Second Primary Malignant Neoplasms : A Clinicopathological Analysis from a Cancer Centre in India

The occurrence of multiple neoplasms is not rare. The reported incidence ranges from 0.734-11.3 % depending on whether the study is ante mortem or postmortem (Spratt and Hoag, 1966; Hadju and Hadju, 1968; Berge et al., 1969; Haddow et al., 1972; Berg and Schottenfeld , 1977; Bordin et al., 1977; Newell and Krementz, 1977; Lee et al., 1982; Watanabe et al., 1984; Flannery et al., 1985; Storm et al., 1985; Teppo et al., 1985; Engin, 1994; Aydiner et al., 2000). The Second primary malignancy (SPM) is a second denovo malignant neoplasm occurring in a patient with known cancer. A SPM can arise either synchronously or metachronously. The criteria used for the diagnosis of multiple primary cancers were first given by Warren and Gates (Table 1) and refined later (Warren and Gates, 1932; Moertel et al., 1961; Curtis and Ries,


RESEARCH ARTICLE
Second Primary Malignant Neoplasms: A Clinicopathological Analysis from a Cancer Centre in India Narendra Hulikal 1 *, Satadru Ray 2 , Joseph Thomas 3 , Donald J Fernandes 4 2006; Morris et al., 2010).The presence of dysplastic changes in the second primary site strongly suggests a new primary.The aim of the study was to report our observation of increasing incidence of multiple primary cancers particularly synchronous malignancies.Further, with the newer treatment modalities cancer patients are surviving longer to develop metachronous new primary which may in part be related to the treatment of earlier malignancy.It is also true that with the newer and improved diagnostic modalities such as positron emission tomography (PET), rates of picking up indolent tumors have increased contributing further to the apparent increase in incidence of multiple primary malignancies (Agrawal, 2007;Gursel et al., 2011).Data regarding the occurrence and outcome of such multiple tumors particularly from the Indian subcontinent are limited to a few case reports only.Hence we came up with this study to document such an occurrence and review the relevant literature (Agrawal, 2007).

Materials and Methods
The study is a retrospective collection of the prospective data from the hospital database of patients either presenting with histologically proven synchronous or metachronous double primaries as defined by the

Table 1. Warren and Gates Criteria for Diagnosis of Multiple Primary Malignancies
1.Each of the tumors must be malignancy confirmed by histology 2. Each must be geographically separate and distinct.The lesions should be separated by normal mucosa.3. Probability of one being the metastasis of the other must be excluded.
above criteria over a period of five years from July 2008 to June 2012.The time interval to differentiate between synchronous or metachronous was taken as 6 months as reported by several authors (Moertel, 1977;Gluckman and Crissman, 1983;Poon et al., 1998;Suzuki et al., 2002;Cheng et al., 2005;Morris et al., 2010)

Results
Over a period of 5 years total 38 cases of multiple primary malignancies were observed out of which 13 were synchronous (35%).The median age at the diagnosis of primary malignancy was 51 years (range 30-81).Twenty one of 38 double malignancies were observed in females.The most common site of primary tumor was head and neck (21 cases) followed by breast (9 cases), gastrointestinal tract (4 cases), gynecological cancer (3 cases) and soft tissue tumor (1 case) (Figure 1).The age range for the second primary was 36-84.Among the second malignancy most common site was again head and neck (17 cases), followed by gastrointestinal tract (7 cases), genitourinary and gynecological cancers (3 cases each) (Figure 2).

Synchronous SPM
The median age at diagnosis was 60 years and age range was 48-81 years.There were 9 female patients in this group.Among synchronous lesions majority were diagnosed incidentally either during evaluation of the primary (8 cases) or at surgery or on final histopathology (1 each).One patient with lip cancer developed acute urinary retention in the postoperative period, evaluation of which lead to the detection of incidental prostate cancer.Three others had specific symptoms on further evaluation of which they were found to harbor second cancer.The age at presentation ranged from 55-81 years and 9 of the 13 patients were female (69%).Total 6 of the 13 (46%) patients underwent primary surgery for both the primary and secondary tumor at a single stage.Later they were referred for adjuvant treatment if any depending on the final histopathology report.Two patients received primary concurrent chemoradiation for both the tumors.One of the patients refused treatment.One patient underwent TURBT for bladder tumor and received neoadjuvanct chemotherapy for breast cancer and finally underwent mastectomy and chest wall irradiation.Three other patients underwent surgery for only primary and did not turn up for the treatment of second tumor.Total 3 of the 8 patients available for follow up in this group developed metastatic disease and expired.Only 5 patients are alive and disease free.The details are depicted in the Figure 3 and Table 2.

Metachronous SPM
The age at development of second tumor ranged from 36-84 years (see Table 3 and Figure 4).The median age at primary diagnosis was 49 years and for the development of SPM was 55 years.There were 13 male patients in this group.The time interval between appearance of primary and secondary in the metachronous group varied from 8 DOI:http://dx.doi.org/10.7314/APJCP.2012.13.12.6087 Second Primary Malignant Neoplasms: A Clinicopathological Analysis from a Cancer Centre in India months to 18 years.Among the 25 tumors 20 patients had received prior radiotherapy with or without concurrent or sequential chemotherapy.A total of 12 patients developed second tumor within the (50%) radiation field.The time interval between completion of the treatment and appearance of the second tumor ranged from 9 months to 17 years.The most common combination was a head and neck primary developing another head and neck primary (13 of 24 cases, 54%).Total 22 patients completed treatment for the second malignancy, 21 of them

Discussion
The occurrence of multiple primary malignancies can be due to various genetic events or common environmental risk factors.Various syndromes associated with the DNA microsatellite instability such as Lynch I and II syndromes are associated with the development of multiple primary tumors in different organs.Mutation in multiple tumor suppressor genes such as p16, p53, PTEN and Rb gene are linked to development of tumors in breast, soft tissue, esophagus and other sites.Patients with head and neck squamous cell cancer (HNSCC) are known to have 36% cumulative life time risk of developing SPM over 20 years (Morris et al., 2011).This is attributed to field carcinogenesis related to exposure to common risk factors like tobacco smoking and alcohol consumption (Morris et al., 2010;2011).In our study also head and neck cancers were the most common group to harbor of develops a new primary (21 of 38 cases).Among the head and neck cancer survivors who developed second head and neck cancer was 66% (14 of 21 cases).Another factor to be considered particularly among metachronous tumors is second cancers induced by prior irradiation or chemotherapy.Second tumors induced by prior radiation or chemotherapy usually manifest after a latent period of 15-20 years (Oddou et al., 1998).
Most of the synchronously diagnosed second tumors in our study were incidentally diagnosed.They were detected during the staging evaluation of the primary tumor.Only 3 patients had symptoms attributable to their second tumor.When such tumors are incidentally detected they should not be dismissed as metastatic disease.Any unusual site of metastasis should be thoroughly evaluated to rule out the rare possibility of second primary.A baseline PET-CT may aid in the diagnosis of such multiple tumors and in some cases this helps in the therapeutic plan (Ishimori et al., 2005;Narendra et al., 2012).When multiple tumors are pathologically confirmed at the time of presentation itself, each tumor should be evaluated and staged as independent tumors.They should be treated aggressively with the curative intent depending on the stage of each disease to achieve maximum therapeutic benefit.If surgery is needed for both the tumors, it can be done in a single stage in majority of the cases with low rates of morbidity and mortality (Slip et al., 2002;Suzuki et al., 2002).In our study we have done safely right hemicolectomy with esophagectomy and modified radical mastectomy with radical nephrectomy as single stage procedures.Only duration of the surgery and need for transfusion increased.
The development of metachronous malignant tumors in the upper aerodigestive tract in the presence of an index HNSCC is well described.The reported risk of developing SPM in a known case of HNSCC is estimated to be 2-6% per year of follow up (Tepperman et al., 1981;Sturgis and Miller, 1995;Leon et al., 1999;Slip et al., 2002;Yamamoto et al., 2002 ;Morris et al., 2011).This has been linked to exposure to common carcinogens and concept of field cancerization and condemned mucosa (Morris et al., 2010;Morris et al., 2011).The treatment related SPM tumors may arise in the setting of use of certain chemotherapeutic agents such as alkylating agents, topoisomerase II inhibitors or therapeutic irradiation of the index primary (Amemiya et al., 2005;Gursel et al., 2011).Such radiation induced tumors arise in the field of radiation and usually after a latent period of 10-15 years.Hence a close clinical follow up is recommended for long periods to detect SPM at the earliest.Again a strong clinical suspicion and thorough evaluation is needed to differentiate between metastatic disease and a SPM neoplasm.Before embarking on curative treatment of the new tumor, every effort should be made to look for the sites of metastasis from the primary tumor.If detected none, aggressive treatment of the SPM is advisable to achieve maximum clinical benefit.One special issue in the management of metachronous head and neck SPM affecting a HNSCC patient which may compromise the outcome is the radiation tolerance.Further, it could be a difficult task on the part of the treating clinician to educate patient and his relatives regarding the occurrence of two primary tumors.A considerable proportion of these patients, on detection of the new primary refuse any further treatment due to psychological distress, socioeconomic and other reasons.The present study has shown that when such tumors are detected and treated appropriately they do achieve prolonged survival or disease free status.As a part of preventive strategy, the patients particularly with HNSCC should be encouraged to stop use of alcohol and tobacco in any form, adopt healthy diet and exercise regularly.At present there is no evidence to recommend use of chemo preventive agents such as beta carotenoids and antioxidants in the prevention of SPM (Day et al., 1994a;1994b;Khuri et al., 2001).
In conclusion, SPM is not uncommon, can occur synchronously or metachronously.With the advent of newer diagnostic and staging modalities as well as progress in the management of common cancer the detection of SPM has increased.A strong clinical suspicion and thorough evaluation would go a long way in the management of these tumors.Most of the operable synchronously occurring SPM can be resected in single stage.A regular follow up can detect most of the metachronous SPMs at an early stage.

Figure
Figure 1.Site Distribution of the Primary Malignancy

Table 2 . Summary of Synchronous SPM
IDC Left breast MRM, chemotherapy, EBRT Clear cell histology left kidney: incidental Radical nephrectomy* Alive and disease

Table 3 . Summary of Metachronous SPM (n=25)
for the tumor, and one patient with ovarian carcinoma who developed lung primary received chemotherapy alone.Three patients refused treatment.Seven patients developed metastasis or recurrent disease and died.One patient died postoperatively and another developed bile leak due to second surgery and expired within one month of surgery.Four patients lost follow up and one patient is alive with the disease.Remaining 12 patients (50%) are alive and are free of disease.