Subsequent endometrial carcinoma with adjuvant tamoxifen treatment in Japanese breast cancer patients

Abstract. Nishimura N, Hachisuga T, Saito T, Kawarabayashi T. Subsequent endometrial carcinoma with adjuvant tamoxifen treatment in Japanese breast cancer patients.
This study aimed to detail the clinicopathologic features of endometrial carcinomas that developed in Japanese patients receiving adjuvant tamoxifen treatment for breast cancer patients. Ten endometrial carcinomas in tamoxifen-treated breast cancer patients were collected from two medical centers. The endometrial carcinomas included two stage Ia, four stage Ib, two stage Ic and two stage IIIc. Three tumors were Grade 1, six were Grade 2, and one was Grade 3. The tumor was limited to the endometrium in two cases. Myometrial invasion was limited to the inner half of the myometrium in five cases and involved the outer half in three. A mild degree of lymphovascular space invasion was identified in five cases. Deep cervical invasion was recognized in one case. The cell types comprised nine endometrioid adenocarcinomas and one serous carcinoma. Five of eight postmenopausal endometrial carcinomas were associated with polypoid endometrial lesions composed of cystically dilated atrophic and proliferative glands widely separated by fibrotic stroma. Two patients with retroperitoneal lymph node metastases died of endometrial cancer. One patient developed a contralateral breast cancer during tamoxifen treatment. No patient died of breast cancer. We did not demonstrate a higher frequency of either high-grade tumors or unfavorable histologic subtypes in tamoxifen-treated Japanese breast cancer patients.     

Abnormalities detected on transvaginal ultrasonography in tamoxifen-treated postmenopausal breast cancer patients may represent endometrial cystic atrophy

OBJECTIVE: This study was conducted to examine the histopathologic changes in tamoxifen-treated postmenopausal patients with endometrial thickness ≥5 mm with transvaginal ultrasonography. STUDY DESIGN: Thirty-five tamoxifen-treated postmenopausal breast cancer patients underwent transvaginal pelvic ultrasonography with endometrial thickness ≥5 mm followed by either curettage-hysteroscopy (n = 24), or hysterectomy (n = 11). Endometrial histopathologic findings were examined. RESULTS: Overall, endometrial polyps were the most common histopathologic finding (23 of 35 patients). Endometrial cystic atrophy was uncommonly detected in patients undergoing curettage-hysteroscopy (1 of 24 patients) compared with patients undergoing hysterectomy (9 of 11 patients). No cases of endometrial cancer or hyperplasia were detected. CONCLUSIONS: Endometrial polyps were a frequent finding in tamoxifen-treated postmenopausal women who had endometrial thickness ≥5 mm with the use of transvaginal ultrasonography. Endometrial cystic atrophy may explain “thickened endometrium” on transvaginal ultrasonography in this patient population with no evidence of endometrial polyps, hyperplasia, or adenocarcinoma after surgical evaluation. (Am J Obstet Gynecol 1998;178:1145-50.)     

乳腺癌患者服用三苯氧胺后子宫内膜病变150例临床病理分析

目的分析乳腺癌患者服用三苯氧胺(tamoxifen,TAM)后子宫内膜的病理变化,以期制定随访中的相应对策。方法对北京大学第一医院1993年1月至2008年8月乳腺癌患者术后服用三苯氧胺期间或停药后,因妇科问题而住院诊治者150例进行回顾性分析。结果绝经前53例,绝经后97例。与使用三苯氧胺有关的子宫内膜病理结果为:内膜息肉、内膜单纯性增生、内膜非典型增生和内膜癌的例数在绝经前组合计为10例(10/53,18.9%),在绝经后组中49例(49/97,50.5%)。子宫内膜非典型增生和子宫内膜癌均发生在绝经后组。乳腺癌患者服用三苯氧胺后,发生子宫内膜息肉等病理表现与患者是否绝经、是否有阴道出血这两个因素呈正相关,而与三苯氧胺服用时间、剂量及乳腺癌患病年限无明显相关性。结论应重视并加强对绝经后乳腺癌患者服用三苯氧胺期间和之后的随访工作,对绝经后服用三苯氧胺的患者,建议用药前进行妇科评估,包括B超了解子宫内膜厚度,并加强用药期间的随访工作。     

Malignant endometrial polyps in postmenopausal breast cancer tamoxifen-treated patients.

BACKGROUND: Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure. It is generally accepted that the occurrence of malignancy in endometrial polyps among healthy women is up to 0.5%. However, no one has yet described the incidence of this malignant transformation among postmenopausal breast cancer tamoxifen-treated patients. Objective. The aim of this study was to study the exact rate of malignant changes in endometrial polyps recovered from postmenopausal breast cancer tamoxifen-treated patients. METHODS: We reviewed the pathological results and medical records of all postmenopausal breast cancer patients in whom endometrial polyps were recovered following at least 6 months of tamoxifen treatment in our institute. We also looked for the rate of malignant changes in polyps recovered from all healthy postmenopausal controls with endometrial polyps in our institute during the period of the study. RESULTS: Two (3.0%) of 67 endometrial polyps recovered from postmenopausal breast cancer tamoxifen-treated patients revealed malignant features. None of the clinical variables tested, including risk factors for endometrial cancer, was significantly different between the groups. In the controls only 5 (0.48%) of 1034 polyps were malignant. CONCLUSION: Up to 3.0% of endometrial polyps recovered from postmenopausal breast cancer tamoxifen-treated patients may show malignant changes. This rate is higher than that found in our controls as well as that reported in the general female population.     

A randomised controlled trial of prophylactic levonorgestrel intrauterine system in tamoxifen-treated women

Objective  To study the prophylactic use of levonorgestrel intrauterine system (LNG-IUS) in the prevention of endometrial pathology in women having breast cancer treated with tamoxifen.
Design  Randomised controlled trial.
Setting  A tertiary teaching hospital.
Population  One hundred and thirteen women (66 premenopausal/47 postmenopausal) who required adjuvant tamoxifen for breast cancer after the completion of postoperative radiotherapy and chemotherapy.
Methods  Women were randomised to treatment group (prophylactic LNG-IUS insertion before the commencement of tamoxifen) or control group. Uterine cavity was examined by outpatient hysteroscopy and endometrial biopsy before and at 12 months after commencement of tamoxifen.
Main outcome measures  De novo endometrial pathology at 1 year of tamoxifen.
Results  Women in the treatment group had a much lower incidence of endometrial polyp (1.8 versus 15.5%, P = 0.017) (relative risk: 0.12; 95% CI: 0.02–0.91) at 12 months. There was no significant difference in the incidence of submucosal fibroid between the two groups (1.8 versus 3.4%, P = 1.0). LNG-IUS was retained in 95% women in the treatment group at 1 year.
Conclusion  LNG-IUS reduces the occurrence of de novo endometrial polyp in women treated with tamoxifen for breast cancer.     

Surgical cytoreduction in stage IV endometrioid endometrial carcinoma

Objective

To evaluate the role of surgical cytoreduction and the amount of residual disease in patients with newly diagnosed stage IV endometrioid endometrial carcinoma (EC).

Methods

Patients with stage IV EC of endometrioid histology who underwent surgery at our institution from 1977 to 2003 were identified. Patients with microscopic stage IV disease were excluded. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier method and compared with log-rank test.

Results

A total of 58 patients were identified, of which 9 (15.5%) had no gross residual (NGR) after surgery, 11 (19.0%) had residual disease ≤ 1 cm, 32 (55.1%) had residual disease > 1 cm, and 6 (10.3%) had no cytoreduction attempted. The median PFS was 11.1 months (95% CI, 9.8-12.3) and the median OS was 19.2 months (95% CI, 8.5-29.9) for the cohort. The median PFS was 40.3 months (95% CI, 0-93.9) for patients with NGR disease, 11 months (95% CI, 9.9-12.1) for patients with any residual disease, and 2.2 months (95% CI, 0.1-4.2) for patients who did not have attempted cytoreduction (P < 0.001). The median OS was 42.2 months (95% CI, not estimable) for patients with NGR disease, 19 months (95% CI, 13.9-24.1) for patients with any residual disease, and 2.2 months (95% CI, 0.1-4.2) for patients that did not have attempted cytoreduction (P < 0.001).

Conclusion

Though stage IV endometrioid EC has a poor prognosis, surgical cytoreduction to no gross residual disease in a highly select group of patients is associated with improved survival.     

Angiogenesis in endometrial carcinoma

Increasing microvessel density correlates with adverse prognosis in many tumors. The aim of this study was to quantify angiogenesis in a range of endometrial carcinomas, by measuring microvessel density in the stroma, and to explore any relationship with known prognostic features. Sections from 60 hysterectomy specimens were stained with Factor VIII related antigen, and the microvessel count per mm² of stroma was determined for each case. Carcinomas arising in an atrophic or inactive endometrium had a significantly higher stromal vascular density than those arising in a hyperplastic or proliferative endometrium. There was no significant association between stromal vascular density, and age, histologic grade, tumor type, presence of lymphovascular space permeation, or depth of myometrial invasion. We conclude that higher stromal vascularity is a feature of the more aggressive subtype of endometrial carcinomas arising in an atrophic endometrium but does not correlate with any other prognostic features.     

Protein kinase C alpha expression is inversely related to ER status in endometrial carcinoma: possible role in AP-1-mediated proliferation of ER-negative endometrial cancer

OBJECTIVE: Tamoxifen is the most widely used antiestrogen to treat all stages of estrogen-receptor (ER)-positive breast cancers. However, tamoxifen acts as a partial estrogen in the uterus and is known to increase the risk of endometrial cancer by two- to threefold. Recent evidence indicates that there is a connection between tamoxifen resistance and activation of the activator protein-1 (AP-1) pathway. We have previously reported a possible role for overexpression of protein kinase C alpha (PKCalpha), an upstream activator of the AP-1 pathway, in hormone-independent breast cancer and antiestrogen-stimulated endometrial tumors. We hypothesize that alterations of the PKC isozyme profile of endometrial carcinomas are similar to that of hormone-independent breast cancer and determine whether specific PKC isozyme alterations correlated with known clinicopathological features of endometrial cancer. METHODS: The PKC isozyme profile of endometrial carcinomas from 42 patients who were not previously exposed to antiestrogens was examined by Western blot. The relationship between PKC isozyme expression and key prognostic factors for endometrial carcinoma including hormone receptor status, tumor grade, stage, size, and depth of myometrial invasion was examined using the Spearman's rho correlation coefficient. RESULTS: As previously found in breast cancers, PKCalpha and estrogen receptor alpha (ERalpha) expression are inversely related (r(s) = -0.35, P = 0.046). We report significant inverse correlations among ER/progesterone receptor (PR) expression and tumor grade (r(s) = -0.49, P = 0.001 and r(s) = -0.44, P = 0.004, respectively), ER, and depth of myometrial invasion (r(s) = -0.40, P = 0.009). There were no other significant correlations between PKC isozyme expression and other key prognostic factors examined. CONCLUSION: This study indicates that, similar to what was previously observed in breast cancer, PKCalpha and ER expression is inversely related in endometrial cancer. PKCalpha expression may be a useful prognostic indicator in endometrial cancers. A model is offered which describes the putative role of PKCalpha overexpression in activation of the AP-1 pathway and increased proliferation of ER negative endometrial cancers.     

Psychological impact of endometrial monitoring in tamoxifen-treated postmenopausal breast cancer patients

In view of the higher incidence of endometrial pathology in tamoxifen-treated breast cancer patients, it has been recommended that endometrial surveillance be performed on these women by means of transvaginal sonography. Our study investigated how breast cancer patients experience the endometrial surveillance and which personality factors influence this experience. We also studied compliance with the recommended examination. Fifty-three consecutive asymptomatic postmenopausal breast cancer patients who had taken tamoxifen for at least 6 months were included. Our results show that 23% of the women felt very anxious just before the examination. One woman in five evaluated the procedure as annoying, unpleasant, invasive and awkward, but only 3% found it really unacceptable. Difficulties in coping with mastectomy as well as anxiety negatively affected the experience of the examination. One in six women were doubtful about their ability to comply with such an examination in the future. Women who have difficulties in coming to terms with the mastectomy, anxious women, and women with a low tolerance towards common medical procedures are at especial risk of becoming dropouts. Suggestions are made for developing strategies that might improve these women's compliance.     

Metastasis of lobular breast carcinoma to the cervix

Breast cancers without previous dissemination occasionally result in hematogenous metastases in gynecologic organs, particularly in the cervix. This case report examines a multimodally treated lobular breast cancer patient who was 52 months later diagnosed with malignancy in the uterus. After a tumor was detected at the endocervical and isthmic part of the uterus, a complete hysterectomy with bilateral salpingo-oophorectomy was carried out. The malignant cells were highly positive for carcino-embrional antigen and gross cystic disease fluid protein-15, sensitive breast cancer markers. In conclusion, as breast carcinoma can metastasize to atypical places (cervix, endometrium, etc.), regular surveillance of patients should include gynecologic control.     

Two-year follow-up of patients with endometrial carcinoma after preoperative fluid hysteroscopy

Gücer F, Tamussino K, Reich O, Moser F, Arikan G, Winter R. Two-year follow-up of patients with endometrial carcinoma after pre-operative fluid hysteroscopy. Int J Gynecol Cancer 1998; 8 :476–480.
The aim of the present study was to analyze whether pretherapeutic hysteroscopy increases the recurrence rate in patients with endometrial cancer confined to the uterus. Between January 1993 and December 1995 a total of 33 patients with endometrial carcinoma underwent surgical staging following diagnostic fluid hysteroscopy and curettage at our department. Twenty-seven patients who had disease confined to the uterus without involvement of the uterine serosa formed the study group. Fifty-five patients with endometrial carcinoma confined to the uterus who had undergone surgery after diagnostic curettage without hysteroscopy during the same period were identified as controls. The median follow-up in the hysteroscopy group and the controls was 29 months (range 26–46) and 30 months (range 10–48), respectively. In the hysteroscopy group, no patient died of disease but one patient (3.7%) developed a local recurrence 37 months after primary treatment. In the control group, one patient (1.8%) had a local and para-aortic recurrence 20 months after primary treatment. Preceding diagnostic fluid hysteroscopy does not seem to increase the risk of early recurrence in patients with endometrial carcinoma histologically confined to the uterus.     

子宫内膜癌激素替代治疗

子宫内膜癌(endometrial cancer,EMC)患者的激素替代治疗(hormone replacement therapy,HRT)相关研究有限,且至今为止医学界尚未对此达成统一观点。大部分妇产科医生考虑到雌激素是EMC的重要发病因素之一,并不建议给予EMC患者HRT治疗。目前认为EMC并非一定是HRT治疗的禁忌证。选择恰当的剂量和药物种类不会引起EMC的复发和死亡率增加,并可对EMC患者起到适当保护作用。HRT在提高骨密度和减轻未绝经期血管收缩症状已被证实有一定裨益,但在降低冠心病、癌症发病率,以及提高认识力和健康相关生活质量上并没有相关研究支持。由于数据有限,且大部分来自具有选择偏差的回顾性研究或小型前瞻性非随机研究,妇产科医生在评估EMC患者是否需要HRT治疗时一定要充分考虑利弊,个体化治疗。     

生存素在正常子宫内膜、增生子宫内膜及子宫内膜癌中的表达研究

目的探讨生存紊(surviving)在正常子宫内膜、增生子宫内膜以及子宫内膜癌中的表达；并探讨生存紊与子宫内膜癌的临床分期、病理级别及浸润子宫肌层深度的关系。方法取正常周期、单纯增生、不典型增生子宫内膜各20例；萎缩性子宫内膜10例以及子宫内膜癌20例，应用人生存紊多克隆抗体，采用免疫组织化学SSCP法，观察其表达情况。结果生存紊在20例分泌期子宫内膜中全部表达，细胞浆呈均匀染色；20例增殖期子宫内膜，60％呈细胞浆均匀染色染色；10例萎缩型子宫内膜均不表达生存紊；20例单纯增生子宫内膜全部表达生存紊，细胞浆均匀染色；20例非典型增生子宫内膜全部表达生存紊，但问质细胞表达弱于腺上皮细胞；30例子宫内膜癌细胞100％表达生存紊，特点是100％浆表达，间质细胞表达明显弱于腺上皮细胞，同时43．33％核表达，且核表达率与临床期别、病理级别、侵犯基层深度有密切关系，统计学差异显著结论生存紊不是子宫内膜癌特有的标志蛋白，但可能是预后判断和监测治疗的指标。     

Coexisting endometrial cancer in patients with a preoperative diagnosis of atypical endometrial hyperplasia

AIM: To investigate the possibility of coexisting endometrial cancer (EC) in patients with atypical endometrial hyperplasia (AEH). METHODS: Forty-six consecutive women who underwent hysterectomy for AEH were analyzed. RESULTS: Final histopathological evaluation of hysterectomy specimens revealed EC in 11 patients (23.9%). Preoperative diagnosis of AEH was established by pipelle biopsy in eight patients and curettage was performed in the remaining patients. Of the patients with pipelle biopsy, two had a diagnosis of EC (25%), whereas nine women who underwent curettage, were further diagnosed as having EC (23.7%) (P > 0.05). Four (13.3%) of 30 women who had frozen sections at hysterectomy, were diagnosed with EC. Diagnosis of EC was missed in two patients (50%) at frozen section. In contrast, seven of 16 women (43.7%) who did not have frozen section, had EC. CONCLUSION: A relatively high incidence of EC is seen in patients with a diagnosis of AEH. Diagnostic results of pipelle biopsy and curettage were comparable. Frozen sections of hysterectomy specimens does not guarantee to exclude the possibility of EC, especially in patients with no myometrial invasion.     

子宫内膜癌1299例临床病理分析

目的分析子宫内膜癌临床病理特点及变化趋势,探讨子宫内膜癌诊治中的相关问题。方法回顾性分析1989年1月至2007年6月经四川大学华西第二医院手术治疗的1299例子宫内膜癌患者的临床病理资料,并分3时段进行对比分析(第1时段:1989-1995年,290例;第2时段:1996-2003年,499例;第3时段:2004-2007年6月,510例)。结果(1)我院3时段年均收治手术治疗子宫内膜癌患者分别为41、62、146例,呈逐年显著上升趋势。(2)3时段<45岁患者所占比例分别为5.5%、14.4%及18.6%,呈上升趋势(P<0.05)。(3)特殊病理类型(非子宫内膜样腺癌)所占比例第3时段上升至13.5%,高于第1时段的0.3%和第2时段的7.6%(P<0.05)。(4)每个时段内临床分期误差率以Ⅱ期为最高,3时段分别为80.5%、67.5%及77.8%。结论(1)子宫内膜癌发病逐年增多,且发病年龄有年轻化趋势。(2)特殊病理类型子宫内膜癌所占比例显著增加。(3)子宫内膜癌临床Ⅱ期分期误差率仍较高。     

Post treatment surveillance of type II endometrial cancer patients

Objective

There are few studies analyzing surveillance for Type II endometrial cancer recurrence. Our objective was to determine the types of post treatment surveillance tests performed in our institution and the efficacy of these tests in detecting recurrence in type II endometrial cancer patients.

Methods

One hundred and thirty six cases of type II endometrial cancers at Cedars-Sinai Medical Center from January of 2000 to August of 2011 were identified and 106 patients met inclusion criteria. Medical charts were reviewed for surveillance methods and number of follow up visits. For patients who underwent a recurrence of disease, the surveillance method utilized for detection was documented.

Results

Forty-seven of the 106 (44%) patients developed recurrence with a mean progression free interval of 11 months. All patients had a history and physical at each surveillance visit, 78% had Pap testing, 57% had CA-125 levels drawn, 59% had CT (computed tomography) scans done, 6% had PET (positron emission tomography) scans done for surveillance. In our cohort, recurrence was detected by symptoms in 16, by CA-125 in 11, by physical exam in 7, by CT scan in 12, and by PET scan in one patient. No patients had recurrence detected by vaginal cytology.

Conclusions

Although performed in the majority of patients, Pap testing did not detect any recurrences within this cohort. History and physical exam detected the most recurrences. These findings suggest that educating patients about relevant symptoms and performing thorough follow-up exams may be the most important aspects of detecting type II endometrial cancer recurrence.