Molecular characteristics of endometrial cancer coexisting with peritoneal malignant mesothelioma in Li-Fraumeni-like syndrome
© Chao et al.; licensee BioMed Central. 2015
Received: 5 August 2014
Accepted: 6 January 2015
Published: 15 January 2015
Endometrial cancer that occurs concurrently with peritoneal malignant mesothelioma (PMM) is difficult to diagnose preoperatively.
A postmenopausal woman had endometrial cancer extending to the cervix, vagina and pelvic lymph nodes, and PMM in bilateral ovaries, cul-de-sac, and multiple peritoneal sites. Adjuvant therapies included chemotherapy and radiotherapy. Targeted, massively parallel DNA sequencing and molecular inversion probe microarray analysis revealed a germline TP53 mutation compatible with Li-Fraumeni-like syndrome, somatic mutations of PIK3CA in the endometrial cancer, and a somatic mutation of GNA11 and JAK3 in the PMM. Large-scale genomic amplifications and some deletions were found in the endometrial cancer. The patient has been stable for 24 months after therapy. One of her four children was also found to carry the germline TP53 mutation.
Molecular characterization of the coexistent tumors not only helps us make the definite diagnosis, but also provides information to select targeted therapies if needed in the future. Identification of germline TP53 mutation further urged us to monitor future development of malignancies in this patient and encourage cancer screening in her family.
KeywordsEndometrial cancer Peritoneal malignant mesothelioma Massively parallel DNA sequencing Molecular inversion probe microarray
Simultaneous occurrence of primary cancers from the breast, ovary, and colon has been reported with endometrial cancer . However, coexistence of mesothelioma with endometrial cancer is rare with only three reported cases [2–4]. The diagnosis of endometrial cancer is usually made via endometrial curettage prior to definitive surgery whereas the mesothelioma would not be discovered until surgery.
In the present study, we describe a patient with advanced endometrial cancer and a concomitant peritoneal malignant mesothelioma (PMM). Hematoxylin and eosin stains and the immunoprofile of tumor tissues differentiated the two tumors. Furthermore, we used targeted, massively parallel sequencing (MPS) and molecular inversion probe (MIP)-based microarray analysis to molecularly characterize these tumors. The genetic make-up of the concomitant tumors of this patient was determined, and identification of a germline TP53 mutation indicating Li-Fraumeni-like syndrome in this patient encouraged further screening for this mutation in her family members.
The patient received chemotherapy with cisplatin (75 mg/m2) and premetrexed (Alimta, 500 mg/m2) every 3 weeks for a total of 6 cycles. She also received concurrent radiation to the pelvis (5040 cGy) with brachytherapy (200 cGy) for cervical extension and positive vaginal margins of the endometrial cancer. Subsequently, small field radiation therapy was given to the hepato-renal region (6000 cGy/25 fractions) to treat the PMM. The patient has remained clinically stable for 24 months though her follow-up computed tomography did show stationary lesions at Morrison’s pouch at the 24-month follow-up visit.
Summary of mutated genes in endometrial cancer (Em Ca) and peritoneal malignant mesothelioma (PMM) measured using massively parallel sequencing (MiSeq) and molecular inversion probe microarray (OncoScan)
Em Ca (35%)‡
Amino acid change
OncoScan MIP microarrayξ
OncoScan MIP microarrayξ
215G > C
1624G > A
973 T > C
703C > T
To our knowledge, this is the first case of endometrial cancer complicated by PMM where molecular characterization has been performed. Immunohistochemical results of calretinin (+), CK5/6 (+), ER (-), and PR (-) in PMM were instrumental in differentiating between the two tumors. A negative Ber-EP4 suggests that the PMM was not a tumor metastasized from the gastrointestinal tract .
Surgery for advanced endometrial cancer is challenging. Optimal cytoreduction provides a survival benefit for patients with advanced endometrial cancer . However, the accurate preoperative evaluation of the disease extent to predict the demands of optimal debulking during primary surgery remains difficult. In this case, preoperative imaging studies of MRI and PET did not show evidence of lymph node metastasis. Concurrence of another second primary malignancy further complicated treatment course. In this case, extensive peritoneal implants were mistakenly considered as tumor metastasis. Therefore, the findings of peritoneal metastatic sites during operation should remind operators of the possibility of a co-existing primary cancer. Adjuvant therapies of patients with concurrent endometrial cancer and PMM have not yet been standardized. Radiation therapy has been reported to be the adjuvant therapy of choice, and effective systemic chemotherapies have improved response rates in endometrial cancer [1,8]. Premetrexed has been used in combination with a platinum-base chemotherapy as the treatment for PMM .
Because the diagnosis of multiple concurrent primary cancers is often made based on micropathological results, the tissues available for further molecular characterization are in FFPE blocks. For FFPE DNA, targeted MPS  and MIP microarrays  have proved to be useful in analyzing genomic alterations. Targeted MPS can detect mutations in 48 cancer related genes (Additional file 1). Copy number variations (gains or losses) and LOH in cancer genomes can be further identified using MIP microarrays. Her endometrial cancer had somatic cancer mutations in PIK3CA, which is frequently reported in endometrial cancer . Identification of these mutations may have therapeutic implications. For instance, dysfunctions in the PIK3CA pathways have been successfully treated with PI3K/AKT/mTOR pathway inhibitors . Though copy number variations were found only in small genomic regions of PMM, it harbored GNA11. Mutation of GNA11 in uveal melanoma  leads to the activation of downstream mitogen-activated protein kinase (MAPK/ERK) pathways. Clinical trials of inhibitors that disrupt MAPK pathways are being assessed in the treatment of metastatic uveal melanoma . Given the fast pace of current development of targeted drugs aiming at common cancer mutated genes, the identification of multiple mutations in this case may justify her enrollment in future clinical trials of targeted therapy.
Germline TP53 mutations have been reported in 80% of families who have classical Li-Fraumeni syndrome, and 20-40% of families who meet the criteria for Li- Fraumeni-like syndrome . The prevalence of Li-Fraumeni syndrome is rare, with approximately 400 families reported worldwide . However, Li-Fraumeni syndrome may be under reported due to the strict requirement of clinical features and detailed family histories to make the diagnosis.
The Pro72Arg variants of TP53 has been associated with various cancer susceptibility and poor outcomes , such as human papillomavirus 16-positive cervical cancer , laryngeal tumors , head and neck cancers , non-small cell lung cancer , and bladder cancer . Hisada et al reported an increased risk of developing second cancer in patients with a germline TP53 mutation, with a cumulative probability of 57% of developing a second cancer at 30 years after diagnosis of the first cancer . Clinical management of the patient may include tumor surveillance of other organs such as breast examination . It is advisable that family members take a systematic approach to cancer screening and participate in TP53 research programs .
In conclusion, concurrent endometrial cancer and PMM are difficult to be diagnosed pre-operatively. Effective treatments for such patients are not standardized, and the prognosis is unclear. Molecular characterization of the coexistent tumors not only helps us make definitive diagnosis but also provides information for choosing targeted therapies in the future. In cases of Li-Fraumeni-like syndrome, family members should also be enrolled in cancer screening.
Written informed consents were obtained from the patient and her kindred, to publish this case report and accompanying images.
This study was supported by Chang Gung Medical Foundation: CMRPG3C0931/2 to Chao A, CMRPG3A0471-3 to Wang TH , and CMRPG3C1351-3 to Lai CH. The authors thank Mr. Kevin Lin (Cold Spring Harbor Biotechnology, Taiwan) for technical support, and Dr. Shihtien Wang (Assistant Professor, Children’s Hospital of the University of IL Med. Ctr., Chicago, IL 60612) for English editing.
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