression was not considered positive. Statistics Analyses were performed to compare the prevalence of endometrial entities and their clinicopathologic characteristics for the different histologic subtypes of EOC. Furthermore, the © American Society for Clinical Pathology
AJCP / Original Article
A
B
C
D
E
F
❚Image 1❚ A, Normal endometrial epithelium (×200). Endometrial lesions identified in the endometrium of women with ovarian carcinoma: (B) endometrial simple hyperplasia (×200), (C) endometrial atypical hyperplasia (×100), (D) endometrial atypical hyperplasia (×200), (E) endometrial intraepithelial carcinoma (×200), and (F) synchronous primary endometrial carcinoma (×200). © American Society for Clinical Pathology
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prevalence of risk factors for endometrial proliferation was compared between the group of patients diagnosed with an atypical hyperplastic endometrium and the group diagnosed with normal endometrium. Variables were expressed as frequencies and percentages for discrete data and as median and 25th to 75th quartiles for continuous data. Statistical comparison of medians from independent samples was performed using the Kruskal-Wallis and Mann-Whitney U tests. Pearson c2 and, if appropriate, the Fisher exact test were used to test associations between categorical variables. All statistical analyses were performed using SPSS software version 18.0 (SPSS, Chicago, IL), and P < .05 (two-sided test) was considered statistically significant.
Results Clinical data were analyzed for 186 patients with EOC included in the study ❚Table 1❚. The median age at diagnosis was 60 years, median BMI was 24.6 kg/m², and 71% were postmenopausal (Table 1). Most patients had an advanced stage of disease at diagnosis, with a FIGO stage IV in 29 (16%) patients, stage III in 114 (63%), stage II in nine (5%), and stage I in 29 (16%). Median age at diagnosis, menopausal state, and FIGO stage were significantly different for histologic subtypes of EOC (P = .009, P = .007, and P < .001, respectively; Table 1). Patients diagnosed with serous or clear cell carcinomas had a median age of 60 years, whereas
patients with endometrioid and mucinous carcinomas were younger and more often premenopausal. Results of histologic assessment of the endometrium are shown in ❚Table 2❚. In 105 (56%) patients, the endometrium was without abnormalities. In 81 (44%) patients, an endometrial lesion was identified, and in 58 (31%) patients, this lesion was (pre)malignant. The latter included a double primary endometrial carcinoma in six (3%) patients, EIC in seven (4%), and atypical hyperplasia in 45 (24%). In two patients diagnosed with double primary endometrioid carcinoma, atypical hyperplasia also was found in the preexistent endometrium. In all cases, the background endometrium was assessed to confirm that endometrial lesions arise from the endometrial tissue instead of representing detached fragments of the concurrent ovarian carcinoma. Atypical hyperplasia was frequently identified in all histologic subtypes of EOC but most common in concurrence with endometrioid cancers (Table 2). In patients with endometrioid EOC, atypical hyperplasia was found in nine (47%) of 19 patients. In other histologic subtypes of EOC, the prevalence of atypical hyperplasia was three (33%) of nine for undifferentiated carcinomas, two (29%) of seven for clear cell carcinomas, 32 (24%) of 136 for serous carcinomas, and one (7%) of 15 for mucinous carcinomas. Furthermore, EIC was found in seven (5%) of 136 patients with serous EOCs and was limited to the serous histology type. Double primary endometrial carcinomas were identified in four (3%) of 136 patients with serous EOC and
❚Table 1❚ Histologic Subtypes and Clinicopathologic Characteristics of Patients With Epithelial Ovarian Cancera Population Characteristic
Total
Serous
Endometrioid
Clear Cell
Mucinous
Undifferentiated
No. of patients
186 (100)
P Value
136 (73)
19 (10)
7 (4)
15 (8)
9 (5)
Age at diagnosis, median (IQR), y 60 (50-68)
60 (52-69)
52 (44-68)
60 (51-68)
41 (40-56)
63 (57-68)
.009b
Menopausal state Premenopausal Postmenopausal Missing
50 (29) 125 (71) 11
32 (25) 97 (75) 7
10 (53) 9 (47) —
1 (17) 5 (83) 1
7 (54) 6 (46) 2
0 8 (100) 1
.007c
Parity, median (IQR)
2.0 (1.0-3.0)
2.0 (1.0-3.0)
0.5 (0.0-2.0)
3.0 (1.0-5.0)
2.0 (0.0-2.3)
2.0 (2.0-4.0)
.15b
FIGO stage I II III IV Unknown
29 (16) 9 (5) 114 (63) 29 (16) 5
8 (6) 6 (5) 94 (71) 24 (18) 4
7 (39) 2 (11) 8 (44) 1 (6) 1
2 (29) 1 (14) 4 (57) 0 —
11 (73) 0 3 (20) 1 (7) —
1 (11) 0 5 (56) 3 (33) —
75 4 0 5 51-75 6 51-75 7 51-75
EIC, % 51-75 — >75 0 51-75 0 0
EIC, endometrial intraepithelial carcinoma; EOC, epithelial ovarian cancer. a WT1 expression: 0%, 1% to 50%, 51% to 75%, or more than 75%.
The prevalence of synchronous endometrial carcinomas is comparable to other studies reporting on endometrial carcinomas in patients with EOC.3-5 Synchronous atypical hyperplasia was common in patients with EOC, and similar to the prevalence of synchronous endometrial carcinoma, atypical hyperplasia had the highest prevalence in patients with endometrioid EOC. Atypical hyperplasia is known as a premalignancy of endometrioid endometrial carcinoma.16 It is thought that endometrial atypical hyperplasia progresses to endometrial carcinoma in 23% of patients, and if so, progression occurs over a mean duration of 4 years.17,18 The development of atypical hyperplasia is thought to be influenced by unopposed estrogens.16,19 In the present study, BMI was the only clinical variable that was significantly higher in women diagnosed with endometrial atypical hyperplasia than in those diagnosed with a normal endometrium. Other variables, including neoadjuvant chemotherapy, did not differ between both groups of women. Atypical hyperplasia could represent an adverse effect of increased estrogen production by the EOC. Normal ovarian surface epithelial cells and/or ovarian tumors are capable of the production of steroids, and occasionally EOC has been reported to produce high estrogen levels.20-25 However, this is a retrospective study, and we were not informed of estrogen levels of the included cases. Furthermore, most reported estrogen-producing ovarian tumors are of endometrioid histology, and estrogen production is only very rarely described for the more common serous EOC.19-21,23,24 Still, in the current study, atypical hyperplasia was also identified in one-fourth of patients with serous EOC. All but two (4%) patients with EOC diagnosed with concurrent atypical hyperplasia did not report signs of abnormal vaginal bleeding at presentation. Eleven patients diagnosed with atypical hyperplasia were premenopausal, and none showed specific signs of endometrial disease at presentation. Preoperative ultrasound on endometrial thickness could not always be retrieved from the medical records of included cases. If an ovarian carcinoma was suspected, less focus was © American Society for Clinical Pathology
given to describing the endometrial thickness. Furthermore, neoadjuvant chemotherapy often had started before preoperative ultrasound was performed at the RUNMC. Other limitations of the current study are that clinical variables could not always be retrieved from the medical records, and no follow-up was available on the endometrial pathology of patients without a hysterectomy. Genetic counseling for a BRCA mutation or Lynch syndrome was offered to women with a family history at risk of hereditary cancer syndrome. However, results were not always available in the medical record, or genetic counseling was not or had not been performed because of refusal by the patient or rapid progression of the disease. Furthermore, the cohorts of nonserous EOC were relatively small, and the endometrium was embedded according to routine protocol. Therefore, only a part of the endometrium was available for histologic assessment. Endometrial intraepithelial carcinomas were limited to the serous subtype of EOC and identified in 5% of this group. It is known as a precursor of serous endometrial carcinoma and defined as noninvasive serous endometrial carcinoma.16,26 Recently, the endometrium was also suggested as a potential source of precursor lesions for a limited proportion of serous EOC.27,28 Serous tubal intraepithelial carcinoma (STIC) is thought to be an intraepithelial carcinoma of serous ovarian carcinoma and can be found in the fallopian tubes of 19% to 61% of women diagnosed with serous EOC.29-33 STIC has also been suggested as a putative precursor of tubal and primary peritoneal serous carcinoma and rarely of serous endometrial carcinoma.34 WT1 staining is thought to be able to discriminate between primary serous EOC and serous endometrial carcinoma.35 Half of the analyzed cases showed strong expression for WT1 in both the serous EOC and concurrent EIC, which is suggestive of a primary serous EOC. One patient showed negative expression in both lesions, suggestive of primary endometrial carcinoma, although in two patients, the WT1 staining was suggestive of a primary serous EOC as well as a primary endometrial carcinoma. In the latter, the EIC showed no expression of WT1, whereas the concurrent serous EOC showed strong and diffuse WT1 staining. Immunohistochemical staining showed comparable expression patterns for EIC and concurrent serous EOC. The expression pattern of atypical endometrial hyperplasia was more distinct. It showed strong exhibition of ER and PR, as well as negative to moderate Ki-67 and p53 staining. This expression pattern of atypical hyperplasia is comparable to the expression pattern known for endometrioid endometrial carcinoma.36 Therefore, atypical hyperplasia and concurrent serous EOC are most likely two independent lesions. Prevalence of endometrial pathology seemed significantly higher concurrent to endometrioid EOC in comparison with other histologic subtypes. To confirm this finding
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in a larger cohort, we selected patients with endometrioid EOC operated on at the Canisius Wilhelmina Hospital from 1996 through 2010 (unpublished data). Twenty-two women diagnosed with endometrioid EOC could be identified, and sections were retrieved from the pathology archives to review the endometrium and confirm tumor histology. In six (27%) patients, a benign endometrium was found, whereas 11 (50%) had atypical hyperplasia and five (23%) had endometrioid endometrial carcinoma. The high prevalence of atypical hyperplasia concurrent to endometrioid EOC was confirmed in these additionally selected cases and did not differ from findings in the initial cohort (nine [47%] of 19 vs 11 [50%] of 22). In patients diagnosed with EOC, the presence of a concurrent endometrial premalignancy has to be taken into account. However, the clinical importance of these often asymptomatic endometrial lesions has not yet been clarified. Most likely, concurrent atypical hyperplasia represents a premalignant stage of synchronous endometrioid endometrial carcinoma. Lynch syndrome in families with hereditary nonpolyposis colorectal cancer could explain the frequent presence of an endometrial carcinoma as well as ovarian carcinoma. However, the chance that these women develop endometrial carcinoma or colorectal cancer as their first malignancy is much higher compared with ovarian carcinoma, with a 40% to 60% chance of developing endometrial carcinoma first.37 Occasionally, conservative surgery is performed in women diagnosed with early stage EOC, sparing the uterus and contralateral ovary.38 Studies investigating recurrence risk in these women showed that a recurrence was mostly found in the contralateral ovary, and in only 0% to 3% of cases did carcinoma recur in the endometrium.39-41 However, all women included in these studies were aged 40 years or younger. Women investigated in the current study had a median age of 60 years. This is comparable to the median age in which EOC is diagnosed.36 Therefore, the cohorts included in studies analyzing conservative surgery are not comparable to the current study. However, we support the recommendation of performing endometrial sampling at the time of conservative surgery, since endometrial atypical hyperplasia was also found in patients with early stage disease.41,42 In the current study, eight patients with a FIGO stage I EOC were diagnosed with atypical hyperplasia, and three (38%) were premenopausal. In conclusion, in 31% of women diagnosed with EOC, the endometrium showed a (pre)malignant endometrial lesion. In patients with endometrioid EOC, atypical hyperplasia occurred in half. Identified endometrial premalignancies are vital when considering treatment options for these women. If conservative surgery is considered with preservation of the uterus, attention should be given to the possibility of concurrent endometrial pathology.
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Address reprint requests to Dr Mingels: Dept of Obstetrics & Gynecology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands; M.Mingels@ obgyn.umcn.nl. This study was supported by the Ruby & Rose Foundation.
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14. Zheng W, Schwartz PE. Serous EIC as an early form of uterine papillary serous carcinoma: recent progress in understanding its pathogenesis and current opinions regarding pathologic and clinical management. Gynecol Oncol. 2005;96:579-582. 15. Tashiro H, Isacson C, Levine R, et al. p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol. 1997;150:177-185. 16. Kurman RJ, McConnell TG. Precursors of endometrial and ovarian carcinoma. Virchows Arch. 2010;456:1-12. 17. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia: a long-term study of “untreated” hyperplasia in 170 patients. Cancer. 1985;56:403-412. 18. Montgomery BE, Daum GS, Dunton CJ. Endometrial hyperplasia: a review. Obstet Gynecol Surv. 2004;59:368-378. 19. Reed SD, Newton KM, Clinton WL, et al. Incidence of endometrial hyperplasia. Am J Obstet Gynecol. 2009;200:678. e1-6. 20. Jongen VH, Sluijmer AV, Heineman MJ. The postmenopausal ovary as an androgen-producing gland: hypothesis on the etiology of endometrial cancer. Maturitas. 2002;43:77-85. 21. Ivarsson K, Sundfeldt K, Brannstrom M, et al. Production of steroids by human ovarian surface epithelial cells in culture: possible role of progesterone as growth inhibitor. Gynecol Oncol. 2001;82:116-121. 22. Abrahamsson G, Janson PO, Kullander S. Steroid release from two human epithelial ovarian tumors: evidence for an intrinsic production in vitro. Gynecol Oncol. 1997;64:99-104. 23. MacDonald PC, Grodin JM, Edman CD, et al. Origin of estrogen in a postmenopausal woman with a nonendocrine tumor of the ovary and endometrial hyperplasia. Obstet Gynecol. 1976;47:644-650. 24. Poels LG, Jap PH, Ramaekers FF, et al. Characterization of a hormone-producing ovarian carcinoma cell line. Gynecol Oncol. 1989;32:203-214. 25. Ridderheim M, Mahlck CG, Selstam G, et al. Steroid production in different parts of malignant and benign ovarian tumors in vitro. Cancer Res. 1993;53:2309-2312. 26. Fader AN, Boruta D, Olawaiye AB. Uterine papillary serous carcinoma: epidemiology, pathogenesis and management. Curr Opin Obstet Gynecol. 2010;22:21-29. 27. Massuger L, Roelofsen T, Ham M, et al. The origin of serous ovarian cancer may be found in the uterus: a novel hypothesis. Med Hypotheses. 2010;74:859-861. 28. Roelofsen T, van Kempen LC, van der Laak JA, et al. Concurrent endometrial intraepithelial carcinoma (EIC) and serous ovarian cancer: can EIC be seen as the precursor lesion? Int J Gynecol Cancer. 2012;22:457-464. 29. Piek JM, van Diest PJ, Zweemer RP, et al. Tubal ligation and risk of ovarian cancer. Lancet. 2001;358:844.
© American Society for Clinical Pathology
30. Kindelberger DW, Lee Y, Miron A, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol. 2007;31:161-169. 31. Roh MH, Kindelberger D, Crum CP. Serous tubal intraepithelial carcinoma and the dominant ovarian mass: clues to serous tumor origin? Am J Surg Pathol. 2009;33:376383. 32. Przybycin CG, Kurman RJ, Ronnett BM, et al. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol. 2010;34:1407-1416. 33. Tang S, Onuma K, Deb P, et al. Frequency of serous tubal intraepithelial carcinoma in various gynecologic malignancies: a study of 300 consecutive cases. Int J Gynecol Pathol. 2012;31:103-110. 34. Jarboe EA, Miron AC, Carlson JW, et al. Coexisting intraepithelial serous carcinomas of the endometrium and fallopian tube: frequency and potential significance. Int J Gynecol Pathol. 2009;28:308-315. 35. Al-Hussaini M, Stockman A, Foster H, et al. WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma. Histopathology. 2004;44:109-115. 36. Seidman JD, Ronnett BM, Kurman RJ. Surface epithelial tumors of the ovary. In: Kurman RJ, ed. Blaustein’s Pathology of the Female Genital Tract. New York, NY: Springer; 2011:679-784. 37. Tafe LJ, Riggs ER, Tsongalis GJ. Lynch syndrome presenting as endometrial cancer. Clin Chem. 2014;60:111-121. 38. Eskander RN, Randall LM, Berman ML, et al. Fertility preserving options in patients with gynecologic malignancies. Am J Obstet Gynecol. 2011;205:103-110. 39. Colombo N, Chiari S, Maggioni A, et al. Controversial issues in the management of early epithelial ovarian cancer: conservative surgery and role of adjuvant therapy. Gynecol Oncol. 1994;55:S47-S51. 40. Park JY, Kim DY, Suh DS, et al. Outcomes of fertility-sparing surgery for invasive epithelial ovarian cancer: oncologic safety and reproductive outcomes. Gynecol Oncol. 2008;110:345353. 41. Zanetta G, Chiari S, Rota S, et al. Conservative surgery for stage I ovarian carcinoma in women of childbearing age. Br J Obstet Gynaecol. 1997;104:1030-1035. 42. Morice P, Camatte S, Wicart-Poque F, et al. Results of conservative management of epithelial malignant and borderline ovarian tumours. Hum Reprod Update. 2003;9:185192.
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High Prevalence of Atypical Hyperplasia in the Endometrium of Patients With Epithelial Ovarian Cancer Marjanka J. J. M. Mingels, MD,1 Rina Masadah, MD, PhD,2,3 Yvette P. Geels, MD,1 Irene Otte-Höller,2 Ineke M. de Kievit, MD, PhD,4 Jeroen A. W. M. van der Laak, PhD,2 Maaike A. P. C. van Ham, MD, PhD,1 Johan Bulten, MD, PhD,2 and Leon F. A. G. Massuger, MD, PhD1 From the Departments of 1Obstetrics and Gynecology and 2Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 3Department of Pathology, Hasanuddin University, Makassar, Indonesia; and 4 Department of Pathology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands. Key Words: Epithelial ovarian cancer; Atypical hyperplasia; Endometrial intraepithelial carcinoma; Endometrium Am J Clin Pathol August 2014;142:213-221 DOI: 10.1309/AJCPTGJOPXUW6RVO
ABSTRACT Objectives: The aim of the present study is to determine the prevalence of endometrial premalignancies in women diagnosed with epithelial ovarian cancer (EOC). Methods: Endometrial and ovarian specimens of 186 patients with EOC were retrospectively selected using the nationwide pathology network and registry, and sections were comprehensively reviewed: 136 (73%) serous, 19 (10%) endometrioid, 15 (8%) mucinous, seven (4%) clear cell, and nine (5%) undifferentiated. Immunohistochemical phenotypes were compared for patients with serous EOC with concurrent endometrial pathology. Results: In 31%, endometrial (pre)malignancy was found: carcinoma in 3%, endometrial intraepithelial carcinoma (EIC) in 4%, and atypical hyperplasia in 24%. Atypical hyperplasia was found in 47% of endometrioid EOCs but in 7% to 33% of other subtypes. Body mass index was higher concurrent to atypical hyperplasia (P = .001). Serous EOC and EIC immunophenotypes were comparable, whereas atypical hyperplasia was expressed differently. Conclusions: Apart from synchronous endometrial carcinoma, endometrial premalignancies should be taken into account when determining optimal treatment for women diagnosed with EOC.
© American Society for Clinical Pathology
Epithelial ovarian cancer (EOC) is a highly aggressive and rapidly progressive tumor. Surgical management of EOC includes primary debulking or interval debulking after neoadjuvant chemotherapy. All international guidelines recommend a hysterectomy in these women to accomplish complete debulking, since the serosa of the uterus is one of the most frequent sites of peritoneal spread, and complete debulking surgery is associated with improved overall survival.1,2 Another justification to perform routine hysterectomy in patients with EOC includes the presence of a double primary carcinoma in the endometrium in 10% of endometrioid ovarian carcinomas and in 2% to 5% of serous, clear cell, and mucinous carcinomas.3-5 Knowledge of the prevalence of synchronous endometrial premalignancies in these women is nevertheless poor. In studies reporting on EOC and concurrent endometrial carcinomas, no additional information is given on the prevalence of endometrial premalignancies. One study investigated a small cohort of extraovarian carcinomas and reported endometrial hyperplasia in 13% of cases, in addition to synchronous endometrial carcinoma in 6%.1 The few studies analyzing the endometrium in general (asymptomatic) populations reported a much lower prevalence of endometrial lesions, with hyperplasia found in 1% to 2%, atypical hyperplasia in 1%, and carcinoma in 0.5%.6-10 The aim of this study was to extensively review the endometrium of a large cohort of patients with EOC to assess the prevalence of endometrial pathology in these women. Correlations were analyzed between endometrial lesions and clinical risk factors that are known to influence endometrial proliferation. Furthermore, immunohistochemical expression patterns of the most common type of
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ovarian carcinomas, serous ovarian carcinomas, and concurrent endometrial lesions were analyzed.
Materials and Methods Patient and Samples All patients surgically treated for EOC in the Radboud University Nijmegen Medical Centre (RUNMC) from April 1996 through December 2010 were selected. The search term ovarian carcinoma was entered in the Dutch nationwide network and registry of histopathology and cytopathology (PALGA), yielding 311 patients satisfying these constraints. In total, 108 patients were excluded because hysterectomy was not performed at the RUNMC; in 34 patients, hysterectomy already had been performed for benign reasons or at primary incomplete debulking in another institution, and in 48 patients, the uterus remained in situ because of an inability to achieve complete debulking or uterus preservation. Twentysix patients visited our institution only for a second opinion on treatment management and revision of pathologic diagnosis. For the remaining 203 patients, all available H&E-stained endometrial and ovarian sections were retrieved from the pathology archive of the RUNMC. Embedding of endometrial tissue was performed according to routine protocol. Seventeen patients had to be excluded because not all sections were available for review. Therefore, the final study population contained 186 patients with EOC: 136 (73%) women diagnosed with serous carcinoma, 19 (10%) with endometrioid carcinoma, 15 (8%) with mucinous carcinoma, seven (4%) with clear cell carcinoma, and nine (5%) with undifferentiated carcinoma. Medical records and surgical and pathology reports were retrieved to determine pertinent clinical and pathologic data. Data obtained included age, menopausal state, BRCA mutation status, International Federation of Gynecology and Obstetrics (FIGO) stage, and treatment management. Patients were staged in accordance with the FIGO surgical staging adopted in 1988.11 Conditions that are able to cause unopposed estrogen stimulation were retrieved from medical records: late menopause, high body mass index (BMI; by peripheral conversion of androstenedione to estrogen in adipose tissue of obese women), or an estrogen-producing tumor. On behalf of the research ethics committee of the RUNMC, the study was carried out in accordance with the applicable rules concerning the review of research ethics committees and informed consent. Histopathology All ovarian and endometrial sections were reviewed by two pathologists with extensive experience in gynecopathology. In case of a discrepancy in diagnosis, consensus was 214 214
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reached between both pathologists. The following endometrial entities were scored in the endometrium: normal endometrium, hyperplasia, atypical hyperplasia, endometrial intraepithelial carcinoma (EIC), and invasive carcinoma ❚Image 1❚. A classification scheme developed by Kurman et al12 and adapted by the World Health Organization was used to interpret endometrial hyperplasia with or without atypia. For the identification of EIC, previously published criteria were used that define EIC morphologically as the replacement of endometrial surface epithelium and glands, without myometrial or stromal invasion, by malignant cells that are identical to serous carcinoma cells.12-14 Immunohistochemical Analysis Immunohistochemical stainings were performed on sections from formalin-fixed, paraffin-embedded samples in which endometrial atypical hyperplasia or EIC was identified in patients diagnosed with serous EOC. A representative sample of the ovarian carcinoma was added in each case. Sections of 5 µm were sliced and incubated with monoclonal antibodies against p53 (dilution 1:250, clone DO-7; Neomarkers, Fremont, CA), WT1 monoclonal antibody (dilution 1:20, clone 49, NCL-L-WT1-562; Leica Biosystems, Newcastle Upon Tyne, UK), Ki-67 (dilution 1:100, clone MIB-1; DAKO, Glostrup, Denmark), estrogen receptor (ER) (dilution 1:100, clone SP-1; Thermo Scientific, Fremont, CA), progesterone receptor (PR) (dilution 1:500, clone PgR636; DAKO), and p16 (dilution 1:500, clone 16PO4; Neomarkers). Antigen retrieval was processed according to the manufacturers’ guidelines, and antigen-antibody complexes were localized using the standard streptavidin-biotin technique (Vector Laboratories, Burlingame, CA) with diaminobenzidine as chromogen. Normal endometrial tissue was used as a control in each case, and a positive control was included in each batch of staining. Immunohistochemical stainings were interpreted by two authors (J.B. and M.J.J.M.M.). Expression of nuclear staining for p53, p16, and WT1 was scored as the percentage of positive stained tumor cells and classified as follows: 1% to 50%, 51% to 75%, more than 75%, or complete absence of expression. Intense expression of p53 in more than 75% of tumor cells or complete absence of expression was considered strongly correlated with the presence of a TP53 mutation.15 Expression of nuclear staining for Ki-67, ER, and PR was scored as the percentage of positive stained cells and classified as follows: less than 5% (–, negative), 5% to 20% (+, weak), more than 20% to 50% (++, moderate), and more than 50% (+++, strong). Membranous and/or cytoplasmic expression was not considered positive. Statistics Analyses were performed to compare the prevalence of endometrial entities and their clinicopathologic characteristics for the different histologic subtypes of EOC. Furthermore, the © American Society for Clinical Pathology
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A
B
C
D
E
F
❚Image 1❚ A, Normal endometrial epithelium (×200). Endometrial lesions identified in the endometrium of women with ovarian carcinoma: (B) endometrial simple hyperplasia (×200), (C) endometrial atypical hyperplasia (×100), (D) endometrial atypical hyperplasia (×200), (E) endometrial intraepithelial carcinoma (×200), and (F) synchronous primary endometrial carcinoma (×200). © American Society for Clinical Pathology
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prevalence of risk factors for endometrial proliferation was compared between the group of patients diagnosed with an atypical hyperplastic endometrium and the group diagnosed with normal endometrium. Variables were expressed as frequencies and percentages for discrete data and as median and 25th to 75th quartiles for continuous data. Statistical comparison of medians from independent samples was performed using the Kruskal-Wallis and Mann-Whitney U tests. Pearson c2 and, if appropriate, the Fisher exact test were used to test associations between categorical variables. All statistical analyses were performed using SPSS software version 18.0 (SPSS, Chicago, IL), and P < .05 (two-sided test) was considered statistically significant.
Results Clinical data were analyzed for 186 patients with EOC included in the study ❚Table 1❚. The median age at diagnosis was 60 years, median BMI was 24.6 kg/m², and 71% were postmenopausal (Table 1). Most patients had an advanced stage of disease at diagnosis, with a FIGO stage IV in 29 (16%) patients, stage III in 114 (63%), stage II in nine (5%), and stage I in 29 (16%). Median age at diagnosis, menopausal state, and FIGO stage were significantly different for histologic subtypes of EOC (P = .009, P = .007, and P < .001, respectively; Table 1). Patients diagnosed with serous or clear cell carcinomas had a median age of 60 years, whereas
patients with endometrioid and mucinous carcinomas were younger and more often premenopausal. Results of histologic assessment of the endometrium are shown in ❚Table 2❚. In 105 (56%) patients, the endometrium was without abnormalities. In 81 (44%) patients, an endometrial lesion was identified, and in 58 (31%) patients, this lesion was (pre)malignant. The latter included a double primary endometrial carcinoma in six (3%) patients, EIC in seven (4%), and atypical hyperplasia in 45 (24%). In two patients diagnosed with double primary endometrioid carcinoma, atypical hyperplasia also was found in the preexistent endometrium. In all cases, the background endometrium was assessed to confirm that endometrial lesions arise from the endometrial tissue instead of representing detached fragments of the concurrent ovarian carcinoma. Atypical hyperplasia was frequently identified in all histologic subtypes of EOC but most common in concurrence with endometrioid cancers (Table 2). In patients with endometrioid EOC, atypical hyperplasia was found in nine (47%) of 19 patients. In other histologic subtypes of EOC, the prevalence of atypical hyperplasia was three (33%) of nine for undifferentiated carcinomas, two (29%) of seven for clear cell carcinomas, 32 (24%) of 136 for serous carcinomas, and one (7%) of 15 for mucinous carcinomas. Furthermore, EIC was found in seven (5%) of 136 patients with serous EOCs and was limited to the serous histology type. Double primary endometrial carcinomas were identified in four (3%) of 136 patients with serous EOC and
❚Table 1❚ Histologic Subtypes and Clinicopathologic Characteristics of Patients With Epithelial Ovarian Cancera Population Characteristic
Total
Serous
Endometrioid
Clear Cell
Mucinous
Undifferentiated
No. of patients
186 (100)
P Value
136 (73)
19 (10)
7 (4)
15 (8)
9 (5)
Age at diagnosis, median (IQR), y 60 (50-68)
60 (52-69)
52 (44-68)
60 (51-68)
41 (40-56)
63 (57-68)
.009b
Menopausal state Premenopausal Postmenopausal Missing
50 (29) 125 (71) 11
32 (25) 97 (75) 7
10 (53) 9 (47) —
1 (17) 5 (83) 1
7 (54) 6 (46) 2
0 8 (100) 1
.007c
Parity, median (IQR)
2.0 (1.0-3.0)
2.0 (1.0-3.0)
0.5 (0.0-2.0)
3.0 (1.0-5.0)
2.0 (0.0-2.3)
2.0 (2.0-4.0)
.15b
FIGO stage I II III IV Unknown
29 (16) 9 (5) 114 (63) 29 (16) 5
8 (6) 6 (5) 94 (71) 24 (18) 4
7 (39) 2 (11) 8 (44) 1 (6) 1
2 (29) 1 (14) 4 (57) 0 —
11 (73) 0 3 (20) 1 (7) —
1 (11) 0 5 (56) 3 (33) —
75 4 0 5 51-75 6 51-75 7 51-75
EIC, % 51-75 — >75 0 51-75 0 0
EIC, endometrial intraepithelial carcinoma; EOC, epithelial ovarian cancer. a WT1 expression: 0%, 1% to 50%, 51% to 75%, or more than 75%.
The prevalence of synchronous endometrial carcinomas is comparable to other studies reporting on endometrial carcinomas in patients with EOC.3-5 Synchronous atypical hyperplasia was common in patients with EOC, and similar to the prevalence of synchronous endometrial carcinoma, atypical hyperplasia had the highest prevalence in patients with endometrioid EOC. Atypical hyperplasia is known as a premalignancy of endometrioid endometrial carcinoma.16 It is thought that endometrial atypical hyperplasia progresses to endometrial carcinoma in 23% of patients, and if so, progression occurs over a mean duration of 4 years.17,18 The development of atypical hyperplasia is thought to be influenced by unopposed estrogens.16,19 In the present study, BMI was the only clinical variable that was significantly higher in women diagnosed with endometrial atypical hyperplasia than in those diagnosed with a normal endometrium. Other variables, including neoadjuvant chemotherapy, did not differ between both groups of women. Atypical hyperplasia could represent an adverse effect of increased estrogen production by the EOC. Normal ovarian surface epithelial cells and/or ovarian tumors are capable of the production of steroids, and occasionally EOC has been reported to produce high estrogen levels.20-25 However, this is a retrospective study, and we were not informed of estrogen levels of the included cases. Furthermore, most reported estrogen-producing ovarian tumors are of endometrioid histology, and estrogen production is only very rarely described for the more common serous EOC.19-21,23,24 Still, in the current study, atypical hyperplasia was also identified in one-fourth of patients with serous EOC. All but two (4%) patients with EOC diagnosed with concurrent atypical hyperplasia did not report signs of abnormal vaginal bleeding at presentation. Eleven patients diagnosed with atypical hyperplasia were premenopausal, and none showed specific signs of endometrial disease at presentation. Preoperative ultrasound on endometrial thickness could not always be retrieved from the medical records of included cases. If an ovarian carcinoma was suspected, less focus was © American Society for Clinical Pathology
given to describing the endometrial thickness. Furthermore, neoadjuvant chemotherapy often had started before preoperative ultrasound was performed at the RUNMC. Other limitations of the current study are that clinical variables could not always be retrieved from the medical records, and no follow-up was available on the endometrial pathology of patients without a hysterectomy. Genetic counseling for a BRCA mutation or Lynch syndrome was offered to women with a family history at risk of hereditary cancer syndrome. However, results were not always available in the medical record, or genetic counseling was not or had not been performed because of refusal by the patient or rapid progression of the disease. Furthermore, the cohorts of nonserous EOC were relatively small, and the endometrium was embedded according to routine protocol. Therefore, only a part of the endometrium was available for histologic assessment. Endometrial intraepithelial carcinomas were limited to the serous subtype of EOC and identified in 5% of this group. It is known as a precursor of serous endometrial carcinoma and defined as noninvasive serous endometrial carcinoma.16,26 Recently, the endometrium was also suggested as a potential source of precursor lesions for a limited proportion of serous EOC.27,28 Serous tubal intraepithelial carcinoma (STIC) is thought to be an intraepithelial carcinoma of serous ovarian carcinoma and can be found in the fallopian tubes of 19% to 61% of women diagnosed with serous EOC.29-33 STIC has also been suggested as a putative precursor of tubal and primary peritoneal serous carcinoma and rarely of serous endometrial carcinoma.34 WT1 staining is thought to be able to discriminate between primary serous EOC and serous endometrial carcinoma.35 Half of the analyzed cases showed strong expression for WT1 in both the serous EOC and concurrent EIC, which is suggestive of a primary serous EOC. One patient showed negative expression in both lesions, suggestive of primary endometrial carcinoma, although in two patients, the WT1 staining was suggestive of a primary serous EOC as well as a primary endometrial carcinoma. In the latter, the EIC showed no expression of WT1, whereas the concurrent serous EOC showed strong and diffuse WT1 staining. Immunohistochemical staining showed comparable expression patterns for EIC and concurrent serous EOC. The expression pattern of atypical endometrial hyperplasia was more distinct. It showed strong exhibition of ER and PR, as well as negative to moderate Ki-67 and p53 staining. This expression pattern of atypical hyperplasia is comparable to the expression pattern known for endometrioid endometrial carcinoma.36 Therefore, atypical hyperplasia and concurrent serous EOC are most likely two independent lesions. Prevalence of endometrial pathology seemed significantly higher concurrent to endometrioid EOC in comparison with other histologic subtypes. To confirm this finding
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in a larger cohort, we selected patients with endometrioid EOC operated on at the Canisius Wilhelmina Hospital from 1996 through 2010 (unpublished data). Twenty-two women diagnosed with endometrioid EOC could be identified, and sections were retrieved from the pathology archives to review the endometrium and confirm tumor histology. In six (27%) patients, a benign endometrium was found, whereas 11 (50%) had atypical hyperplasia and five (23%) had endometrioid endometrial carcinoma. The high prevalence of atypical hyperplasia concurrent to endometrioid EOC was confirmed in these additionally selected cases and did not differ from findings in the initial cohort (nine [47%] of 19 vs 11 [50%] of 22). In patients diagnosed with EOC, the presence of a concurrent endometrial premalignancy has to be taken into account. However, the clinical importance of these often asymptomatic endometrial lesions has not yet been clarified. Most likely, concurrent atypical hyperplasia represents a premalignant stage of synchronous endometrioid endometrial carcinoma. Lynch syndrome in families with hereditary nonpolyposis colorectal cancer could explain the frequent presence of an endometrial carcinoma as well as ovarian carcinoma. However, the chance that these women develop endometrial carcinoma or colorectal cancer as their first malignancy is much higher compared with ovarian carcinoma, with a 40% to 60% chance of developing endometrial carcinoma first.37 Occasionally, conservative surgery is performed in women diagnosed with early stage EOC, sparing the uterus and contralateral ovary.38 Studies investigating recurrence risk in these women showed that a recurrence was mostly found in the contralateral ovary, and in only 0% to 3% of cases did carcinoma recur in the endometrium.39-41 However, all women included in these studies were aged 40 years or younger. Women investigated in the current study had a median age of 60 years. This is comparable to the median age in which EOC is diagnosed.36 Therefore, the cohorts included in studies analyzing conservative surgery are not comparable to the current study. However, we support the recommendation of performing endometrial sampling at the time of conservative surgery, since endometrial atypical hyperplasia was also found in patients with early stage disease.41,42 In the current study, eight patients with a FIGO stage I EOC were diagnosed with atypical hyperplasia, and three (38%) were premenopausal. In conclusion, in 31% of women diagnosed with EOC, the endometrium showed a (pre)malignant endometrial lesion. In patients with endometrioid EOC, atypical hyperplasia occurred in half. Identified endometrial premalignancies are vital when considering treatment options for these women. If conservative surgery is considered with preservation of the uterus, attention should be given to the possibility of concurrent endometrial pathology.
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Address reprint requests to Dr Mingels: Dept of Obstetrics & Gynecology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands; M.Mingels@ obgyn.umcn.nl. This study was supported by the Ruby & Rose Foundation.
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