healthcare

Article
Triple Primary Malignancies: Tumor Associations, Survival,
and Clinicopathological Analysis: A 25-Year
Single-Institution Experience
Iulia Almasan 1,2, * and Doina Piciu 1,2

1 Department of Endocrine Tumors and Nuclear Medicine, Institute of Oncology, 400015 Cluj-Napoca, Romania
2 Ph.D. School of Iuliu Hat, ieganu, University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
* Correspondence: almasan.iulia@gmail.com

Abstract: The detection of multiple primary malignancies is on the rise despite their rare occurrence
rate. This research aims to determine the prevalence, tumor association patterns, overall survival,
and the correlation between survival time and independent factors in patients with triple primary
malignancies. This single-center retrospective study included 117 patients with triple primary
malignancies admitted to a tertiary cancer center between 1996 and 2021. The observed prevalence
was 0.082%. The majority of patients (73%) were over the age of fifty at the first tumor diagnosis, and
regardless of gender, the lowest median age occurred in the metachronous group. The most common
tumor associations were found between genital–skin–breast, skin–skin–skin, digestive–genital–breast,
and genital–breast–lung cancer. The male gender and being over the age of fifty at the first tumor
diagnosis are associated with a higher risk of mortality. Compared with the metachronous group,
patients with three synchronous tumors demonstrate a risk of mortality 6.5 times higher, whereas
patients with one metachronous and two synchronous tumors demonstrate a risk of mortality three
times higher. The likelihood of subsequent malignancies should always be considered throughout
cancer patients’ short- and long-term surveillance to ensure prompt tumor diagnosis and treatment.

Keywords: synchronous tumors; metachronous tumors; triple primary malignancies; tumor

association patterns
Citation: Almasan, I.; Piciu, D. Triple
Primary Malignancies: Tumor
Associations, Survival, and
Clinicopathological Analysis:
A 25-Year Single-Institution
1. Introduction
Experience. Healthcare 2023, 11, 738. Multiple primary malignancies (MPMs) are defined as two or more malignant tumors
https://doi.org/10.3390/ that are histologically distinct and arise in the same or a different organ. Identifying
healthcare11050738 multiple primary tumors in the same individual is not a recent construct. In 1889, Theodor
Academic Editor: Clara Benna
Billroth [1] described the first case of MPMs, whereas later, in 1932, Warren and Gates [2]
established the defining criteria for MPMs as follows: (a) Each primary tumor had to be
Received: 7 February 2023 histologically proven as malignant; (b) each primary tumor had to be anatomically distinct
Revised: 18 February 2023 from one another; and (c) it had to be confirmed that one tumor was not a metastatic
Accepted: 27 February 2023 lesion or recurrence of the other. The first identified malignancy is referred to as the index
Published: 2 March 2023
tumor, while the subsequently diagnosed malignancies are defined as either synchronous
(diagnosed within a 6-month time frame) or metachronous (occurring more than six months
after the previous malignancy).
Copyright: © 2023 by the authors.
According to Global Cancer Statistics 2020, GLOBOCAN, the global cancer burden
Licensee MDPI, Basel, Switzerland. is estimated to have risen to 19.3 million new cases and is expected to reach 28.4 million
This article is an open access article by 2040. At the moment, female breast cancer is the most commonly diagnosed type of
distributed under the terms and cancer (11.7%), followed by lung (11.4%), colorectal (10.0%), prostate (7.3%), and stomach
conditions of the Creative Commons cancer (5.6%) [3]. The detection of MPMs is on the rise mainly due to a significant upsurge
Attribution (CC BY) license (https:// in new cancer cases, increased longevity, and improved cancer survival rates on account of
creativecommons.org/licenses/by/ advancements in cancer treatment and diagnostic procedures [4]. A 2003 comprehensive
4.0/). review of the literature indicated an incidence of multiple primary malignancies between

Healthcare 2023, 11, 738. https://doi.org/10.3390/healthcare11050738 https://www.mdpi.com/journal/healthcare

Healthcare 2023, 11, 738 2 of 16

0.7% and 11.7% [5], while in 2017, another literature review reported an incidence between
2.4% and 17.2% [6]. The most common tumor location for multiple primary malignancies
varies among the existing studies. In a US population study, a higher incidence of MPMs
was found in patients with bladder (24%), skin (melanoma) (21.7%), kidney (21.6%), lung
(20.5%), and colorectal cancer (19.8%) [7]. In Turkey, the most frequent tumor sites were the
skin (17.1%), bladder (8.9%), and digestive system (small intestine, colorectum, anus) (7.7%),
whereas, in China, MPMs were observed more frequently in patients with head and neck
(5.65%) and urinary tumors (4.19%) [8,9]. Likewise, a number of different malignant tumor
associations have been reported, including breast-breast, ovary–colon, ovary-breast [10],
breast-uterine, head and neck-esophageal, head and neck-lung, head and neck-head and
neck, prostate-bladder, prostate-colorectal, and colorectal-colorectal tumors [11].
The pathogenesis of multiple primary cancers is complex and not entirely understood.
Cancer survivors may be prone to developing subsequent malignancies due to various
intrinsic and extrinsic factors, including hormonal, lifestyle, environmental factors, genetic
predisposition, and late carcinogenic effects of prior therapies.
Modifiable lifestyle factors, such as obesity, smoking, and alcohol consumption, are
responsible for the great majority of cancer cases [12]. An increase in body mass index of
5 kg/m2 was strongly associated with esophageal adenocarcinoma and renal cancer in both
men and women [13]. Cancer patients who had smoked tobacco regularly either before or at
diagnosis have an increased risk of subsequent oral/pharyngeal, esophageal, stomach, lung,
and hematological malignancies compared with never-smokers [14]. In regard to alcohol
consumption, heavy drinkers present an increased risk of oral/pharyngeal, esophageal
(squamous cell carcinoma), colorectal, laryngeal, and female breast cancer when compared
with non-drinkers [15].
In certain individuals, the association of multiple primary tumors can be indicative
of an underlying genetic susceptibility. Some well-known examples of hereditary cancer
syndromes include Lynch syndrome (colon and endometrial cancer), von Hippel–Lindau
disease (retinal and central nervous system hemangioblastomas, phaeochromocytomas,
clear cell renal cell carcinomas, and pancreatic neuroendocrine tumors), multiple endocrine
neoplasia type 2A (medullary thyroid cancer and pheochromocytoma), hereditary breast
and ovarian cancer syndrome (breast and ovarian cancer), and Li-Fraumeni syndrome
(sarcoma, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma) [6].
In addition, cancer survivors may be prone to developing multiple primary malignan-
cies due to the late carcinogenic effects of prior cancer therapies. Prostate cancer patients
have a significant risk of subsequent bladder, colon, and rectal cancer if treated with ex-
ternal beam radiation therapy (EBRT) [16]. Survivors of Hodgkin’s lymphoma treated
with chemotherapy (CHT) showed an elevated risk of secondary leukemia, non-Hodgkin’s
lymphoma, pleural, liver, and lung cancer, whereas the combined treatment of EBRT and
CHT showed an increased risk for developing leukemia, non-Hodgkin lymphoma, small
intestine, bone, soft tissue, lung, and thyroid cancer [17].
Most MPMs presented and analyzed in clinical studies include dual primary malig-
nancies. The association of three or more primary tumors is a rare occurrence and is thus
often included in case reports and case series. In the literature, the reported frequency of
triple primary malignancies ranges between 0.04% and 0.81% [18–24].
This research aims to determine the prevalence and clinicopathological characteristics
of patients with triple primary malignancies, triple tumor association patterns, overall
survival, and the correlation between survival time and independent factors.

2. Materials and Methods

This single-center retrospective study was conducted at the Institute of Oncology,
“Prof. Dr. Ion Chiricut, ă”, Cluj-Napoca, a Romanian tertiary cancer center. The study
population was identified through the institutional electronic medical records, and the
study protocol was approved by the Ethics Committee of the Institute of Oncology, “Prof.
Dr. I. Chiricut, ă”, Cluj-Napoca, approval number and date 234/18 February 2022. The study
Healthcare 2023, 11, 738 3 of 16

was conducted according to the principles of the Declaration of Helsinki, the International
Conference on Harmonization Guideline on Good Clinical Practice, and Romanian laws
and regulations. All patients signed the institutional informed consent for diagnostic and
treatment procedures and for the use of their data in scientific reports, with personal data
protection respected.
Over a twenty-five-year period, starting in 1996, 141,662 patients having at least
one primary malignant tumor were admitted to our Oncology Institute. One hundred
seventeen patients with triple primary malignancies, synchronous or metachronous, met
the established eligibility criteria and were included in the study. The selection criteria
included patients having three distinct histopathological malignant lesions, all confirmed
by histopathological examination. Cases having MPMs that developed in the same organ
or system were included in this study. We excluded the patients without histopathological
confirmation of each tumor or with incomplete or ambiguous histopathological reports and
in whom the second or third malignancy was suspected to be a metastasis, a recurrence,
or an extension of previous tumors. In addition, patients with carcinoma of unknown
primary origin were excluded from the analysis. Data such as gender, date of birth, time of
diagnosis, site of origin, histology, survival from the first diagnosis, and date of death, if
applicable, were gathered and recorded for each malignancy.
Tumors were organized into nine condensed groups as follows: head and neck (mouth
and oropharynx, nasopharynx, larynx), digestive system (esophagus, stomach, small
intestine, colorectum, liver, gallbladder), genital tract (cervix uteri, corpus uteri, ovary,
vulva, prostate, testis), urinary tract (kidney, bladder), lung, skin, breast tissue, lymphoid
and hematopoietic tissue, and others (thyroid gland, mediastinum, bone, joint, soft tissue,
eye, brain, and central nervous system).
Every set of three primary tumors was sorted into groups based on the time of diag-
nosis as follows: (1) synchronous group (sMPMs), which includes three distinct primary
tumors diagnosed within a six-month time frame, (2) metachronous group (mMPMs), which
includes three distinct primary tumors diagnosed more than six months from each other,
and (3) synchronous–metachronous group (smMPMs), which includes one metachronous
and two synchronously occurring malignancies.
Collected data were statistically analyzed using the SPSS (version 25.0; SPSS Inc.,
Chicago, IL, USA) program. The Chi-squared test was used to evaluate intergroup differ-
ences, the Kaplan-Meier method was used to obtain the survival probabilities, and the Cox
proportional hazard model was used to investigate the association between survival time
and independent factors. All p values < 0.05 were considered statistically significant.

3. Results
3.1. Patient Characteristics
Out of 141,662 patients admitted to our Oncology Institute during the investigation
period, 117 patients with triple primary malignancies, synchronous or metachronous, were
included in the study. The observed prevalence of triple primary malignancies was 0.082%.
Of these, 50.4% (n = 59) had one metachronous and two synchronous primary tumors
(smMPMs), 32.4% (n = 38) had three metachronous tumors (mMPMs), and 17% (n = 20)
had three synchronous tumors (sMPMs). In addition, 43.5% (n = 51) were male, and 56.5%
(n = 66) were female, with a female-to-male ratio of 1.3:1. The median age at the first
primary tumor diagnosis was 57. The median age observed in the sMPM, mMPM, and
smMPM groups, respectively, was 70 (31–78), 49 (24–79), and 61 (17–79). During the
observation period, 67.5% (n = 79) of patients included in the study had died, of which
thirty-nine patients were female (49.3%), and forty (50.7%) were male (Table 1). At the first,
second, and third tumor diagnosis, 73.5% (n = 86), 90.6% (n = 106), and 92.3% (n = 108) of
patients were over the age of fifty (Table 2).
Healthcare 2023, 11, 738 4 of 16

Table 1. Patient characteristics.

sMPMs 1 mMPMs 2 smMPMs 3 Total (p)

No. of
20 (17) 38 (32.4) 59 (50.4) 117 (100)
Patients n (%)
Gender Distribution n (%)
Male 11 (9.4) 10 (8.5) 30 (25.6) 51 (43.5)
0.031
Female 9 (7.6) 28 (24) 29 (24.7) 66 (56.5)
Median Age (years) at Index Tumor Diagnosis [range]
Total 70 (31–78) 49 (24–79) 61 (17–79) 57 (17–79) <0.001
Male 70 (31–78) 53 (35–79) 64 (17–79) 60 (17–79) 0.025
Female 61 (43–78) 47 (24–70) 57 (31–78) 55 (24–78) <0.001
State at the End of the Observation Period–Deceased n (%)
Total 11 (14) 22 (28) 46 (58) 79 (100) 0.051
Male 6 (15) 7 (17.5) 27 (67.5) 40 (100) 0.039
Female 5 (13) 15 (38) 19 (49) 39 (100) 0.639
State at the End of the Observation Period–Alive n (%)
Total 9 (24) 16 (42) 13 (34) 38 (100)
Male 5 (45) 3 (27) 3 (27) 11 (100)
Female 4 (15) 13 (48) 10 (37) 27 (100)
1sMPMs—three synchronous primary tumors, 2 mMPMs—three metachronous primary tumors, 3 smMPMs—one
metachronous and two synchronous primary tumors.

Table 2. Age distribution based on gender and tumor groups.

sMPMs 1 mMPMs 2 smMPMs 3

Age Total Overall 4 n (%)
(n) (n) (n)
Years
n (%) M F M F M F M F
Age at 1st
<50 31 (26.5) 1 2 5 16 4 3 10 (19.6) 21 (31.8)
Diagnostic
>50 86 (73.5) 10 7 5 12 26 26 41 (80.4) 45 (68.2)
Age at 2nd
<50 11 (9.4) 1 2 1 2 3 2 5 (9.8) 6 (9.1)
Diagnostic
>50 106 (90.6) 10 7 9 26 27 27 46 (90.2) 60 (90.9)
Age at 3rd
<50 9 (7.7) 1 2 1 0 3 2 5 (9.8) 4 (6.1)
Diagnostic
>50 108 (92.3) 10 7 9 28 27 27 46 (90.2) 62 (93.9)
1sMPMs—three synchronous primary tumors, 2 mMPMs—three metachronous primary tumors, 3 smMPMs—one
metachronous and two synchronous primary tumors; 4 Overall—sMPM, mMPM, and smMPM groups; F—female,
M—male; >50–age over fifty, <50—age under fifty.

3.2. Time Interval between Tumor Diagnoses

The time interval between tumor diagnoses (time between the first and second,
the second and third diagnosis) was evaluated for the synchronous–metachronous and
the metachronous tumor groups. In the mMPMs group, the median time interval was
94.5 months between the first and the second tumor (ranging from 13 to 368 months) and
54 months between the second and the third tumor (ranging from 13 to 284 months). In the
smMPMs group, the median time interval was six months between the first and the second
tumor (ranging from 0 to 243 months), and eight months between the second and the third
tumor (ranging from 0 to 165 months).

3.3. Distribution According to the Histological Type

Adenocarcinomas and squamous cell carcinomas account for 50% of all histological
types identified. The most common histological types of the index tumor were squamous
cell carcinoma (23%, n = 27), adenocarcinoma (21.4%, n = 25), and hematological malig-
Healthcare 2023, 11, 738 5 of 16

nancies (10%, n = 12). The most common histological types of the second primary tumor
were adenocarcinomas (20.5%, n = 24), squamous cell carcinomas (17%, n = 20), followed
by basal cell carcinomas and other specific carcinomas, which each accounted for 10.3%
(n = 12). The most common histological types of the third primary tumor were adeno-
carcinoma (30.8%, n = 36), squamous cell carcinoma (16.2%, n = 19), and other specific
carcinomas (15.4%, n = 18) (Table 3).

Table 3. Histological type distribution based on gender and the time of diagnosis.

First Second Third Overall 4

Tumor Type Total (n) (n) (n) n (%)
n (%)
M F M F M F M F
Squamous Cell
66 (18.8) 13 14 11 9 12 7 36 (23.5) 30 (15.2)
Carcinoma
Adenocarcinoma 85 (24.2) 15 10 15 9 16 20 46 (30.1) 39 (19.7)
Endometrioid
25 (7.1) - 11 - 11 - 3 - 25 (12.6)
adenocarcinoma
Transitional cell
13 (3.7) 3 0 4 1 3 2 10 (6.5) 3 (1.5)
carcinoma
Basal cell carcinoma 18 (5.1) 3 1 4 8 1 1 8 (5.2) 10 (5.1)
Renal cell carcinoma 13 (3.7) 1 2 4 1 3 2 8 (5.2) 5 (2.5)
Invasive ductal
19 (5.4) 1 7 0 7 0 4 1 (0.7) 18 (9.1)
carcinoma
Invasive lobular
10 (2.8) 0 7 0 3 0 0 0 (0.0) 10 (5.1)
carcinoma
Melanoma 12 (3.4) 2 2 1 2 2 3 5 (3.3) 7 (3.5)
Bone and soft tissue
6 (1.7) 2 0 0 1 1 2 3 (2.0) 3 (1.5)
sarcomas
Hematological
31 (8.8) 7 5 8 3 4 4 19 (12.4) 12 (6.1)
Malignancies 1
Other specific
39 (11.1) 2 7 2 10 7 11 11 (7.2) 28 (14.1)
Carcinomas 2
Other 3 14 (4.0) 2 0 2 1 2 7 6 (3.9) 8 (4.0)
Total 351 (100) 51 66 51 66 51 66 153 (100) 198 (100)
1 leukemia, Hodgkin and non-Hodgkin lymphoma, multiple myeloma; 2 undifferentiated carcinoma, papillary
carcinoma, papillary microcarcinoma, neuroendocrine carcinoma, ductal carcinoma in situ, small cell carcinoma,
Merkel cell carcinoma, mucinous carcinoma, ampullary carcinoma, medullary carcinoma; 3 seminoma, germinal
cell tumor, nonseminomatous germ cell tumor, glioblastoma multiforme, anaplastic astrocytoma, neuroendocrine
tumor, mesothelioma, mixed Müllerian tumor; 4 Overall—sMPMs, mMPMs, smMPMs; first—first diagnosed
primary tumor; second—second diagnosed primary tumor; third—third diagnosed primary tumor; F—female,
M—male.

Among female patients, the majority of the histological types were adenocarcinomas
(32.3%, n = 64), squamous cell carcinomas (15%, n = 30), and other specific carcinomas (14%,
n = 28). Among male patients, the most frequent histological types were adenocarcinomas
(30%, n = 46), followed by squamous cell carcinomas (24%, n = 36), and hematological
malignancies (12.4%, n = 19) (Table 4).
Healthcare 2023, 11, 738 6 of 16

Table 4. Histological type distribution based on gender.

Total sMPMs 4 mMPMs 5 smMPMs 6

Histology Type Overall 7 n (%)
n (%) (n) (n) (n)
M F M F M F M F
Squamous cell
66 (18.8) 2 4 10 18 24 8 36 (23.5) 30 (15.2)
carcinoma
Adenocarcinoma 85 (24.2) 7 5 15 16 24 18 46 (30.1) 39 (19.7)
Endometrioid
25 (7.1) 0 3 0 7 0 15 0 (0.0%) 25 (12.6)
adenocarcinoma
Transitional cell 10
13 (3.7) 6 0 0 2 4 1 3 (1.5)
carcinoma (6.5%)
Basal cell carcinoma 18 (5.1) 2 0 1 5 5 5 8 (5.2) 10 (5.1)
Renal cell carcinoma 13 (3.7) 5 1 0 2 3 2 8 (5.2) 5 (2.5)
Invasive ductal
19 (5.4) 0 2 1 11 0 5 1 (0.7) 18 (9.1)
carcinoma
Invasive lobular
10 (2.8) 0 0 0 4 0 6 0 (0.0) 10 (5.1)
carcinoma
Melanoma 12 (3.4) 2 1 0 2 3 4 5 (3.3) 7 (3.5)
Bone and soft tissue
6 (1.7) 1 0 0 2 2 1 3 (2.0) 3 (1.5)
sarcomas
Hematological
31 (8.8) 4 2 2 2 13 8 19 (12.4) 12 (6.1)
Malignancies 1
Other specific
39 (11.1) 2 7 0 11 9 10 11 (7.2) 28 (14.1)
Carcinomas 2
Other 3 14 (4.0) 2 2 1 2 3 4 6 (3.9) 8 (4.0)
Total 351 (100) 33 27 30 84 90 87 153 (100) 198 (100)
1 leukemia, Hodgkin and non-Hodgkin lymphoma, and multiple myeloma; 2 undifferentiated car-cinoma,
papillary carcinoma, papillary microcarcinoma, neuroendocrine carcinoma, ductal carci-noma in situ, small cell
carcinoma, Merkel cell carcinoma, mucinous carcinoma, ampullary carci-noma, medullary carcinoma; 3 seminoma,
germinal cell tumor, nonseminomatous germ cell tumor, glioblastoma multiforme, anaplastic astrocytoma,
neuroendocrine tumor, mesothelioma, mixed Müllerian tumor; 4 sMPMs—three synchronous primary tumors;
5 mMPMs—three metachronous primary tumors; 6 smMPMs—one metachronous and two synchronous primary

tumors; 7 Overall—sMPMs, mMPMs, smMPMs; F—female, M—male.

3.4. Distribution According to the Tumor Site

Overall, the most common tumor sites included the genital organs (21%, n = 74),
digestive organs (15.4%, n = 54), skin (14.8%, n = 52), and breast tissue (12%, n = 42).
Among women, tumors were commonly found within the genital organs (27.7%, n = 55),
breast tissue (20.2%, n = 40), and digestive system (12.6%, n = 25), while in men, they were
mostly found within the digestive system (18.9%, n = 29), skin (18.3%, n = 28), and urinary
tract (13.7%, n = 21) (Table 5).

Table 5. Tumor site distribution based on gender.

sMPMs 3 mMPMs 4 smMPMs 5

Overall 6 n (%)
Total (n) (n) (n)
Tumor Site
n (%)
M F M F M F M F
Head and neck 19 (5.4) 0 2 5 3 7 2 12 (7.8) 7 (3.5)
Digestive organs 54 (15.4) 3 7 13 10 13 8 29 (18.9) 25 (12.6)
Lung 25 (7.1) 1 1 4 5 9 5 14 (9.1) 11 (5.5)
Healthcare 2023, 11, 738 7 of 16

Table 5. Cont.

sMPMs 3 mMPMs 4 smMPMs 5

Overall 6 n (%)
Total (n) (n) (n)
Tumor Site
n (%)
M F M F M F M F
Genital organs 74 (21) 6 6 3 22 10 27 19 (12.4) 55 (27.7)
Urinary tract 31 (8.8) 12 1 1 6 8 3 21 (13.7) 10 (5.0)
Breast 42 (12.0) 1 5 0 21 1 14 2 (1.3) 40 (20.2)
Bone, soft tissue 5 (1.4) 1 0 0 1 2 1 3 (1.9) 2 (1.0)
Eye, brain, CNS 1 3 (0.9) 0 0 0 0 0 3 0 (0.0) 3 (1.5)
Skin 52 (14.8) 5 2 2 10 21 12 28 (18.3) 24 (12.1)
Lymphoid,
31 (8.8) 4 2 2 2 13 8 19 (12.4) 12 (6.1)
hematopoietic tissue
Other 2 15 (4.3) 0 1 0 4 6 4 6 (3.9) 9 (4.5)
Total 351 (100) 33 27 33 81 93 84 153 (100) 198 (100)
1 CNS–central nervous system; 2 Other—thyroid gland and mediastinum; 3 sMPMs—three synchronous primary
tumors; 4 mMPMs—three metachronous primary tumors; 5 smMPMs—one metachronous and two synchronous
primary tumors; 6 Overall—sMPMs, mMPMs, smMPMs; F—female, M—male.

The first primary tumor occurred mainly in the genital organs (28.2%, n = 33), breast
tissue (15.4%, n = 18), and skin (12.8%, n = 15). The second primary tumor occurred in the
genital organs (20.5%, n = 24), skin (19.7%, n = 23), and digestive organs (14.5%, n = 17).
Most third primary tumors occurred in the digestive organs (22.2%, n = 26), genital organs
(14.5%, n = 17), and skin (12%, n = 14) (Table 6).

Table 6. Tumor site distribution based on the time of tumor diagnosis.

Total sMPMs 3 (n) mMPMs 4 (n) smMPMs 5 (n) Overall 6 n (%)

Tumor Site
n (%) 1st 2nd 3rd 1st 2nd 3rd 1st 2nd 3rd 1st 2nd 3rd
Head and neck 19 (5.4) 0 1 1 4 2 2 6 1 2 10 (8.5) 4 (3.4) 5 (4.3)
Digestive organs 54 (15.4) 4 2 4 4 7 12 3 8 10 11 (9.4) 17 (14.5) 26 (22.2)
Lung 25 (7.1) 0 1 1 2 2 5 3 4 7 5 (4.3) 7 (6.0) 13 (11.1)
Genital organs 74 (21) 4 5 3 12 5 8 17 14 6 33 (28.2) 24 (20.5) 17 (14.5)
Urinary tract 31 (8.8) 3 7 3 0 3 4 4 3 4 7 (5.9) 13 (11.1) 11 (9.4)
Breast 42 (12.0) 1 2 3 9 9 3 8 3 4 18 (15.4) 14 (12.0) 10 (8.5)
Bone, soft tissue 5 (1.4) 0 0 1 0 0 1 2 0 1 2 (1.7) 0 (0.0) 3 (2.6)
Eye, brain, CNS 1 3 (0.9) 0 0 0 0 0 0 0 1 2 0 (0.0) 1 (0.9) 2 (1.7)
Skin 52 (14.8) 3 1 3 5 7 0 7 15 11 15 (12.8) 23 (19.7) 14 (12.0)
Lymphoid,
31 (8.8) 4 1 1 1 2 1 7 8 6 12 (10.3) 11 (9.4) 8 (6.8)
hematopoietic tissue
Other 2 15 (4.3) 1 0 0 1 1 2 2 2 6 4 (3.4) 3 (2.6) 8 (6.8)
Total (n) 351 (100) 20 20 20 38 38 38 59 59 59 117 (100) 117 (100) 117 (100)
1 2 3
CNS—Central nervous system; Other—thyroid gland and mediastinum; sMPMs—three synchronous primary
tumors; 4 mMPMs—three metachronous primary tumors; 5 smMPMs—one metachronous and two synchronous
primary tumors; 6 Overall—sMPMs, mMPMs, smMPMs; 1st—first diagnosed primary tumor; 2nd—second
diagnosed primary tumor; 3rd—third diagnosed primary tumor.

When we look in more detail at the expanded groups, we notice that the most common
tumor sites were the skin (14.8%, n = 52), breast tissue (12%, n = 42), colorectum (9.7%,
n = 34), the lymphoid, hematopoietic tissue (8.8%, n = 31) and lungs (7.1%, n = 25). Among
male patients, the most common tumor sites were the skin (18.3%, n = 28), lymphoid,
Healthcare 2023, 11, 738 8 of 16

hematopoietic tissue (12.4%, n = 19), colorectum (11.7%, n = 18), prostate (10.4%, n = 16),
while among female patients, the most common tumor sites were the breast (20.2%, n = 40),
skin (12%, n = 24), corpus uteri (11.6%, n = 23), colorectum (8%, n = 16) (Table 7).

Table 7. Tumor site distribution based on gender–the expanded groups.

Tumor Site n (%) Male n (%) Female n (%)

Head and Neck
Mouth and oropharynx 9 (2.6) 7 (4.5) 2 (1.0)
Larynx 7 (2.0) 4 (2.6) 3 (1.5)
Nasopharynx 3 (0.9) 1 (0.6) 2 (1.0)
Total 19 (5.4) 12 (7.8) 7 (3.5)
Digestive Organs
Colorectum 34 (9.7) 18 (11.7) 16 (8.0)
Small intestine 8 (2.3) 3 (1.9) 5 (2.5)
Stomach 7 (2.0) 5 (3.2) 2 (1.0)
Liver 3 (0.9) 2 (1.3) 1 (0.5)
Gallbladder 1 (0.3) 0 (0.0) 1 (0.5)
Esophagus 1 (0.3) 1 (0.6) 0 (0.0)
Total 54 (15.4) 29 (18.9) 25 (12.6)
Lungs 25 (7.1) 14 (9.1) 11 (5.5)
Genital Organs
Corpus uteri 23 (6.6) – 23 (11.6)
Cervix uteri 16 (4.6) – 16 (8.0)
Prostate 16 (4.6) 16 (10.4) –
Ovary 12 (3.4) – 12 (6.0)
Vulva 4 (1.1) – 4 (2.0)
Testis 3 (0.9) 3 (1.9) –
Total 74 (21) 19 (12.4) 55 (27.7)
Urinary Tract
Kidney 16 (4.6) 9 (5.8) 7 (3.5)
Bladder 15 (4.3) 12 (7.8) 3 (1.5)
Total 31 (8.8) 21 (33.7) 10 (5.0)
Breast 42 (12.0) 2 (1.3) 40 (20.2)
Bone, soft Tissue 5 (1.4) 3 (1.9) 2 (1.0)
Eye, brain, central nervous system 3 (0.9) 0 (0.0) 3 (1.5)
Skin 52 (14.8) 28 (18.3) 24 (12.1)
Lymphoid, hematopoietic tissue 31 (8.8) 19 (12.4) 12 (6.1)
Other
Thyroid 14 (4.0) 5 (3.2) 9 (4.5)
Mediastinum 1 (0.3) 1 (0.6) 0 (0.0)
Total 15 (4.3) 6 (3.9) 9 (4.5)
Total (%) 351 (100) 153 (100) 198 (100)

In patients under the age of fifty, the most common tumor sites were the breast (17.8%,
n = 5), cervix uteri (17.8%, n = 5), uterus (10.7%, n = 3), and skin (10.7%, n = 3) in women,
and the hematopoietic, lymphoid tissue (21%, n = 4), colon (15.7%, n = 3) and testis (15.7%,
n = 3) in men. In this age category, the most common associations were between genital
tract tumors (cervical, uterine, ovarian), and breast cancer (26%, n = 5) in women, and
hematopoietic, lymphoid tissue malignancies (lymphoma), and testicular cancer (33%,
n = 3) in men.
In female patients, breast cancer was mainly associated with uterine (16%, n = 13),
breast (15%, n = 12), skin (15%, n = 12), lung (10%, n = 8), colorectal (9%, n = 7), ovarian
(7.5%, n = 6), and cervical cancer (7.5%, n = 6). When breast cancer is diagnosed as the index
tumor, it is mostly associated with genital tract cancer (30.5%, n = 11) and contralateral
Healthcare 2023, 11, 738 9 of 16

breast cancer (13.8%, n = 5) as the second or third malignancy. The most frequently observed
tumor associations in breast cancer patients were between breast–breast–uterine/cervical
cancer (10%, n = 4). When genital tract cancer is diagnosed as the index tumor, it is
commonly associated with genital tract (22%, n = 11), breast (14%, n = 7), and skin cancer
(14%, n = 7) as the second or third malignancy. The most frequent tumor associations were
between cervical–breast (18%, n = 6), uterine–breast (28%, n = 13), uterine–skin (17%, n = 8),
ovarian–breast (25%, n = 6), and ovarian–uterine (16%, n = 4).
In male patients, prostate cancer was mostly associated with bladder (25%, n = 8),
lung (21%, n = 7), hematopoietic, lymphoid tissue (15%, n = 5), and colorectal malignancies
(12.5%, n = 4). When prostate cancer is diagnosed as the index tumor, it is predominantly
associated with bladder (28.5%, n = 4), colorectal (14%, n = 2), lung (14%, n = 2), and kidney
cancer (14%, n = 2) as the second or third malignancy. The most commonly observed
associations in prostate cancer patients were between prostate–kidney–bladder cancer
(12.5%, n = 2).
Lung cancer was commonly associated with breast (16%, n = 8), prostate (14%, n = 7),
upper aerodigestive tract (14%, laryngeal n = 3, mouth and oropharyngeal n = 2, nasopha-
ryngeal n = 1, esophageal n = 1), bladder (12%, n = 6), and gastrointestinal cancer (10%,
n = 5). In female patients, lung cancer is associated with genital tract (31%, cervical n = 3,
uterine n = 2, ovarian n = 2) and breast cancer (31%, n = 7), whereas in male patients, it is
associated with prostate (25%, n = 7) and bladder cancer (21%, n = 6). In this group, the
most frequently observed associations were between lung–bladder–prostate cancer (21%,
n = 3) in men and lung–breast–uterine/cervical cancer (36%, n = 4) in women.
In patients with bladder cancer, the second and third malignancies were primarily
prostate (26%, n = 8), kidney (20%, n = 6), and lung cancer (20%, n = 6). In this group, the
most frequently observed associations were between bladder–breast–kidney cancer (66%,
n = 2) in women and bladder–lung–prostate cancer (25%, n = 3) in men.
Kidney cancer was mostly associated with bladder (18%, n = 6), gastrointestinal (15%,
n = 5), breast (15%, n = 5), hematopoietic, lymphoid tissue (12%, n = 4), and prostate cancer
(9%, n = 3). The most commonly observed associations in kidney cancer patients were
between kidney–bladder–prostate cancer (12.5%, n = 2).
Skin cancer was most frequently associated with skin cancer (32%, n = 34), hematopoi-
etic, lymphoid tissue malignancies (14%, n = 15), and breast cancer (11.5%, n = 12).
In female patients, skin cancer was associated with breast (25%, n = 12), uterine (16%,
n = 8), and hematopoietic, lymphoid tissue malignancies (14.5%, n = 7), with the association
of skin–breast–uterine cancer (12.5%, n = 3) being the most common. In male patients,
skin cancer was primarily associated with other skin cancer lesions (50%, n = 28), and
hematopoietic, lymphoid tissue malignancies (14%, n = 8), with the association of three
skin malignancies being the most frequent (14.2%, n = 4).
An overall look at patients with colorectal cancer indicates that it is most commonly
associated with colorectal (26%, n = 18), skin (11.7%, n = 8), breast (10%, n = 7), and
prostate cancer (6%, n = 4). In women, colorectal cancer is associated with colorectal (37.5%,
n = 12), uterine (15%, n = 5), and breast cancer (15%, n = 7), whereas in men, it is associated
with colorectal (16%, n = 6), skin (16%, n = 6), prostate (11%, n = 4), and hematopoietic,
lymphoid tissue malignancies (11%, n = 4).
When considering the nine condensed groups, the most commonly observed associa-
tions of three malignant tumors were between the genital tract–skin–breast tissue tumors
(n = 5), skin–skin–skin tumors (n = 4), digestive system–genital tract–breast tissue tumors
(n = 4), and genital tract–breast tissue–lung tumors (n = 4), accounting for 14.5% of all
tumor associations (Figure 1).
Healthcare 2023, 11, 738 10 of 16

Figure 1. Distribution of triple tumors Association patterns. A—Digestive system; B—Genital tract;
C—Lung; D–Skin; E—Breast tissue; F—Lymphoid and hematopoietic tissue; G—Other (includes
the thyroid gland, mediastinum, bone, joint, soft tissue, eyes, brain, and central nervous system);
H—Head and neck.

3.5. Survival and Prognostic Factors

The median overall survival (OS) after the diagnosis of the first primary tumor was
148 months, with a 95% confidence interval (CI) (115–181). The median OS for the sMPMs
group was 32 months, with a 95% CI (0–109), compared with 284 months, 95% CI (209–359)
for the mMPMs group, and finally, 108 months, 95% CI (67–149) for the smMPMs group
(Figure 2).

Figure 2. Kaplan–Meier survival curves comparing the overall survival in MPM tumor groups.
M—Metachronous; S—Synchronous; SM—Synchronous–Metachronous.

The 1-, 2-, 5- and 10-year survival rates for the mMPMs group were 0.97, 95% CI (0.92,
1.02), 0.97, 95% CI (0.92, 1.02), 0.95, 95% CI (0.88, 1.02) and 0.87 95% CI (0.76, 0.97). The 1-,
2- and 10-year survival rates for the sMPMs group were 0.70, 95% CI (0.5, 0.9), 0.59, 95%
CI (0.37, 0.81), and 0.24, 95% CI (–0.11, 0.58). The 1-, 2-, 5- and 10-year survival rates for the
Healthcare 2023, 11, 738 11 of 16

smMPMs group were 0.95, 95% CI (0.89, 1.01), 0.92, 95% CI (0.84, 0.99), 0.76, 95% CI (0.65,
0.87) and 0.45, 95% CI (0.32, 0.58).
In order to avoid the accumulation of a type I error, we performed an overall compar-
ison between the three MPMs group, which suggested that significant differences exist:
chi-square(2) = 38.14, p < 0.001. Given that the overall comparison was statistically signifi-
cant, we performed a pairwise comparison to detect the significant differences between
specific MPMs group. We found significant differences regarding the median survival
time between mMPM–sMPM groups, chi-square = 21.92, p < 0.001, and between mMPM–
smMPM groups, chi-square = 31.06, p < 0.001. No significant differences were found
regarding the median survival time between the sMPM–smMPM groups, chi-square = 2.99,
p = 0.08.
The overall model containing the three MPM groups, age, and gender, was statistically
significant: chi-square(4) = 47.31, p < 0.001. The male gender is associated with a higher
mortality risk (0.56, 95% (0.35–0.90), p = 0.016) compared with the female gender. In
addition, being over the age of fifty at the first tumor diagnosis increases the risk of
mortality by 1.73, 95% (0.93, 3.22), but with no statistical significance (p = 0.086). In the
sMPMs group, it was observed that the risk of mortality was 6.56 times higher 95% (2.74,
15.69), p < 0.001, than in the mMPMs group, whereas in the smMPMs group, the risk of
mortality was 3.16 times higher, 95% (1.62, 6.19), p = 0.001, than in the mMPMs group.

4. Discussion
Cancer survivors may be prone to developing second and third primary malignancies
due to various intrinsic and extrinsic factors, including hormonal, lifestyle, and environ-
mental factors, genetic predisposition, and late carcinogenic effects of prior therapies [6].
The association of three or more primary tumors is a rare occurrence and is thus of-
ten included in case reports and case series. Among the existing data, the frequency of
three primary tumors ranges between 0.04% and 0.81% [18–24]. In our study, the prevalence
of triple primary malignancies was 0.08%, with a slight predominance of female patients
(54.3%) and a female-to-male ratio of 1.3:1, as opposed to other reports on multiple primary
malignancies where male patients were mostly predominant [18,25–29].
In agreement with the current literature [18,21,25,29], we also found that most patients
(73%) were over the age of fifty at the first tumor diagnosis. When comparing the median
age at the initial diagnosis, it was observed that regardless of gender, the lowest median age
occurred in the metachronous group (p < 0.001), in agreement with a previous study stating
that young people are more likely to develop metachronous tumors [26]. In addition, note
that in female patients, the initial tumor occurred earlier, with over 31% being under the
age of fifty.
Regarding gender distribution within the three groups, the majority of men were
found in the smMPMs group, whereas the female patients were mainly distributed between
the mMPM and smMPM groups. The synchronous–metachronous group was the most
commonly found tumor setting, followed by the metachronous and the synchronous group.
Similar results were presented in an epidemiological study analyzing 57 patients with at
least three primary malignancies, where the “mixed form” (synchronous–metachronous)
accounted for the majority of cases (58%), followed by the metachronous (33.3%) and the
synchronous groups (8.8%). Gender distribution also showed that, among men, the “mixed
form” is predominant (66.7%) [21].
According to GLOBOCAN 2020 [3], reports on cancer statistics revealed that the most
prevalent cancers in Romania are colorectal, lung, and breast. Lung and prostate, followed
closely by colorectal cancer, are most frequent among men, while breast, colorectal, and
cervical cancer are most frequent among women.
We found that over half of the tumors were localized within the genital organs,
digestive system, and skin. When analyzing the expanded groups, the most frequent tumor
sites were the skin, breast tissue, and colorectum. Regardless of gender and consistent
with previous findings [26], adenocarcinomas and squamous cell carcinomas account for
Healthcare 2023, 11, 738 12 of 16

most histological types. When looking into other reports analyzing patients with at least
three primary malignancies, a study on 23 patients reported colorectum, lymphoid tissue,
and prostate as the most prevalent tumor sites [29], while another reported colorectum,
bladder, and prostate as the most frequent [21]. As opposed to our study, in both of these
reports, the male gender was predominant, which may explain the differences.
Skin cancer (melanoma and non-melanoma) proved to be the most prevalent ma-
lignancy in our study (14.8%). The majority of skin cancer cases (71%) were diagnosed
as the second or third primary malignancy and were mostly associated with other skin
cancer lesions (32%). A higher occurrence of skin malignancies has been previously found
in a study from a hospital-based cancer registry in Turkey, where the most common lo-
calization for multiple primary malignancies was also the skin (17.1%) [8]. It is believed
that patients with basal cell carcinoma, squamous cell carcinoma, and melanoma have
an increased risk of developing a second malignancy, especially skin melanoma in male
patients [30]. Male patients with non–melanoma skin cancer have eight times the risk
of later developing melanoma, while female patients have four times the risk compared
with the general population [31]. These findings might be due to various factors, such as
ultraviolet radiation exposure, phototype, personal or family history of skin cancer, type
and degree of cumulative sun exposure, sun protection behavior [32], and possibly due
to subsequent screening and complete clinical examination following the diagnosis of the
index tumor.
Among female patients, the most common tumor sites for MPMs were the breast,
skin, corpus uteri, and colorectum. Breast cancer was most frequently associated with
uterine, breast, skin, lung, and colorectal cancer. In addition, 47% of patients with breast
cancer as the initial tumor were later diagnosed with breast or genital tract tumors as the
second or third malignancy. Women diagnosed with breast cancer present a greater risk of
developing second gynecologic tumors [33], and according to other authors, there is also
an increased risk of colorectal, lymphoma, melanoma, endometrium, and kidney cancers
as second malignancies [34]. When evaluating the prevalence of primary malignancies
occurring before breast cancer, malignant melanoma, gynecological malignancies, and
gastrointestinal tumors were found to be the most common [35].
Skin malignancies have previously been reported to be associated with breast
cancer [36–38]. A review of several epidemiological studies showed a significant asso-
ciation between cutaneous melanoma and breast carcinomas due to different epidemio-
logical, genetic, and biological factors [39]. Concurrently, a study including 70,246 post-
menopausal women found no significant association between non–melanomatous skin and
breast cancer [40].
Among male patients, the most common tumor sites for MPMs were the skin, lym-
phoid and hematopoietic tissue, colorectum, and prostate. Patients with prostate cancer
as their initial tumor were later diagnosed with bladder, lung, colorectal, and kidney
cancer as the second or third malignancy. Prostate cancer survivors have an increased
risk of subsequent primary malignancies of the lung, colorectum, and bladder [41]. Ad-
ditionally, it has been shown that radiotherapy for prostate cancer was associated with
a significant risk of later developing bladder, colon, and rectum cancer compared with
unexposed patients [16].
Even though lung cancer is the leading cause of cancer death in our country [3], the
number of triple primary malignancies involving the lungs was low (7.1%), and only 20% of
lung cancer cases occurred as the initial diagnosis. It is worth considering that developing
subsequent malignancies relies upon the prognosis and overall survival of the previous
tumors. For this reason, patients with MPMs involving the lungs as the initial diagnosis
have early-stage tumors compared with those having subsequent lung malignancies [42].
Lung cancer was most frequently associated with breast, prostate, bladder, gastrointestinal,
and upper aerodigestive tract cancers.
In patients with bladder cancer, the second and third malignancies were primarily
lung and prostate cancer. A 2016 study on second primary malignancies among survivors
Healthcare 2023, 11, 738 13 of 16

of common cancers revealed that bladder and lung cancer patients carry the highest
risk of developing second primary malignancies. In addition, lung and prostate cancer
were the most common subsequent malignancies among bladder cancer survivors [41].
These associations may underline common risk factors, such as tobacco consumption or
exposure. It is known that tobacco products cause a variety of cancers, including lung,
upper aerodigestive tract, digestive, bladder, and kidney [43]. Even though alcohol and
tobacco use are a significant part of a patient’s history, part of the examined medical records
lacked documentation regarding alcohol and tobacco use; therefore, we could not evaluate
these common risk factors.
Colorectal cancer was most commonly associated with colorectal, skin, breast, and
prostate cancer. Patients with colorectal cancer were most frequently diagnosed with a
different colorectal cancer lesion as the second or third malignancy. This is in accordance
with previous findings stating that patients with colorectal cancer demonstrate a higher
risk of subsequent colorectal malignancies than the general population [44]. Additionally,
pelvic radiation therapy has been associated with an increased rate of pelvic malignancies.
Several studies demonstrated a greater risk of second primary rectal cancer in patients who
received radiation therapy for prostate cancer [45–47]. Regarding the common association
between breast and colorectal cancer, studies suggest that primary breast cancer does not
increase the risk of subsequent colorectal malignancies [48,49].
Overall, the most common associations of triple primary malignancies include genital
and breast tumors associated with either digestive, skin, or lung cancer, as well as the
association of triple skin malignancies.
When considering the median overall survival, the mMPMs group showed a better
median OS than the sMPM and smMPM groups. Patients with three synchronous tumors
had a risk of mortality 6.5 times higher than those in the metachronous group, whereas
patients with one metachronous and two synchronous tumors had a risk of mortality
three times higher than those in the metachronous group.
Previous reports also revealed that tumor status was statistically significant in favor
of metachronous tumors regarding OS [24,25,50]. We also observed that the male gender
(0.56, p = 0.016), and being over the age of fifty at the first primary tumor diagnosis (1.73,
p = 0.086) are associated with a higher risk of mortality in patients with triple primary
malignancies. Our findings are in agreement with previous studies highlighting them as
independent risk factors for mortality in patients with MPMs [26,51,52].
The association patterns of triple primary malignancies observed in the current study
may underline common cumulative risk factors, such as environmental exposure to car-
cinogens and genetic susceptibility. Concurrently, the diagnosis and treatment of the
first primary malignancy entail numerous tests and procedures over an extended period,
along with regular screening for recurrence and subsequent malignancies, resulting in can-
cer survivors initially receiving more frequent screening for new primary breast, cervical,
colorectal, and prostate cancer [53].
This study has several limitations. First, in order to address these rare events, we
conducted a single-center retrospective study on a limited sample size, which can be
subjected to various biases and may prevent our findings from being extrapolated. For
these reasons, this study should not be used alone to draw strong conclusions about risk
or causative factors. Second, this study was based on institutional electronic medical
records that were not initially intended for research; therefore, variables, including family
history, smoking status, alcohol consumption, dietary habits, and radiation exposure, were
unavailable. Lastly, in our case, identifying triple tumor associations regarding the MPM
groups (sMPMs, mMPMs, smMPMs) was found to be unfeasible.

5. Conclusions
Although our findings reinforce that triple primary malignancies are a rare occurrence,
with an observed prevalence of 0.082%, the likelihood of a subsequent malignancy should
always be considered throughout the short- and long-term surveillance of cancer patients
Healthcare 2023, 11, 738 14 of 16

to ensure prompt tumor diagnosis and treatment. The most common associations of triple
primary malignancies include genital and breast tumors associated with either digestive,
skin, or lung cancer, as well as the association of triple skin malignancies. Regarding
tumor setting, the metachronous group showed better median overall survival than the
sMPMs and smMPMs. Patients with three synchronous tumors demonstrated a risk of
mortality 6.5 times higher than those in the metachronous group. In contrast, patients with
one metachronous and two synchronous tumors showed a risk of mortality three times
higher than those in the metachronous group. The male gender and being over the age of
fifty at the first primary tumor diagnosis are also associated with a higher risk of mortality.

Author Contributions: Conceptualization, I.A. and D.P.; methodology, I.A.; software, I.A.; validation, I.A.
and D.P.; formal analysis, I.A.; investigation, I.A.; resources, I.A.; data curation, I.A.; writing—original
draft preparation, I.A.; writing—review and editing, I.A. and D.P.; visualization, I.A.; supervision,
D.P.; project administration, D.P. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted in accordance with the Declaration
of Helsinki, the International Conference on Harmonization Guideline on Good Clinical Practice, and
the Romanian laws and regulations. The study protocol was approved by the Ethics Committee of the
Institute of Oncology, “Prof. Dr. I. Chiricut, ă”, Cluj-Napoca, approval number and date 234/18.02.2022
for studies involving humans.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author.
Conflicts of Interest: The authors declare no conflict of interest.

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