Marit Arnes

Treatment results of endometrial hyperplasia after prospective D-score classification A follow-up study comparing effect of LNG-IUD and oral progestins versus observation only

OBJECTIVES Three different treatment options for endometrial hyperplasia were evaluated in a prospective long-time follow-up study, comparing effects of intrauterine levonorgestrel impregnated device (LNG-IUD), low oral dose of medroxyprogesterone acetate (MPA) and no treatment (observation only). To select patients with high probability for co-existing or future carcinoma we used the objective morphometric algorithm, D-score, stratifying patients into three different risk groups. As far as we know, this is the first prospective long-time follow-up study in which treatment recommendation and outcome is based on the D-score assessment. METHODS From a total of 370 patients initially diagnosed with endometrial hyperplasia from eight different hospitals in North Norway, 258 were available for long-time follow-up. After D-score classification, one of three different treatment options was chosen: LNG-IUD, low oral dose of MPA or observation only. Follow-up controls were performed and biopsies taken in the local hospitals. RESULTS Among the 370 investigated cases with endometrial hyperplasia, only ten endometrial cancers were detected at the entrance of the study, all belonging to the high risk group (D-score <0). No further cancers were detected during follow-up, irrespective of risk group. After 6 months treatment with LNG-IUD proved significantly superior to oral treatment (p=0.001 for D-score >1 and p=0.003 for D-score 0-1 groups) and observation only (p=0.001 for D-score >1 and p=0.001 for D-score 0-1 groups). After 56 to 108 months the LNG-IUD proved significantly superior to oral treatment and to the observation group. Comparison of oral therapy to observation only showed no significant differences, neither after 6 months nor after long-time observation. CONCLUSIONS LNG-IUD is the optimal treatment for endometrial hyperplasia. Outcome after oral low-dose MPA regimen is comparable to expectation.

Levonorgestrel‐impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial

The purpose of this study was to investigate if the levonorgestrel‐impregnated intrauterine device (LNG‐IUS, Mirena®) is safe and effective as therapy for low‐risk and medium‐risk endometrial hyperplasia compared with oral medroxyprogesterone (MPA).

Loss of expression of MLH1, MSH2, MSH6, and PTEN related to endometrial cancer in 68 patients with endometrial hyperplasia

Derangements in the tumor suppressor gene PTEN and the mismatch-repair genes, hMLH1, hMSH2, and hMSH6, have an important role in endometrial carcinogenesis. The purpose of this study was to assess immunohistochemically the pattern of protein expression for these genes in 68 patients with endometrial hyperplasia and to determine the relation of protein expression to cancer development or coexistence of cancers. Loss of expression of these genes also was evaluated as potential tumor markers for clinical use. PTEN and hMLH1 both showed loss of expression in 55% of specimens from 18 patients with subsequent or coexisting carcinoma. D&C specimens from 50 patients who did not develop cancer (10 patients underwent hysterectomy within 2 years; 40 had no hysterectomy; follow-up of 10–20 years), expressed protein at a much higher frequency (92% for PTEN and 98% for hMLH1). The parameter with the strongest independent relation to subsequent or coexisting carcinoma in a stepwise multiple logistic regression analysis was hMLH1. Evaluation of the investigated factors as prognostic markers for tumor development showed high specificity (92% for PTEN, 98% for MLH1) at the expense of sensitivity (56% for PTEN, 56% for MLH1). The results were compared with the results of the computerized image analysis algorithm, the D-score.

Down-regulated progesterone receptor A and B coinciding with successful treatment of endometrial hyperplasia by the levonorgestrel impregnated intrauterine system

Objective. To investigate whether regression of endometrial hyperplasia observed after 3 months of treatment with levonorgestrel impregnated intrauterine system device (LNG‐IUS) was sustained after 6 months and whether these effects were still occurring synchronously with extinguished expression of progesterone receptors and increased apoptosis. Design. Retrospective population‐based observational study. Setting. Six local hospitals and one university hospital in northern Norway. Population. Patients (n = 41) with low and medium risk endometrial hyperplasia. Methods. Histopathological treatment response comparing LNG‐IUS (n = 25) and standard per oral medroxyprogesterone (n = 16). Expression of progesterone receptor A (PR‐A), progesterone receptor B (PR‐B), ER‐alpha, ER‐beta, Bcl‐2, BAX, Caspase‐3 and metallothionein (MT) were investigated by immunohistochemistry; results were evaluated by a semi‐quantitative H‐score. Main outcome measures. Response to progestin treatment. Results. All the LNG‐IUS treated patients had therapy response after 6 months. PR‐A and PR‐B in glands were almost extinguished for IUD users compared to the oral group. Estrogen receptors were also reduced. Co‐existent changes in apoptosis were differently modulated in glands and stroma in the two treatment groups. Bcl‐2 was different in glands and stroma in responders and non‐responders to oral therapy. Conclusion. The study confirms that LNG‐IUS can be safely used for 6 months as treatment for endometrial hyperplasia. The clinical effect is accompanied by almost extinguished PR‐receptors in glands coinciding with modulation of apoptosis. The results strongly indicate that progestins activate non‐classical initiated signaling pathways.

Prognosis of early cervical cancer (FIGO Stages IA2, IB, and IIA) in northern Norway predicted by malignancy grading score and objective morphometric image analysis.

Summary Recurrence of early-stage cervical cancer after primary surgery represents a considerable clinical problem, and, so far, few reliable markers for prediction of recurrence exist. Thus, the prognostic value of the malignancy grading score (MGS) classification system was evaluated in 82 patients with early-stage cervical cancer (International Federation of Gynecology and Obstetrics stages IA2, IB, and IIA) and long-time follow-up (5-16 years). Recurrence or not, the likelihood of lymph node metastases and reproducibility of the MGS semiquantitative system were tested. The prognostic power of the MGS to identify high-risk cases prone to recurrence in patients lacking lymph node metastases at primary surgery was a main purpose of the present study. The semiquantitative MGS classification system was performed independently by 2 pathologists unaware of prognosis and clinical data using light microscopy. Routine hematoxylin and eosin sections from surgical specimens were used, and investigation area was defined in the deep part of the tumor. Data-based image analysis was also used to investigate if objective morphometric parameters could add any prognostic power to MGS. The 5-year survival for the whole patient group was 92%. Malignancy grading score of greater than 17 risk points was statistically highly significant in predicting relapse and lymph node metastases (n = 82). High-risk cases lacking lymph node metastases (n = 70) were also statistically associated with high MGS. Depth of invasion and vascular invasion were statistically related to recurrence. Objective image analysis of nuclear parameters was of no additional statistical value for the prediction of outcome. The MGS classification system proved to be a useful tool in predicting recurrence and lymph node metastases and, most importantly, was a predictor of high-risk patients without metastases at primary surgery.

Relapse risk of endometrial hyperplasia after treatment with the levonorgestrel‐impregnated intrauterine system or oral progestogens

To investigate relapse rates after the successful treatment of patients with non‐atypical endometrial hyperplasia who were randomised to either a levonorgestrel‐impregnated intrauterine system (LNG‐IUS; Mirena®) or two regimens of oral medroxyprogesterone acetate (MPA) after primary histological response.

Prognostic markers for coexistent carcinoma in high‐risk endometrial hyperplasia with negative D‐score: significance of morphometry, hormone receptors and apoptosis for outcome prediction

Objectives. Hysterectomy represents the current routine therapy for high‐risk endometrial precancers. More sophisticated methods are needed for treatment decision among women who want to preserve fertility and seriously ill patients. Among women diagnosed with high‐risk hyperplasia, approximately 40% show signs of endometrial cancer in the hysterectomy specimen. Thus, more sophisticated methods are needed to select the women at risk. Setting. University Hospital of Tromsø, Regional Center for Gynecological Oncology in northern Norway. Population. From 1999 to 2004, 258 consecutive patients had endometrial hyperplasia diagnosed by D‐score; 57 among these were high‐risk cases (D‐score < 0) and 10 had coexisting endometrial carcinoma. No further cancers were detected after long‐term follow‐up (4–10 years). Design. From the initial histological specimens, material from the 10 patients with cancer and from the 13 cases without cancer (high‐risk D‐score < 0) was analyzed with selected histomorphometric (architectural and nuclear) and immunohistochemical (hormone receptors and apoptotic) features blinded to the investigator. Method. Original slides were used for computerized histomorphometry (4‐class rule and related procedures). Serial sections from the paraffin embedded material were used for immunohistochemical investigations. Immunohistochemical expression in glands and stroma was evaluated by the semi‐quantitative H‐score (ER‐α, ER‐β, PR‐A, PR‐B, RCAS‐1, Bcl‐2, BAX, and Caspase‐3). Results. The histomorphometric 4‐class rule differentiates between presence and absence of cancers with a sensitivity of 80% and specificity of 77%. Several morphometric and immunohistochemical features were significantly different in cases with cancer and hyperplasia. Conclusions. Histomorphometry seems superior in predicting coexistent carcinoma in high‐risk endometrial hyperplasia and should be considered for clinical use.

HE4 is a novel tissue marker for therapy response and progestin resistance in medium- and low-risk endometrial hyperplasia

HE4 is a novel tissue marker for therapy response and progestin resistance in medium- and low-risk endometrial hyperplasia