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Table of Contents
Year : 2021  |  Volume : 9  |  Issue : 2  |  Page : 122-124

Epidermal growth factor receptor mutated lung cancer presenting as synchronous with a recurrent nonhuman papillomavirus-related head-and-neck squamous cell carcinoma

1 Department of Laboratory Medicine, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, Telangana, India
2 Department of Surgical Oncology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, Telangana, India
3 Department of Medical Oncology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, Telangana, India

Date of Submission12-Jun-2021
Date of Decision27-Oct-2021
Date of Acceptance28-Dec-2021
Date of Web Publication15-Mar-2022

Correspondence Address:
Dr. Daphne Fonseca
Department of Laboratory Medicine, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad - 500 034, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jihs.jihs_17_21

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A patient with nonhuman papillomavirus (HPV)-related head-and-neck cancers is at an increased risk of developing second primary malignancies. We present a case of non-HPV-related squamous cell carcinoma (SCC) of the left lower alveolus who presented with locoregional recurrence in the left upper lip 3 years after initial treatment with chemoradiotherapy along with a synchronous Epidermal growth factor receptor(EGFR)mutated lung adenocarcinoma. Comprehensive genomic profiling will guide diagnosis and therapy in these cases. Registry of synchronous tumors would help design protocols for better management.

Keywords: Mutated lung adenocarcinoma, genomic profiling, nonhuman papillomavirus-related head-and-neck squamous cell carcinoma, second primary malignancy

How to cite this article:
Fonseca D, Arya SS, Kunteepuram V, N. Raju K V, Rajappa S. Epidermal growth factor receptor mutated lung cancer presenting as synchronous with a recurrent nonhuman papillomavirus-related head-and-neck squamous cell carcinoma. J Integr Health Sci 2021;9:122-4

How to cite this URL:
Fonseca D, Arya SS, Kunteepuram V, N. Raju K V, Rajappa S. Epidermal growth factor receptor mutated lung cancer presenting as synchronous with a recurrent nonhuman papillomavirus-related head-and-neck squamous cell carcinoma. J Integr Health Sci [serial online] 2021 [cited 2023 Jun 10];9:122-4. Available from: https://www.jihs.in/text.asp?2021/9/2/122/339644

  Introduction Top

Second primary malignancy (SPM) is considered synchronous when the cancer is diagnosed at the same time as an index tumor or during its initial workup.[1] Second primary lung cancer generally has a poor prognosis in patients having nonhuman papillomavirus (HPV)-related head-and-neck squamous cell cancer (HNSCC).[2],[3] Young patients who develop non-HPV-related HNSCC have an aggressive disease, but owing to lesser comorbidities, they generally have longer overall survival even after recurrence.[4] Although locoregional control of HNSCC has improved over the last couple of decades, owing to distant metastasis and SPM, long-term survival has minimally improved.[5] We report a case of HNSCC who presented with locoregional recurrence and synchronous oncogenic driver mutation-related lung adenocarcinoma after 3 years of initial treatment.

  Case Report Top

A 41-year-old male diagnosed as squamous cell carcinoma (SCC) of the left lower alveolus underwent left composite resection followed by radiotherapy and chemotherapy that was on regular follow-up presented to our institute 3 years after initial treatment with an ulcerative lesion on his upper lip, right side. On examination, a 3 cm × 3 cm ulceroproliferative lesion was noted over the upper lip right side involving half of the lip. A multi-slice spiral computed tomography chest performed as a preoperative workup revealed a 3 cm × 2.8 cm soft-tissue density in the superior segment of the left lower lobe with the differential diagnosis of metastasis or a second primary in the lung. On histopathological examination, a diagnosis of SCC was rendered for lip lesion and non-small cell cancer favors adenocarcinoma for lung lesion [Figure 1].
Figure 1: (a) Photomicrograph showing an infiltrating lesion as sheets and islands, (b) Photomicrograph showings dysplastic squamous nests with dyskeratosis, hyperchromatic nucleus, and prominent nucleoli, (c) Negative for p16 IHC, (d) Grossly, lung showing an infiltrating firm gray-white lesion, (e) Photomicrograph showing tumor arranged in papillary pattern lined by oval cells with moderate amount of cytoplasm, hyperchromatic nucleus, and prominent nucleoli, (f) EGFR: c. 2235_2249delGGAATTAAGAGAAGC, p. (Glu746_Ala750del) – next-generation sequencing reads as from the integrative genomic viewer software showing blank region indicating the deletion (red arrow) of exon 19 of the EGFR gene

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The patient underwent wide local excision for the lip lesion with bilateral advancement flap followed by left lung lower lobectomy along with mediastinal lymph node dissection with an interval of 3 weeks which was followed by adjuvant chemotherapy. Follow-up till date has been uneventful.

  Discussion Top

Gluckmann classified multiple primary malignancies (MPMs) based on time interval between diagnoses of two malignancies as synchronous or metachronous. Second malignancies are classified as synchronous when two malignancies are present simultaneously or occur within a 6-month period of diagnosis of first tumor and as metachronous when second malignancy is diagnosed beyond 6-month interval.[1]

MPMs occur with long latency period in other organs at different time points owing to shared etiology (history of smoking/tobacco chewing), early genetic, epigenetic events, and treatment-related causes.[6],[7]

The occurrence of MPMs can be a random event driven by distinct somatic gene mutation and can have a distinct mutation profile even under identical genetic background.[8]

MPMs either synchronous or metachronous are seen in 9.7% of head-and-neck cancer patients, and 46.9% of these include synchronous malignancies.[7],[9]

SPMs either synchronous or metachronous occur frequently in the lung (45.8%) and esophagus (10.3%). Risk of metachronous second primary lung cancer following HNSCC is 5.8%, 11.4%, and 16.4% at 5, 10, and 15 years, respectively. Recurrences in HNSCC often manifest in the first 3 years after treatment.[10]

In head-and-neck epithelial cancers, field cancerization leads to genetic variation like aberrant DNA methylation (epigenetic changes) which results in development of second primary tumor at different upper aerodigestive tract (UADT) sites. However, for origin of tumor with different histologies in non-UADT sites, multiple etiologies and/or risk factors are involved.[7]

Molecular classification proposed by Braakhuis et al. classifies SPM after index HNSCC by comparing molecular patterns between index tumor and the second tumor as a recurrence/metastasis if the second tumor shares the same molecular alterations with the index tumor, as a second field tumor if the index tumor and the second tumor share only some genetic alterations, and as a SPM if the genetic profiles of two tumors are unrelated.[11]

Simultaneous presentation of lung malignancy as synchronous or metachronous with head-and-neck cancer is a major challenge. Genomic profiling of MPMs helps in better understanding and treatment of these patients. To exclude a metastasis in a tumor with similar histologies occurring simultaneously, single-nucleotide polymorphism-based loss of heterozygosity plays a role.[11]

To determine whether the distinct tumors in the same patient arise from a common ancestral cell or not, clonal-relatedness studies are performed which include studies comparing patterns of losses of heterozygosity and genome-wide copy number changes evaluated by whole-exome sequencing (WES) on the tumors.[8],[12]

However, the somatic fingerprints of the tumors may be different even if the tumors are clonal because somatic changes may have occurred after the tumors have evolved separately.[8],[12]

The lung tumor of our patient was analyzed for 22 mutations and 4 fusion genes (ALK, ROS1, RET, and NTRK1) by next-generation sequencing (NGS)-based target gene testing, and it harbored a 15-bp deletion in exon 19 of EGFR gene, i.e., EGFR: C. 2236_2249, p. (Glu746_Ala750del) which is an oncogenic driver mutation.[13]

However, no fusions were detected. The identified variant has also been reported by Sandoval et al. in a patient with synchronous head-and-neck and lung cancers.[9]

Non-HPV-associated HNSCCs have a 15% increased risk of developing SPM and worse survival as compared to patients with HPV-associated HNSCC.[2] Our patient tested negative for p16 (surrogate marker for HPV) performed on the upper lip SCC.

As compared to NGS-based target gene panel, the WES panel typically contains a greater number of genes and hence may provide more comprehensive genomic information to guide diagnosis and therapy. Thus, NGS-based target gene panels may not detect a shared mutation in tumor pairs that are truly clonal.[8],[12]

  Conclusion Top

A registry on patients with synchronous tumors analyzing the incidence, time to development, and risk factors of second malignant tumor in head-and-neck cancer patients can help in designing effective screening and preventive measures. Earlier detection of synchronous lung cancer in HNSCC may improve survival. Our findings and review of the literature suggest that CT screening for lung cancer may be warranted in HNSCC during initial workup and follow-up after treatment for better outcomes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Fonseca D, Musthyala B, Ahmed F, Murthy SS, Raju KV. A tale of synchronous lung carcinoma and diffuse large B-cell lymphoma of ileum: A rare combination. Lung India 2015;32:398-401.  Back to cited text no. 1
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Adjei Boakye E, Buchanan P, Hinyard L, Stamatakis K, Osazuwa-Peters N, Simpson MC, et al. Risk and outcomes for second primary human papillomavirus-related and -unrelated head and neck malignancy. Laryngoscope 2019;129:1828-35.  Back to cited text no. 2
Dequanter D, Shahla M, Lardinois I, Gilbert O, Hanquet O, Tragas G, et al. Second primary lung malignancy in head and neck cancer patients. Eur Ann Otorhinolaryngol Head Neck Dis 2011;128:11-3.  Back to cited text no. 3
Dougherty MI, Dougherty W, Kain JJ, Hughley BB, Shonka DC Jr, Fedder KL, et al. Non-HPV-Related Head and Neck Squamous Cell Carcinoma in a Young Patient Cohort. Ear Nose Throat J 2021;100:1101-6.  Back to cited text no. 4
Adeel M, Siddiqi MI. Metachronous second primary malignancy in head and neck cancer patients: Is five years of follow-up sufficient? J Korean Assoc Oral Maxillofac Surg 2018;44:220-4.  Back to cited text no. 5
Nyqvist J, Persson F, Parris TZ, Helou K, Kenne Sarenmalm E, Einbeigi Z, et al. Metachronous and synchronous occurrence of 5 primary malignancies in a female patient between 1997 and 2013: A case report with germline and somatic genetic analysis. Case Rep Oncol 2017;10:1006-12.  Back to cited text no. 6
Krishnatreya M, Rahman T, Kataki AC, Lahkar K. Synchronous primary cancers in the head and neck region and upper aero digestive tract: Role of triple endoscopy. Indian J Cancer 2015;52:53-6.  Back to cited text no. 7
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Li D, Yu M, Zhou P, Yang J, Wang Y. Whole-exome sequencing in a patient with synchronous triple primary malignancies involving lung cancer: A case report. Precis Clin Med 2020;3:306-10.  Back to cited text no. 8
Sandoval ML, Rimner A, Lee N, Gelblum D. Outcomes of patients with synchronous head and neck and lung cancers who were treated for cure with multi-modality approach. Int J Radiat Oncol Biol Phys 2019;105:E381-2.  Back to cited text no. 9
Griffioen GH, Louie AV, de Bree R, Smit EF, Paul MA, Slotman BJ, et al. Second primary lung cancers following a diagnosis of primary head and neck cancer. Lung Cancer 2015;88:94-9.  Back to cited text no. 10
Sunpaweravong S, Bunbanjerdsuk S, Pongrujikorn T, Naktang C, Sunpaweravong P, Nitiruangjaras A, et al. Clonal relationship of synchronous head and neck cancer and esophageal cancer assessed by single nucleotide polymorphism-based loss of heterozygosity analysis. BMC Cancer 2019;19:1174.  Back to cited text no. 11
Mauguen A, Seshan VE, Ostrovnaya I, Begg CB. Estimating the probability of clonal relatedness of pairs of tumors in cancer patients. Biometrics 2018;74:321-30.  Back to cited text no. 12
Valencia JD, Bermejo RT, Rodelo L, Castillo IM. 4CPS-266 Afatinib as firstline treatment for advanced lung adenocarcinoma in a patient harbouring exon 19 deletion in EGFR: A case report. Eur J Hosp Pharm 2021;28;A1-184.  Back to cited text no. 13


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