VOLUME
32
䡠
NUMBER
6
䡠
FEBRUARY
20
2014
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
Diagnostic and Treatment Dilemma of Dual Pathology of Lung Cancer and Disseminated Tuberculosis Case Report An 80-year-old male smoker was referred to us with a 1.5month history of chest pain and breathlessness, with diagnosis of right-sided pleural effusion and left lower lobe mass. He had an Eastern Cooperative Oncology Group performance status of 2. On examination, he had right supraclavicular lymphadenopathy and decreased breath sounds on the right side of chest. Fine needle aspiration cytology (FNAC) of the lung lesion was consistent with adenocarcinoma, and FNAC from the supraclavicular lymph node revealed necrotizing granulomatous lymphadenitis suggestive of tuberculosis (TB). Acid-fast bacillus (AFB) culture or DNA tests were not attempted on the FNAC specimen; however, AFB stain was done which was negative. Pleural fluid analysis revealed strawcolored fluid with glucose of 106 mg/dL, protein 5.4g/dL, LDH 279 U/L, and adenosine deaminase of 98.16 U/L (range for tubercular
I N
O N C O L O G Y
pleurisy being ⬎ 40 U/L). The fluid was not sent for AFB culture. Cell count and differential was not performed; however, on cytology, many lymphocytes were seen, therefore it was reported to be a lymphocyte-rich effusion, and it was cytologically negative for malignancy. Thus, the patient was diagnosed with adenocarcinoma of the lung with concurrent TB. The positron emission tomography (PET) scan (Figs 1A, 1C, and 1E) revealed a spiculated 2.8 ⫻ 3.0 cm mass, with standardized uptake value (SUV) of 7.15 in the lower lobe of left lung, right loculated pleural effusion, multiple right pleural deposits (SUV, 12.8) and multiple lymph nodes in the following areas: cervical (SUV, 5.03), bilateral supraclavicular (SUV, 7.9), bilateral axillary (SUV, 13.9), mediastinal (SUV, 14.2), periportal (SUV, 13.4), bilateral external iliac (SUV, 3.7) and right inguinal (SUV, 12.9). There were also multiple discrete peritoneal deposits (SUV, 18.6) and multiple hypermetabolic skeletal lesions. The staging of lung cancer was complicated by the concurrent TB. The patient was discussed in the thoracic multidisciplinary conference, and a decision was made to give the patient anti-TB therapy (ATT; isoniazid, rifampicin, ethambutol, pyrazinamide) and to reassess with a repeat PET computed tomography (CT) after 3 to 4
A
B
C
D
E
F
Fig 1. Journal of Clinical Oncology, Vol 32, No 6 (February 20), 2014: pp e7-e9
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OTAGO on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 139.80.149.115
e7
Shetty et al
weeks. Despite our counseling, the patient did not follow up for the next 5 months but did continue ATT. After 5 months of only ATT, with no anti-neoplastic therapy, he was again referred to us by his family doctor for management of the lung mass. Repeat PET-CT (Figs 1B, 1D, and 1F) revealed increase in size of the left lower lobe lung mass to 5.4 ⫻ 5.2 cm (SUV, 20.6) with complete regression of all the lymph nodes, pleural effusion, peritoneal deposits, and skeletal lesions. At this point, the patient was staged as T2N0M0 adenocarcinoma of the left lung, and he underwent curative left lower lobectomy for the lung lesion. The resection margins were negative, and only one hilar lymph node was positive for metastasis. Many other lymph nodes showed features of granulomatous inflammation of probable tubercular etiology. Pathological staging was pT2b N1 M0. Adjuvant chemotherapy was offered, but the patient refused. He was then continued on ATT. Discussion This patient had dual pathology of adenocarcinoma of lung with concomitant disseminated TB. There was great diagnostic dilemma while interpreting the PET-CT, deciding the stage of his lung cancer, and planning therapy. His lung lesion was suggestive of malignancy, but the biopsy from supraclavicular node revealed granulomatous lymphadenitis, the pleural fluid was cytologically negative, and other tests were suggestive of lymphocyte-rich exudative effusion. It is well reported that the interpretation of PET-CT with concurrent tubercular and neoplastic etiology is complex because TB has been a common mimic of malignancy on PET-CT.1-3 Because the study clearly had features suggesting the possibility of coexisting TB—such as the pattern of lymph node involvement and the pleural deposits— biopsy was done from extra thoracic lesion (supraclavicular node) that confirmed the finding. After adequate ATT, PET-CT revealed complete regression of all the lymph nodes, pleural effusion, peritoneal deposits, and skeletal lesions and an increase in size of the left lower lobe lung mass. There is no definite time frame to assess response of TB to ATT on fluorodeoxyglucose (FDG) PET, though several studies have performed follow-up imaging at various time points, as early as 8 weeks after initiation of ATT to as late as after completion of the entire course of ATT. In a study by Martinez et al,4 PET was used as an early marker of therapeutic response to ATT at 4 weeks. Our rationale to perform PET at 4 weeks was to triage the TB lesions early enough so that a definitive treatment could be planned for lung carcinoma. The change in the PET-CT study as a result of anti-TB therapy confirmed the pretreatment possibility of coexisting TB, and the response to ATT ruled out multidrug resistant TB. The basic principle of FDG- PET imaging is based on the accumulation of the radiopharmaceutical FDG in areas of increased glucose metabolism and significantly higher metabolic rate in malignant tissue than in normal tissue,5 but inflammatory cells also show similar FDG uptake. In most studies, the SUV cutoff value is 2.5 for benign versus malignant lesions. The multiple site FDG uptake in this case was due to granulomatous inflammation and possible macrophage phacogytosis of Mycobacterium tuberculosis. TB lesions have a wide range of SUVs, which show a significant overlap with that of malignant lesions. Hence, SUVs cannot be used to diagnose or differentiate TB from cancer. Higher SUV may result from tubercular inflammation, which can then decrease soon with treatment. Neoplastic lesions are unlikely to resolve in a month with only ATT. High FDG uptake in e8
© 2014 by American Society of Clinical Oncology
slow inflammatory processes, especially inflammatory granulomatous pulmonary diseases such as TB, creates a diagnostic and therapeutic dilemma in the field of oncology. This can be a problem in countries where TB is endemic and often can coexist with malignancy. High FDG uptake is also seen in other pulmonary abnormalities like pneumonia, aspergillosis, histoplasmosis, Cryptococcus, lung abscess, Wegener granuloma, sarcoidosis, inflammatory pseudo tumor, Schwannoma, and mesothelioma.6,7 The exact role of FDG PET and PET-CT in TB and other inflammatory diseases is evolving, and there is early evidence to show that they could be used for evaluating treatment response of some granulomatous diseases.8-10 The intense FDG uptake in the pleural lesions, lymph nodes, lung nodules, and skeletal lesions is a pattern that is common to both TB and lung adenocarcinoma11 (as was seen in our report). Attempts to differentiate between the two can, on occasion, be extremely difficult and at best speculative, and a biopsy is often needed to confirm the etiology. In situations where a biopsy is technically challenging or there is multiplicity of imaging findings, a follow-up PET scan a few weeks into the course of ATT might be useful to single out the tubercular lesions, as resolution of glucose metabolism would precede actual morphological regression of the lesions. This approach can be judiciously used in such difficult clinical situations so as to have greater confidence in patient counseling and planning of the optimal treatment strategy. Increased FDG uptake may lead to erroneous interpretation particularly with such confounding dual clinical presentation. The medical oncologists and clinicians should be aware of the interpretation issues of PET CT, particularly in countries where TB is endemic. A carefulwork-up,highindexofsuspicion,biopsy,andcautionininterpreting PET-CT are the only solution in such scenarios.
Nishitha Shetty, Vanita Noronha, Amit Joshi, Venkatesh Rangarajan, Nilendu Purandare, Prasanta Raghab Mohapatra, and Kumar Prabhash Tata Memorial Centre, Mumbai, India
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Yang CM, Hsu CH, Lee CM, et al: Intense uptake of [F-18]-fluoro-2 deoxy-D-glucose in active pulmonary tuberculosis. Ann Nucl Med 17:407-410, 2003 2. Sazon DA, Santiago SM, Soo Hoo GW, et al: Fluorodeoxyglucose-positron emission tomography in the detection and staging of lung cancer. Am J Respir Crit Care Med 153:417-421, 1996 3. Sharma P, Singh H, Basu S, et al: Positron-emission tomographycomputed tomography in the management of lung cancer: An update. South Asian J Cancer 2:193-200, 2013 4. Martinez V, Castilla-Lievre MA, Guilet-Caruba C, et al: (18)F-FDG PET/CT in tuberculosis: An early non-invasive marker of therapeutic response. Int J Tuberc Lung Dis 16:1180-1185, 2012 5. Graeter TP, Hellwig D, Hoffmann K, et al: Mediastinal lymph node staging in suspected lung cancer: Comparison of positron emission tomography with F-18-fluorodeoxyglucose and mediastinoscopy. Ann Thorac Surg 75:231-236, 2003 6. Lin WY, Chang GC, Wang SJ: Effectiveness of FDG-PET scans in the evaluation of patients with single pulmonary nodules in Taiwan. Ann Nucl Med Sci 17:63-68, 2004 7. Yang CM, Hsu CH, Hsieh CM, et al: F-18 FDG PET in a clinical unsuspected axillary tuberculous lymphadenitis mimicking malignancy. Ann Nucl Med Sci 16:107-110, 2003 8. Demura Y, Tsuchida T, Uesaka D, et al: Usefulness of 18Ffluorodeoxyglucose positron emission tomography for diagnosing disease activity and monitoring therapeutic response in patients with pulmonary mycobacteriosis. Eur J Nucl Med Mol Imaging 36:632-639, 2009 JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OTAGO on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 139.80.149.115
Diagnosis in Oncology
9. Tian G, Xiao Y, Chen B, et al: FDG PET/CT for therapeutic response monitoring in multi-site non-respiratory tuberculosis. Acta Radiol 51:1002-1006, 2010 10. Yahata T, Itsukaichi M, Mashima Y, et al: Antituberculosis treatment for a patient with massive ascites: The role of f-18-fluorodeoxyglucose positron emission tomography. Obstet Gynecol 116:523-525, 2010 (suppl 2)
11. Mi B, Wan W, Yu C, et al: The value of extra-lung lesions on 18F-FDG PET/CT in improving diagnosis of lung cancer. Zhongguo Fei Ai Za Zhi 15:78-83, 2012
DOI: 10.1200/JCO.2012.46.0667; published online ahead of print at www.jco.org on January 6, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OTAGO on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 139.80.149.115
e9
32
䡠
NUMBER
6
䡠
FEBRUARY
20
2014
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
Diagnostic and Treatment Dilemma of Dual Pathology of Lung Cancer and Disseminated Tuberculosis Case Report An 80-year-old male smoker was referred to us with a 1.5month history of chest pain and breathlessness, with diagnosis of right-sided pleural effusion and left lower lobe mass. He had an Eastern Cooperative Oncology Group performance status of 2. On examination, he had right supraclavicular lymphadenopathy and decreased breath sounds on the right side of chest. Fine needle aspiration cytology (FNAC) of the lung lesion was consistent with adenocarcinoma, and FNAC from the supraclavicular lymph node revealed necrotizing granulomatous lymphadenitis suggestive of tuberculosis (TB). Acid-fast bacillus (AFB) culture or DNA tests were not attempted on the FNAC specimen; however, AFB stain was done which was negative. Pleural fluid analysis revealed strawcolored fluid with glucose of 106 mg/dL, protein 5.4g/dL, LDH 279 U/L, and adenosine deaminase of 98.16 U/L (range for tubercular
I N
O N C O L O G Y
pleurisy being ⬎ 40 U/L). The fluid was not sent for AFB culture. Cell count and differential was not performed; however, on cytology, many lymphocytes were seen, therefore it was reported to be a lymphocyte-rich effusion, and it was cytologically negative for malignancy. Thus, the patient was diagnosed with adenocarcinoma of the lung with concurrent TB. The positron emission tomography (PET) scan (Figs 1A, 1C, and 1E) revealed a spiculated 2.8 ⫻ 3.0 cm mass, with standardized uptake value (SUV) of 7.15 in the lower lobe of left lung, right loculated pleural effusion, multiple right pleural deposits (SUV, 12.8) and multiple lymph nodes in the following areas: cervical (SUV, 5.03), bilateral supraclavicular (SUV, 7.9), bilateral axillary (SUV, 13.9), mediastinal (SUV, 14.2), periportal (SUV, 13.4), bilateral external iliac (SUV, 3.7) and right inguinal (SUV, 12.9). There were also multiple discrete peritoneal deposits (SUV, 18.6) and multiple hypermetabolic skeletal lesions. The staging of lung cancer was complicated by the concurrent TB. The patient was discussed in the thoracic multidisciplinary conference, and a decision was made to give the patient anti-TB therapy (ATT; isoniazid, rifampicin, ethambutol, pyrazinamide) and to reassess with a repeat PET computed tomography (CT) after 3 to 4
A
B
C
D
E
F
Fig 1. Journal of Clinical Oncology, Vol 32, No 6 (February 20), 2014: pp e7-e9
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OTAGO on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 139.80.149.115
e7
Shetty et al
weeks. Despite our counseling, the patient did not follow up for the next 5 months but did continue ATT. After 5 months of only ATT, with no anti-neoplastic therapy, he was again referred to us by his family doctor for management of the lung mass. Repeat PET-CT (Figs 1B, 1D, and 1F) revealed increase in size of the left lower lobe lung mass to 5.4 ⫻ 5.2 cm (SUV, 20.6) with complete regression of all the lymph nodes, pleural effusion, peritoneal deposits, and skeletal lesions. At this point, the patient was staged as T2N0M0 adenocarcinoma of the left lung, and he underwent curative left lower lobectomy for the lung lesion. The resection margins were negative, and only one hilar lymph node was positive for metastasis. Many other lymph nodes showed features of granulomatous inflammation of probable tubercular etiology. Pathological staging was pT2b N1 M0. Adjuvant chemotherapy was offered, but the patient refused. He was then continued on ATT. Discussion This patient had dual pathology of adenocarcinoma of lung with concomitant disseminated TB. There was great diagnostic dilemma while interpreting the PET-CT, deciding the stage of his lung cancer, and planning therapy. His lung lesion was suggestive of malignancy, but the biopsy from supraclavicular node revealed granulomatous lymphadenitis, the pleural fluid was cytologically negative, and other tests were suggestive of lymphocyte-rich exudative effusion. It is well reported that the interpretation of PET-CT with concurrent tubercular and neoplastic etiology is complex because TB has been a common mimic of malignancy on PET-CT.1-3 Because the study clearly had features suggesting the possibility of coexisting TB—such as the pattern of lymph node involvement and the pleural deposits— biopsy was done from extra thoracic lesion (supraclavicular node) that confirmed the finding. After adequate ATT, PET-CT revealed complete regression of all the lymph nodes, pleural effusion, peritoneal deposits, and skeletal lesions and an increase in size of the left lower lobe lung mass. There is no definite time frame to assess response of TB to ATT on fluorodeoxyglucose (FDG) PET, though several studies have performed follow-up imaging at various time points, as early as 8 weeks after initiation of ATT to as late as after completion of the entire course of ATT. In a study by Martinez et al,4 PET was used as an early marker of therapeutic response to ATT at 4 weeks. Our rationale to perform PET at 4 weeks was to triage the TB lesions early enough so that a definitive treatment could be planned for lung carcinoma. The change in the PET-CT study as a result of anti-TB therapy confirmed the pretreatment possibility of coexisting TB, and the response to ATT ruled out multidrug resistant TB. The basic principle of FDG- PET imaging is based on the accumulation of the radiopharmaceutical FDG in areas of increased glucose metabolism and significantly higher metabolic rate in malignant tissue than in normal tissue,5 but inflammatory cells also show similar FDG uptake. In most studies, the SUV cutoff value is 2.5 for benign versus malignant lesions. The multiple site FDG uptake in this case was due to granulomatous inflammation and possible macrophage phacogytosis of Mycobacterium tuberculosis. TB lesions have a wide range of SUVs, which show a significant overlap with that of malignant lesions. Hence, SUVs cannot be used to diagnose or differentiate TB from cancer. Higher SUV may result from tubercular inflammation, which can then decrease soon with treatment. Neoplastic lesions are unlikely to resolve in a month with only ATT. High FDG uptake in e8
© 2014 by American Society of Clinical Oncology
slow inflammatory processes, especially inflammatory granulomatous pulmonary diseases such as TB, creates a diagnostic and therapeutic dilemma in the field of oncology. This can be a problem in countries where TB is endemic and often can coexist with malignancy. High FDG uptake is also seen in other pulmonary abnormalities like pneumonia, aspergillosis, histoplasmosis, Cryptococcus, lung abscess, Wegener granuloma, sarcoidosis, inflammatory pseudo tumor, Schwannoma, and mesothelioma.6,7 The exact role of FDG PET and PET-CT in TB and other inflammatory diseases is evolving, and there is early evidence to show that they could be used for evaluating treatment response of some granulomatous diseases.8-10 The intense FDG uptake in the pleural lesions, lymph nodes, lung nodules, and skeletal lesions is a pattern that is common to both TB and lung adenocarcinoma11 (as was seen in our report). Attempts to differentiate between the two can, on occasion, be extremely difficult and at best speculative, and a biopsy is often needed to confirm the etiology. In situations where a biopsy is technically challenging or there is multiplicity of imaging findings, a follow-up PET scan a few weeks into the course of ATT might be useful to single out the tubercular lesions, as resolution of glucose metabolism would precede actual morphological regression of the lesions. This approach can be judiciously used in such difficult clinical situations so as to have greater confidence in patient counseling and planning of the optimal treatment strategy. Increased FDG uptake may lead to erroneous interpretation particularly with such confounding dual clinical presentation. The medical oncologists and clinicians should be aware of the interpretation issues of PET CT, particularly in countries where TB is endemic. A carefulwork-up,highindexofsuspicion,biopsy,andcautionininterpreting PET-CT are the only solution in such scenarios.
Nishitha Shetty, Vanita Noronha, Amit Joshi, Venkatesh Rangarajan, Nilendu Purandare, Prasanta Raghab Mohapatra, and Kumar Prabhash Tata Memorial Centre, Mumbai, India
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Yang CM, Hsu CH, Lee CM, et al: Intense uptake of [F-18]-fluoro-2 deoxy-D-glucose in active pulmonary tuberculosis. Ann Nucl Med 17:407-410, 2003 2. Sazon DA, Santiago SM, Soo Hoo GW, et al: Fluorodeoxyglucose-positron emission tomography in the detection and staging of lung cancer. Am J Respir Crit Care Med 153:417-421, 1996 3. Sharma P, Singh H, Basu S, et al: Positron-emission tomographycomputed tomography in the management of lung cancer: An update. South Asian J Cancer 2:193-200, 2013 4. Martinez V, Castilla-Lievre MA, Guilet-Caruba C, et al: (18)F-FDG PET/CT in tuberculosis: An early non-invasive marker of therapeutic response. Int J Tuberc Lung Dis 16:1180-1185, 2012 5. Graeter TP, Hellwig D, Hoffmann K, et al: Mediastinal lymph node staging in suspected lung cancer: Comparison of positron emission tomography with F-18-fluorodeoxyglucose and mediastinoscopy. Ann Thorac Surg 75:231-236, 2003 6. Lin WY, Chang GC, Wang SJ: Effectiveness of FDG-PET scans in the evaluation of patients with single pulmonary nodules in Taiwan. Ann Nucl Med Sci 17:63-68, 2004 7. Yang CM, Hsu CH, Hsieh CM, et al: F-18 FDG PET in a clinical unsuspected axillary tuberculous lymphadenitis mimicking malignancy. Ann Nucl Med Sci 16:107-110, 2003 8. Demura Y, Tsuchida T, Uesaka D, et al: Usefulness of 18Ffluorodeoxyglucose positron emission tomography for diagnosing disease activity and monitoring therapeutic response in patients with pulmonary mycobacteriosis. Eur J Nucl Med Mol Imaging 36:632-639, 2009 JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OTAGO on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 139.80.149.115
Diagnosis in Oncology
9. Tian G, Xiao Y, Chen B, et al: FDG PET/CT for therapeutic response monitoring in multi-site non-respiratory tuberculosis. Acta Radiol 51:1002-1006, 2010 10. Yahata T, Itsukaichi M, Mashima Y, et al: Antituberculosis treatment for a patient with massive ascites: The role of f-18-fluorodeoxyglucose positron emission tomography. Obstet Gynecol 116:523-525, 2010 (suppl 2)
11. Mi B, Wan W, Yu C, et al: The value of extra-lung lesions on 18F-FDG PET/CT in improving diagnosis of lung cancer. Zhongguo Fei Ai Za Zhi 15:78-83, 2012
DOI: 10.1200/JCO.2012.46.0667; published online ahead of print at www.jco.org on January 6, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UNIVERSITY OTAGO on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 139.80.149.115
e9
