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  Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 1  |  Page : 70-73
 

Every distant deposit is not a metastasis: Synchronous primaries do exist


Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Date of Web Publication4-Apr-2019

Correspondence Address:
Vikas Asati
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_637_17

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 » Abstract 


BACKGROUND: Synchronous occurrence of two malignant tumors is a rare event. With increasing use of sophisticated imaging modalities for staging, synchronous multiple tumors are more commonly detected now. Assuming the second primary malignancy as metastasis will change the intent of treatment from curative to palliative, greater awareness among oncologists is of paramount importance. This study is an example where thorough clinical examination and proper judgment resulted in correct diagnosis and appropriate treatment.
MATERIALS AND METHODS: This is a prospective descriptive study. Patients diagnosed with synchronous primary tumors from January 2016 to November 2017 at our center were reviewed.
RESULTS:
Ten cases of synchronous primary malignancies were detected during this period. A total of 20 primary tumors were diagnosed. Lung carcinoma and gastrointestinal malignancies were the most common (five patients each). The median age was 59.5 years. Seven patients were male. Second primary tumor was suspected in four patients during clinical examination, while in six patients it was suspected on imaging. Even in the presence of two primary tumors, three patients were treated with curative intent.
CONCLUSION: Possibility of synchronous second primary malignancy should always be kept whenever a distant deposit is detected at an unusual site. Histopathological evaluation of the lesion before assuming a metastasis will lead to accurate diagnosis, staging, and appropriate treatment.


Keywords: Double primary, multiple cancer, multiple primary tumors, synchronous malignancies


How to cite this article:
Babu G, Asati V, Lakshmaiah K C, Lokanatha D, Jacob LA, Babu S, Lokesh K N, Rudresh A H, Rajeev L K, Saldanha S, Chethan R, Koppaka D, Premalata C S. Every distant deposit is not a metastasis: Synchronous primaries do exist. Indian J Cancer 2019;56:70-3

How to cite this URL:
Babu G, Asati V, Lakshmaiah K C, Lokanatha D, Jacob LA, Babu S, Lokesh K N, Rudresh A H, Rajeev L K, Saldanha S, Chethan R, Koppaka D, Premalata C S. Every distant deposit is not a metastasis: Synchronous primaries do exist. Indian J Cancer [serial online] 2019 [cited 2019 Apr 19];56:70-3. Available from: http://www.indianjcancer.com/text.asp?2019/56/1/70/255490





 » Introduction Top


Multiple primary tumors are the occurrence of two or more different invasive malignancies at the same time (synchronous multiple primaries) or detected one after the other (metachronous multiple primaries) in the same individual. Surveillance Epidemiology and End Results (SEER) project and the International Association of Cancer Registries and International Agency for Research on Cancer (IACR/IARC) are two different organizations which provide the definition of multiple primaries for epidemiological purpose.[1] The incidence of multiple primary tumors varies between 2.15% and 17.4% depending on the definition used, duration of follow-up, and study being antemortem or postmortem.[2],[3],[4] With routine use of sophisticated imaging modalities such as positron emission tomography-computed tomography (PET/CT), even small asymptomatic lesions are being detected. Although histopathological examination is the definitive tool for confirmation, clinical acumen which includes detailed history, thorough examination, and different radiological features will save the patient from repeated biopsies.


 » Materials and Methods Top


Study type and objective

This was a prospective descriptive study carried out at Kidwai Cancer Institute, Bengaluru, India, from January 2016 to November 2017. The objective was to determine the clinicopathological characteristics of patients diagnosed with synchronous multiple invasive tumors and pattern of treatment offered.

Eligibility criteria

All newly diagnosed patients with synchronous multiple primary invasive tumors were included. The diagnosis at each primary site was proven by histological examination and appropriate immunohistochemical (IHC) markers. Multiple lesions in a single organ (eg. multiple invasive tumors in colon) were not considered synchronous even in the presence of histopathological evidence. In addition, isolated bilateral organ involvement (eg. breast or ovary) was not considered synchronous as their occurrence is quite common.

Methods

All patients with suspected synchronous multiple tumors, either detected clinically or on imaging modalities, were discussed in multidisciplinary meetings comprising medical oncologist, surgical oncologist, radiation oncologist, onco-pathologist, radiologist, and palliative care specialist. Adjuvant chemotherapy after definitive treatment was planned whenever indicated. If adjuvant chemotherapy was needed for more than one primary tumor, the chemotherapeutic agents with activity in both malignancies were planned. If the intent was palliative, the malignancy with aggressive nature was treated. Every possible effort was made to maintain the quality of life, in collaboration with palliative care unit.


 » Results Top


A total of 10 patients with synchronous primary tumors were diagnosed with 20 different primary tumors. Lung carcinoma and gastrointestinal malignancies were most common (five patients each). The median age was 59.5 years. Seven patients were male [Table 1].
Table 1: Summary of clinical, pathological, treatment, and outcome of all patients

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Imaging work-up for metastatic work-up resulted in detection of second tumor in six patients [three lung cancer, two renal cell carcinoma (RCC), and one rectal cancer]. RCCs are known to be detected incidentally, but detection of lung cancer is not common. Second primary tumor in four patients was diagnosed during clinical examination (two breast cancers and one floor of mouth cancer, one base of tongue) which highlights the importance of thorough clinical examination in a known cancer patient [Figure 1].
Figure 1: (a) Cranio-caudal view. (b) Mediolateral view. Mammogram showing nodular irregular homogeneous density present in the upper outer quadrant of right breast (BIRADS V – highly suggestive of malignancy)

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Mere presence of multiple malignant tumors is not a contraindication for treatment with curative intent. We could offer treatment with curative intent in 3 of 10 patients. Two primary tumors were RCC which were addressed with radical nephrectomy, two primary tumors were breast cancers which were treated with modified radical mastectomy, and another two primary tumors were rectal cancer and ovarian cancer treated by low anterior resection and interval cytoreduction, respectively. After surgery, these patients also received adjuvant chemotherapy (and radiotherapy if applicable) and currently are on regular follow-up. Palliative chemotherapy was offered to four patients.

Development of a new lesion may not always represent disease progression especially when the primary tumor is responding to therapy. In our series, one patient while receiving definitive radiation to lung cancer (squamous cell carcinoma) developed liver lesions. Biopsy of liver lesion detected adenocarcinoma, primary tumor being another new primary tumor (carcinoma rectum).


 » Discussion Top


Billroth published the first report of multiple primary malignancies in 1869.[5] Warren and Gates' criteria first tried to define the multiple tumors as either synchronous or metachronous in 1932. According to these criteria, each tumor must present with a definite picture of malignancy, each must be distinct, pathologically proven, and the possibility that one is a metastasis of the other must be excluded.[6] SEER project and IACR/IARC provides slightly different criteria for diagnosing multiple primary tumors.[1] IACR/IARC criteria are mostly used in the European countries. There are two important differences between these criteria. First, according to IACR/IARC, several groups of topography codes of International Classification of Diseases for Oncology 3rd Edition (ICD-O-3) are considered one site in the definition of multiple primaries (IARC 2004). For example, the colon is regarded as one site, whereas SEER considers single tumors of different parts of the colon as single tumors. Second, as per SE ER database, 2 months is the time period to differentiate between synchronous and metachronous primary tumor, whereas this period is 6 months as per IACR.[7]

The burden of second primary tumor is increasing due to increased participation in screening programs, use of sophisticated imaging modalities including PET/CT more frequently for staging of index primary tumor, and finally improved treatment in the past few decades. Treatment-related secondary malignancy usually hematological malignancies (acute myeloid leukemia) do occur with increased frequency when compared with general population.[8] Here are few important findings which helped us identify second primaries in our patients.

Unusual site of metastasis

Every tumor has specific site for metastasis, eg. lung cancer usually spreads to adrenal gland. In our study, patient number 2 presented with symptoms pertaining to carcinoma of the pancreas. Imaging revealed distant lesion in the right kidney which is not the usual site of metastasis for pancreatic cancer. Hence, before assuming renal deposit as a metastatic deposit, it is important to get tissue for the diagnosis.

Pattern of metastasis

Tumors follow a specific path for distant metastasis. Involvement of lung without involving the retroperitoneal lymph nodes in a patient of carcinoma cervix should raise the possibility of multiple tumors.

Common carcinogenicity (field cancerization)

Tobacco smoking is a common risk factor for multiple malignancies. Due to common exposure to lungs, head and neck regions, and upper gastrointestinal tract, multiple tumors may involve multiple organs either synchronously or metachronously.[9],[10] Patient numbers 1 and 4 are classical examples.

Suspicious lesion on imaging

Sometimes imaging performed for staging purpose also provides valuable information. Typical spiculated solid mass in the lung with mediastinal lymphadenopathy in the patient of rectal cancer made us rethink before considering pulmonary metastasis (patient number 9).

History of prior treatment of cancer

Cancer survivors always remain at increased risk for developing second primary tumors. The reason may be due to an increased genetic predisposition, continued exposure to carcinogen (smoking), and/or effect of prior therapy (radiation, chemotherapy).[11],[12]

The management of synchronous primary malignancies is a challenge and treatment depends on multiple factors. Surgery or radiation/chemoradiation can be offered if both primary tumors can be treated simultaneously (patient number 3) [Figure 2].[13],[14] PET/CT can also aid in decision-making and avoid unnecessary surgery, associated morbidity, and cost.[15]
Figure 2: (a) Adenocarcinoma rectum Grade I; (b) renal cell carcinoma

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The next question is whether both tumors need treatment or not? In our study, patient number 5 had prostate cancer (Gleason score 6) which was localized and lung cancer with adrenal metastasis (stage IV). The survival will be decided by the natural history of lung cancer and hence this patient needed treatment for only lung cancer. If both primary tumors need treatment, there can be a situation when one primary tumor can be treated with curative intent and other may require some neoadjuvant treatment. Patient number 2 one such example. RCC can be treated with radical nephrectomy. Pancreatic cancer is locally advanced and needs neoadjuvant treatment. If there is good response, pancreatic cancer can be addressed with second surgery (although intraoperatively omental deposit from pancreatic cancer was found). One can also argue to give neoadjuvant chemotherapy first and then address both primary tumors at a time, as we did in patient number 6. In such case, we should carefully choose the chemotherapeutic agents. Another situation is when both tumors need treatment and cure is not possible. In this situation, choosing a chemotherapy which is active in both malignancies may be the most practical option. In patient number 1, a combination of taxane and platinum agent will be effective for lung cancer and carcinoma base of tongue. Sometimes the performance status is poor and palliative care is the only option (patient number 5).

Sometimes multiple tumors develop due to common genetic defect. If this genetic defect can be targeted with single therapeutic agent, it will be effective in both malignancies. The use of poly-ADP-ribose polymerase (PARP) inhibitors in patients whose tumors display DNA repair defects (BRCA1/2) is a classical example. Patients with BRCA1/2 are at increased risk of multiple malignancies. In such cases, PARP inhibitors can be safe and effective. Patients with multiple tumors should also be evaluated for underlying inherited genetic conditions.[16],[17],[18]


 » Conclusion Top


Possibility of synchronous second primary malignancy should always be kept whenever a suspected distant deposit is detected at an unusual site. Histopathological evaluation of the lesion before assuming a metastasis will lead to accurate diagnosis, staging, and appropriate treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Coyte 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.  Back to cited text no. 1
    
2.
Gaskin HS, Hardy RE, Fletcher RL. Multiple primary malignancies in black patients. J Natl Med Assoc1981;73:1065-8.  Back to cited text no. 2
    
3.
Buiatti E, Crocetti E, Acciai S, Gafà L, Falcini F, Milandri C,et al. Incidence of second primary cancers in three Italian population-based cancer registries. Eur J Cancer 1997;33:1829-34.  Back to cited text no. 3
    
4.
Amer MH. Multiple neoplasms, single primaries, and patient survival. Cancer Manag Res 2014;6:119-34.  Back to cited text no. 4
    
5.
Bacon HE, Tavenner MC. Multiple primary malignant tumours involving the colon and rectum. Am J Surg1952;55:83-5.  Back to cited text no. 5
    
6.
Warren S, Gates O. Multiple primary malignant tumors: A survey of the literature and a statistical study. Am J Cancer 1932;16:1358.  Back to cited text no. 6
    
7.
Amer MH. Multiple neoplasms, single primaries, and patient survival. Cancer Manag Res 2014;6:119-34.  Back to cited text no. 7
    
8.
Vogt 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.  Back to cited text no. 8
    
9.
Morris LGT, Sikora AG, Patel SG, Hayes RB, Ganly I. Second primary cancers after an index head and neck cancer: Subsite-specific trends in the era of human papillomavirus– associated oropharyngeal cancer. J Clin Oncol 2010;29:739-46.  Back to cited text no. 9
    
10.
Morris LG, Sikora AG, Hayes RB, Patel SG, Ganly I. Anatomic sites at elevated risk of second primary cancer after an index head and neck cancer. Cancer Causes Control 2011;22:671-9.  Back to cited text no. 10
    
11.
Amemiya K, Shibuya H, Yoshimura R, Okada N. The risk of radiation-induced cancer in patients with squamous cell carcinoma of the head and neck and its results of treatment. Br J Radiol2005;78:1028-33  Back to cited text no. 11
    
12.
Gursel B, Meydan D, Özbek N, Ozdemir O, Odabas E. Multiple primary malignant neoplasms from the black sea region of Turkey. J Int Med Res2011;39:667-74  Back to cited text no. 12
    
13.
HeroiuCataloiu AD, Danciu CE, Popescu CR. Multiple cancers of the head and neck. Maedica (Buchar) 2013;8:80-5.  Back to cited text no. 13
    
14.
Zhang Z, Gao S, Mao Y, Mu J, Xue Q, Feng X,et al. Surgical outcomes of synchronous multiple primary non-small cell lung cancers. Sci Rep 2016;6:23252.  Back to cited text no. 14
    
15.
Ishimori T, Patel PV, Wahl RL. Detection of unexpected additional primary malignancies with PET/CT. J Nucl Med2005;46:752-7.  Back to cited text no. 15
    
16.
Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol 2005;23:276-92.  Back to cited text no. 16
    
17.
Paluch-Shimon S, Cardoso F, Sessa C, Balmana J, Cardoso MJ, Gilbert F, et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO clinical practice guidelines for cancer prevention and screening. Ann Oncol 2016;27:v103-10.  Back to cited text no. 17
    
18.
Balmaña J, Balaguer F, Cervantes A, Arnold D; ESMO Guidelines Working Group. Familial risk-colorectal cancer: ESMO clinical practice guidelines. Ann Oncol 2013;24:vi73-80.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

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