Abstract
We report on a case of synchronous endometrial and ovarian cancer in a patient with Lynch syndrome. An endometrial biopsy performed during routine screening revealed microsatellite instability (MSI) and loss of expression of human mutL homolog-1 (MLH1) and postmeiotic segregation increased-2 (PMS2) in a setting of complex hyperplasia. Whereas gynaecological screening including clinical examination, pelvic ultrasound, and endometrial biopsy, has not proven its benefit, our case report points out the place of MSI analysis and immunohistochemical investigation of mismatch repair protein expression in endometrial samples during gynaecological screening.
Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by a germline inactivating mutation in one of the mismatch repair (MMR) genes, human mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog-6 (MSH6), or postmeiotic segregation increased-2 (PMS2). When a somatic second hit inactivates the relevant MMR gene, the consequence is instability of DNA repeat sequences such as microsatellites and the tumors are referred to as having a microsatellite instability (MSI) phenotype (1).
Besides a well-known risk of colorectal cancer, women with LS are at enhanced risk of gynaecological neoplasia, with a life-time risk for endometrial cancer of 40-60%, and for ovarian cancer of 5-12% (2). Compared with sporadic cancer, the incidence of synchronous endometrial and ovarian cancer in LS is higher (3). As a result, gynaecological screening is recommended (4), and includes clinical examination, pelvic scan, endometrial biopsy, plasma cancer antigen 125 (CA125) level measurement and hysteroscopy.
Although the basic concept of endometrial cancer tumourigenesis is a gradual progression through an atypical hyperplasia–carcinoma sequence with progressive cytological atypia (5), it is unknown whether this pattern of tumourigenesis applies to LS–associated endometrial carcinoma. Ichikawa et al. reported that endometrial hyperplasia without atypia may indicate early development of endometrial cancer in women with LS, and tumour exhibited MSI (6). This last point could be of utmost importance during gynecological screening, allowing for earlier diagnosis of endometrial cancer.
We here report on a complex case of synchronous endometrial and ovarian cancer discovered in a young woman with LS, in whom complex hyperplasia with MSI and loss of expression of MLH1 and PMS2 were identified on endometrial biopsy performed during routine screening.
Case Report
A patient with LS underwent her first gynaecological screening, including normal clinical examination, pelvic ultrasound, endometrial biopsy and CA125 levels, when she was 32 years old. A mutation of MLH1 was diagnosed. Lost to follow-up, she returned 10 years later, being asymptomatic. Clinical examination and CA125 level were normal. Pelvic scan revealed a left functional ovarian cyst, which disappeared one menstrual cycle later. Hysteroscopy found a right cornual polyp, which was removed; the histological report confirmed its benignity without loss of expression of MLH1, PMS2, MSH2, and MSH6 on immunohistochemistry [anti-MLH1 (clone ES05; DAKO, Carpinteria, CA, USA), anti-PMS2 (clone A16-4; BD Biosciences Pharmingen, USA), anti-MSH2 (clone Ab-2; Calbiochem, La Lolla, CA, USA), and anti-MSH6 (clone 44/MSH6; BD Biosciences Pharmingen, USA) antibodies]. MSI analysis, including mononucleotide repeat markers BAT25, BAT26, NR21, NR24, and NR27, was performed and did not show instability.
At the age of 45, she presented for her annual gynaecological follow-up at our multidisciplinary center (7). She was asymptomatic and her clinical examination was once again normal. CA125 levels were within the normal range. Endometrial biopsy revealed simple hyperplasia without atypia, associated with loss of expression of MLH1, and PMS2, and MSI-high (Figures 1 and 2). The diagnostic hysteroscopy discovered a polypoid mass of the anterior wall of the uterine cavity, and new endometrial biopsy revealed complex hyperplasia with atypia and the same loss of expression of MLH1, and PMS2 and instability. The pelvic scan performed on the same day found an 8 mm-endometrial thickness, and the ovaries appeared normal.
The patient complained of persistent pelvic pain following colonoscopy, and the abdomino-pelvic computed tomography-scan revealed a vascularized right ovarian cyst, interpreted as a corpus luteum by the radiologist, but not concordant with her cycle. Pelvic magnetic resonance imaging showed a normal uterus with thin endometrium, a simple left ovarian cyst, and a 46-mm right ovarian cystic mass with a solid portion and intermediate signal intensity on T2-weighted images, enhancement on T1 fat suppression-weighted images after gadolinium injection, and high signal intensity on diffusion-weighted images. Nevertheless, the mass presented progressive enhancement on dynamic contrast-enhanced image (curve type 1).
The patient declined the recommended prophylactic total abdominal hysterectomy with bilateral salpingo-oophorectomy. A hysteroscopic endometrectomy and laparoscopic right salpingo-oophorectomy were performed two weeks later. Intraoperative findings showed a non suspicious right ovarian cyst, adherent to the ovarian fossa, and non suspicious polypoid endometrial mucosa. However, final histology found right unstable grade 1 ovarian endometrioid adenocarcinoma, with loss of expression of MLH1 and PMS2, associated with unstable grade 1 in situ endometrial endometrioid adenocarcinoma, with loss of expression of MLH1 and PMS2 (Figures 1 and 2). Surgery was hence completed with total abdominal hysterectomy, left salpingo-oophorectomy, peritoneal cytology, infragastric omentectomy, and pelvic and para-aortic lymphadenectomy. Final histology displayed synchronous unstable International Federation of Gynecology and Obstetrics (FIGO) stage IC ovarian cancer and FIGO stage IA intramucous endometrial carcinoma of the uterine corpus without lymphovascular space involvement. After a follow-up of six months, recovery was uneventful.
Discussion
We report on a case of synchronous in situ endometrial carcinoma and bilateral ovarian cancer in an asymptomatic patient with LS, discovered at the time of routine gynaecological screening. Three main points make this medical history remarkable: first the synchronicity of endometrial and ovarian cancer, second the rapid onset of neoplasm despite previous normal screening, and finally the detection of MSI in endometrial biopsy prior the discovery of the neoplasm.
Our patient presented synchronous grade 1 stage IA endometrial endometrioid adenocarcinoma and grade 1 stade IC ovarian endometrioid adenocarcinoma. Synchronous primary carcinomas of the endometrium and ovary, defined by tumours diagnosed within a two-month range of each other, have been identified in about 8% of patients with LS (3, 8). To our knowledge, no case has been reported during systematic gynaecological follow-up, thus, we report the first case of asymptomatic synchronous endometrial and ovarian cancer discovered at the time of screening.
Endometrial carcinomas in LS are characterized by younger age at onset, higher histological grade, prominent lymphovascular invasion, increased rate of deep myometrial invasion, and higher stage (9). Apart from young age, our patient did not fulfil these criteria, as she presented with an in situ carcinoma. Although non-endometrioid histological types (10, 11), as well as carcinoma of the lower uterine segment (12), are common in cases with MSH2 mutation, both are extremely rare in the group with methylated MLH1, which is consistent with our case. Likewise, ovarian cancer in LS generally occurs in young patients, and is more likely to be epithelial tumour and moderately to well-differentiated, with only a few cases of advanced stage (1, 13). A higher incidence of endometrioid and clear cell carcinomas have been reported, particularly for MSH6-associated tumours (14, 15). Our patient's ovarian tumour presented all these characteristics.
Whereas endometrial cancer usually presents with abnormal bleeding, the patient was asymptomatic, probably due to the early stage of the disease. Furthermore, it is noteworthy that progression from simple hyperplasia to in situ carcinoma was very quick, underlining the potential aggressiveness of oncogenesis in LS.
Screening of ovarian cancer has failed to prove efficient in the general population, as well as in hereditarily predisposed patients (16). To date, no case of ovarian cancer has been revealed by screening in LS. Our report is in agreement with this, as the diagnosis required further imaging in the face of new-onset symptoms. Although the natural history of ovarian cancer in LS has been poorly studied, it is interesting to note that in our case the tumour developed very quickly. This fact underlines once again the particular pattern of oncogenesis during LS, and reinforces the need for alternative tools to diagnose pre-cancerous lesions. Furthermore, MSI status in LS-associated ovarian cancer has been poorly studied, but Aysal et al. reported that ovarian carcinomas of endometrioid and clear cell type were more likely to have MSI-high tumours and that most patients with abnormal MMR expression in ovarian tumour also had a concurrent uterine tumour (1). Our report extends the findings of these prior investigations by pointing out the place of MSI analysis and immunohistochemical investigation of MMR protein expression of endometrial samples during gynaecological screening.
Microscopic examination. Normal endometrium [A; Hematoxylin Eosin Safran (HES) ×200]: presence of nuclear staining with anti-human mutL homolog 1 (MLH1) [B; ×400] and anti-postmeiotic segregation increased 2 (PMS2) [C; ×400] in endometrial glands. Simple endometrial hyperplasia without atypia [D; HES ×200]: absence of nuclear staining with anti-MLH1 [E; ×200] and anti-PMS2 [F; ×200]. Grade 1 endometrioid adenocarcinoma [G; HES ×200]: absence of nuclear staining with anti-MLH1 [H; ×400] and anti-PMS2 [I; ×400]. Arrow: Internal positive control, marking nuclear staining of normal endometrial glands or of chorionic cells.
Capillary electrophoresis results of microsatellite instability (MSI) analysis. The markers BAT26, NR27, and NR24 exhibited an MSI pattern in both simple hyperplasia without atypia and grade 1 in situ endometrial endometrioid adenocarcinoma (deviations in the electrophoretic patterns compared with normal tissue). This analysis revealed a polymorphic pattern for marker BAT25.
MSI analysis on endometrial samples could provide with interesting data in gynaecological screening, as investigated in urothelial carcinoma (17). Indeed, ultrasound was not contributive, macroscopic hysteroscopic features were not suspicious, and endometrial biopsy did not show any obvious atypia or endometrial carcinoma. Crucial problematic elements were the presence of MSI and loss of expression of MLH1 and PMS2. MSI analysis associated with complex hyperplasia warranted performing of further investigations, including hysteroscopic endometrectomy, which revealed endometrial carcinoma.
Furthermore, this case appears of great interest in appreciating the natural history of endometrial cancer in LS. Indeed, loss of MMR protein expression and MSI appeared in the setting of simple and then complex hyperplasia a couple of weeks before the development of carcinoma, suggesting rapid oncogenesis in LS.
The detection of MSI at a single locus is the basis of a stool-based screening test for LS (18). Hewitt et al. reported the first study to present evidence of MSI in blind endometrial samples taken from women known to have endometrial cancer (19). Our observation raises the possibility of a non-invasive screening tool for LS-related endometrial cancer and paves the way for a broader use of MSI analysis in LS (20).
To conclude, gynaecological screening in LS yields is limited in detecting pelvic cancer. Development of new molecular tools such as MSI analysis of endometrial samples might allow for diagnosis of pre-cancerous transformation and requires further experimental and clinical investigations.
- Received June 29, 2013.
- Revision received July 16, 2013.
- Accepted July 17, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
