Indian Journal of Pathology and Microbiology

: 2021  |  Volume : 64  |  Issue : 4  |  Page : 725--731

Distinct patterns of occurrence, common associations, and survival of patients with second primary maligancies: A 5-year single institute experience with review of literature

Rohit Avinash Vadgaonkar1, Sonali Susmita Nayak2, Subhashreddy Doni3, Leela Digumarti4, Sujith Kumar Mullapally5, Raghunadharao Digumarti6,  
1 Department of Radiation Oncology, Homi Bhabha Cancer Hospital and Research Centre, Aganampudi, Visakhapatnam, Andhra Pradesh, India
2 Department of Pathology, Homi Bhabha Cancer Hospital and Research Centre, Aganampudi, Visakhapatnam, Andhra Pradesh, India
3 Department of Radiodiagnosis, SVS Medical College, Mahabubnagar, Telangana, India
4 Department of Gynecology, KIMS ICON Hospitals, Visakhapatnam, Andhra Pradesh, India
5 Department of Medical Oncology, Apollo Proton Cancer Center, Chennai, India
6 Department of Medical Oncology, KIMS ICON Hospitals, Visakhapatnam, Andhra Pradesh, India

Correspondence Address:
Sonali Susmita Nayak
Department of Pathology, Homi Bhabha Cancer Hospital and Research Centre, Aganampudi, Visakhapatnam - 530 053, Andhra Pradesh


Background: Multiple primary malignancy (MPM) is defined as occurrence of two or more synchronous or metachronous primary malignancies. With the rise in cancer burden and meticulous screening of index primary malignancy (IPM) during treatment, increased incidence of second primary malignancy (SPM) is expected. This study was undertaken with an attempt to analyze the incidence, commonest associations, management strategies, and clinical outcomes of MPM. Materials and Methods: This is an observational retrospective study carried out in a single institute with patients registered between 1st January 2015 and 31st August 2019. The International Association of Cancer Registries and International Agency for Research on Cancer (IACR/IARC) definition was used for identification of IPM and SPM. Synchronous SPM was defined as malignancy occurring within 6 months from the diagnosis of IPM. Results: Out of 16,461 registered patients during the study interval, 44 (0.26%) cases were found to have MPM. A total of 31 (70.5%) cases were women and 13 (29.5%) cases were men. Median age at presentation of IPM was 48 years and of SPM was 56 years, with median duration between two primaries being 38 months. Seven patients (15.9%) had synchronous malignancies. Gynecological tumors were the most common site of IPM presentation (n = 14, 31.8%) followed by breast (n = 09, 20.5%) and head and neck tumors (n = 07, 15.9%), respectively. The most common SPM was gynecological tumors (n = 12, 27.3%) followed by gastrointestinal malignancies (n = 10, 23.3%). Curative treatment was offered to 88% of patients with IPM and 70% patients with SPM. At a median follow-up of 365 days, 21 (47.72%) patients were disease free, six (13.6%) died of disease and nine (20.5%) were lost to follow-up. Conclusion: The study emphasizes the importance of detecting SPM as a result of improved diagnostic and screening procedures. Clinicians should be aware of it and offer multidisciplinary management.

How to cite this article:
Vadgaonkar RA, Nayak SS, Doni S, Digumarti L, Mullapally SK, Digumarti R. Distinct patterns of occurrence, common associations, and survival of patients with second primary maligancies: A 5-year single institute experience with review of literature.Indian J Pathol Microbiol 2021;64:725-731

How to cite this URL:
Vadgaonkar RA, Nayak SS, Doni S, Digumarti L, Mullapally SK, Digumarti R. Distinct patterns of occurrence, common associations, and survival of patients with second primary maligancies: A 5-year single institute experience with review of literature. Indian J Pathol Microbiol [serial online] 2021 [cited 2023 Feb 3 ];64:725-731
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Full Text


Management of cancer has evolved significantly over the last four decades. Advancements in screening techniques have led to early diagnosis, whereas use of standardized and evidence-based treatment has improved cancer survivorship.[1] This increase in longevity of cancer surviving population has led to consequences of dealing with long-term treatment toxicities, risk of recurrence, and susceptibility for second primary malignancy (SPM). Tumors arising in different organs with different histology are considered as distinct primaries. Cautious evaluation of multicentricity and multifocality of the index primary malignancy (IPM) should be made before classifying a tumor as SPM. Though there is enough evidence describing incidence, risk factors, and outcomes of multiple primary malignancy (MPM) in western population, limited reports are available from Indian subcontinent.[2],[3],[4],[5],[6] Hence, this study was undertaken with an attempt to analyze the incidence of MPM, commonest associations of IPM and SPM, possible genetic syndrome associations, management strategies, and to observe the impact of MPM on clinical outcomes.

 Materials and Methods

The study is an observational retrospective analysis of a prospectively maintained database of patients with MPM registered between 1st January 2015 and 31st August 2019 at our tertiary care cancer hospital. The patients diagnosed, treated, and followed-up at our institute for IPM along with those referred for the diagnosis and treatment of SPM developed during the course of follow-up were included in the study.

The International Association of Cancer Registries and International Agency for Research on Cancer (IARC/IACR) definition was used for identification of IPM and SPM[7] which is based on the following rules:

Existence of two or more primaries does not depend on time.Primary cancer should not be an extension, or a recurrence, or a metastasis.Only one tumor shall be recognized as arising in an organ or pair of organs (except for systemic malignancies having potential to involve different organs or neoplasms having different morphologies).

Synchronous second primary is defined as malignancy occurring within 6 months interval from the diagnosis of index primary; otherwise primaries were categorized as metachronous.[8]

Information relating to demographic profile, clinical, histopathological characteristics along with treatment and follow-up of the patients were obtained from the electronic medical records and hospital case sheets. The data were analyzed using IBM SPSS Statistics for Windows, Version 26.0. (Armonk, NY: IBM Corp.).


During the study interval, a total 16,461 cancer patients were registered in our institute. Out of these, 44 patients (0.26%) were identified to have MPM. None of the cases were identified to have more than two primaries. Patient characteristics are depicted in [Table 1]a and [Table 1]b. Out of 44 patients, 31 (70.5%) were women and 13 (29.5%) were men. Median age for presentation of IPM was 48 years (range: 8–77 years) and of SPM was 56 years (range: 20–80 years). Most common age of presentation with IPM was in the 4th to 6th decade (n = 31, 70.7%), whereas SPM was in the 5th to 6th decade (n = 22, 50%). Eight cases (18.2%) developed SPM after the 6th decade of life.{Table 1}

The observed median duration between IPM and SPM was 38 months (range: 0–423 months) [Figure 1]. Twelve patients (27.3%) developed SPM after 10 years of diagnosis of IPM. Seven cases (15.9%) developed synchronous malignancies. Characteristics of synchronous primaries are depicted in [Table 2]. Out of these seven patients, four patients had gynecological malignancies, with ovarian carcinoma in three of these patients.{Figure 1}{Table 2}

The histopathological diagnosis was available for all cases of SPM. Immunohistochemistry was used to confirm the diagnosis and differentiate the second primary from the recurrence of index primary. However, two cases of IPM, both of which were carcinoma cervix, did not have any prior histologic diagnosis on clinical records. Of these two cases, one developed a neuroendocrine tumor of the colorectum and the other developed adenocarcinoma of rectum.

The development of adenocarcinoma rectum was 20 years after the diagnosis of first primary suggesting it to be a SPM rather than a local recurrence.

Gynecological tumors were the most common site of index primary presentation (n = 14, 31.8%) followed by breast (n = 09, 20.5%) and head and neck tumors (n = 07, 15.9%), respectively [Table 1]b. The most common SPM was also gynecological tumors (n = 12, 27.3%) followed by gastrointestinal malignancies (n = 10, 23.3%). Among the gynecological malignancies, ovary was the most common site for index primary (n = 7; 50%). The most common pattern of association of SPM in gynecological index primary was ovary with breast carcinoma (n = 03, 21.4%); and cervical with colorectal carcinoma (n = 03, 21.4%), followed by endometrial with breast carcinoma (n = 02, 14.3%) [Table 3]. Of the nine cases having index breast primary, the most common second primary was ovary and cervical carcinoma, each with two cases (22.2%). One patient developed contralateral breast cancer after 2 years of index breast cancer diagnosis.{Table 3}

Of the 15 patients treated with radiotherapy for IPM, three (20%) cases developed SPM within the previous radiation portals, and two patients developed hematological malignancies. Out of the three cases of in-field second primaries, two cases had received radiation to the pelvis with development of second primary in colorectum; whereas the third case is a breast primary which received radiotherapy to chest wall and supraclavicular fossa, developing SPM in the thyroid.

[Table 4] demonstrates clinical scenarios and certain potential genetic cancer syndromes associated with multiple primaries. Of these, the combination of breast and ovarian malignancy was seen in six cases (13.6%). Two cases of breast cancer with sarcoma (4.5%); single cases each of ovarian with endometrial carcinoma and ovarian with pancreatic cancer (2.3%) was noted.{Table 4}

More than 50% patients had received multimodality treatment for both index and second primaries [Table 5]. Curative treatment was offered to 88% of patients with index primary and 70% patients with second primary. At a median follow-up of 365 days (0–5600 days) from the diagnosis of second primary, 21 patients were disease free [Figure 2], six (13.6%) died of disease and nine (20.5%) were lost to follow-up.{Table 5}{Figure 2}


Diagnosis of multiple primaries in cancer survivors is not an uncommon finding.[9],[10] Owen reported an incidence rate of 4.2% of MPM among 3000 cancer patients way back in 1921.[9] Following this primordial work, multiple retrospective and prospective studies have reported a highly variable prevalence of MPM ranging from 0.2% up to 17%.[8],[11] Multiple factors have been quoted for this observed variation including use of different definitions for documenting MPM,[7],[12] age of presentation of IPM,[13] length of follow-up,[13],[14] and inclusion of autopsy series.[11]

Definitions of multiple primary malignancies

With the improvement in knowledge of multiple neoplasms, the definition of MPM has also evolved over the time. In 1932, Warren and Gates published one of the largest series of 1259 patients with multiple primary malignancy[15] and led down first definite rules for defining MPM. Their criteria stated that each tumor must be distinct, pathologically proven, and the possibility of metastasis from the other should be excluded. In 2004, IACR/IARC redefined the criteria for diagnosis of MPM.[7] The Surveillance Epidemiology and End Results (SEER) project group has also given recommendations that are frequently used in the United States.[8] It slightly differs from that of IACR/IARC criteria, as it considers different parts of single organs as different sites, whereas IACR/IARC recommend groups led by of topography codes of International Classification of Diseases for Oncology 3rd Edition (ICD-O-3) as one site. SEER database defines intervals for reporting synchronous primaries of two months as compared to 6 months given by IACR/IARC.

Impact of different rules on incidence and outcomes was evaluated by Weir et al., where they found that more MPMs were registered when SEER definition was used as compared to IACR/IARC definition (15.8 vs. 14.4% among men; 17.2 vs. 14.5% among women); however, survival estimates were not different in both the groups.[16] In our study, we have used IACR/IARC rules to define multiple primaries. One of the patients with infiltrating duct carcinoma of breast developed a second primary in contralateral breast after 2 years. These two tumors were considered as distinct primaries as stated in IACR/IARC recommendations.[7]

Risk factors

Multiple risk factors have been associated with the development of second primaries. Cancer predisposing lifestyle like smoking, alcohol and obesity[8]; exposure to environmental carcinogens[8],[16]; interaction between hosts with an influence of genetic predisposition have significant contributions to the development of MPM.[8] Tumors having inherited genetic predisposition tend to have multiple primaries at a young age and are also seen to affect other family members. Few of such syndromes include the hereditary breast and ovarian cancer syndrome (HBOCS), Li-Fraumeni syndrome, Lynch syndrome/hereditary nonpolyposis colon cancer (HNPCC), von Hippel Lindau disease where genomic study should be carried out for confirmation. In our study, a suspicion of HBOCS with six cases having combination of breast and ovarian malignancy (13.6%) and a single case of bilateral breast carcinoma was noted.

HNPCC and Li-Fraumeni syndromes were suspected in 6.8% of patients. However, genetic testing was not carried out to confirm familial cancer syndromes. Ethnicity is an important risk factor for developing multiple primaries. Certain genetic cancer predisposition syndromes are more common in distinct ethnic populations like HBOCS is more common in Ashkenazi Jews population.[8]

Age of an individual is considered as a significant risk factor. Risk of developing multiple malignancies nearly doubles for an individual who is in his 8th decade of life as compared to those who are in their 6th decade.[17],[18] In our study 18.2% of patients who developed second primary were beyond the 6th decade. This reflects the effective management of the index primary leading to increased survival. Also, the longer the patients are followed-up after a primary cancer diagnosis with a strict surveillance, the chance of detecting SPM increases.

MPM appears to occur more frequently in women as compared to men.[16] In our population, 70.5% patients were women and the most common IPM associated with MPM was gynecological malignancies (31.8%) followed by breast cancer (20.6%).

Incidence of multiple primaries was also found to vary with respect to diagnosis of index primary. SEER database analysis has shown that the highest incidence of SPM was observed with bladder cancer (16%) followed by corpus uteri (11%), kidney and renal pelvis (10%).[19] In the present study, the most common index primary associated with development of SPM was breast cancer (20.6%), followed by ovarian cancer (15.9%). Probable reason for this observed difference in our study is the bias introduced by use of hospital-based registry rather than using population based registry.[19],[20] Also, different ethnicity and other environmental factors must have contributed additionally.

Previous treatment of index primary in itself is considered to be a significant risk for developing new primary.[17],[18] Both radiotherapy and systemic therapies in the form of chemotherapy and hormonal therapy are considered to be one of the causative factors for initiation of new primary.[16],[18] Second primary usually develops as an acute sequelae to chemotherapy administration occurring within a few months to years, whereas radiotherapy or hormonal therapy lead to a chronic sequelae of development with a relatively longer latent period.[17] In our study population, chemotherapy was offered to half of the patients and radiation was delivered in one third of patients for management of index primary. Median duration of development of the second primary after chemotherapy was 21 months (range: 0–188 months) as compared to 44 months (range: 0–423 months) postradiotherapy. Three patients who developed in-field second primary in relation to radiotherapy portals, SPM was observed at intervals of 102, 388, and 423 months. Various chemotherapy regimens are known for its leukemogenic effects.[21] In our study, acute myeloid leukemia (AML) was observed as the second primary in two cases, of which a single case was managed with chemotherapy. Anthracycline and taxane based chemotherapy was delivered to this breast cancer patient who developed AML after 30 months of latency.

In an era of targeted therapy, few drugs used for cancer control targeting a specific cell cycle pathway, might actually lead to development of another tumor.[22],[23] BRAF (rapidly accelerated fibrosarcoma) inhibitor vemurafenib, used for treatment of melanoma shows an increased rate of secondary cutaneous malignancies and requires careful and regular dermatological evaluation for patients on treatment.[22] Also, for the Poly (ADP-ribose) Polymerase (PARP) inhibitor olaparib used in treatment of ovarian carcinoma, cases of myelodysplastic syndromes, and AML have been observed and careful monitoring of patients for hematological toxicity is recommended.[22],[23] Hormonal therapy in breast cancer increases the risk for endometrial, gastric, colon, and ovarian cancers. The association of tamoxifen administration for breast carcinoma with increasing risk for endometrial carcinoma is well known.[24] In our study, hormonal therapy was administered in two breast cancer patients who later developed duodenal adenocarcinoma and malignant mixed mullerian tumor of the uterus.

Treatment and survival outcomes

Primaries can present either as a synchronous or metachronous cancer. Their management goals create a dilemma for the treating clinician.[8] For metachronous presentation, factors such as tumor burden of index primary, intent with which index primary was treated, toxicities of anti-neoplastic agents, and latent interval between two primaries should be used while making a decision. Carcinogenic and genetic factors predisposing to second primary should be addressed. However, management of synchronous primaries appear to be more challenging due to rarity of this scenario and lack of level I evidence in managing these cancers. In our population, management of two patients of ovarian cancer along with the second primary of uterine cervix and uterine corpus raised particular concerns. Both these patients were offered initial chemotherapy followed by surgery and radiation. Discussion in multidisciplinary team meetings and multimodality treatment is required in most of the patients.

Age of presentation, disease site, clinical stage, performance status, interval between two primaries, and toxicities of antineoplastic therapies determine overall survival after diagnosis of second primary.[18],[25] In our population, at a median follow-up 365 days, 21 patients were found to be disease free for both the primaries.

Limitations of the study

Our study is a retrospective analysis of data of patients obtained from our hospital-based registry and might not represent the true incidence of dual primaries in the population. The lack of data on genetic testing has further restricted our analysis. However, in this study we have attempted to evaluate a relatively heterogeneous group of patients presenting to a single institute with varied diagnosis and different stages. Also, this is one of the few studies that reports treatment modalities and clinical outcomes, with a reasonably longer follow up period of patients presenting with multiple primaries.


Second primaries are not uncommon. The study emphasizes the importance of detecting second primary in all cancer patients with stringent surveillance, improved diagnostic and screening procedures. Clinicians should be aware of it and offer multidisciplinary management to improve clinical outcomes.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Parry C, Kent EE, Mariotto AB, Alfano CM, Rowland JH. Cancer survivors: A booming population. Cancer Epidemiol Biomarkers Prev 2011;20:1996–5.
2Rajalingam R, Javed A, Gondal R, Arora A, Nag HH, Agarwal AK. Non-familial double malignancy of the colon and ampulla of vater: A case report and review of literature. Saudi J Gastroenterol 2012;18:143-5.
3Angurana SL, Kapoor R, Kumar P, Khosla D, Sharma SC, Patel FD. Quadruple malignancy in a single patient: A case report and comprehensive review of literature. J Can Res Ther 2010;6:230-2.
4Kumar V, Singh K, Tatke M, Rathi AK, Shekhar S, Bahadur AK. Synchronous anaplastic oligodendroglioma and carcinoma tongue: A rare association. J Cancer Res Ther 2010;6:227–9.
5Bishen KA, Singh A. A case of dual malignancy: Presenting the necessity for extensive sampling for pathologic examination. J Oral Maxillofac Pathol 2011;15:306–10.
6Jena A, Patnayak R, Lakshmi AY, Manilal B, Reddy MK. Multiple primary cancers: An enigma. South Asian J Cancer 2016;5:29–32.
7Working Group Report. International rules for multiple primary cancers (ICD-0 third edition). Eur J Cancer Prev 2005;14:307-8.
8Vogt A, Schmid S, Heinimann K, Frick H, Herrmann C, Cerny T, et al. Multiple primary tumours: Challenges and approaches, a review. ESMO Open 2017;2:e000172.
9Owen LJ. Multiple malignant neoplasm. JAMA 1921;76:1329-33.
10Vaamonde P, Martín C, del Río M, LaBella T. Second primary malignancies in patients with cancer of the head and neck. Otolaryngol Head Neck Surg 2003;129:65–70.
11Etiz D, Metcalfe E, Akcay M. Multiple primary malignant neoplasms: A 10-year experience at a single institution from Turkey. J Cancer Res Ther 2017;13:16–20.
12Coyte A, Morrison DS, McLoone P. Second primary cancer risk - the impact of applying different definitions of multiple primaries: Results from a retrospective population-based cancer registry study. BMC Cancer 2014;14:272.
13Demandante CGN, Troyer DA, Miles TP. Multiple primary malignant neoplasms. Am J Clin Oncol 2003;26:79-83.
14Spratt JS Jr, Hoag MG. Incidence of multiple primary cancers per man-year of follow up: 20-year review from the Ellis Fischel State Cancer Hospital. Ann Surg 1966;164:775–84.
15Warren S, Gates O. Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer 1932;16:1358–414.
16Weir HK, Johnson CJ, Thompson TD. The effect of multiple primary rules on population-based cancer survival. Cancer Causes Control 2013;24:1231–42.
17Coebergh J-W, Martín-Moreno JM, Soerjomataram I, Renehan AG. The long road towards cancer prevention: 4 steps backward and 8 forward. Eur J Cancer 2010;46:2660–2.
18Amer MH. Multiple neoplasms, single primaries, and patient survival. Cancer Manag Res 2014;5:119–34.
19Hayat MJ, Howlader N, Reichman ME, Edwards BK. Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 2007;12:20–37.
20Hankey BF, Ries LA, Edwards BK. The surveillance, epidemiology, and end results program: A national resource. Cancer Epidemiol Biomarkers Prev 1999;8:1117–21.
21Leone G, Fianchi L, Voso MT. Therapy-related myeloid neoplasms. Curr Opin Oncol 2011;23:672-80.
22Lacouture ME, O'Reilly K, Rosen N, Solit DB. Induction of cutaneous squamous cell carcinomas by RAF inhibitors: Cause for concern? J Clin Oncol 2012;30:329–30.
23Ricks TK, Chiu H-J, Ison G, Kim G, McKee AE, Kluetz P, et al. Successes and challenges of PARP inhibitors in cancer therapy. Front Oncol 2015;14:222.
24Kushner CJ, Hwang W-T, Wang S, Solin LJ, Vapiwala N. Long-term risk of second malignancies in women after breast conservation therapy for ductal carcinoma in situ or early-stage breast cancer. Breast Cancer Res Treat 2018;170:45–53.
25Kollias J, Ellis IO, Elston CW, Blamey RW. Prognostic significance of synchronous and metachronous bilateral breast cancer. World J Surg 2001;25:1117–24.