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Everything you need to know about Computed Tomography (CT) & CT Scanning


Use of Combined PET-CT Imaging in Evaluation of the Solitary Pulmonary Nodule: Benefits, Pitfalls, and Diagnostic Algorithm

Single pulmonary nodule (SPN) is defined as a focal, round or oval area of increased opacity in the lung that measures less than 3 cm in diameter (1). Nearly 1 in every 500 chest radiographs taken reveals a newly diagnosed SPN. More than 150,000 SPNs are detected annually in the United States alone (2). This estimate is mainly based on chest radiographs. Now, with increasing use of chest CT for screening of lung cancer, and chest CTA for diagnosing pulmonary embolus and for cardiac evaluation, this number is rapidly increasing. Early data on the use of CT screening from ELCAP and Mayo studies showed that 1917 nodules were found among 2520 participants (3). It is important to note that although overall survival in lung cancer is poor, patients with stage IA (T1N0M0) have nearly 80% 5-year survival (3), and thus early resection of malignant nodule can make a large difference in patient outcome. However, with only 30% of SPNs representing a malignancy, either primary or metastatic, appropriate course of action is a challenge.

Growth rate assessment is a good differentiating factor, but given that typical doubling time of a malignant nodule is between 30 and 400 days, most commonly proposed follow-up protocol is at 3 months intervals for up to a year and then every 6 months for another year. Many patients, however, consider waiting even 3 months, not to mention up to 2 years, an unacceptable option. Additionally evaluation of growth in a small nodule is often quite imprecise. Morphologic characteristics of the SPN are often helpful in determining etiology. Thin-section CT can improve detection of calcification within a SPN, however majority of pulmonary nodules will remain indeterminate following thin-section imaging. It has also been shown that despite all the accumulated data on morphologic characteristics of benign and malignant nodules, simple Bayesian analysis of patient characteristics and selected radiological features is superior to evaluation by experienced radiologists in the stratification of benign and malignant nodules (4).

Of course surgical resection of the nodule would be a curative treatment, however morbidity and expense associated with this approach make resection of many benign nodules simply impractical. Biopsy has not been proven to be a viable option either. Transthoracic needle aspiration yields a positive tissue diagnosis in about 60% of lesions less than 2 cm, with pneumothorax rate of 15 to 30%. Bronchoscopy has a lower complication rate, yet diagnostic yield for nodules less than 2 cm is about 10%, and it is only 40 to 50% for nodules 2 to 4 cm in diameter (5) (Figure 1).

Figure 1
54 yo male with 20 pack/year smoking history and a renal transplant 10 year ago.PET-CT showed left upper lobe mass with intense metabolic activity highly suspicious for malignancy. Initial biopsy was negative, but left upper lobectomy demostrated infiltrating moderately to poorly differentiated adenocarcinoma.

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Use of contrast enhancement on CT was reported to have high sensitivity (98%) for malignant nodule, however specificity and overall accuracy were shown to be much less (4).

The problem facing clinician is even greater if more than one nodule present, which is not that uncommon, especially after a CT in a patient initially presented with a SPN on a chest x-ray. Granulomatous disease, lung cancer with metastases and metastases from a remote primary all can present with multiple nodules. In patients without known malignancy there is no clear algorithm to follow, especially since resection of all the nodules is quite impractical. A different problem along the same lines is a SPN in a patient with a recent or remote history of malignancy, but without known metastatic disease (Figures 2-4).

Figure 2
71 yo male with 55 pk/yr smoking history and history of COPD, and prostate cancer resected 7 years ago and treated by radiation therapy. Mediastinal and lung window CT demonstrates central calcification in the right upper lobe nodule. Left upper lobe nodule is indeterminate by CT criteria. Minimal mediastinal lymphadenopathy is present. On PET the right upper lung nodule has no increased metabolic activity. There is a mild diffuse increased activity in the right mid lung consistent with inflammatory changes. The left upper lobe nodule has intense metabolic activity highly suspicious of cancer. No lymph node uptake was seen on this study. Left upper lobectomy showed moderately to poorly differentiated non-small cell carcinoma with necrosis. Resected lymph nodes and surgical margins were negative for tumor.

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Figure 3
56 yo male with history of TB, 60 pack/year smoking history and found 2 months ago infiltrating moderately differentiated squamous cell carcinoma of the left tonsil/oropharynx with nodal disease presenting with a right mid lung infiltrate and two left lung nodules, one possibly cavitating. PET-CT demonstrated increased uptake in left tonsilar fossa consistent with recurrent disease and a high uptake in left upper lobe nodule. Left lower lung nodule with possible cavitation did not demonstrate any increased uptake. Left upper lobectomy demostrated poorly differentiated infiltrating non-small cell carcinoma with neuroendocrine features (high grade large cell neuroendocrine carcinoma).

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Figure 4
50 yo male non-smoker with history of Grade II malignant fibrous histiocytoma (myxoid variant), in the left groin found during routine inguinal canal surgery for a presumed hernia. Immediate follow-up CT showed 4 pulmonary nodules, largest – 2cm with central calcifications. PET-CT showed a large left groin mass with high FDG uptake (not shown) and very minimally increased FDG uptake in the nodules, confirming probable granulomatous nature of the lung nodules. Wedge resections of the right lower and middle lobes demonstrated multiple hyalinized and calcified granulomas with rare yeast forms in them, consistent with histoplasma.

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Recently, an FDG-PET (PET) has come to the aid of clinicians. PET uses a radioactive glucose analogue, fluorine-18-labeled fluoro-2-deoxy-D-glucose (FDG), to map metabolic activity of tissues based on their utilization of blood glucose. To quantify FDG distribution, the amount of FDG uptake in a particular lesion is compared to the total body administered dose. The standardized uptake value (SUV), which is the ratio of FDG concentration in the lesion to the average FDG concentration in the body, of more than 2.5 has been shown to be sensitive and specific for malignant lesions, although SUV of 2 or 3 is used as the cut-off in some institutions (6) (Figures 5-9).

Figure 5
66 yo male with history of smoking and prostate cancer. Recent chest CT revealed spiculated nodule in the right upper lobe which has been slowly increasing in size. On PET the nodule has intense increase in metabolic activity consistent with primary lung CA. Spiculated appearance on CT is also suggestive of malignancy. Right upper lobectomy demostrated infiltrating moderately differentiated adenocarcinoma without invasion.

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Figure 6
74 yo male with 40 pack/year smoking history until 12 years ago and with a right pulmonary nodule found incidentally during a work-up for an aortic aneurysm repair. Right lower lobectomy showed small cell carcinoma of the lung with angiolymphatic invasion.

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Figure 7
78 yo male with 30 pack/year smoking history 20 years ago. History of COPD. PET-CT shows mild to moderate increase in FDG uptake, slightly less than typically seen in cancer but higher than in inflammatory conditions. There is also moderate emphysema seen. Left upper lobectomy showed infiltrating moderately differentiated adenocarcinoma.

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Figure 8
78 yo asymptomatic female with diabetes, remote history of snuff tobacco use and 2 daughters with tuberculosis as children. A nodule was discovered on chest X-ray during a work-up of pancreatitis. PET-CT shows focal area of intensely increased metabolic activity in the right mid lung consistent with primary lung cancer. Right upper lobectomy showed infiltrating moderately to poorly differentiated adenocarcinoma with papillary features.

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Figure 9
56 yo male with a history of infiltrating salivary duct adenocarcinoma of the left parotic gland. PET-CT demonstrated a few subcentimeter nodules with increased FDG uptake suspicious for metastatic process. Wedge resections demonstrated salivary gland metastases.

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Benign lesions typically demonstrate no uptake or uptake in 1-2 SUV range (Figures 10-11).

Figure 10
53 yo female with 25 pack/year smoking history. Recent CT revealed 1 x 1.4 cm noncalcified right lower lung nodule and diffuse mild emphysema. The patient reports no prior granulomatous pulmonary disease. Clinical exam revealed a palpable left supraclavicular node. PET-CT demonstrates no increased uptake in the nodule or anywhere else in the chest. 7 month CT follow-up showed no change in the nodule size or appearance.

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Figure 11
63 yo male with remote history of cigarette and pipe smoking and incidentally found left lung nodule. Patient had a recent cholecystectomy where pathology revealed carcinoma-in-situ in the gallbladder. PET-CT no increase in FDG uptake in the centrally calcified nodule consistent with granuloma. Left lower lobe wedge resection showed calcified hyalinized granuloma with fungal organisms morphologically suggestive of histoplasmosis.

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PET has overall sensitivity of 95-100% and specificity of 80-89% for detection of malignant nodules. The numbers are somewhat lower for smaller (<1.5-2cm) nodules and even higher for larger lesions. Association between FDG uptake and cell differentiation, and in turn prognosis, has been also suggested by available data (5).

In addition to characterizing a nodule, PET has been shown to be more sensitive and specific than CT in staging mediastinum and detecting distant metastases. PET has produced better results in nodal staging of bronchogenic carcinoma compare to CT, MRI and even mediastinoscopy. The diagnostic accuracy of PET is 92% compare to 75% for CT. Positive predictive value for PET is 90% compare to 50% for CT, and negative predictive value is 93% compare to CT’s 85% (7) (Figure 12).

Figure 12
74 yo female non-smoker with diabetes, 1 year history of cough and a newly discovered left lower lung mass. PET-CT in figure A shows left lower lung lesion with intense metabolic activity highly suspicious of cancer. Figure B demonstrates one left hilar lymph node with intense metabolic activity seen, highly suspicious for metastasis. Note the size of the lymph node, it would probably be considered benign by size criteria. Left lower lobe resection revealed infiltrating moderately differentiated adenocarcinoma with clear cell features. Metastatic adenocarcinoma was present in one of five peribronchial lymph nodes.

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Also in cases of metastatic disease, PET can be helpful in finding a primary malignancy, or reversly, ruling out one, since the whole body is imaged without additional radiation exposure (Figures 13-14).

Figure 13
66 yo female with 15 pack/year smoking history five years ago and longstanding COPD. Patient recently had a multilobar pneumonia and now presents with persistent right middle lobe and right upper lobe infiltrate associated with multiple nodules. Recent bronchoscopy was negative. Figure A. PET-CT shows large, heterogeneous, somewhat linear area of intensely increased metabolic activity in the right lung extending from mid to lower lungs. Although the shape of the lesion suggests inflammatory process, given high FDG uptake it is worrisome for a neoplastic process and biopsy was advised. Figure B. PET-CT shows small focal area of moderately increased activity in the left mid breast and further evaluation with mammogram was strongly recommended. Left breast biopsy revealed intraductal and infiltrating moderate to well differentiated mammary carcinoma with predominantly ductal features. Lung findings were due to a metastatic process.

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Figure 14
84 yo female with history of right breast cancer 6 years ago, status post lumpectomy and treated with follow-up radiotherapy. She also has history of two basal cell skin cancers on her face. A recent chest x-ray taken preoperatively for assessment of a "frozen left shoulder" showed lung nodules. CT showed 3 lung masses and a renal mass and raised possibility of metastatic disease from prior breast cancer or a renal cell cancer. Figure A. PET-CT shows 3 lesions with high metabolic activity in the right lung consistent with malignancy. These most likely represent metastases or a primary carcinoma of the lung with 2 metastases. Figure B. Renal mass seen on CT has no metabolic activity and unlikely to be neoplasm. Thus renal cancer metastatic to lung is unlikely. Right upper lung transthoracic biopsy demonstrated adenocarcinoma consistent with breast primary. Renal lesion did not change on follow-up.

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PET finds metastatic disease in approximately 10% of patients that were metastasis-free on a routine CT scan. PET can improve a diagnostic yield of a biopsy, by guiding intervention to the metabolically active lesions (5).

PET, unfortunately, has some shortcomings and blind spots. Inflammatory and granulomatous processes, such as tuberculosis, histoplasmosis, aspergillosis, coccidiomycosis, sarcoid, Wegener’s and even pneumonia can produce false-positive results, especially in cases of a fulminate process (Figure 15).

Figure 15
55 yo male non-smoker with history of type I diabetes. CT showed mediastinal lymphadenopathy. PET-CT demonstrated high uptake in mediastinal nodes worrisome for neoplastic process such as lymphoma or metastases. Resection revealed necrotizing granulomatous inflammation.

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Yet in majority of the cases PET is still able to provide a correct diagnosis. If post-obstructive pneumonia is suspected, or infiltrate does not resolve in short time interval with treatment, PET can still be of significant diagnostic value (Figure 16).

Figure 16
53 yo male with HIV, Hep C and significant smoking history. Recent CT showed left mid ling process worrisome for infection, but with associated lung nodule. In immunosupressed patient MAI or TB would also be a consideration. On PET-CT the left lung lesion has increased metabolic activity most compatible with tumor rather than inflammatory or infectious conditions. Left mediastinal lymph nodes with increased metabolic activity are seen, suspicious of metastatic disease. Transbronchial biopsy demonstrated small cell carcinoma.

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Neoplasms with low metabolic activity such as bronchoalveolar cell carcinoma and carcinoid, sometimes can give a borderline or a false-negative result (Figure 17).

Figure 17
67 yo female with history of obesity, osteoarthritis, CHF and diabetes. A 13 mm nodule in the left upper lung was seen on thorax MRI done to evaluate questionable extrinsic compression seen on cine- esophagram done for work-up of dysphasia. PET-CT demonstrates mildly increased uptake in the left upper lung nodule likely representing an inflammatory process or neoplasm. Left upper lobectomy showed encapsulated carcinoid tumor without invasion or lymph node extension.

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Two other causes of false-negative result are related to the technique itself. In patients with high blood glucose levels (>250 mg/dL) during the study tumor uptake of FDG can be competitively inhibited by blood glucose. Thus it is very important to check patient’s glucose level before injecting FDG. The second PET shortcoming is low spatial resolution, resulting in false-negative results in lesions less than 7 mm in size or even up to 1cm.

Giving the success of PET and a large volume of data on lesion morphologic characteristics on CT, it was only logical to combine physiologic and anatomic imaging into a single study – PET-CT. While having the benefits of both studies, PET-CT demonstrated additional available synergies. CT allows acquisition of attenuation correction data in about a minute, compare to approximately 10 minutes it takes during a regular PET study. This decrease in exam time increases number of exams that can be performed in a day, thus improving patient access to this new and exciting, but not yet readily available technology. Given that patient has to lie still for the entire exam and any motion degrades quality of the data, the decrease in exam time results in data improvement, especially in mildly claustrophobic or anxious patients. The improvement is especially noticeable in small lesions, PET’s blind spot. Fusion with high spatial resolution CT images is also most helpful in the small lesions. Co-registering thoracic CT and PET data sets has been reported to improve tumor localization or correct interpretation of less metastatic involvement (8).

Also when lesion has areas of different metabolic activity, such as cystic area or region of necrosis, PET-CT is invaluable in guiding intervention towards metabolically active portion of the lesion, thus improving a diagnostic yield of a biopsy (Figure 18).

Figure 18
52 yo asymptomatic male with a positive PPD. CXR 2 years ago showed a right upper lung mass. At that time decision was made to follow the mass, but due to lack of medical coverage patient did not return for a follow-up. Mass has increased in size compare to 2 years ago. PET-CT demonstrates markedly increased FDG uptake in a lower half of the right upper lobe lung mass consistent with malignancy. Biopsy guided to the lower portion of the mass demonstrated bronchiolo-alveolar carcinoma with extensive mucin production.

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When only one of two or more small lesions located in vicinity of each other is metabolically active, PET-CT is again an irreplaceable tool (Figure 19).

Figure 19
54 yo asymptomatic male with 40-80 pack/year smoking history presenting with right upper lobe lung lesion discovered incidentally during admission for hernia repair. PET-CT shows mass in right upper lung consistent with neoplasm. Right upper lobectomy showed moderately differentiated infiltrating adenocarcinoma with angiolymphatic invasion. The tumor showed papillary features, and growth in a bronchioloalveolar pattern at its periphery.

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Another benefit of simultaneous acquisition is in patient positioning. Although vast majority of the patients can lie supine for 15-45 second CT scan, back pain or other problems make it difficult for some patients to lie flat for 45 minutes that is acquisition time of a typical PET scan. We were able to accommodate a patient in semi-decubitus position for the PET-CT study, still producing excellent co-registration images

Figure 20
77 yo male with mediastinal lymphadenopathy.PET demonstrates activity in right medial lung or mediastinum. Fusion image shows that metabolic activity is in the osteophyte. Compare the PET portion of this figure with the next one, to see how CT component helps define if uptake is in the spine or in parenchymal lesion.

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PET-CT helps one localize lesions better compare to a low-spatial resolution PET, easily solving problems such as osteophyte in thoracic spine or a rib trauma vs a peripheral lung lesion (Figure ). Although co-registration in PET-CT is vastly better than fusion of images done days or even weeks apart on different scanners, one still needs to be aware of some pitfalls. Patient motion can degrade the quality of the data. In evaluation of lesions near the diaphragm one needs to be aware that breathing can sometimes results in misregistration. Also good CT training is a must for the person interpreting the study, to avoid CT interpretation pitfalls. Overall, however, PET-CT appears to be a large step forward compare to the CT or PET alone. In our experience it is also much better accepted by both patients and referring physicians. Almost all of our clinical PET studies are now done in PET-CT unit, which is our current routine standard for all PET studies. A testament to the referring physicians’ satisfaction is the fact that when the PET-CT device is unavailable due to routine servicing, these physicians generally prefer to re-schedule their patients rather than have them undergo separate PET and /or CT studies.

Even emergence of PET-CT did not produce a clear best algorithm for evaluation of a SPN. However, new options allow for more patient-friendly and cost-effective protocols. It has been already shown that, given a low prevalence of malignant SPNs, either PET with radiologic follow-up for 2 years or PET and CT with follow-up produced net cost reduction of $1600 per patient versus CT alone with follow-up. The majority of savings came from reducing the number of invasive procedures, which also means decreased patient morbidity (6). Given availability of PET-CT at our institution, we often use it as the most appropriate next step in a work-up of any indeterminate or suspicious for malignancy SPN, diagnosed initially by chest x-ray or CT. Nodules that are clearly benign by CT appearance or demonstrate no FDG uptake at all can be followed at 3, 6, 12, 18 and 24 months. Nodules that demonstrate intermediate FDG uptake (>1, but < 2.5 SUV) deserve a close follow-up with CT or PET-CT or a biopsy, depending on possibility of inflammatory process by clinical symptoms or history, and patient’s level of comfort with a follow-up. A similar conservative strategy of using chest CT and PET has shown a potential cost savings of $1150 per patient with no loss in life expectancy. This strategy uses biopsy of all positive sites on CT and PET that are consistent nonresectable disease, so that 100% of surgical candidates are definitively identified. The largest component of the cost savings comes from preventing unnecessary mediastinoscopy and thoracotomy (6).

In conclusion, PET-CT is a safe, non-invasive technique that frequently allows fast accurate diagnosis of a SPN. It should be a part of routine algorithm for evaluation of the SPN. Its value is especially evident in patients with SPN that are intermediate by CT criteria, in heterogeneous in appearance masses or when clinical history is complicated by previous malignancy.

References:

1 – Erasmus JF et al.: Solitary pulmonary nodules: Part I. Morphologic evaluation for differentiation of benign and malignant lesions. Radiographics 2000, 20: 43-58

2 – Liptay MJ: Solitary pulmonary nodule treatment options. Chest 1999, 16: 517S

3 – Midthun DE: Solitary pulmonary nodule: time to think small. Current Opinion in Pulmonary Medicine 2000, 6: 364-370

4 - Erasmus JF et al.: Solitary pulmonary nodules: Part II. Evaluation of the indeterminate nodule. Radiographics 2000, 20: 59-66

5 – Line BR et al.: PET imaging of lung and esophageal cancer. Applied Radiology 2002, 6: 9-17

6 – Goldsmith SJ, Kostakoglu L: Nuclear medicine imaging of lung cancer. Radiologic Clinics of North America 2000, 38(3)

7 – Wahl RL. Targeting glucose transporters for tumor imaging: "Sweet" idea, "sour" result. J Nucl Med. 1996; 37: 1038-1041

8 – Aquino SL et al.: Improved image interpretation with registered thoracic CT and PET data sets. AJR 2002, 178: 939-944

© 1999-2019 Elliot K. Fishman, MD, FACR. All rights reserved.