LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
MEDICINE ACADEMY
FACULTY OF MEDICINE
DEPARTMENT OF PATHOLOGICAL ANATOMY
Serhiy Bosy
Final Master’s Thesis
COMPARATIVE ANALYSIS OF SYNCHRONOUS AND
METACHRONOUS TUMORS
Principal supervisor: dr. Dainius Jančiauskas
TABLE OF CONTENTS
SUMMARY 3
ACKNOWLEDGEMENTS 4
CONFLICT OF INTEREST 5
CLEARANCE ISSUED BY ETHICS COMMITTEE 5
ABBREVIATIONS 6
INTRODUCTION 7
AIM AND OBJECTIVES OF RESEARCH 8
1. LITERATURE REVIEW 9
1.1. Definition of multiple primary malignant tumors 9 1.2. Epidemiology of multiple primary malignant tumors 9 1.3. Ethiopathogenesis of multiple primary malignant tumors 10 1.4. General comparison between synchronous and metachronous tumors 10 1.5. Synchronous and metachronous adenocarcinomas of the large intestine 12
2. RESEARCH METHODOLOGY AND METHODS 17
3. RESULTS 18
4. DISCUSSION OF THE RESULTS 27
5. CONCLUSIONS 28
6. PRACTICAL RECOMMENDATIONS 29
SUMMARY
Author of master thesis: Serhiy Bosy
Master thesis: “Comparative analysis of synchronous and metachronous tumors”. Supervisor of master thesis: dr. Dainius Jančiauskas, MD
Aim of research: To determine similarities and differences between the synchronous and
metachronous multiple primary malignant tumors (MPMT) groups according to the patient’s characteristics, anatomical localizations of MPMT group neoplasms and associative patterns of MPMT neoplasms.
Objectives of research: 1. To evaluate and compare synchronous and metachronous MPMT groups
according to the patient’s characteristics (age and gender). 2. To compare synchronous and metachronous MPMT groups according to the most and least likely anatomical localizations of MPMT group neoplasms. 3. To compare synchronous and metachronous MPMT groups by determining the associative patterns of MPMT according to the anatomical localizations of neoplasms.
Methods: Object of master thesis research were patients diagnosed with MPMT for the last 10 years at
LUHSH Kaunas Clinics. Retrospective research of patients’ clinical data was performed at the department of Pathological Anatomy (LUHSH Kaunas Clinics). Clinical data regarding patient’s gender, age, types and anatomical localizations of MPMT were collected. Statistical analysis was performed by applying “Excel for Mac 2011” (Cupertino, California, USA) and “SPSS statistics” (IBM Corporation, Armonk, New York, USA). Statistical significance was p<0.05.
Results: Biopsies and surgical material of 580 patients of the Department of Pathological anatomy of
LUHSH Kaunas Clinics were diagnosed with two MPMT, whereas 73 patients were diagnosed with three MPMT and 7 patients had four MPMT. 31.94% patients were diagnosed with both synchronous and metachronous MPMT, synchronous MPMT – in 6.94% cases and metachronous MPMT – 66.11% in cases. Men are more likely to be diagnosed with MPMT in both synchronous and metachronous MPMT groups (66,66%). The median age of patients with diagnosis of synchronous tumors are 66.33 years old, meanwhile with diagnosis of metachronous are 66.85 years old. The most common anatomical localizations of MPMT group tumors were colorectal, skin and prostate, respectively. Most common associations of synchronous MPMT group were: “colon – liver”, “colon – skin” and “colon – lung”. Meanwhile, most common associations of metachronous MPMT group were: “colon – skin”, “skin – prostate” and “prostate – colon”.
Conclusions: 1. Men who are more than 50 years old are more frequently affected by both
synchronous and metachronous MPMT, and patients in metachronous MPMT are older compared to synchronous MPMT group. 2. Colon is the most common localization of neoplasms in both synchronous and metachronous MPMT groups, prostate gland is more affected by neoplastic process in metachronous MPMT group, whereas skin is more affected by neoplasms in synchronic MPMT group. 3. Most common associations of synchronous MPMT group were “colon – liver”, “colon – skin” and “colon – lung”, and most common associations of metachronous MPMT group were “colon – skin”, “skin – prostate” and “prostate – colon”.
ACKNOWLEDGEMENTS
This research is a part of my integrated studies in the Lithuanian University of Health Sciences as a Final Master Thesis, during my 6!!year of medical studies.
I would like to thank personally dr. Dainius Jančiauskas and prof. habil. dr. Dalia Pangonytė who helped, taught and advised me throughout the whole research work.
CONFLICT OF INTEREST
The author reports no conflicts of interest.CLEARANCE ISSUED BY ETHICS COMMITTEE
ABBREVIATIONS
MPMT –Multiple primary malignant tumors. MEN – Multiple endocrine neoplasia.
HPV – Human papillovirus. HBV – Hepatitis B virus. OS – Overall survival.
mMPMT- Metachronous multiple primary malignant tumors. sMPMT- Synchronous multiple primary malignant tumors.
INTRODUCTION
Nowadays the presence of multiple primary malignant tumors (MPMT) is a clinical condition frequently diagnosed.
Patients with MPMT are progressively increasing; these tumors may be metachronous or synchronous. This distribution implies important diagnostic and therapeutic challenges. From diagnostic point of view the different patterns of MPMT should be considered[1].
Karl Thiersch described in 1865, for the first time, the MPMT of the breast, and Billroth in 1889 found it in various other localizations [2].
Warren and Gates, in 1932, through the study of 1.259 cases of the literature, gives to MPMT definitive clinical entity, and Moertel, in 1977, establish the first classification given the multicentricity and histological type; that classification it is changed in 1988, using a etiopathogenetic criteria, due to actual epidemiologic and genetic knowledge [3].
As the knowledge of carcinoma has increased and confidence in our ability to distinguish between primary tumors and metastases has been gained, there has been liberalization in the requirements for making a diagnosis.
Comparative analysis of synchronous and metachronous tumors provides useful information for studying tumors and is important for clinical diagnosis.
AIM AND OBJECTIVES OF RESEARCH
Aim: To determine similarities and differences between the synchronous and metachronous
MPMT groups according to the patient’s characteristics, anatomical localizations of MPMT group neoplasms and associative patterns of MPMT neoplasms.
Objectives:
1. To evaluate and compare synchronous and metachronous MPMT groups according to the patient’s clinical characteristics (age and gender).
2. To compare synchronous and metachronous MPMT groups according to the most and least likely anatomical localizations of MPMT group neoplasms.
3. To compare synchronous and metachronous MPMT groups by determining the associative patterns of MPMT according to the anatomical localizations of neoplasms.
1. LITERATURE REVIEW
1.1. Definition of multiple primary malignant tumors
Are called multiple primary malignant tumors (MPMT) to neoplasia that are presented in the same patient, simultaneously or successively [4].
The criteria necessary to make a diagnosis of MPMT were first formulated by Billroth, in 1889, as follows:
• Each tumor must have an independent histologic appearance. • The tumors must arise in different situations.
• Each tumor must produce its own metastases.
Since then most authors have objected to the third requirement of Billroth, which has been considered as obviously too strict, and the following criteria observed by Warren and Gates have been accepted by most authors:
• Each tumor must present a different picture of malignancy. • Each tumor must be distinct.
• The probability of one metastasizing from the other must be excluded.
The diagnosis of the tumors can be successive (called metachronous), or simultaneous (called synchronous).
Each tumor can present with proper symptoms or can be a find in the course necessary for the diagnosis, staging or following of the first tumor, or even just be found post mortem, during the necropsy [2].
1.2. Epidemiologyof multiple primary malignant tumors
The literature review and the analysis of the material compiled since 1984 till the date, permit us to establisha variable incidence, between 4 and 12 % of oncologic patients according to the authors [5].
A little more than 37% turn out to be multicentric tumors in the same organ. The single organs affected by multicentric tumors were: breasts, urinary bladder, lung, colon, melanomas, stomach, liver, kidney, thyroid gland and esophagus, in that order of frequency [5].
The rest is made up by associations of 2 or more independent tumors in different organs on same patient: 56% present 2 MPMT; 6% present 3 MPMT and a little bit more than 0.50% 4 or more MPMT [5,6].
The association of organs commonly involved and their relative percentages are: • 53% breast, endometrium, ovary and colon.
• 14% oropharynx, larynx, lung, urinary bladder and esophagus. In females, a 4,4% of the patients with cervix tumor can be associated with lung cancer.
• 28,6% other associations statistically significant, but less frequent, involve: lymphomas, myelodysplasias, leukemias, sarcomas, lung tumors, breast, urinary bladder, thyroid gland, retinoblastomas, neuroblastomas, carcinoids, multiple endocrine neoplasia (MEN), pelvic tumors and various syndromes like xeroderma pigmentosum (XP), etc [5,6].
1.3. Ethiopathogenesis of multiple primary malignant tumors
The high frequency observed in the presentation of certain associations, make us to suspect the necessary intervention of hereditary factors or ecologic causes in a broad sense that include some variations with geographic or cultural distribution, and in other way can be therapeutic consequence [7,8].
Clinical and experimental investigations permit to establish, quite clearly, the origin of some MPMT:
• Intervention of genetic mutations of hereditary character (proper for patient with MEN) or acquired (deletions of gene p53 in patient with breast cancer).
• Exposure to carcinogenic agents or environmental promoters that includes smoking. • Some virus: Human Papillovirus (HPV), Hepatitis B virus (HBV).
• Ingestion of foods with influence over mechanisms related with hormonal effector organs (excess of saturated fats), or deficit other (carrier of protection substances or fiber).
• Industrial human technology (use of mono vinyl), agrarian (pesticides), therapeutic (nitrogen mustard), natural radiation (UV sun rays), or produced by human (atomic radiation).
• Complex geographic or cultural factors (Balkan nephropathy) [8,9].
1.4. General comparison between synchronous and metachronous tumors
During 10-year period (1987- 1996) of a study realized in University of Istanbul, Turkey, 26,255 patients with cancer were admitted to clinic and, of these, 271 (1%) patients had MPMT. Ninety-two (34%) patients had synchronous tumors (synchronous group), and 179 (66%) patients had metachronous tumors (metachronous group). The mean age at first diagnosis was higher in the former group. The ratio of men to women was 1.36 in the synchronous group. Breast cancer and lung cancer
were most prevalent, and associations between head/neck and lung cancer and between breast and breast cancer were the most frequent associations in both the synchronous and metachronous group. The frequency of aerodigestive tumors was higher and that of mesenchymal tumors was lower in the synchronous group that in the metachronous group. Localization in the medial region and in the head/neck was more frequent in the synchronous group that in the case of metachronous secondary tumors [9].
One hundred twenty-two patients with MPMT analyzed retrospectively who were admitted to the Radiation Oncology Department in Turkey from 2004 to 2013. The patient characteristics and relation with overall survival (OS) were examined. The overall incidence of MPMT was found 1.2%. The median age was 59 (range 29-80) years. Male: female ratio was 54.5:45.5%, and metachronous multiple primary malignant tumors (mMPMT): synchronous multiple primary malignant tumors (sMPMT) ratio was 69.9: 30.1%. The most common three 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 sMPMT and mMPMT were 30 (3-105) and 91 (4-493) months. 2, 3 and 5 years OS of patients with sMPMT were 86%, 75%, 63% and with mMPMT were 92%, 88%, 80% respectively[10].
Clinical characteristics and prognosis of patients with MPMT in a hospital in China from 2008 to 2015, also there is an examination of risk factors associated with poor prognosis for patients with MPMTs. The incidence of MOMTs has been reported to range from 0.52% to 11.7% in various studies from different countries. In different geographical regions, the incidence, characteristics and survival rates associated with MPMTs have been found to be diverse. Further studies are needed to help understand this disease. A total of 15,683 patients, at University Hospital in China, were diagnosed with malignant tumors, of these, 161 (1.0%) patients were diagnosed with MPMTs. Of these 161 patients, 78 (48,4%) had 2 synchronous tumors, and 83 (51,6%) patients had 2 metachronous tumors. Most clinical and pathological features were similar in both groups. Most patients with MPMTs were men and older patients (more than 50 years old), and adenocarcinoma was the most frequent pathology type. The most frequent location of all MPMTs was the digestive tract. The leading tumor association was between digestive – digestive tumors, also. However, patients with synchronous tumors and MPMTs of the digestive system showed a shorter survival time. In the metachronous cancer group, the median interval time was 60 months, and a short interval time (≤60 months) was associated with a shorter survival time. In addition, survival time was increased in the younger age group (≤50 years old) and in patients who accepted surgery– based comprehensive therapy. However, only interval time (≤60 months) was an independent prognostic factor associated with survival for the metachronous group. Therefore, careful surveillance and follow-up are especially important in these patients (Table 1) [11].
Table 1. Clinical characteristics of patients with synchronous and metachronous tumors Variable Synchronous (n [%]) Metachronous (n [%]) Total (n [%]) P No. of patients 78 (48.4) 83 (51.6) 161 Median age, y 64 57 (for primary
tumor) 63 (for second
tumor)
Median interval, mo. 60
Age at diagnosis of the primary tumor, y ≤50 ≥50 12 (15.4) 66 (84.6) 24 (28.9) 59 (71.1) 36 (22.4) 125 (77.6) 0.058 Gender Female Male 24 (30.8) 54 (69.2) 39 (47.0) 44 (53.0) 63 (39.1) 98 (60.9) 0.038 Family history No Yes 71 (91.0) 7 (9.0) 74 (89.2) 9 (10.8) 145 (90) 16 (10) 0.80
1.5. Synchronous and metachronous adenocarcinomas of the large intestine
The synchronous and consecutive (metachronous) of two or more primary adenocarcinomas accounts for 3 to 5% of cases of colorectal cancer. The aim is review the management of patients with synchronous and metachronous lesions, and reach conclusion regarding their optimal diagnosis, treatment and follow up [12].
Multiple primary carcinomas often occur in the rectum and colon. The time lag between the first and second malignant transformation is variable. Two or more primary carcinomas can coexist at the time of diagnosis (synchronous), or develop consequently (metachronous), sometimes years after resection of the first primary.
According to Cunliffe et al, synchronous adenocarcinomas can be two or more in number, detected either pre/ intraoperatively, or in a 6-month period postoperatively [13]. They should be distinctly separate by at least 4 cm distance and they should not consist of submucosal spread or a satellite lesion of each other. In any other case, they are considered as regional spread or metastatic
lesions. In contrast, metachronous carcinomas can be defined as those diagnosed 6 months after the operation for the primary lesion, and located in a different part of the large intestine, so as to not represent a recurrence.
Hereditary colorectal cancer syndromes, such as familial adenomatous polyposis (FAP), and inflammatory bowel disease, such as ulcerative colitis predispose to the development of multiple colorectal carcinomas. These patients, as well as patient with carcinoma in situ were excluded from this study. Factors contributing to the development of synchronous and metachronous lesions were investigated in all patients studied.
Two hundred and eighty patients operated for colorectal cancer during the period of 1987-2004 were retrospectively studied. Two hundred and sixty-eight patients (95.7%) had a single and 12 (4.3%) multiple primary cancers (Table 2).
Table 2. Distribution of carcinomas according to patients’ sex
Patients % Male % Female %
Single tumors 268 95.7 157 58.6 111 41.4
Multiple tumors 12 4.3 7 58.3 5 41.7
Patients with synchronous and metachronous lesions comprised of seven men (58.3%) and five women (41.7%). Their mean age was 67.5 years (range 47-83). The tumors were synchronous in three patients (25%, two male and one female) and metachronous in nine (75% five males and four females). Metachronous adenocarcinomas were identified 18 months to 14 years after excision of the primary lesion. The tumors were located more frequently in the rectum, followed by the sigmoid colon (Table 3).
Table 3.Distribution of the tumors to the different parts of the large intestine
Synchronous Metachronous Total %
Rectum 2 4 6 50 Sigmoid 3 3 25 Descending 1 1 8.3 Transverse Ascending 1 1 8.3 Caecum 1 1 8.3
In two patients with synchronous carcinomas the diagnosis was suspected on barium enema and confirmed with colonoscopy and biopsy. In the third patient, the diagnosis was made intra- operatively, since he was operated urgently because of bowel obstruction and perforation. A barium enema was performed in all patient with metachronous tumors. The examination was diagnostic in all patients; but in 8 of them the diagnosis was confirmed with colonoscopy and biopsy. Colonoscopy was helpful in the discovery and removal of adenomatous polyps in three patients (a patient with synchronous and two with metachronous carcinomas). Three polyps were benign on histological examination. An abdominal CT scan was performed in all patients for staging purposes.
All patient underwent surgery. Three patients with synchronous tumors had two primary lesions that were removed with extensive colectomy. Nine patients with metachronous lesions underwent consecutive operations for tumor removal. Operations were radical and considered curative in 10 patients. Two patients underwent a palliative resection because of liver metastases (a patient with metachronous carcinoma), and locally extensive disease (a patient with synchronous carcinomas) (Table 4).
Table 4. Types of surgical operations performed
Radical operations Patients Palliative operations Patients
Multistage subtotal colectomy 1 Deviation with anastomosis 1 Typical restricted colectomy 4 Terminal colostomy 1 Multistage extended colectomy 2
Single stage extended colectomy 3
Two patients who underwent curatively intended surgery had synchronous carcinomas. Histological examinations lesions, according to the Astler – Coller classification showed stage B2 lesions while the remaining eight patients belonged to the metachronous carcinoma group. In two, it was impossible to locate the histological results of the primary cancers because they were operated in a different hospital, and more than 10 years passed before the metachronous lesion diagnosis. Tumor stage of the metachronous lesions was B2 according to the Astler – Coller classification. In the remaining patients, the tumors were of stages A, B1, B2 and C2 (Astler – Coller classification) (Table 5).
Table 5. Colorectal cancer staging (Astler Coller and TNM classification)
Astler – Collar stage TNM
A T1N0M0
B1 T2N0M0
B2 T3N0M0
C1 T2N1M0, T2N2M0
C2 T3N1M0, T4N2M0
Results and discussion: there is a higher incidence of multiple adenocarcinomas in male patients (41.7%). Czerny described multiple primary adenocarcinomas of the large intestine for the first time in 1880. The reported incidence rates vary from 2 to 8% [13-15]. The actually percentage is probably higher, considering the fact that not all tumors are discovered (diagnostic difficulties) and because some patients undergo palliative operations. The incidence of multiple primary adenocarcinomas in this study was 4.3% [16].
The preoperative diagnosis of multiple synchronous colorectal carcinomas remains difficult. The results are still not satisfactory and the second location is often missed, although there has been a major improvement in the available techniques. The identification of a tumor that justifies the clinical symptoms usually suspends further investigation. Thus, persistence in diagnostic approach is necessary [17-19].
Another case study was performed; in this case the purpose of the study was to evaluate the clinical characteristics, the accuracy of diagnostic examinations and the survival of these patients. From 1970 to 1999, 1160 patients with colorectal cancer were admitted. During follow up examination 50 patients (4.3%) were found to present with multiple primary colon cancers. 52% were synchronous and 48 metachronous tumors. The overall 5-year survival of the patients was 45.87%. Mortality was 10% for multiple primaries; while in patients with single cancer was 4.1%. The overall 5-year survival of the patients with multiple primaries tumors was 46.67% [20].
2. RESEARCH METHODOLOGY AND METHODS
Research planning (organization): First of all, collection of literature and theoretical knowledge of problem, creating design of investigation and collecting permissions and data. At the end, statistical analysis, results and presentation preparing.
The object of study: Incidence of synchronous and metachronous tumors in seventy-two patients who suffered three or four benign and/or malignant tumors in the past 10 years and their data were send to Department of Pathological Anatomy, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, for biopsies and analysis.
Participant selection (population, sample): Seventy-two patients diagnosed with three or four tumors in the past 10 years and their data were send to Department of Pathological Anatomy, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, to analyzehistologically.
Research methods: This research was an observational case study. First was necessary to review the case histories from seventy-twopatients, obtaining their data like age, sex, histological type of tumor, date of diagnosis and affected organ.
Methods of data analysis: The analysis was performed using “Excel for Mac 2011” and SSP to calculate the total amount of patients, amount of tumors divided by types, the gender, the date of biopsy diagnosis, the age of the patients, histological type of tumor and affected organ. The chi-square test was used to examine the relationship or association between few categorical variables. All given values are presented as mean ± standard deviation (SD). The level of statistical significance (p) of 0.05 was selected for all variables.
3. RESULTS
The aim of the study is to make a comparative analysis between synchronous and metachronous tumors. To distinguish synchronous and metachronous neoplasms, should be, at least, 6 months between diagnosis of neoplasms, each tumor must present a different picture of malignancy, each tumor must be distinct and the probability of one metastasizing tumor from the other must be excluded.
In the Department of Pathological Anatomy, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, Kaunas, were analyzed biopsies and operative material of 580 patients with two neoplasms, seventy-three with 3 neoplasms, and seven patients with four neoplasms. For our study the total selected patients were seventy-two, with three or four neoplasms each. After the study and analysis of those patients, it´s obtained the next data:
- The total amounts of neoplasms in seventy-two patients were 235 neoplasms. - The ratio men – women were 66,66% (men) – 33,33% (women)(Fig. 1).
Fig. 1. Ratio men – women of all analyzed patients (72 patients with three or four neoplasms)
- The median age was 66,7 years old (range 30-89 years).
In our case, when the patients have at least three tumors, it´s necessary to remember that each patient can be diagnosed with both MPMT, synchronous and metachronous type of tumors.
- Patients with synchronous tumors: 28 patients (38,88%). - Patients with metachronous tumors: 67 patients (93,05%).
- Patients with both synchronous and metachronous tumors: 23 patients (31,94 %) (Fig. 2). Men (66,66%) Women (33,33%)
- Patients with only synchronous tumors: 5 patients (6,94%). - Patients with only metachronous tumors: 44 patients (61,11%).
Fig. 2. Amount of both synchronous and metachronous MPMT, only synchronous and only metachronous
The localization of all reviewed tumors, in order from most common to less common are: Colorectal (30,63%), Skin (12,76%), Prostate (11,48%), Uterus and Cervix uteri (5,10%) and Urinary Bladder (5,10) (Figure 3).
Fig. 3. Localization of all reviewed tumors
Only synchronous (6,94%) Only metachronous (61,11%) Both synchronous and metachronous (31,94%) 0,00% 5,00% 10,00% 15,00% 20,00% 25,00% 30,00% 35,00% Co lo re ctal Sk in Pr os tate U te ru s an d ce rv ix u te ri U rin ar y bl ad de r Lung Sto m ac h Ki dn ey Bl ood Th yr oi d gl an d Liv er O var y Br eas t N er vo us s ys te m Ey e Mu co sal o ral c av ity Es op hag us Pap ill a Vate ri Vag in a Bon e Mi no r l ip N as op har yn x Pan cr eas Ly m ph ati c sy ste m Par ath yr oi d gl an d Bi le d uc t % of the total % of the total
The most affected systems of all reviewed tumors, in order from most common to less common are: Digestive system (39,11%), Reproductive system (21,66%), Integumentary system (14,03%), Urinary system (9,35%), Respiratory system (5,10%), Circulatory system (3,82%), Nervous system (3,4%), Endocrine system (2,97%) and Skeletal system (0,42%). Also we can observe that the male reproductive system is slightly more affected than the female (Table 6).
Table 6.Most affected systems of all reviewed tumors
Affected system % Of all reviewed tumors
1 Digestive system 39,11%
2 Reproductive system (male and female) 21,66% (Male - 11,48%, Female – 10,18%) 3 Integumentary system 14,03% 4 Urinary system 9,35% 5 Respiratory system 5,10% 6 Circulatory system 3,82% 7 Nervous system 3,4% 8 Endocrine system 2,97% 9 Skeletal system 0,42%
The total amount of both synchronous and metachronous tumors associations are 153 MPMT. Forty-one (41) are synchronous and one hundred twelve (112) are metachronous.
Most common associations of synchronous tumors, in order from most common to less common are: Colon – Liver (7,31%), Colon – Skin (7,31%), Colon – Lung (7,31%), and Prostate – Kidney (4,87%) Skin – Prostate (4,87%), Thyroid gland – Skin (4,87%), Colon – Blood (4,87%), Colon – Rectum (2,43%), Lymph nodes – Urinary Bladder (2,43%), Bile duct – Colon (2,43%), Colon – Eye (2,43%), Rectum – Esophagus (2,43%), Ovary – Rectum (2,43%), Uterus and cervix uteri – Liver (2,43%), Uterus and Cervix uteri – Oral (2,43%), etc. (Figure 4).
Fig. 4. Most common relations of synchronous tumors
The most common associations of systems in patients with synchronous tumors are Digestive – Digestive systems (14,6%), Digestive – Respiratory systems (14,6%) and Digestive – Reproductive systems (12,15%), following by Digestive – Integumentary (9,74%), Reproductive – Integumentary (9,74%), Reproductive – Urinary (7,31%), etc. (Table 7).
Table 7. Synchronous associations organized by systems
Associations of systems % Of synchronous tumors 1 Digestive - Digestive 14,6% 2 Digestive - Respiratory 14,6% 3 Digestive – Reproductive 12,15% 4 Digestive - Integumentary 9,74% 5 Reproductive – Integumentary 9,74% 6 Reproductive – Urinary 7,31% 0,00% 1,00% 2,00% 3,00% 4,00% 5,00% 6,00% 7,00% 8,00% Colon - Liv er Colon - Sk in Colon - Lung Pr os tate - Ki dn ey Sk in - Pr os tate Th yr oi d gl an d - S ki n Colon - Blood Co lo n - Re ctu m Ly m ph n od es - U rin ar y bl ad de r Bi le d uc t - C ol on Colon - Ey e Re ctu m - Es op hag us O var y - Re ctu m U te ru s an d ce rv ix u te ri - L iv er U te ru s an d ce rv ix u te ri - O ral Pr os tate - Bl oo d U te ru s an d ce rv ix u te ri - S ki n U te ru s an d ce rv ix u te ri - C ol on Lu ng - Sto m ac h Sk in - Sto m ac h Pr os tate - Lu ng Ki dn ey - Re ctu m Re ctu m - Bl oo d Bl ood - S ki n Br ai n - B lo od N as op har yn x - C ol on Colon - Bone U te ru s an d ce rv ix u te ri - Pr os tate - Co lo n Associations of synchronous tumors, % of the total
7 Digestive – Circulatory 7,31% 8 Endocrine – Integumentary 4,87% 9 Digestive – Nervous 4,87% 10 Circulatory – Urinary 2,43% 11 Reproductive – Circulatory 2,43% 12 Reproductive – Respiratory 2,43% 13 Circulatory – Integumentary 2,43% 14 Circulatory – Nervous 2,43% 15 Digestive – Skeletal 2,43%
Most common associations of metachronous tumors, in order from most common to less common are: Colon – Skin (8,42%), Skin – Prostate (7,14%) and Prostate – Colon (6,25%) (Figure 5; all the 63 associations do not fit in the graphic, so just the first 25 will appear in the graphic).
Fig. 5. Most common associations of metachronous tumors
0,00% 1,00% 2,00% 3,00% 4,00% 5,00% 6,00% 7,00% 8,00% 9,00% 10,00% Associations of metachronous tumors, % of the total
The most common associations of systems in patients with metachronous tumors are Digestive – Reproductive systems, Digestive – Integumentary systems and Respiratory – Integumentary systems, respectively (Table 8).
Table 8. Metachronous associations organized by systems
Associations of systems % Of metachronous tumors 1 Digestive - Reproductive 16,93% 2 Digestive - Integumentary 12,49% 3 Respiratory - Integumentary 11,59% 4 Digestive - Urinary 8,9% 5 Reproductive – Urinary 7,14% 6 Digestive – Digestive 6,25% 7 Digestive - Respiratory 5,35% 8 Digestive - Circulatory 4,45% 9 Digestive – Endocrine 3,57% 10 Digestive – Nervous 2,67% 11 Reproductive – Reproductive 2,67% 12 Urinary – Integumentary 2,67% 13 Reproductive – Circulatory 2,67% 14 Reproductive – Respiratory 1,78% 15 Respiratory – Nervous 1,78% 16 Circulatory – Urinary 0,89% 17 Urinary – Urinary 0,89% 18 Respiratory – Integumentary 0,89% 19 Integumentary – Integumentary 0,89% 20 Respiratory – Endocrine 0,89% 21 Reproductive - Endocrine 0,89% 22 Respiratory – Circulatory 0,89% 23 Nervous – Nervous 0,89% 24 Urinary – Endocrine 0,89%
The median age of patients with diagnosis of synchronous tumor:
- 66,33 years old is the median age of both males and females with diagnosis of synchronous tumor.
- 58,5 years old is the median age of females with diagnosis of synchronous tumor. - 69,7 years old is the median age of males with diagnosis of synchronous tumor.
The median age of patients with diagnosis of metachronous tumor:
- 66,85 years old is the median age of both males and females with diagnosis of synchronous tumor.
- 58,85 years old is the median age of females with diagnosis of synchronous tumor. - 70,32 years old is the median age of males with diagnosis of synchronous tumor.
Comparison women-men with diagnosis of synchronous tumor:
From the total of 28 patients with diagnosis of synchronous tumor, there are 28,57% of women (8 patients) and 71,42% of men (20 patients) (Fig. 6).
Fig. 6. Men – Women ratio with diagnosis of synchronous tumors
Men (71,42%) Women (28,57%)
Comparison women – men with diagnosis of metachronous tumor:
From the total of 67 patients with diagnosis of metachronous tumor, there are 30,30% of women (20 patients) and 69,69% of men (47 patients) (Fig.7).
Fig. 7. Men – Women ratio with diagnosis of metachronous tumors
Men (69,69%) Women (30,30%)
4. DISCUSSION OF THE RESULTS
In our study we analyzed seventy-two patients and a total amount of 235 neoplasms. After obtaining all the results we can compare it with results obtained by scientists in the field.
First of all, we should remember that our study is a little bit different that other comparative analysis of synchronous and metachronous tumors, but we will try to compare all the obtained results. Also it should be noted that in our cases study and review the patients have three or four neoplasms, that means that each patient can have both synchronous and metachronous tumors, only synchronous or only metachronous.
In Radiation Oncology Department in Turkey from 2004 to 2013 the median age was 59 (range 29 – 80), in our study we obtain a median age 66,7 (range 30-89), that is considerably more. In the same Department in Turkey the male – female ratio was 54,5% - 45,5%, in our study was 66,6 % males and 33,3% females. That shows that in our study are more prominent the male gender, even more than in Oncology Department in Turkey.
The ratio of metachronous and synchronous tumors in Radiation Oncology Department in Turkey (2004 – 2013) was 69,9% - 30,1%. In the Pathological Anatomy Department in Kaunas, in the past ten years, the ratio of metachronous, synchronous and both tumors are: 61,11% only metachronous, 6,94% only synchronous, and 31,94% both synchronous and metachronous tumors. 38,88% of all the patient were diagnosed with synchronous tumors and 93,05% of all the patient were diagnosed with metachronous type of tumor, that is because one patient, in our case, can have both type of tumors, synchronous and metachronous.
In a hospital in China (2008 - 2015), was made a similar study, and they obtain results that showing a 48,4% of synchronous tumors and a 51,6% of metachronous tumors. In the Department of Pathological Anatomy, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, in the past ten years, shows that in Kaunas the amount of metachronous tumors is major, but the amount of synchronous tumors are minor.
In a hospital in China (2008 – 2015) most patient with MPMTs were men and older patients (more than 50 years old), and adenocarcinoma was the most frequent pathology type. In our study in Kaunas, that results coincide totally, because adenocarcinoma was the most frequent affecting mostly patient of male gender and older than 50 years. In China also, the most frequent location of all MPMTs was the digestive tract, like in our study.
In China the leading tumor association was between digestive - digestive tumors, our results from Department of Pathological Anatomy, Hospital of Lithuanian University of Health Sciences Kauno Klinikos are similar, showing us that the leading tumor association digestive – digestive in synchronous tumors and digestive – reproductive in metachronous.
5. CONCLUSIONS
1. Men who are more than 50 years old are more frequently affected by both synchronous and metachronous MPMT, and patients in metachronous MPMT are older compared to synchronous MPMT group.
2. Colon is the most common localization of neoplasms in both synchronous and metachronous MPMT groups (30,63%), prostate gland is more affected by neoplastic processes in metachronous MPMT group (11,48%), whereas skin is more affected by neoplasms in synchronic MPMT group (12,76%).
3. The most common associations of synchronous MPMT group were “colon – liver” (7,31%), “colon – skin” (7,31%) and “colon – lung” (7,31%), and the most common associations of metachronous MPMT group were “colon – skin” (8,42%), “skin – prostate” (7,14%) and “prostate – colon” (6,25%).
6. PRACTICAL RECOMMENDATIONS
After this study of synchronous and metachronous MPMTs, it is necessary to confirm that knowledge about that types of tumors is very useful at the time of diagnosis, prevention and treatment of that tumors. Helping us, especially in the diagnosis and possibility of the possible next or existing tumor in the patient. Comparative analysis of synchronous and metachronous tumors provides useful information for studying tumors and is important for clinical diagnosis, and when a doctor find and treat one tumor he cannot calm down, but must want the patient and thoroughly examine patient for possible another synchronous tumor and perform later regularly check for possible another metachronous tumors.
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