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Year : 2017  |  Volume : 13  |  Issue : 1  |  Page : 16-20

Multiple primary malignant neoplasms: A 10-year experience at a single institution from Turkey

Department of Radiation Oncology, Medical Faculty, Eskisehir Osmangazi University, 26480 Eskisehir, Turkey

Date of Web Publication16-May-2017

Correspondence Address:
Evrim Metcalfe
Department of Radiation Oncology, Medical Faculty, Eskisehir Osmangazi University, 26480 Eskisehir
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.183219

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 > Abstract 

Purpose: The development of improved diagnostic techniques, increased survival, and life expectancy of cancer patients have all contributed to the higher frequency of multiple primary malignant neoplasms (MPMN). MPMN can be divided into two main categories: Synchronous MPMN (sMPMN) and metachronous MPMN (mMPMN).
Materials and Methods: 122 patients with MPMN analyzed retrospectively who were admitted to the Radiation Oncology Department of Eskisehir Osmangazi University Medical Faculty from January 2004 to December 2013. The patient characteristics and relation with overall survival (OS) were examined.
Results: The overall incidence of MPMN was found 1.2% in our institution. The median age was 59 (range: 29–80) years. Male:female ratio was 54.5:45.5%, and mMPMN:sMPMN ratio was 69.9:30.1%. The most common 3 cancers were head and neck (22%), breast (20%), and gastrointestinal (20%) for first primary; and gastrointestinal (22%), lung (19%), gynecologic tumors (15%) for second primary cancers, respectively. The median OS in patients with sMPMN and mMPMN were 30 (3–105) and 91 (4–493) months. 2, 3, and 5 years OS of patients with sMPMN were 86%, 75%, 63%, and with mMPMN were 92%, 88%, 80%, respectively (P < 0.005).
Conclusion: OS was found longer in female patients with sMPMN (P < 0.05), and in all group with mMPMN (P < 0.005).

Keywords: Metachronous, multiple primary malignant neoplasms, neoplasms, synchronous

How to cite this article:
Etiz D, Metcalfe E, Akcay M. Multiple primary malignant neoplasms: A 10-year experience at a single institution from Turkey. J Can Res Ther 2017;13:16-20

How to cite this URL:
Etiz D, Metcalfe E, Akcay M. Multiple primary malignant neoplasms: A 10-year experience at a single institution from Turkey. J Can Res Ther [serial online] 2017 [cited 2022 Jun 29];13:16-20. Available from: https://www.cancerjournal.net/text.asp?2017/13/1/16/183219

 > Introduction Top

The development of improved diagnostic techniques, increased survival, and life expectancy of cancer patients have all contributed to the higher frequency of multiple primary malignant neoplasms (MPMN). The incidence of MPMN ranged from 0.7% to 11.7% in the literature. Quite different values reported in the literature studies on the prevalence of MPMN. Because of the long evaluation period and the inclusion of autopsy series, there are differences between the studies.[1],[2] MPMNs are defined as two or more unrelated primary malignant tumors that originate from different organs and occur in the body at the same time or one after another.[3]

Although not published until 1869, Billroth described two patients in both of whom developed more than one primary malignant neoplasm.[4] Warren and Gates have described that if the interval is under 6 months it is accepted as synchronous MPMN (sMPMN), and if the interval is over 6 months, then it is accepted as metachronous MPMN (mMPMN).[5] sMPMN are defined if the tumors occur simultaneously or within 6 months of one another, whereas mMPMN are indicated if the interval time is more than 6 months. The diagnosis of MPMN was determined by the criteria established by moertel and classified with historical perspectives [Table 1].[6] Since that time, the occurrence rate of MPMN increased and became the commonplace medical problem of the cancer survivors. The first treatment taken for primary tumor, shared risk factors such as genetic predispositions, smoking, and alcohol are among the other accused factors. Double primary malignancy has relatively higher frequency in patients with MPMN while the probability of three primary tumor is 0.5% and the chance of four primary malignancy being seen is 0.1%.[7]
Table 1: Classification of multiple primary malignant neoplasms

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Clinically, MPMN is often confused with recurrence or distant metastasis of primary tumors since both are characterized by new lesions. Metastatic tumors are derived from the primary lesion, with both showing the same pathological characteristics and similar developmental processes and prognosis.[8] Conversely, MPMN refers to the development of a new malignant tumor, and the characteristics of the new lesions are completely different from those of the original tumor lesions.[9] Therefore, the prognosis, metastasis, and recurrence are also completely different between MPMN and the metastasis or recurrence of primary cancer.

Owing to the fact that an increased MPMN occurrence, we aimed to evaluate the clinical characteristics, diagnosis, treatment principles, and prognosis of MPMN patients retrospectively who treated at our institution in 10 years period.

 > Patients and Methods Top

Diagnostic principles

The diagnostic criteria of MPMN were based on the following standards described by Warren and Gates in 1932:[5] (1) Each tumor is malignant, (2) each tumor has its own pathological features, (3) tumors occur in different parts or organs, and are not continuous with each other, and (4) each tumor has its own metastatic pathway and the diagnosis of metastatic or recurrent tumors can be excluded.

According to the time interval, the tumors are defined as sMPMN if the elapsed time is <6 months, and mMPMN if the time is over 6 months.[5],[10]


Clinical data of 9,772 cancer patients collected and 122 patients with MPMN from this data analyzed retrospectively who were admitted to the Radiation Oncology Department of Eskisehir Osmangazi University Medical Faculty from January 2004 to December 2013. The patient characteristics and relation with overall survival (OS) were examined. Data collection included personal, family, and medical histories of patients, age, gender, primary tumor location, and administered treatment. In line with the diagnostic principles described above, 122 patients who had complete follow-up data were diagnosed with MPMN, representing an overall rate of 1.2%. Sixty-seven (54.5%) cases were males and 56 (45.5%) cases were females; the median age was 59 (range: 29–80) years. Eighty-six (69.9%) patients were diagnosed as mMPMN, and 37 (30.1%) cases were diagnosed as sMPMN.

Follow-up and statistical analysis

OS was used as indicators to assess the survival time. OS was calculated from the tumor diagnosis date to the death or last follow-up date; if the patient was lost, the last follow-up date were defined as an evaluation endpoint. For patients with sMPMN, the survival time was calculated according to the confirmed date of first cancer, whereas for patients with mMPMN, survival time was calculated from the confirmed date of the last diagnosis of cancer. A total of 122 patients were followed up with the deadline of March 31, 2015, by either telephone or in-patient. Eight (6%) cases were lost, and the follow-up rate was 94%.

All collected data were statistically analyzed using the SPSS 16.0 software (SPSS for Windows, Version 16.0. Chicago, USA, SPSS Inc.); Kaplan–Meier method to obtain survival curves and the Chi-squared test to evaluate differences in the location in mMPMN and sMPMN were used. The log-rank test was used to compare the OS time between different groups, and P< 0.05 was considered to be statistically significant.

 > Results Top

Tumor distribution and interval time

In all groups, the most common first primary tumor localizations were breast (21%), gynecologic (9%), gastrointestinal (8%) for women; and head and neck (22%), gastrointestinal (12%), and genitourinary (8%) for men, respectively. The most common second primary tumor localizations were gynecologic (15%), breast (11%), gastrointestinal (8%) for women; and lung (20%), gastrointestinal (14%), and genitourinary (7%) for men, respectively. The median age at which first and second primary cancer were 56 (range: 30–80) and 62 (range: 35–85) years. The median time between the two primary tumors was 68 (7–408) months [Table 2].
Table 2: Patient characteristics of all data (n=122)

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Taking into consideration the first primary cancer diagnosis, the first 5 most frequent cancer types were head and neck (27 patients, 22%), breast (25 patients, 20%), gastrointestinal (25 patients, 20%), gynecologic (11 patients, 9%), and genitourinary cancers (10 patients, 8%).

Taking into consideration the second primary cancer diagnosis, the first 5 most frequent cancer types were gastrointestinal (27 patients, 22%), lung (24 patients, 19%), gynecologic (18 patients, 15%), breast (13 patients, 11%), and genitourinary cancers (9 patients, 7%).

In women, the most frequent 3 first primary tumor types were uterine (6 patients, 5%), breast (3 patients, 2%), and gastrointestinal (2 patients, 1%) in sMPMN group, and breast (22 patients, 18%), gastrointestinal (8 patients, 6%), and gynecologic tumors (5 patients, 4%) in mMPMN group. Most frequently observed tumor pairs in women were breast-gynecologic (3 patients, 2%), gynegologic-gynecologic (3 patients, 2%) and breast-breast (2 patients, 1%) in sMPMN group, and breast-gynecologic (11 patients, 9%), breast-thyroid (7 patients, 5%), and gynecologic-gastrointestinal (7 patients, 5%) in mMPMN group [Table 3] and [Table 4].
Table 3: The most common synchronous multiple primary malignant neoplasms in female and male patients (n=36)

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Table 4: The most common metachronous multiple primary malignant neoplasms in female and male patients (n=86)

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In men, the most frequent 3 first primary tumor types were lung (7 patients, 5%), gastrointestinal (7 patients, 5%) and larynx (5 patients, 4%) in sMPMN group, and head and neck (22 patients, 18%), genitourinary (10 patients, 8%), and gastrointestinal tumors (8 patients, 6%) in mMPMN group. Most frequently observed tumor pairs in men were genitourinary-gastrointestinal (5 patients, 4%), head and neck-lung (4 patients, 3%) and head and neck-genitourinary (3 patients, 2%) in sMPMN group, and head and neck-lung (12 patients, 10%), head and neck-gastrointestinal (6 patients, 5%), and head and neck-genitourinary (5 patients, 4%) in mMPMN group [Table 3] and [Table 4].

Sixty-six (54%) patients were treated with radiotherapy for the first primary cancer while 79 (65%) patients for the second primary cancer.

Survival and prognostic factors

The median OS rates in patients with sMPMN and mMPMNs, were 30 (range: 3–105) and 91 (range: 4–493) months, respectively. 2, 3, and 5 years OS were 46%, 38%, 11% in patients with sMPMN, and 93%, 83%, 61% in patients with mMPMN, respectively (P < 0.05).

For all of the patients evaluated in the univariate analysis, age (≤60 years vs. >60 years, P = 0.51) and gender (female versus male, P = 0.21) were no significant difference while tumor status (sMPMN vs. mMPMN, P< 0.005) was statistically significant in favor of metachronous tumors for OS [Figure 1]. Gender female: mean 92.2 (76–108) months (standard error [SE] = 8.2 versus male: 41 [31–51] months, SE = 5.1, P< 0.05) was statistically significant in favor of female patients with sMPMN for OS [Figure 2]. In multivariate analysis (Cox regression), tumor status (sMPMN versus mMPMN) was statistically significant (exp [β] = 4.74, 1.64–13.68, 95% confidence interval, P< 0.005) in favor of metachronous tumors for OS.
Figure 1: The relationship between overall survival and malignancy type

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Figure 2: The relationship between overall survival and gender

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 > Discussion Top

This study evaluated 122 MPMN cases followed at the Radiation Oncology Department of Eskisehir Osmangazi University Medical Faculty from January 2004 to December 2013. In addition, a review of the occurrence and characteristics of MPMN reported in the literature was carried out. MPMN incidence rate in our clinic was found as 1.2%. The relevant literature reports quite different results about the frequency of MPMN incidences. It varies between 0.7% and 11.7%.[10],[11] This discrepancy between studies stems from the fact that some studies have longer analysis duration, and some others are added autopsy series.[10],[11] Environmental-genetic factors, treatment history for first primary tumor and exposure to smoking are thought to be related to the development of these tumors. For the long-living patients, second primary malignity possibility is higher as well. Risk-increasing factors could be family history, environmental factors, treatments such as Radiotherapy-Chemotherapy and hormonetherapy, and smoking.[3],[12],[13],[14]

Particularly, the hormone therapy for breast carcinoma is known to increase uterine carcinoma risk. That breast and uterine carcinoma have common risk factors (e.g., nulliparity, obesity, late postmenopausal situation, and use estrogen) increase the metachron/synchron possibility for these tumors. The relevant literature, similar to our current study, demonstrates that for the patients with previous breast carcinoma diagnosis, as the second primary, there is a higher rate of gynecological tumor.[15],[16],[17] Due to this close tracking, as the second primary, the possibility of identifying uterine carcinomas at an early stage increases. In our study, the most frequent mMPMN pair for women was breast-uterine carcinomas. In 5/7 of these patients, there was a history of hormonotherapy for breast carcinoma. Of the uterine carcinoma diagnosed cases, two were at the local advanced stage, while five patients were diagnosed at the early stage.

In the cases where there is a previous respiratory or digestive tumor, depending on epitelial carcinogene exposure, second primary cancers may develop. In our study, for synchronous tumors, male gender was more dominant, and lung-larynx carcinoma pairs were more frequent in snychronous tumors. All patients were current or ex-smoker. In cases that received larynx cancer diagnosis, lung cancer as second primary possibility is about 10%. In case of clinical doubt, to be able to clearly distinguish between metastasis and second primary tumor, biopsy must be taken.[12],[18] Smoking is a risk factor for many cancers. In our study, lung-larynx carcinoma is the most common tumor pair in synchronous tumors, and the second most frequent in metachronous tumors. It is also asserted that for the cases that are diagnosed head and neck cancer and tracked with no relapse for 5 years, the rate for developing lung cancer drops to 22%.[18] The prognosis for head and neck cancer and lung cancer pair is rather dismal.

The survival rate for metachronous tumors is thought to have been increased by a patient who was diagnosed with early stage larynx carcinoma and received lung cancer diagnosis later than other pairs, and whose OS was 227 months. While the advances in larynx carcinoma treatment increase the survival rates above the expected rates, shortens the survivals from lung cancer carcinomas, which are seen as the second primary. Thus, for the larynx carcinoma, second primary cancer screening during the loco-regional relapse tracking is gaining importance. In our study, of the 8 lung carcinoma cases that were identified after larynx carcinoma, 7 were at local advanced stage, and one is metastatic at diagnosis, in the tracking two cases became exitus due to lung carcinoma. Catching the cases as advanced stage under oncological tracking is thought to result from the patients' not regularly coming to their scheduled tracking or the rules for requesting examination in the existence of a symptom as suggested by the handbooks.

As a conclusion, considering the increased survival rates and second primary cancer incidences, it is thought to be necessary to revise the tracking handbooks, to do a closer tracking of asymptomatic oncological cases for second primary cancer, and to carry out periodical radiological imaging for the asymptomatic cases. Throughout the follow-up, analyses should not only aim to identify the primary tumor relapse or metastasis, but also in breast cancer cases, uterine cancer needs to be tracked as well, and in larynx cancer cases, close tracking for lung cancer need to be carried out. The relevant literature reveals tumor pairs that are similar to the ones in our study. To better define the clinical progress of MPMN, a higher number of patients and further studies are necessary.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

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Billroth CA. Die Allgemeine Chirurgische Pathologie und Therapie. Berlin: Georg Reimerverlag; 1889. p. 908.  Back to cited text no. 4
Warren S, Gates O. Multiple primary malignant tumors. Am J Cancer 1932;16:1358.  Back to cited text no. 5
Moertel CG, Dockerty MB, Baggenstoss AH. Multiple primary malignant neoplasms. I. Introduction and presentation of data. Cancer 1961;14:221-30.  Back to cited text no. 6
Campbell LV Jr., Watne AL. Multiple primary malignant neoplasms. Arch Surg 1969;99:401-5.  Back to cited text no. 7
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Papajík T, Myslivecek M, Sedová Z, Buriánková E, Procházka V, Raida L, et al. Synchronous second primary neoplasms detected by initial staging F-18 FDG PET/CT examination in patients with non-Hodgkin lymphoma. Clin Nucl Med 2011;36:509-12.  Back to cited text no. 9
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Mukaiyama Y, Suzuki M, Morikawa T, Mori Y, Takeshima Y, Fujimura T, et al. Multiple primary malignant neoplasms of the glottis, renal pelvis, urinary bladder, oral floor, prostate, and esophagus in a Japanese male patient: A case report. World J Surg Oncol 2014;12:294.  Back to cited text no. 12
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Gulhan I, Eser S, Yakut C, Bige O, Ilhan E, Yildirim Y, et al. Second primary gynecologic cancers after breast cancer in Turkish women. Int J Gynecol Cancer 2009;19:648-50.  Back to cited text no. 16
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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]

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