Multiple Primary Malignancies: A Clinicopathological Pro ﬁ le of Patients at a Tertiary Center of North India — A Retrospective Hospital-Based Observational Study

Introduction The incidence, prevalence, as well as survival of cancer patients, is increasing day by day due to the use of screening and improved diagnostic modalities. Simultaneously, the development of multiple primary malignancies (MPMs) in cancer survivors is not uncommon in recent years, because of an improved understanding of biology and effective management of cancer in the form of local (i.e., surgery/ radiotherapy) and systemic (chemotherapy/targeted therapy) treatment, leading to improved survival and subsequent development of more malignancies. The study was conducted to describe the clinicopathological pro ﬁ le of patients diagnosed with MPMs. Objective To study the clinicopathological pro ﬁ le of MPMs and to look for treatment patterns of these patients. Materials and Methods This was a retrospective hospital-based observational study. Medical records of 73 patients with MPMs, who were registered in the department of medical and surgical oncology between January 2016 and December 2018, were enrolled in the study. The statistical analysis was done by using IBM SPSS Statistics for Windows from IBM Corp. Categorical data were expressed in the form of frequencies and


Background
Multiple primary malignancies (MPMs) in cancer patients are not very rare because of prolonged survival due to advances made in the treatment of cancer patients.The probability of recurrence or a secondary from the initial malignancy may delay treatment and impact the overall prognosis and survival, making the diagnosis of MPMs complicated.The most common presentation of MPMs is double malignancies. 1,2MPMs were first described by Billroth 3 in 1889 and reported in a detailed study by Warren and Gates 4 in 1932.The criteria for diagnoses of MPM, as proposed by Warren and Gates, include: (1) histological confirmation of malignancy in both the index and second primary tumors; (2) there should be at least 2 cm of normal mucosa between the tumors; if the tumors are in the same location, then they should be separated in time by at least 5 years; (3) probability of one being the metastasis of the other must be excluded.Double primary malignancies could be divided into two categories, depending upon the interval between tumor diagnoses.Synchronous malignancies are defined where second tumor develops simultaneously or within 6 months after the diagnosis of first malignancy, whereas in metachronous malignancies, second tumor develops after 6 months or more after the diagnosis of the first malignancy. 5he aim of our study was to assess the clinical and pathological profile of patients diagnosed with MPMs in our region.

Material and Methods
This was a retrospective hospital-based observational study.Medical records of 73 patients with MPMs who were registered in the department of medical and surgical oncology between January 2016 to December 2018 were enrolled in the study.The patient's details were entered in a set proforma, which include age, sex, family history, smoking and drinking history, histology of synchronous and metachronous lesions, and treatment received.

Inclusion Criteria
Patients with two or more lesions at different sites with different histology or those with two lesions at different sites with similar histology but with different immunohistochemistry markers were included in the study.The tumors were divided into synchronous and metachronous lesions depending upon the time interval between the occurrence of two lesions.Synchronous tumors developed simultaneously or within 6 months of each other, whereas metachronous lesion occurred more than 6 months apart from each other.

Exclusion Criteria
Patients with malignancy at different sites but with same immunohistochemistry or disease at same site within 5 years of first malignancy were excluded from the study.

Sample Size
Sample size was calculated by using the Cochran's formula n ¼ (1.96) 2 p(1-P)/d 2 , p ¼ 0.73%, d ¼ 0.10%, and thus, the calculated sample size is 76.Case records of three patients were incomplete and were excluded from the study, so the final sample size of our study was 73 patients having 85% power of study.

Primary Outcome
To study the clinicopathological profile of MPMs.

Secondary Outcome
To study the treatment patterns of MPM patients.

Statistical Analysis
The data analysis was done on a computer running Microsoft Windows.The data were initially entered into a Microsoft Excel spreadsheet to be checked for mistakes.The IBM Corp.'s IBM SPSS Statistics for Windows was used for the statistical analysis (released 2020, Version 27.0.Armonk, New York, USA).The frequency and percentage representations of categorical variables were displayed.

Results
Out of 13,852 newly diagnosed cancer cases, 73 patients were diagnosed to have MPMs comprising of 0.51% of the total cases enrolled during the study.Two patients had triple malignancies, whereas 71 patients had double malignancies.In the two patients with triple malignancy, one had non-Hodgkin's lymphoma and developed metachronous squamous cell carcinoma of esophagus and adenocarcinoma of sigmoid colon.In another patient with index squamous cell carcinoma of skin (thigh), developed two metachronous malignancies, i.e., renal cell carcinoma and adenocarcinoma stomach.For rest of discussion purposes, we will exclude triple malignancies.Of the 71 cases of double malignancy, 39 most common histologies seen in primary, whereas adenocarcinoma was the most common histology seen in second primary malignancy.Conclusions The phenomenon of MPMs is not an uncommon presentation due to longer survival and side effects of treatment (radiotherapy/chemotherapy).It should always be kept in consideration in any cancer survivor during surveillance in order to detect it and treat at the earliest.
(54.92%) were men and 32 (45.07%) were women with a male to female ratio of 1.21:1.Median age of our patients was 55 (30-80) with median time to diagnosis of second cancer of 36 months (12-228).

Discussion
Recently, there has been a sharp increase in the prevalence of MPMs, ranging from 0.7 to 11.7% among various populations. 6This can be due to multitude of reasons including the improved survival of cancer patients due to improved treatment modalities, better diagnostic modalities, and more stringent surveillance of cancer survivors. 7The prevalence of MPMs in the studied group was 0.51%.
MPMs are a special phenomenon in the tumorigenesis.A number of studies have been conducted worldwide leading to better understanding of this phenomenon.The etiopathogenesis of MPMs can be attributed to genetic events or the common environmental risk factors. 8Various other mechanisms like aging, an unhealthy lifestyle, cancer treatments, or interactions between any of these factors are also believed to contribute to the development of MPMs. 9 The increased risk of MPMs can be attributed to field carcinogenesis due to exposure to tobacco, smoking, and alcohol consumption. 10In our study population, 32% patients had smoking history, and none had history of alcohol consumption.
The treatment of primary malignancy by chemotherapy and/ or radiotherapy may contribute to increased risk of second malignancy as both ionizing radiation and cytotoxic agents (etoposide, cyclophosphamide, and Adriamycin etc.) can cause DNA damage leading to carcinogenesis.The harmful effects of these treatments as well as of the tumor microenvironment on the patient's immune system may be an important contributing factor allowing future renegade mutant cancer cells from  escaping the body's defense mechanisms.Children and young adults may be especially prone to such iatrogenically induced cancers. 11This was also seen in our patient population, as around 40% of the patients in total and 51.71% patient in metachronous group had received either chemotherapy/radiotherapy or both as treatment for their primary cancers.
In the present study, the incidence of multiple primaries was more common in men as compared with women with a male to female ratio of 1.21:1.3][14][15][16] The median age in our study was 55 years (range 30-80 years).Etiz et al in their study had male to female ratio of 1.19:1 with a median age of 59 years (range 29-80 years), 17 consistent with our study.The interval between index primary and second primary in our study was 12 to 228 months (median 36 months), which is consistent with other studies 9,18 (comparison between different studies given in ►Table 4).
0][21][22] In a study by Aydiner et al, 14 synchronous malignancies constituted 34%, whereas metachronous malignancies constituted 66%, consistent with our study with synchronous and metachronous malignancy of 27 and 73%, respectively.The most common system involved in first primary as well as second primary malignancy in our study was GI (30.99 and 39.44%) with lung being the most    common second primary malignancy after GI (16.9%).In a retrospective study, Zhai et al 9 found that the most common pairs were digestive-digestive (25.75%) followed by digestivelung pairs (19.16%), which coincides with our findings.In another study conducted by Etiz et al, the most common second primary malignancies were GI (22%) and lung (19%), similar to present study. 17There is high prevalence of GI malignancies in this region of country, which is presumed due to geographic, dietary, and cultural reasons.In a study from the region by Khan et al, 23 which included 22,180 patients, cancer of esophagus, stomach, and colon were second, third, and sixth most common causes of cancer incidence.This could explain the reason for GI tract being the most common site in both synchronous and metachronous groups.
The possibility of existence of MPMs must always be considered during pretreatment evaluation.There is some evidence that screening will improve outcomes among patients who may develop second malignancies, although the data are limited.The optimal screening modalities and strategies to reduce mortality from second malignancies remain to be defined for most tumor sites. 21With careful monitoring, second primary tumors can be detected early, and with appropriate intervention might be better managed, without compromising survival.
A sizable prospective study needs to be conducted to better understand the profile and outcome of MPMs in order to better develop the various strategies for screening and early identification of second primary malignancies and to enhance outcomes.

Limitations
The small sample size and retrospective nature of our study are its primary limitations.

Conclusion
In conclusion, second primary malignancies are not rare.They can be synchronous or metachronous.Improvements in diagnostic and staging modalities and improved survival after management of primary cancers have increased the detection of second primary malignancies.A strong clinical suspicion and thorough evaluation would be beneficial in the management of these tumors.A regular follow-up in a patient diagnosed and treated for primary malignancy would help not only to detect recurrence but also could detect most of the metachronous second primary malignancies at an early stage.

Table 1
System wise invasion sites Abbreviation: CI, confidence interval.

Table 3
Summary of metachronous double malignancies