Multiple Primary Tumours, How Frequent we Can Offer Curative Therapy?

Multiple-primary cancers are defined as primary malignant tumours of different histological origins in a single patient. Recently, there has been an increase in the number of patients diagnosed with multiple-primary cancers; attributed to improved diagnostic techniques and prolonged life span of patients with malignancy. Now we are aware that most multiple primary cancers are double primary cancers [1-2-3]. The incidence of Multiple-Primary Malignancies has Abstract


Introduction
Multiple-primary cancers are defined as primary malignant tumours of different histological origins in a single patient. Recently, there has been an increase in the number of patients diagnosed with multiple-primary cancers; attributed to improved diagnostic techniques and prolonged life span of patients with malignancy. Now we are aware that most multiple primary cancers are double primary cancers [1-2-3].
The incidence of Multiple-Primary Malignancies has Omima Elemam 1,2 , Seham Abdelkhalek 1,3 , Doaa Abdelmoety 4 , Reem Baraka 5 , Mervat Yousef 1, 6 been common among cancer patients [4]. One of the earliest statistical analyses of Double-Primary Malignancies was carried out by Bugher in 1934, he derived an equation for the probability of death from cancer during a specified period of age with a coincidental Second Malignancy [5]. According to the definition used, the overall reported frequency of Multiple-Primary Cancers ranges from 2% to17% [6]. The criteria used for the diagnosis of Double-Primary malignancies has been primarily given by Warren and Gates [7]. While, the two most commonly used definitions were provided by the SEER Program (Surveillance, Epidemiology, and End Results) and the IACR/IARC (International Association of Cancer Registries and International Agency for Research on Cancer) [8].
The SEER database considers single tumours at different sites in the same organ (e.g., colon) as multiple sites. The IACR/IARC rules are more limited; only one tumour is recorded for an organ, regardless of time, unless there are histologic differences. Additionally, The SEER database advocates the use of a 2-month period to distinguish between Synchronous and Metachronous Multiple-Primaries, whereas IARC recommends a 6-month period [9][10].
The theory regarding the origin of the majority of Multiple-Primary cancers is that they arise due to random chance, but different mechanisms have been suggested to be involved in Multiple-Primary Cancers, such as the family history, immunologic, genetic defects, exposure to carcinogens, radiation, chemotherapy, and field cancerization [11].
Germline mutations in mismatch repair genes can produce susceptibility to cancers of the colorectum, ovary, stomach, small bowel, upper uroepithelial tract, hepatobiliary tract, and brain. Li-Fraumeni syndrome (LFS), an autosomal-dominant disorder, features the occurrence of breast cancer in young women and of soft tissue sarcomas, osteosarcomas, brain tumours, acute leukaemia, and adrenocortical tumours in children and young adults [12]. Germline mutations in the p53 tumour suppressor gene (also known as TP53) have been identified in approximately one-half of LFS families in the literature [13] and cigarette smoking that affects the risk of several cancer types.
All the information about double malignancy came from case reports with very few centers reporting their experience and none from our region. We needed to collect our experience in treating those cases. Collecting information will aid us in expecting the impact of prior therapies and teach us how to best treat them. This is a retrospective study with a single medical facility's experience with Multiple-Primary cancer cases. This study aims to report cases of Double-Primary Malignancy in our society and see if we have a special predilection of certain Double-Primary cancers based on different geographic and environmental risk factors.

Materials and Methods
This was a retrospective observational study carried out at King Abdullah Medical City, Makkah, Saudi Arabia, from January 2012 to December 2019. All Patients with malignant tumors of different histological origins were defines as histologically confirmed Multiple-Primary Malignancy cases. Patients were identified through a retrospective review of medical records excluding patients with insufficient histopathological data.
The data collected were the patients' characteristics, pathological data, and outcome information. Moreover, this research protocol was approved by the Institutional Review Board Committee. Since the study performed is retrospective, we obtained a waiver of informed consent from IRB.
The most common sites for synchronous, Table 1, are breast and endometrial cancer. Metastasis at diagnosis was present in 7 patients (23%). The median age of diagnosis for synchronous tumours was 61 years (range: 27 to 83 years), 4 patients were male (26%). CT scan for staging workup resulted in the detection of a second tumour in 21 patients 5 patients of which was diagnosed during pathological examination. Curative treatment could be offered in 19 patients (73%).
For metachronous tumours, Table 2, the median age of diagnosis for the second primary neoplasm was 54years (range: 34 to 82years) 3 patients of which were male. The median interval of six years was observed, the most common sites of a primary tumour were breast, the most common second malignancy was colorectal cancer and Metastasis at diagnosis were present in 7 patients (25%). Curative treatment could be offered in 15 patients (53%).

Discussion
Multiple primaries [14] are more than one tumour arising in different sites and or of different histology either synchronous or metachronous depends on the duration between them, 2-month according to SEER data [15] and 6 months according to IARC. In our study, we used the definition of IARC. The burden of multiple tumours is expected to increase due to the use of accurate imaging techniques. In a single facility in Saudi Arabia, we collected 54 cases over 7 years. Multiple-Primary did not always signify a bad prognosis as we treated all non-metastatic cases with curative intent.
It is most imperative to diagnose it early before the patient reaches the metastatic stage. This means that we should have a high degree of suspicion. The role of the radiologist is crucial as usually, radiologists are first to flag for suspicion of multiple tumours. In our study, most of the synchronous tumours were detected initially by CT scan then confirmed pathologically. Examples from our study as CT scan done for a patient with ovarian cancer showed a breast mass or CT scan showed a speculated lung lesion in a patient with breast cancer or showed renal mass in a patient with nasopharyngeal cancer.
The response to therapy is always an alarm for the physician to review his pathology by repeating the biopsy of the metastatic disease. In our study a patient with breast cancer who developed lung nodules treated treated with chemotherapy as. Metastatic breast then the poor response to chemotherapy urged us to biopsy the largest metastatic nodule and to our surprise came to be second primary  For patients with breast cancer, the incidence of second primaries studied and has been reported to range from 4.1% to 16.4% [15][16]. An excess risk of endometrial cancer is reported with the use of Tamoxifen [17] Genetic factors as BRCA1 BRCA2 mutations are well-known risk factors for Multiple-Primary [18]. In this study, we reported 7 cases of the Synchronous Second-Primary with breast cancer, 3 cases with ovarian cancer. Also, we reported endometrial cancer in patients with hormone receptor-positive breast cancer with BRCA mutation. AML can be triggered during the first 2 years after radiation therapy and it is also a late effect of chemotherapy. For metachronous tumour in patients with breast cancer, We reported two cases of AML which may be chemotherapy related.
Patients with prostate cancer who received external beam radiotherapy are at increased risk of bladder cancer, rectal cancer and sarcomas within the radiation field after being disease-free for at least 5 years [19]. Second primaries can also occur in patients with prostate cancer owing to genetic factors, especially BRCA mutation [20]. In our study, we reported prostate cancer, rectal cancer, and prostate cancer and sarcoma synchronously. The most important cause of mortality in Hodgkin's lymphoma is a Second-Primary cancer [21]. We reported a case of colon cancer synchronously with Hodgkin's lymphoma and thyroid cancer. Also, breast cancer that occurred 12 years after ABVD for Hodgkin's lymphoma.
Smoking is an important risk factor not only for lung cancer but also for a Second-Primary Cancer. A 7.9%of lung cancer cases who acquire a second primary have  SCLC [22]. In this study, we reported colon cancer 1 year after lung cancer and gastroesophageal cancer that was diagnosed 18 months after the lung cancer diagnosis. The treatment decision of synchronous tumours is not straightforward and usually requires a multidisciplinary approach, one of our patients had a synchronous breast and endometrial cancer. We discussed the case in our tumour board, and we decided to give her neoadjuvant chemotherapy followed by surgery MRM and TAH&BSO in the operating room by two surgeons.
We treated our patients with curative intent in more than 60% of cases so, we should always be aware of the possibility of a second primary cancer. Late metastatic spread in a patient with triple-negative breast cancer led us to suspect second primary and diagnose pancreatic cancer. Also, low tumour marker in ovarian cancer patient which was initially high was found to have a second primary neuroendocrine tumour, continued smoking history should alert us about this possible important carcinogen.
We should inform our patients about the late side effects of their treatment, particularly Second-Primary Malignancies, by including it in the consent form. Such actions would educate patients on the value of continuous surveillance and avoiding all possible carcinogens especially smoking in addition to encouraging them for a healthy lifestyle [23][24].
Patients with multiple primaries are usually excluded from clinical trials and there are no established guidelines to treat these cases. we need clinical trials to study the new histology non-specific medications like (immunotherapy, biologic therapy. etc) Finally, in our medical facility, we adopted the policy of referring our cases with Multiple-Primary to our genetic oncology clinic for evaluation and genetic testing; this hopefully will help us gain more knowledge about patients with hereditary cancer. we will report these data separately.
In conclusion, we are expecting an increase in the prevalence of Multiple-Primary tumours due to increased accuracy of diagnostic techniques in addition to novel target therapy that may increase the risk. Hereditary cancer syndrome, smoking, cancer therapy are all risk factors. we need to pick these cases as early as possible before the development of metastasis as this has a marked impact on patient survival. Treatment decisions for these cases should be based on a multidisciplinary approach. Research on this topic is an unmet need particularly the genetic background for developing second primary cancers. To reflect more of a real-life population, we need clinical trials investigating those patients in detail to increase the physician's awareness that these cases are not rare, and they need to be treated with curative intent in most situations.