Multiple primary cancer (MPC) is a specific malignant tumor type, manifesting as more than one primary tumor diagnosed in the same patient, either simultaneously or sequentially. The diagnostic criteria [1] include: 1) the cancer must be clearly malignant as determined by histological evaluation; 2) each cancer must be geographically separate and distinct; 3) the possibility that the second tumor represents a metastasis should be excluded. Synchronous multiple primary cancer (SMPC) is defined as two or more tumors occurring within six months of each other, while heterochronic multiple primary cancer is a subset of SMPC where the second cancer occurs more than six months after the first. As previously reported [2], the major hematological conditions in patients with multiple malignancies include multiple myeloma, myelodysplastic syndromes, non-Hodgkin's lymphoma, and chronic myelogenous leukemia (CML). The major sites of MPC occurrence, sans hematological malignancies, include the stomach, colon, breast, and esophagus. The incidence of SMPC is very low, and it is even less common than synchronous presentation of a solid tumor with a hematological malignancy. The mechanism of pathophysiology remains poorly understood, and risk factors involved in MPCs may include tobacco and alcohol intake, infections and immunosuppression, genetic predisposition, and toxic effects related to treatment by chemotherapy or radiotherapy [2]. Herein, we report five cases of synchronous solid tumor and hematological malignancy, and discuss the treatment of such rare malignancies.

From January 2008 to January 2010, five patients diagnosed with synchronous solid tumor and hematological malignancy were admitted to the medical oncology department at Zhongshan Hospital at Fudan University in Shanghai, China. The SMPC diagnosis for these five cases accounted for 0.5% of all newly diagnosed cancerous patients during this time period. The mean age of these patients was 53.8 years old and their median survival time was 14.0 months (95% confidence interval, 6.12 to 21.88 months). The detailed clinical data is listed in Table 1.

The precise mechanism of SMPC has remained unknown and there are no uniform treatment guidelines. Recent studies have demonstrated evidence of a possible spread of cancerous cells from a single clone to multiple sites [5,6]. It was reported whether or not genetic defects involving the mismatch repair system constituted an important risk factor in patients with MPC [7]. An Argentine research group found 32% of MPC patients had a family history of oncologic diseases [8]. In this report, we found only one patient (case 5, accounting for 20%) who carried this genetic tendency. Both his father and uncle had died from cancer.

A literature review of 1,104,269 cancer patients concluded that the prevalence of MPC is between 0.73% and 11.7% [9]. The wide variation in reporting was concluded to be associated with the varying capabilities and experience of hospitals and their doctors. At our one hospital we received five SMPC patients in a relatively short time, and it reminded us to carefully consider the appearance of such diseases. In these cases, there is a change not only in disease spectrum, but also the cancer spectrum. With increased availability of methods with greater sensitivity for screenscreening organs susceptible to MPCs, there may be an increase of frequency in the identification of multiple primaries in the coming years.

Although it is both impractical and unnecessary to obtain biopsies for every metastatic lesion that may appear in a case of MPC, awareness of the different biological behaviors between solid tumors and hematologic malignancies should be considered. In this report, some patients came to the hospital presenting solid tumors symptoms, and others for hematologic malignancies. But some symptoms couldn't be controlled effectively while treating a single tumor, and other lesions appeared to defy the routine metastatic rule. These clinical observations should remind us to investigate the possibility of SMPC. A re-biopsy is the only way to verify suspicion of SMPC. Published literature has reported that such diseases are often located at the same organ, such as simultaneous Hodgkin's lymphoma and adenosquamous carcinoma in the uterine cervix, and adenocarcinoma and lymphoma in the stomach [10-12].

Lacking guidelines in the management of such diseases, the treatment modality should be determined using the doctor experience and close attention to the characteristics of the patient's illness and performance status. The EMP in case 1 was early stage with good prognosis, so therapy was not delivered as it was not expected to affect patient survival time. We chose the NP regimen instead of gemcitabine plus cisplatin or paclitaxel plus cisplatin, because vinorelbine is a kind of vinca alkaloid drug, and the regimen is appropriate to both lung cancer and plasmatic disease. Because epidermal growth factor receptor (EGFR) mutation status was not detected, pemetrexed instead of gefitinib was chosen as the second-line chemotherapy. In case 2, the patient's WBC count decreased rapidly after just one week of hydroxyurea treatment, but the patient did not recover from the dyspnea symptoms. This raised the suspicion that another primary cancer was involved, which was revealed by VATS to be lung cancer. Because CML and lung cancer were found at the same time, hydroxyuria was chosen for its effectiveness in reducing WBC counts rapidly. Because the CML was controlled well and had little effect on long-term survival, the patient received six cycles of NP regimen and gefitinib maintenance therapy. During treatment for NSCLC, the patient did not receive any therapy for CML because routine blood tests were normal. The initial diagnosis for case 3 was lymphoid tissue reactive hyperplasia of the neck, but then, sigmoid colon cancer was found and a radical resection was administered. After the operation, the left neck mass enlarged. This observation triggered the biopsy to be repeated and lead to a diagnosis of lymphoma. As the pair of tumors were both early stage, the patient had a good prognosis with a long survival time. The case 4 patient presented two severe tumors, MM (stage III) and colon cancer (stage IV). Choosing a proper regimen was difficult because both the WBC and hemoglobin counts were low. We treated the MM mainly with dexamethasone and adriamycin, and controlled the colon cancer using low dose intensity capecitabine in hopes that the blood test results would improve. Then, we administered the standard chemotherapy to treat the advanced colon cancer, but the disease had progressed too quickly. Simultaneous abdominal lymphoma and gastric cancer were found in case 5. Because the abdominal lymphoma was extensive, the treatment regimen followed the lymphoma guideline. Consideration was also made for the gastric cancer. Cyclophosphamide was displaced by cisplatin in the regimen.

After the lymphoma was satisfactorily controlled, only then was the gastric cancer operated on. After the operation, two lymph nodes of twenty remained. Unfortunately the tumors were not early stage and overall survival time was short.

SMPCs are difficult to deal with because clinicians might not be able to provide simultaneous treatment for both disease types, such as one treatment resulting in competing toxicities for treating the other. The treatment choice depends on the tumor location and may involve curative surgical resection of each cancer, radiotherapy, and chemotherapy [13,14]. Our main approach to treating SMPCs was to abide by the therapeutic principles associated with each tumor and to consider both when treating one of the malignant diseases. We recommend that doctors formulate individual therapeutic strategies according to the patient's illness. The therapeutic effects and patient endurance must be evaluated at the same time. Case discussion with a multiple-disciplinary team may be helpful.

According to the literature, the prognosis of MPC patients can be determined independently as a function of the stage of each cancer. We found that the SMPC prognosis would be good if the tumors were all at early stage, otherwise the prognosis was likely poor. When the tumors are advanced stage at diagnosis, it is always a question of whether this is due to a delay in diagnosis or dependent on the biology of the tumor, such as a high grade tumor, etc. As a summarizing thought to consider, when encountering SMPCs, the fewer reported cases available to reference makes treatment that much more of a challenge.