Ali Mohammed Hamza

Lithuanian University of Health Sciences

The value of PET/CT-scan in differential

diagnosis of solitary pulmonary nodules

By

Ali Mohammed Hamza

A thesis submitted in part fulfillment for the

Degree of Master of Medicine

In the Faculty of Medicine

Department of Radiology & Nuclear medicine

Date:

2016-2017

Table of content

6. Ethics committee clearance 4

7. Abbreviation list 5

8. Introduction 6

9. Aim and objectives 7

10. Literature review 7

11. Research methodology and methods 12

12. Results 13

13. Discussion 20

14. Conclusion 21

Summary

Author name: Ali Mohammed Hamza

Title: The value of PET/CT scan in differential diagnosis of Solitary pulmonary nodules (SPN).

Aim: To investigate the limitations of PET/CT imaging in differentiating between benign and malignant SPN lesions.

Objectives:

1. To categorize the patients according to their disease by comparing PET/CT and analyze histological findings and study their case histories.

2. Calculate the ratio between false positive and true positive results.

3. Evaluate the reliability of PET/CT imaging modality in differentiating between benign and malignant SPN lesions.

Methods:

This study was a retrospective qualitative study based on patients diagnosed SPN with PET/CT scan across Kaunas, Lithuania. The patient archive were present in the department of radiology, patients diagnosed with SPN was chosen to be participants of this study. The study measured the ratios produced from PET/CT scans and they were confirmed with biopsy.

Results:

There were 12 subjects (66,67%) that presented with malignant lesions and one with metastasis lesion (5,6%), and this group was the true positives. There were 2 subjects collected for the false positive group (11,11%) and the false negatives consisted of 3 subjects (16,67%).

Conclusion:

The conclusion of this investigation was that by utilizing PET/CT imaging, it was revealed that patients fell into different prevalence groups. In 26.71% of the investigated patients the PET/CT imaging failed to differentiate between benign and malignant lesions. True positive patients in this study represented the major part, making up 72.2% of all cases (of which 33.9% were males and 38.3% were females).

Conflict of interest

Acknowledgements

A special appreciation that I have to acknowledge, please allow me to dedicate my gratitude towards the following significant advisor:

I would like to give special thank to my supervisor Prof. Ilona Kulakienė, for her support, patience and especially her encouragement to always get the best out of me and for giving me the opportunity to write this research under her supervision.

Abbreviations list

1. SPN – Solitary pulmonary nodules. 2. Pt/pts. – Patient/patients.

3. AHF – Adrenal-hepatic fusion 4. TB– Tuberculosis

5. MDR – Multi drug resistance 6. DM – Diabetes mellitus

7. PET/CT scan – Positron emission tomography/computed tomography scan 8. CT – computed tomography

Introduction

Direction of the study problem

This study is based on using PET/CT imaging for differential diagnosis of solitary pulmonary nodule and using the prevalence’s that are formed to determine whether this imaging technique is reliable. The prevalence’s; false positive (benign granulomatous lesion), false negative (benign granulomatous lesion) and true positive (malignant tumorous lesion), will be the ones this study focuses on. Patients that are recognized of different category will be grouped into “other”

This study aims to calculate the different ratios among the patients diagnosed with solitary pulmonary nodule.

Aim of thesis

Calculate the different ratios formed by using PET/CT scan as an instrument to differentiate between benign and malignant lesions in patients diagnosed with solitary pulmonary nodule.

Objectives of the thesis

1. PET/CT scans helps to identify characteristics of the nodule and place the participants in ratio groups.

2. Biopsy/is are used as a conformational investigation to finalize the diagnosis. 3. Patient case histories aids in the general information and understanding about

the participant/s.

Literature review

Many studies presenting their difficulties in diagnosing tuberculosis over malignancy, the fact that there are studies been made not only restricted to one organ system, they have presented similar results to other organ systems in the body. Physicians are always met with backstop in differentiating SPN lesions with PET/CT scans. Therefore, in this review, studies with similar objectiveare used in this literature review.

Studies made outside Lithuania

The first article which was found valuable for this research was published in

forgotten during PET CT scanning of cancer patients: tuberculosis”. [8] This articles

aim was to have follow ups only with cancer patients with suspected tuberculosis, the amount of patients that was followed-up was 14, the list of patient was limited since the specific criteria was needed to be very meticulous. The article states that none of the patients involved in the study had tuberculosis in their personal history, among the patients 5 (35.7%) of them were diagnosed with tuberculosis during the preliminary staging, whereas 9 (64.3%) were diagnosed during the follow-up after the treatment, which means all patients involved in the study was diagnosed with tuberculosis as concomitant. This clearly shows how crucial it is for both physicians and patients to miss tuberculosis diagnosis, “…an old enemy” in this case means tuberculosis (non active phase), that people are affected by this infection but during its latent phase no physician would suspect since no symptoms are presented.

The same article stated, however two of our cases had numerous lymph nodes in mediastinum with high SUV max values in their follow-up PET CT scans, which were performed after the adjuvant treatment. When tuberculosis wasn’t diagnosed, it was considered as recurrence cases (cancer spread), so they received chemotherapy. As their physical performance deteriorated during the chemotherapy, lymph node biopsy was decided to be performed and they were diagnosed with tuberculosis. The study concluded that in such conditions, tuberculosis diagnosis is made only on the basis of microbiological and histological examinations, because none of the available imaging methods is specific or routinely made for tuberculosis.

According to the same study stated that, nodular appearance on FDG-PET with SUVmax above 2.5 should lead to malignancy with 80% sensitivity and 70% specificity in PET CT examinations, but all the patients that were participating in the study, their SUVmax values of involved lymph nodes were above 2.5. But although, SUVmax values relating to tuberculosis in PET CT scans were reported as high in some studies but low in some others, published in the literature. This was clearly for the study that a physician differentiating between cancerous nodule and granulomatous nodule can’t get a precise diagnosis by evaluating the SUVmax [8, 18, 19].

cancerous lesions, but after thorough examination was successfully managed with anti-tuberculosis treatment; according to Jin Mo Goo et al. reported 10 cases with pulmonary nodules and positive PET CT results. Suspected cancerous nodules, biopsy was performed afterwards, results was tuberculosis; and according to GengTian et al. reported 3 cases with abdominal tuberculosis, with signs similar to peritoneal malignancy in PET CT scan, tissue sampling was performed just to make sure that nodules were diagnosed correctly, and they were. All articles had a common conclusion that tuberculosis should always be considered in endemic regions during PET CT scan evaluation and in such circumstances that differentiating TB from cancerous lesions, they are were not helpful to resolve the problem.

Another article that was valuable information for this research was published in the medical journal QJM in 2017 under the title “Tuberculosis mimicking metastases by

malignancy in FDG PET/CT”, [9] it was stated that the PET/CT scans that were used are preferable to differentiate between benign and malignant lesions, but has its faults specially in differentiating malignancies from inflammatory lesions such as TB. This is important to notice since the conclusion of this article clearly state that it’s fundamentally important to correctly diagnose for further intervention and if there’s a doubt in the diagnosis then further investigation is required. [8, 9, 12, 13, 14]

In this study, it was stated that cancer of unknown primary site composes about 4-5% and although TB is common, skeletal TB is rather rare, composing 5% of all TB cases, therefore it was decided for these patients to do PET/CT scan. In addition that fluorodeoxyglucose-avid (FDG) focus in PET CT scan didn’t necessarily mean malignancy and SUV (standardized uptake value) was high in both TB and malignant lesions, the conclusion in these kinds of cases was that TB should be kept in mind, and a biopsy should be followed.

extra-adrenal involvement such as pulmonary tuberculosis, this aids in the diagnosis of adrenal tuberculosis. [10, 17] However, in adrenal tuberculosis direct invasion of adjacent organs has not been reported but is instead suggestive of advanced stage of adrenal malignancy. In the discussion of same study, another article was used based on autopsy studies investigating adreno-hepatic fusion (AHF) and its causes, they exhibited 636 unselected autopsies and 63 incidents found AHF (9,9%), incidence is much higher in older age groups, suggestive that AHF may be an ageing phenomenon and the members of the article did not find any relating etiologies to AHF. Although other aricles reported clinical significance of AHF as follows: (a) could be a route for adrenal metastasis of hepatocellular carcinoma, and (b) the benign adrenal lesions (i.e., adrenocortical adenoma) may mimic adrenal or hepatic malignancies.Although in this article, this patient case was a benign condition, adrenal tuberculosis, and the potential AHF was a route of transmission of Mycobacterium Tuberculosis pathogens to the liver. Therefore it was concluded that adrenal tuberculosis can invade adjucent liver when it occurs in right adrenal gland, because the AHF may exist as a potential route for the spread.

In the same article it was stated that tuberculosis infection in various body organs may show abnormal high uptake on 18F-FDG PET/CT, which often intercept in the correct diagnosis wether it is malignant or not, specially in cases when tuberculosis is misdiagnosed or unsuspected. Also, in adrenal gland, tuberculosis infection is one of representative false-positive cause for the adrenal malignancy because it could show high FDG uptake from adrenal lesion. It was concluded that findings of nonadenoma on dedicated adrenal CT as well as high uptake on 18F-FDG PET/CT can also be seen, as previously reported.

without-tuberculosis (population 712,392) that developed cancer was 1584 subjects (Incidence rate per 10,000 person/year = 2,41); patients with tuberculosis (population 4,480) that developed cancer was 100 subjects (Incidence rate per 10,000 persons/year = 26.3). In conclusion, this cohort study provides evidence supporting the apprehension that patients with pulmonary tuberculosis carried higher rish of developing lung cancer, and patient with tuberculosis with comcomittant chronic obstructive pulmonary disease (COPD) and smoking enchanced the risk of developing lung cancer.

Research methodology and method

The participantsinvolved in this study will be patients diagnosed with SPN by PET/CT scan from the Radiology department in Kauno klinikos. Data collection was approved from the Bioethics committee.

The object of study

This study is designed to acknowledge the prevalence formed from using PET/CT scan as an instrument fordifferential diagnose in patients with SPN between benign and malignant.

Participant selection

For this study, patients with SPN were chosen from same city, only Kaunas district hospital,as there are some limitations. Participants must have had performed a PET/CT scan and were identified by a radiologist. This study identified 57 subjects that was diagnosed with SPN, however only 18 subjects participated in this study. The eligible subjects involved in this study were picked by their diagnosis and their case histories were analyzed from an archive.

Data collection method

The primary data was collected from the Radiology department personal archive (name, date of birth and results of PET/CT scan). Further information if required, will be gathered from the patient case histories, which were collected from an archive located in outpatient department (poliklinika).

Data analysis method

Results

Despite the fact that PET/CT is an image modality that investigates changes in the whole body simultaneously (meaning that PET/CT does not focus on a single area of the body), the analysis in this dissertation focused on the chest region.

As stated previously, we had 18 patients, which were analyzed in this dissertation. Looking through and evaluating the findings that were documented on their PET/CT-scans as well as biopsy results primarily did the analysis.

Table 1.1 Number of false-positive and false-negative findings

Nr of

subjects/biopsy

False positive False negative True positive

Male 0 % 5.56 % 38.9 %

Female 11.1 % 11.1 % 33.3 %

The essential findings of these PET/CT scans as well as biopsy results are summarized in the aforementioned table (Table 1.1). By looking into this table, the first noteworthy thing that can be seen is that the prevalence of false-positive results was 11.1 % (it was found in 2 of the female patients, but there was no false-positive cases in the male patients). Furthermore, we could see that the false-negative results were found in 5.56 % of the male patients, and 11.1 % of the female patients. Finally looking into the true positive results (meaning that these patients actually were diagnosed with malignant lesions by biopsy confirmation), we can see that there is a slight male predominance (38.9 % in males in contrast to 33.3 % in females). Prevalence that characterizes patients as true negative will not be found. 1 patient out of the 18 in true positive group in this study was investigated and found that the additional lesion that was found was metastatic that originated from the primary lesion.

Patient cases

Case nr 1

Date of birth 1946-01-20

Gender Male

Comorb. Hypertension

PET/CT scan Left lung S6 intense pathological FDG accumulation 2,2x1,8 cm. No lymph node involvement. No distant metastasis visible. Most likely tumor.

Biopsy Lung adenocarcinoma, with acinar domination on histology. T2b N0 M0

Case nr 2

Date of birth 1974-01-01

Gender Male

Comorb. Diabetes mellitus (T2) and COPD.

PET/CT scan Right lung S7, intense pathological FDG accumulation 1,9x1,5 cm. No lymph nodal involvement. No distant metastasis visible. Most likely tumor.

Biopsy Squamous cell carcinoma.

T1a N0 M0

Case nr 3

Date of birth 1941-10-22

Gender Female

Comorb. Ovarian cancer (left ovary) -> removed.

PET/CT scan Right lung S6, pathological FDG accumulation 2,3x1,7 cm. Below and medial derivate S6/9 at the border pathological lesion calcinated lymph nodes. No distant metastasis visible .Most likely tumor.

Case nr 4

Date of birth 1952-06-13

Gender Female

Comorb. Autoimmune vasculitis

PET/CT scan Left lung S4, pathological FDG accum. 1,8x1,6 cm. No intense take up of FDG. No lymph nodal involvement. No distant metastasis visible.

Biopsy Inflammatory changes. Vasculitis changes can be secondary to mucosal ulceration, but Autoimmune vasculitis definitive diagnosis. (Surgical biopsy)

Case nr 5

Date of birth 1958-06-20

Gender Female

Comorb. Previous myocardial infarction, diabetes mellitus type 1 and hypertension.

PET/CT scan Left lung S7, pathological FDG accumulation 2,3x2,0 cm. Intense uptake of FDG, no lymph node involvement. No distant metastasis visible. Most likely tumor.

Biopsy Infiltrative lung adenocarcinoma, G 2

Case nr 6

Date of birth 1951-10-07

Gender Female

Comorb. Hypertension, TB exposure

PET/CT scan Right lung, pathological FDG accumulation, 2,0x1,9 cm. Intense uptake of FDG, no visibility of lymph node involved. No distant metastasis visible. Most likely tumor.

Case nr 7

Date of birth 1946-12-10

Gender Male

Comorb. COPD, intestinal carcinoma

PET/CT scan Right lung involvement S5, Pathological FDG accum. 1,8x1,8 cm. Intense FDG uptake. No distant metastasis visible. Most likely tumor.

Biopsy Lung adenocarcinoma well differentiated G1.

Case nr 8

Date of birth 1953-07-14

Gender Female

Comorb. Hypertension, angina pectoris and breast cancer.

PET/CT scan Left lung involvement S7, path. FDG accum. 2,1x1,7 cm. Sign of hilar lymph node calcification. Spiculated shape of lesion. No distant metastasis visible. Most likely tumor.

Biopsy Squamous cell carcinoma T1b N1 M0

Case nr 9

Date of birth 1935-12-05

Gender Male

Comorb. Hypertension (primary); previous myocardial infarction and angina pectoris unstable.

PET/CT scan Left lung involvement S6, path. FDG accum. 1,8x1,6 cm. No signs of lymph node involvement. No distant metastasis visible. Most likely tumor

Case nr 10

Date of birth 1955-08-16

Gender Male

Comorb. TB exposure and poorly treated; and COPD

PET/CT scan Right lung involvement S8, path. FDG accum. 1,9x,1,5 cm. Nodular involvement FDG uptake is noticed. Unsure of likelihood further investigation needed for confirmation. Although no distant metastasis visible.

Biopsy Non caseating granuloma, with inflammatory cells.

Case nr 11

Date of birth 1962-12-18

Gender Female

Comorb. Hypertension

PET/CT scan Right lung involvement S6, path. FDG accum. 2,0x1,7 cm. No nodular involvement is noticed. No distant metastasis visible. Most likely tumorous lesion involvement.

Biopsy Non caseating granuloma, with abnormal inflammatory cells.

Case nr 12

Date of birth 1959-02-06

Gender Male

Comorb. COPD and hypertension

PET/CT scan Right lung involvement S4, pathological accum. 2,4x2,2 cm. Nodular calcification in hilar region. No distant metastasis visible. Most likely tumor involvement.

Case nr 13

Date of birth 1971-05-28

Gender Female

Comorb. Hypertension

PET/CT scan 1st lesion: Right airway involvement S7, pathological FDG accumulation 2,7x2,4 cm. Hilum nodular calcification.

2ndlesion: Left lung involvement S4, pathological FDG accum. 1,5x1,4 cm.

Biopsy Squamous cell carcinoma. T0 N0 M1

Case nr 14

Date of birth 1957-07-23

Gender Female

Comorb. COPD, Hypertension.

PET/CT scan Right lung involvement S6, pathological FDG accumulation 2,1x1,9 cm. No lymph nodal involvement. No distant metastasis visible. Most likely tumor.

Biopsy Adenocarcinoma.

Case nr 15

Name P.S.

Date of birth 1948-06-18

Gender Female

Comorb. Hypertension and TB exposure.

PET/CT scan Left lung involvement S5, pathologicalintense FDG uptake 1,9x1,8 cm. No lymph node involvement. No distant metastasis visible. Most likely tumor.

Case nr 16

Date of birth 1962-04-06

Gender Male

Comorb. COPD and hypertension

PET/CT scan Left lung involvement S5. Path. FDG accumulation 2,5x2,2 cm. Close by hilum, lymph nodal involvement (calcification). No distant metastasis visible. Most likely tumor.

Biopsy Squamous cell carcinoma. T2 N1 M0

Case nr 17

Date of birth 1965-09-18

Gender Female

Comorb. Breast cancer and hypertension.

PET/CT scan Right lung involvement S7. Pathological FDG accum. 2,7x2,3 cm. No lymph nodal involvements visible on PET/CT scan. No distant metastasis visible. Most likely tumor lesion.

Biopsy Adenocarcinoma T2 N0 M0

Case nr 18

Date of birth 1950-11-21

Gender Male

Comorb. COPD and hypertension

PET/CT scan Right lung involvement S6. Pathological FDG accum. 2,6x2,5 cm. Suprahilar lymph nodal involvement. No distant metastasis visible. Most likely tumor.

Discussion

As it was clearly depicted in table 1.1, out of the 18 patients whom were evaluated, only 2 patients showed false-positive results (11.1 %). What is remarkable is that both these patients were females, suggesting that the prevalence might be gender related. False positive on PET/CT illustrates that there was high metabolic activity in the investigated area, whereas the histopathological examinationconfirmed that it was not a malignant lesion.Patients with false negative prevalence, on PET/CT scans their illustration was of different appearance, metabolic activity in investigated area is low, whereas when analyzing the histopathological specimen confirmed that it was indeed not a malignant lesion. Furthermore, false negative patients were totally 3 in number(16,71 % out of the 18 (2 females (11.1 %) and 1 out of them is a male(5,6 %)). Finally when looking into the true positive results, is the patients on PET/CT scans whereas their lesions high metabolic activity resembled those of false positive patients, but on histopathological examination from the biopsy, indeed showed different results from those of false positive patients. We can see that there is a slight male predominance (38,9 % in males in contrast to 33.3 % in females), also that 6 out of the 7 males from the true positive prevalence had chronic obstructive pulmonary disease (COPD) from which was caused by smoking, compared to the females, were only 1 out of the 6 patients have COPD.

Conclusion

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