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Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 586-589

Radiologic progression in a patient with non-small-cell lung cancer


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radio Diagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission13-May-2020
Date of Decision24-May-2020
Date of Acceptance14-Jul-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, HBB - 11th Floor, Tata Memorial Hospital, Dr. Ernst Borges Road, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_193_20

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How to cite this article:
Shetty AK, Noronha V, Patil V, Menon N, Joshi A, Mahajan A, Kumar R, Prabhash K. Radiologic progression in a patient with non-small-cell lung cancer. Cancer Res Stat Treat 2020;3:586-9

How to cite this URL:
Shetty AK, Noronha V, Patil V, Menon N, Joshi A, Mahajan A, Kumar R, Prabhash K. Radiologic progression in a patient with non-small-cell lung cancer. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 26];3:586-9. Available from: https://www.crstonline.com/text.asp?2020/3/3/586/295537




  Case Vignette Top


A 45-year-old man with no smoking history and no comorbidities presented to our hospital in October 2017 with cough, dyspnea, and fatigue. He was diagnosed with adenocarcinoma of the lung (cT4N3M1c), with liver, bone, and contralateral lung metastases. Mutational analysis with a TaqMan Probe-Based Endpoint Genotyping assay by real-time polymerase chain reaction (RT-PCR) revealed that the tumor harbored an exon 19 in-frame deletion in the epidermal growth factor receptor (EGFR) gene. He was enrolled in an ongoing clinical trial at our center.[1] The patient received four cycles of pemetrexed plus carboplatin, followed by two cycles of maintenance pemetrexed along with gefitinib; he had good symptom improvement, and radiological imaging showed a partial response. After the sixth cycle of maintenance pemetrexed, he was clinically asymptomatic, but a radiologic assessment showed a new-onset spiculated nodule 1.5 cm in size with a central cavitation in the left lower lobe of the lung. There was a concurrent decrease in the size of the primary lesion from 3 cm to 2.4 cm, along with a decrease in the adjacent fibrotic opacities and no significant interval change in the mediastinal and right hilar nodes [Figure 1].
Figure 1: Axial sections of computed tomography images of the lung of the patient showing (new-onset) spiculated lesion in the left lower lobe of the lung which was noticed after the 6th maintenance pemetrexed

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What was the diagnosis and what further workup would you recommend? Once you have finalized your answer, please turn to pg. 587 to read on.


  Workup and Clinical Course Top


The patient was deemed to have a progressive disease because of the presence of the new lesion, as per the Response Evaluation Criteria in Solid Tumors criteria. He therefore underwent a repeat biopsy. The biopsy was suggestive of necrotizing granulomatous inflammation, negative for malignancy, and negative for acid-fast bacilli (AFB). Mutational analysis of the liquid biopsy using the RT-PCR assay revealed wild-type EGFR. In view of the strong clinical possibility of disease progression and unequivocal appearance of the new left lower lobe lesion, the diagnosis of progressive disease was retained; no immediate repeat biopsy was planned at this juncture. Options of chemotherapy were discussed, but the patient was unwilling for further intravenous chemotherapy. As the patient desired oral therapy, osimertinib was started, even though there was no evidence of an EGFR T790M mutation.

Two months later, the patient's cough and dyspnea worsened with a new onset of fever. A computed tomography (CT) scan of the thorax and abdomen showed an increase in the size of the left lower lobe lesion to 4.2 cm [Figure 2]. The mass showed increased cavitation and was associated with new-onset consolidation as compared to the previous scan. In addition, there was a 2.4 cm spiculated nodule in the anterior segment of the left upper lobe and a new-onset 2.4-cm cavitary nodule in the apical segment of the right upper lobe. The primary lesion in the right lower lobe and nodes remained stable.
Figure 2: Axial sections of computed tomography images showing an increase in size with cavitation in the left lower lobe lesion after the patient was started on osimertinib

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The patient was diagnosed with progressive disease and underwent a repeat biopsy which was again suggestive of necrotizing granulomatous inflammation strongly suspicious for tuberculosis but negative for AFB staining. However, the sputum analysis was positive for AFB. Sputum analysis using GeneXpert (nucleic acid amplification method) also revealed the presence of the mycobacterium complex with no rifampicin resistance. The presence of mycobacteria was confirmed using the mycobacterial growth indicator tube.

He was initiated on multidrug-antitubercular therapy (ATT) consisting of rifampicin, pyrazinamide, ethambutol, and isoniazid and continued on osimertinib.

The patient required a dose escalation of osimertinib at this point because of its interaction with rifampicin.[2] However, in view of his financial constraints, he continued to take osimertinib at a dose of 80 mg once daily. Two months after the initiation of ATT (completion of the intensive phase), the patient had a significant resolution of symptoms. The CT scan revealed a significant decrease in the cavitary nodules and resolution of the left lower lobe consolidation.

He was switched to the continuation phase of ATT (rifampicin + isoniazid + ethambutol) for a total of nine months. Two months after the completion of ATT, the patient is doing well clinically, with no complaints of cough, dyspnea, or fever. The CT scan of the thorax and abdomen is suggestive of stable disease. As of February 2020, the patient is continuing on osimertinib 80 mg once daily for the last 1 year and 7 months and he is on follow-up and doing well.


  Discussion Top


This case reiterates the need for a biopsy at the time of disease progression, to confirm a diagnosis, to rule out other conditions that may mimic progression, and check for the presence of new mutations if progression is considered.

In a country with an epidemiologically high incidence of tuberculosis, a new onset of cavitary lesions in a patient with carcinoma of the lung could be of tubercular etiology. Hence, new-onset radiological lesions, especially cavitary lesions and those with concurrent systemic symptoms such as fever and night sweats, raise a strong alarm for tuberculosis and mandate investigations along those lines prior to attributing the new lesions or symptoms to disease progression.

A similar case has been reported in the literature where a new-onset lesion in a patient receiving erlotinib for non-small cell lung cancer (NSCLC) was considered as clinical progression. However, bronchoscopy and mucosal biopsy for re-evaluation yielded a diagnosis of tuberculosis.[3]

In addition to tuberculosis, numerous other differential diagnoses of cavitary lesions need to be considered. These include fungal pneumonias (aspergillus and cryptococcal), rare bacterial infections with abscesses presenting with prolonged duration of symptoms, and nontuberculous mycobacterial disease.

Although there are no large case series to provide data, smaller studies have shown that 28%–37% of the cavities are malignant.[4],[5],[6] Conversely, 10%–20% of lung cancers can present as cavitary lesions. Hence, cavities need to be carefully diagnosed and evaluated in the presence of clinical and radiological features.[7],[8]

In our case, in view of the absence of fever and cough, tuberculosis was not considered clinically in the first instance. In the second presentation, however, in view of the presence of these symptoms along with radiological features of a cavity with an associated consolidation, tuberculosis was deemed a possibility.

In a patient with malignancy, an isolated new lesion in the absence of fever and sputum is more likely to be considered as progression than any other differential diagnosis.

However, we do concur that we should have considered the possibility of tuberculosis, and the case highlights this pitfall.

The presence of necrotizing granulomatous inflammation, though a pointer to infectious diseases such as tuberculosis, in the absence of a clinical scenario may not by itself be an indication to start antitubercular therapy.[9],[10] Moreover, all necrotizing granulomatous inflammations are not necessarily due to tuberculosis. A positivity rate of around 47.7% of AFB is reported in biopsy specimens containing necrotizing granulomas.[11]

Furthermore, a notable point in the case is the absence of AFB in the biopsy specimens, which probably contributed to the delay in diagnosis.

In a study (specifically on lung biopsy), the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of histological AFB for the diagnosis of smear-negative pulmonary tuberculosis were 61.7%, 100%, 100%, 48.5%, and 71.8%, respectively. However, the sensitivity, specificity, PPV, and NPV of histological PCR were 89.5%, 95.8%, 98.3%, and 76.7%, respectively.[12] Hence, the lower sensitivity of AFB on biopsies is a matter of concern.

A debatable point is the initiation of osimertinib in our patient. If second-line therapy can offer good survival benefits with minimal toxicities, initiating a second-line therapy at the earliest hint of progression, even in the palliative setting, is clearly indicated. Moreover, despite the off-label indication, osimertinib has been found to be effective in the second-line setting in EGFR T790M-negative NSCLC.[13] In our patient, the refusal of intravenous chemotherapy was the primary reason for considering osimertinib.

This case also highlights the need for repeat biopsies at progression. Rebiopsies are a must at progression; however, many aspects are to be considered while planning them and interpreting their results. First, the complication rate is up to 8.6%, with pneumothorax being the most commonly reported one.[14] Second, the feasibility and patients' consent for a rebiopsy also need to be considered.[15],[16] Repeated immediate biopsies need to be utilized with caution. Third, as observed in our case, the first rebiopsy may show negative results, and these need to be evaluated appropriately. In a prospective study from Japan, at rebiopsy, only 80.6% of the tissue/cytology samples contained tumor cells.[17] The approximately 20% fall out is largely attributed to sampling errors. Fourth, discordance in the mutations at diagnosis and progression has been reported, with disappearance of mutations (8.2%) and reversal from sensitizing mutations to a wild-type state (10.7%).[14]

In the real world, the EGFR mutation status in patients with advanced NSCLC is altered significantly due to tissue resources and therapeutic approaches, thus highlighting the importance of rebiopsy and real-time detection of EGFR mutations to provide data to precisely guide further treatment.[14] Finally, it is necessary to look for mutations, especially the EGFR T790M, in rebiopsied tissues. In previous studies conducted in patients with NSCLC who experienced disease progression with EGFR tyrosine kinase inhibitors, the prevalence of the T790M mutation ranged from 33% to 63%[18] when tissue/cytology samples were used.

Plasma samples, collected using a minimally invasive procedure, may occasionally be insufficient to generate accurate or reliable T790M test results. Hence, the sensitivity of the genomic testing platforms needs to be considered while utilizing liquid biopsy for the detection of mutations.[19],[20],[21]

In conclusion, the case highlights two important features – to consider other diagnostic possibilities in patients with radiological progression with cavities and the cautious interpretation of the results of repeat biopsies.

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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol 2020;38:124-36.  Back to cited text no. 1
    
2.
Tagrisso (Osimertinib). Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2016. Available from: www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf. [Last accessed on 2020 Jul 15].  Back to cited text no. 2
    
3.
Lee HY, Kim JW, Yeo CD. A case of tuberculosis reactivation suspected of cancer progression during oral tyrosine kinase inhibitor treatment in a patient diagnosed as non-small cell lung cancer. J Thorac Dis 2017;9:E709-13.  Back to cited text no. 3
    
4.
Nin CS, de Souza VV, Alves GR, do Amaral RH, Irion KL, Marchiori E, et al. Solitary lung cavities: CT findings in malignant and non-malignant disease. Clin Radiol 2016;71:1132-6.  Back to cited text no. 4
    
5.
Giacomelli IL, Barros M, Pacini GS. Multiple cavitary lung lesions on CT: Imaging findings to differentiate between malignant and benign etiologies. J Bras Pneumol 2020;46:e20190024.  Back to cited text no. 5
    
6.
Woodring JH, Fried AM, Chuang VP. Solitary cavities of the lung: Diagnostic implications of cavity wall thickness. AJR Am J Roentgenol 1980;135:1269-71.  Back to cited text no. 6
    
7.
Gafoor K, Patel S, Girvin F, Gupta N, Naidich D, Machnicki S, et al. Cavitary lung diseases: A clinical-radiologic algorithmic approach. Chest 2018;153:1443-65.  Back to cited text no. 7
    
8.
Parkar AP, Kandiah P. Differential diagnosis of cavitary lung lesions. J Belg Soc Radiol 2016;100:100.  Back to cited text no. 8
    
9.
Yakar F, Yakar A, Büyükpınarbaşılı N, Erelel M. Does every necrotizing granulomatous inflammation identified by NSCLC resection material require treatment? Med Sci Monit 2016;22:1218-22.  Back to cited text no. 9
    
10.
Aubry MC. Necrotizing granulomatous inflammation: What does it mean if your special stains are negative? Mod Pathol 2012;25 Suppl 1:S31-8.  Back to cited text no. 10
    
11.
Tang YW, Procop GW, Zheng X, Myers JL, Roberts GD. Histologic parameters predictive of mycobacterial infection. Am J Clin Pathol 1998;109:331-4.  Back to cited text no. 11
    
12.
Jiang F, Huang W, Wang Y, Tian P, Chen X, Liang Z. Nucleic acid amplification testing and sequencing combined with acid-fast staining in needle biopsy lung tissues for the diagnosis of smear-negative pulmonary tuberculosis. PLoS One 2016;11:e0167342.  Back to cited text no. 12
    
13.
Eide IJ, Helland Š, Ekman S, Mellemgaard A, Holmskov Hansen K, Cicenas S, et al. Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer (the TREM-study). Lung Cancer 2020;143:27-35.  Back to cited text no. 13
    
14.
Kim TO, Oh IJ, Kho BG, Park HY, Chang JS, Park CK, et al. Feasibility of re-biopsy and EGFR mutation analysis in patients with non-small cell lung cancer. Thorac Cancer 2018;9:856-64.  Back to cited text no. 14
    
15.
Li H, Yan S, Liu X, Liu Y, Ma L, Wang Y, et al. Disparities of EGFR Mutations between biopsy and rebiopsy in non-small cell lung cancer patients. Chinese J Lung Cancer 2018;21: 821-7.  Back to cited text no. 15
    
16.
Hong MH, Kim HR, Ahn BC, Heo SJ, Kim JH, Cho BC. Real-world analysis of the efficacy of rebiopsy and EGFR mutation test of tissue and plasma samples in drug-Resistant non-small cell lung cancer. Yonsei Med J 2019;60:525-34.  Back to cited text no. 16
    
17.
Seto T, Nogami N, Yamamoto N, Atagi S, Tashiro N, Yoshimura Y, et al. Real-world EGFR T790M testing in advanced non-small-cell lung cancer: A prospective observational study in Japan. Oncol Ther 2018;6:203-15.  Back to cited text no. 17
    
18.
Zhou J, Zhao C, Zhao J, Wang Q, Chu X, Li J, et al. Re-biopsy and liquid biopsy for patients with non-small cell lung cancer after EGFR-tyrosine kinase inhibitor failure. Thorac Cancer 2019;10:957-65.  Back to cited text no. 18
    
19.
Rajendra A, Noronha V, Joshi A, Patil VM, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. Cancer Res Stat Treat 2019;2:36-53.  Back to cited text no. 19
  [Full text]  
20.
Pandey A, Dutt S, Singh A, Kumar A, Singh S. Outcomes with liquid biopsy to determine the EGFR mutation status in poor performance status, biopsy-ineligible, advanced NSCLC patients. Cancer Res Stat Treat 2019;2:197-203.  Back to cited text no. 20
  [Full text]  
21.
Choughule A, D'Souza H. Liquid biopsy in lung cancer-hope or hype? Cancer Res Stat Treat 2019;2:221-3.  Back to cited text no. 21
  [Full text]  


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