A case report of triple primary malignant tumors including breast,cervical and thyroid cancers with CHEK2 and PIK3CA mutation

Case report Herein, we report a 47-year-old female who was diagnosed with multiple synchronous primary malignancies: cervical squamous-cell carcinoma, invasive ductal carcinoma of left breast, papillary carcinoma of the left thyroid gland and had a gene mutation of both CHEK2 and PIK3CA. We adopted a comprehensive treatment approach . Conclusion


Introduction
Multiple primary malignant tumors(MPMs) are de ned as multiple tumors with different pathogenetic origins in the same individual. Based on the timing of the diagnosis, MPMs are classi ed as synchronous or metachronous. The frequency of MPMs is reported in the range of 2-17% 1 Dual primary malignancies are the most common type, whereas tri-primary and multiple primary malignancies account for only 0.5% and <0.1% of cases, respectively 2 . Here, we report the case of a 47-year-old female who has diagnosed synchronous primary carcinoma of the thyroid, cervix and breast and had treated successfully in the A liated Hospital of Qingdao University, in conjunction with a brief review of related literature.

Patient information
In October 2018, a 47-year-old, premenopausal female with chief complaints of vaginal contact bleeding for 3 months was admitted to her local hospital.There were no relation abdominal pain, nor weight loss or any other speci c complaints. The disease was initially diagnosed from the cervical biopsy as squamous-cell carcinoma(SCC). Then the patients admitted to our hospital for further diagnosis and treatment.The patient was healthy prior to diagnosis and the family history was non-contributory.

Clinical Findings
Physical examination showed a well-delimited, elastic-rm, mobile tumor whose diameter is 2 centimeters in the upper outer quadrant of the left breast. No palpable axillary and supraclavicular lymph nodes.
Gynecologic examination revealed an enlarged rm cervix, and the left parametrial tissue is rm, thickening reaches the pelvic wall while the right parametrial tissue is thickened and stretchy.
Biopsy and imaging examinations At the local hospital, there had a cervix punch biopsy which histological diagnosis documented a squamous cell carcinoma. Then the patient visited our hospital, the histological diagnosis from left breast biopsy turned out to be an invasive ductal carcinoma and the left thyroid gland showed a papillary carcinoma.

Therapeutic Intervention
After a comprehensive multidisciplinary consultation, two courses of taxol/cisplatin chemotherapy were administered rst because of the later stage of cervical carcinoma which is not suitable for surgery. The chemotherapy process went smoothly. Then the following procedures were performed after one month: left breast modi ed radical mastectomy and left lobar thyroid plus isthmus resection with lymphadenectomy and recurrent laryngeal nerve anatomy. Concurrent radio-chemotherapy for pelvic lesions: pelvic IMRT intensity-modulated radiation therapy with the dose of 50Gy/2Gy/25f ( Figure 2A) and point A based cervical cancer brachytherapy with the dose of 6Gy/2Gy/3f ( Figure 2B), combined with one course of taxol/cisplatin chemotherapy was applied after the surgery. However due to grade 2 granulocytopenia during radiotherapy, the fourth fth and sixth cycle of chemotherapy(TC) was performed delayed after radiotherapy. Finally, we jointly applied endocrine therapy Anatrazol tablets and targeted therapy trastuzumab until now.

Follow-up and Outcomes
The patient remained under endocrine therapy Anatrazol tablets plus targeted therapy trastuzumab after six cycle chemotherapy and visited our hospital regularly for examinations. After a follow-up period of 2.5 years, the patient is alive and well with no evidence of tumor recurrence, metastatic disease, or any more MPMs.

Discussion
There are three notable aspects of this case. First, to the best of our knowledge, the special combination of tumors (SCC of the cervix, IDC of the breast, and PTC) has not been reported previously. Second, the patient had a gene mutation of both CHEK2 and PIK3CA. Third, we adopted a comprehensive treatment approach including radical resection, chemotherapy, radiotherapy, endocrinotherapy and targeted therapy.In addition to reporting this case, we decided to conduct an adequate literature review to analyze this case as well as identify new cases.

The State of MPMs
Currently, MPMs(multiple primary malignant tumors) diagnostic criteria still continue to use the 1932 diagnostic criteria proposed by Warren and Gates 3 each tumor must be con rmed by histology and cytology as a malignant tumor with its unique pathological morphology; the possibility of mutual metastasis must be ruled out; tumors occur in different parts, and the two are not continuous with each other. Moertel divides MPMs into synchronous and metachronous multiple primary malignant tumors according to the chronological order of their appearance:≥ 2 types of malignant tumors occur at intervals of ≤ 6 months as synchronous MPMs while >6 months as metachronous MPMs.
Although the underlying mechanisms responsible for the development of MPMs are yet to be fully elucidated, frequently implicated factors can be collated into three broadly de ned categories genetic factors, living environment factors (smoking, alcoholism, obesity, etc.), and iatrogenic factors (radiation therapy, chemotherapy, etc.).
At present, there is no uniform standard for the selection of MPMs treatment options. Whether in patients with synchronous MPMs or metachronous MPMs, the lesions should be completely removed at the same time or sequentially. If the lesion cannot be removed, comprehensive treatment such as immunotherapy, targeted therapy, and chemotherapy can be considered, and the possible impact on second primary cancer treatment during primary tumor treatment should be avoided, such as the accumulation of drug toxicity and the accumulation of radiation dose in the same area.
In our case, the patient's malignancy occurred simultaneously in the thyroid, cervix, and breast. The pathological types of these three tumors are signi cantly different from each other; all three tumors were diagnosed at the same time, consistent with the diagnostic criteria for multiple primary malignant tumors. The cervix, breast, and thyroid glands have certain commonalities in hormone metabolism pathways and have the potential to interact to produce MPMs. On the other hand, the genetic test showed gene mutations of CHEK2 and PIK3CA. She did not use tobacco or alcohol and her family history was unremarkable. The existing treatment guidelines were followed. Radical resection of breast and thyroid cancers was performed. Because cervical cancer has metastasized, we applied palliative care. No tumor progression was found in the patient until today.

Progress of the relationship between thyroid tumor breast cancer and cervical cancer
The relationship between thyroid cancer and breast cancer has attracted widespread attention as early as the 19th century. The study found that patients with a history of thyroid cancer have an increased risk of recurring breast cancer, and breast cancer patients also have an increased risk of recurring thyroid cancer 45 . Kim's research found that breast cancer recurrence ranked rst in patients' second-largest primary tumor 4 . A study from Seoul national university found that 4.3 percent of patients with thyroid cancer had recurrent breast cancer, and 2.6 percent of patients with breast cancer had recurrent thyroid cancer 5 . In addition, the surveillance, epidemiology, and end-result database (http://seer.cancer.gov/) reported that premenopausal women ages 20 to 49 with a history of thyroid cancer had a signi cantly increased risk of subsequent breast cancer, compared with women without a history of thyroid cancer 6 .
But so far, there is no clear conclusion about whether there is a connection between thyroid cancer and breast cancer, and by what way. At present, it is generally believed that hormones play an important role in the occurrence and development of thyroid cancer and breast cancer, as well as genetic susceptibility, autoimmunity, radiation exposure and other factors. Since both the breast and thyroid are hormonedependent endocrine organs, some researchers have suggested that estrogen, thyroid hormone, or related receptors may play a vital role in the MPMs of breast and thyroid cancer. Studies 7 have shown that betaestradiol can signi cantly stimulate the proliferation of thyroid cancer cells in a time and concentrationdependent way, and this effect is inhibited by the estrogen antagonist tamoxifen. Meanwhile, the expression of ER in thyroid cancer tissues is signi cantly higher than that in para-cancer tissues. Under normal circumstances, the thyroid can continuously express the sodium-iodide symporter(NIS), while only the breast during pregnancy or lactation has functional NIS expression, which can mediate the absorption of iodine. However, the expression of the NIS gene can be detected in 80% of breast cancers and 90% of thyroid cancers, suggesting that NIS may play a large role in the co-occurrence of thyroid cancer and breast cancer. Genetic susceptibility has also been studied between the two types of cancer the activation of the protein kinase B PKB gene and the variation of the cell cycle checkpoint kinase CHEK2) gene may be one of the pathogenic factors. In the setting of breast cancer, PIK3CA mutations are extremely common, second only to TP53 mutations. PIK3CA mutation can occur in thyroid cancer but does not seem to be a major genetic event in thyroid cancer in general.
The MPMs of cervical cancer with thyroid cancer cases are rarely reported in clinic, and its main mechanism may be related to the expression of estrogen. Lee et al. 8 found that the incidence of multiple primary cancers in breast cancer patients was 10.5%, among which the incidence of breast cancer combined with gynecological tumors was the second, only second to thyroid cancer.
The causes of both breast and cervical cancers are unknown, but both are associated with long-term oral contraceptives. Chung et al. 9 reported that long-term oral contraceptives and fertility increase the risk of cervical cancer in HPV infected individuals. At the same time, cervical cancer and breast cancer coexistence of estrogen and progesterone receptor may also be carcinogenic factors.
For this patient, the woman has no history of the application of estrogen and progesterone drugs, considering that the patient's multiple primary cancers are associated with mutations in both CHEK2 and PIK3CA. The research results of Chen et al suggest that CHEK2 mutations predispose to familial aggregations of breast and thyroid cancer and to double primary malignant tumors of the breast and thyroid 10 . In the setting of breast cancer, PIK3CA mutations are extremely common, second only to TP53 mutations 11 . PIK3CA mutation can occur in thyroid cancer but does not seem to be a major genetic event in thyroid cancer in general 12 . The carcinogenicity of CHEK2/PIK3CA mutation in cervical cancer has not been reported.

Patient Perspective
During the treatment, the patient said that although the chemotherapy drugs and surgery caused her short-term discomfort, however the bene ts were long-lasting.

Informed Consent
The patient gives informed consent to this case-report.

Conclusion
Multiple primary malignant tumors are thought to be on the increase due to recent advances in diagnosis and treatment. When a cancer patient presents with the clinical manifestation of another tumor, the possibility of synchronous occurrence of multiple primary malignant tumors, as well as tumor metastasis should be considered. In addition, the follow-up time of patients with malignant tumors should be extended, because timely detection and treatment of more primary malignancies may extend the survival time of patients and improve their quality of life.   Pathology Image Histological examination by surgery of the breast a showed invasive ductal carcinoma,thyroid tissue b showed papillary thyroid carcinoma by hematoxylin and eosin stain. Magni cation, x100.

Supplementary Files
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