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  Table of Contents  
Year : 2019  |  Volume : 56  |  Issue : 1  |  Page : 35-36

Second primary malignancies in patients with radiotherapy-treated laryngeal carcinoma - A commentary

1 Department of Radiation Oncology, Max Superspeciality Hospital, Delhi, India
2 Department of Radiation Oncology, MAMC and Lok Nayak Hospital, New Delhi, India

Date of Web Publication4-Apr-2019

Correspondence Address:
Deepti Sharma
Department of Radiation Oncology, Max Superspeciality Hospital, Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_518_18

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How to cite this article:
Sharma D, Sharma N, Goel V. Second primary malignancies in patients with radiotherapy-treated laryngeal carcinoma - A commentary. Indian J Cancer 2019;56:35-6

How to cite this URL:
Sharma D, Sharma N, Goel V. Second primary malignancies in patients with radiotherapy-treated laryngeal carcinoma - A commentary. Indian J Cancer [serial online] 2019 [cited 2020 Oct 31];56:35-6. Available from:

Second primary malignancy (SPM) is defined as a second de novo malignant neoplasm with known cancer. Occurrence of secondary malignancy is fairly common in long-term survivors of laryngeal cancer, and it is also the second leading cause of death in patients with head and neck squamous cell carcinoma (HNSCC). There has been substantial research in characterization on second primary cancers, and as radiotherapy is associated with increased risk of developing SPM, there is need to further delve into the study to quantify dose–response relationships with radiation and chemotherapy.[1] This issue of IJC contains a report by Ozdemir Y and Topkan E which refers to this not uncommon problem that oncologists face.[2] Warren and Gates first gave the criteria used for the diagnosis of SPM. Warren and Gates' criteria for diagnosis of multiple primary malignancies are as follows:[3]

  1. Each of the tumors must be malignant, each confirmed by histology
  2. Each must be geographically separate and distinct. The lesions should be separated by normal mucosa
  3. The probability of one being the metastasis of the other must be excluded.

The criteria were modified by the National Cancer Institute, which states that it can be synchronous, if diagnosed within 6 months of the primary tumor, or metachronous invasive solid cancer developing ≥6 months after an index HNSCC. The second cancer should be of nonsquamous cell origin or should develop in different location to classify as SPM. For an SCC, developing in the same location, it is classified as SPM only if more than 60 months have passed since diagnosis of index malignancy.[4]

SPM is one of the most important causes of mortality in patients with HNSCC during prolonged follow-up.[5] It has been found that SPM has contributed to approximately one-third of HNSCC deaths which is about three times the number of deaths caused due to distant metastases.[6],[7]

Second primary cancers are grouped into three major categories according to predominant etiologic influences (i.e., treatment-related, syndromic, and those due to shared etiologic factors), emphasizing the nonexclusivity of these groups.[8]

Various factors have attributed to SPM in head and neck cancers, for example, environmental carcinogens, such as tobacco and alcohol leading to field cancerization, radiation therapy, and viral infection such as EBV and HPV infection.[9],[10],[11],[12] The most common sites for development of SPM risk after a primary HNSCC are the head and neck, lung, and esophagus.[6],[7],[8]

In field cancerization, there is replacement of the normal cell population by a cancer-primed cell population that may show no morphological change, as a result of long-term exposure to carcinogenic agents, such as tobacco and alcohol leading to common carcinomas of the lung, colon, skin, prostate, and bladder. Due to field cancerization phenomenon, premalignant and malignant changes may emerge in organs at the vicinity of primary cancer site or at more distant organs sharing the same risk factors.[6] In a study by Sharma D et al., 3 cases out of 38 cases of SPM of head and neck region are most probably due to field cancerization.[12]

Radiation is associated with increased risk of second malignancies, and the modified Cahan's criteria for diagnosis of radiation-induced malignancy (RIM) are as follows: (a) an RIM must have arisen in an irradiated field with a gap of more than 4 years between the initial irradiation and the alleged induced malignancy; (b) the two tumors must be of different histology; and (c) the tissue in which the alleged induced tumor arose must have been normal (i.e., metabolically and genetically normal) prior to radiation exposure.

The most common histologic subtypes of RIM are squamous cell carcinoma followed by soft tissue sarcoma. In 1989, a study by Cooper et al. showed 110 second, independent, malignant tumors out of 928 patients with squamous cell carcinoma of head and neck.[13] In a study by Sharma D et al., a total of five cases were developed in previous irradiated field, of which three cases were in the head and neck region.[9]

Studies have demonstrated that SPM is usually associated with decreased overall survival (OS) in patients with Head and neck cancer (HNC). In a study by Chu et al., the 10-year OS was 11% higher in non-SPM patients when compared with those with SPM in patients with laryngeal and hypopharyngeal carcinomas treated with radical surgery with/without radiotherapy (RT).[14] Rennemo et al. evaluated the impact of SPM on survival rates of patients with head and neck primary cancer. They identified that in patients who developed SPT, the overall median survival was 6 years and it was 3 years in those who did not have SPT (P < 0.05).[15]

Overall, it is reported that SPMs in the head and neck region are associated with better prognosis than SPMs in other regions of the body, especially the lung or esophagus. This may be related to the more aggressive tumor types and presentation of disease at an advanced stage. Lin et al. also found better survival in patients with SPM located in the head and neck region when compared with SPM in the lung (66% and 19%, respectively; P < 0.001).[16]

The patients who develop an SPM have a significantly worse prognosis. Thus, the best strategies are prevention and early diagnosis (especially premalignant lesions). After treatment of the primary tumor, it is important to maintain close follow-up of patients and always properly investigate their complaints and any suspicious lesion. In selected cases, the routine use of triple endoscopy helps in the diagnosis of premalignant lesions and invasive tumors. Furthermore, the use of 18F-FDG-PET/CT during follow-up is a promising examination for early detection of SPM.

  References Top

Baxi SS, Pinheiro LC, Patil SM, Pfister DG, Oeffinger KC, Elkin EB. Causes of death in long-term survivors of head and neck cancer. Cancer 2014;120:1507-13.  Back to cited text no. 1
Ozdemir Y, Topkan E. Second primary malignancies in laryngeal carcinoma patients treated with definitive radiotherapy. Indian J Cancer 2019;56:29-34.  Back to cited text no. 2
  [Full text]  
Warren S, Gates O. Multiple primary malignant tumors: A survey of the literature and statistical study. Am J Cancer 1932;16:1358-414.  Back to cited text no. 3
Curtis RE, Freedman DM, Ron E, Ries LAG, Hacker DG, Edwards BK, et al. (eds). New Malignancies among Cancer Survivors: SEER Cancer Registries, 1973-2000. Bethesda, MD: National Cancer Institute; 2006.NIH Publ. No. 05-5302; p. 9-14.  Back to cited text no. 4
Vikram B. Changing patterns of failure in advanced head and neck cancer. Arch Otolaryngol 1981;110:564-5.  Back to cited text no. 5
León X, Quer M, Diez S, Orús C, López-Pousa A, Burgués J. Second neoplasm in patients with head and neck cancer. Head Neck 1999;21:204-10.  Back to cited text no. 6
Garavello W, Ciardo A, Spreafico R, Gaini RM. Risk factors for distant metastases in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2006;132:762-6.  Back to cited text no. 7
Travis LB, Rabkin CS, Brown LM, Allan JM, Alter BP, Ambrosone CB, et al. Cancer survivorship—Genetic susceptibility and second primary cancers: Research strategies and recommendations. J Natl Cancer Inst 2006;98:15-25.  Back to cited text no. 8
Curtius K, Wright NA, Graham TA. An evolutionary perspective on field cancerization. Nat Rev Cancer. 2018;18:19-32.  Back to cited text no. 9
Travis LB. The epidemiology of second primary cancers. Cancer Epidemiology Biomarkers and Prevention 2006;15:2020-6.  Back to cited text no. 10
Chuang SC, Scelo G, Tonita JM, Tamaro S, Jonasson JG, Kliewer EV, et al. Risk of second primary cancer among patients with head and neck cancers: A pooled analysis of 13 cancer registries. Int J Cancer 2008;123:2390-6.  Back to cited text no. 11
Sharma D, Singh G, Kakkar N, Raj S. Second primary malignancy: A retrospective analysis report from a tertiary cancer center of North India. Indian J Cancer 2016;53:595-9.  Back to cited text no. 12
[PUBMED]  [Full text]  
Cooper JS, Pajak TF, Rubin P, Tupchong L, Brady LW, Leibel SA, et al. Second malignancies in patients who have head and neck cancer: Incidence, effect on survival and implications based on the RTOG experience. Int J Radiat Oncol Biol Phys 1989;17:449-56.  Back to cited text no. 13
Chu PY, Chang SY, Huang JL, Tai SK. Different patterns of second primary malignancy in patients with squamous cell carcinoma of larynx and hypopharynx. Am J Otolaryngol 2010;31:168-74.  Back to cited text no. 14
Rennemo E, Zätterström U, Boysen M. Impact of second primary tumors on survival in head and neck cancer: An analysis of 2,063 cases. Laryngoscope 2008;118:1350-6.  Back to cited text no. 15
Lin K, Patel SG, Chu PY, Matsuo JM, Singh B, Wong RJ, et al. Second primary malignancy of the aerodigestive tract in patients treated for cancer of the oral cavity and larynx. Head Neck 2005;27:1042-8.  Back to cited text no. 16


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