Diagnostic Accuracy of 18F-FDG PET - CT Imaging in determining the bone marrow involvement (BMI) in pediatric Hodgkin’s Lymphoma (HL)

Objective: To determine diagnostic accuracy of 18F-FDG PET - CT imaging in determining Bone marrow involvement in pediatric HL by taking bone marrow biopsy as standard. Method: This descriptive cross-sectional study was conducted in the Department of Pediatric Hematology/Oncology, Indus Hospital and Health Network, Karachi from July 2021 to December 2022. Treatment naïve histologically proven pediatric HL patients of both gender and aged between two to 16 years with both 18F-FDG PET - CT and bone marrow biopsy imaging were included. Basic demographics such as age, gender, height, weight, as well as classification and staging of HL was obtained. Results were assessed by expert reviewers who were blinded to clinical outcome. Sensitivity, specificity, positive and negative predictive value, and diagnostic precision were assessed. The data was analyzed via SPSS 26.0. Results: Total 131 participants were included with a male predominance i.e. 104 (79.6%). The mean (±SD) age was 8.7 ± 3.4 years. The present study reported PET/CT to have a sensitivity, specificity diagnostic accuracy, PPV and NPV of 94.1%, 92%, 92%, 64% and 99% respectively. Conclusion: Our findings support the idea that BMB should not be routinely conducted in all patients but rather can be reserved exclusively for patients with dubious 18F-FDG bone marrow findings, as this test has strong diagnostic potential for evaluating BMI involvement in HL.


Lymphomas
is considered as the most frequent cancer worldwide and constitutes 10%-15% of juvenile cancers. 1 Hodgkin lymphoma (HL) is the second most prevalent cancer in developing nations, whereas it is the third most prevalent cancer in affluent nations. 2 In Pakistan, HL makes up 4.9% of the population. 3Approximately 85% of cases of nodular lymphocyte-predominant HL are histologically classified as classic HL mixed cellularity (MC) type, a less frequent subtype. 4In order to tailor therapy protocols as well as stage the disease, evaluation of bone marrow infiltration (BMI) is crucial. 5ematogenous spread or extension from nearby soft tissues both have the potential to cause bone marrow involvement. 6,7Involvement of the bone marrow in lymphoma patients is thought to be a symptom of a more widespread illness and to be associated with a worse prognosis. 5Approximately, 5-14% of patients with HL had BMI, according to studies. 8,9An interesting observation was the significant bone marrow involvement seen in 23 (46%) patients from Children's Hospital Lahore (CHL) as compared to none in Royal Marsden Hospital (RMH), UK patients (p < 0.001). 2 Based on Ann Arbor classification with Cotswolds changes, 10 staging for lymphoma includes a BMB and CT scan. 5The conventional approach for identifying bone marrow involvement is considered to be BMB of dorsal iliac crest, supplemented by MRI when necessary. 11he most accurate way to identify lymphoma infiltration is by a BMB, but this technique is invasive and comes with a number of risks, including bleeding and pain. 12For the identification of BMI in HL staging, fluoro-deoxyglucose positron emission tomography combined with CT (FDG-PET/CT) is better to iliac BMB. 13 It can thoroughly assess condition of bone marrow & has an incredibly high sensitivity for spotting lymphoma invasion. 14FGD-PET/CT employing fluorine-18 (18FFDG-PET/CT) has sensitivity, specificity, and accuracy of 96%-99%, 95%-100%, and 99% respectively, for staging malignant lymphomas. 15As a result, numerous clinical institutes have proposed that PET-CT should be the first option for identifying lymphoma bone marrow invasion rather than bone marrow biopsy.
In view of above, our research was designed to evaluate diagnostic accuracy of FFDG-PET/CT imaging in determining BMI in pediatric HL by taking it as gold standard.To the author's knowledge, there was relatively little literature in this field.Furthermore, because the majority of previously published studies analysed retrospective series of the HL children, there may be a high risk of bias because the researcher had to rely on information gathered by third parties that was not intended for the study.As a result, the data that was made available might not be of high quality.
The current study was carried out prospectively which may give more accurate results.The results of this study would add information in existing pool of literature by providing statistical evidence about the diagnostic accuracy which would help in bringing it in practice in place of BMB.

METHOD
This research was carried out in a span of 18 months i.e. from July 2021 to December 2022 in the Department of Pediatric Hematology/Oncology, Indus Hospital and Health Network, Karachi after the approval of study from Institutional Review Board (IRB) of the hospital (IRD_IRB_2021_05_008; Dated: June 21, 2021).The study's non-probability consecutive sampling technique resulted in the enrollment of 131 patients overall who met the study's eligibility requirements.The patient's parent or legal guardian provided their informed consent.All untreated histological proven pediatric HL patients of either gender of aged between two to 16 years who had their both PET/CT & BMB were included.The study excluded patients who had unilateral iliac crest biopsy, extra cancer, or an unclassified lymphoma.The sample size was calculated by taking the following values. 16r Sensitivity: Sensitivity = 96% 17 For Specificity: Specificity = 95% 17 Prevalence of BM involvement in HL = 46% 2 Prevalence of BM involvement in HL = 46% Presence of malignant nodules detected by both 18 FFDG: PET/CT and BMB labeled the individual as true positive while their absence in both modalities marked him/her as true negative.False positive cases meant positive 18 FFDG: PET/CT scan findings but negative BMB while negative 18 FFDG: PET/CT scan findings but BMB findings meant false negative.
Bone marrow involvement on 18 F-FDG PET -CT imaging was reported as positive, if a high-uptake level of focus in bone marrow was higher than liver (or mean Standard Uptake Values of bone marrow was >2.7).Bone marrow involvement on BMB was labeled as positive if a typical Reid-Sternberg cell in a polymorphous background was observed (Fig. 1&

DISCUSSION
When it comes to staging lymphoma, BMI evaluation is crucial as its existence advances the condition to Stage-IV.The results of recent research describe the effectiveness of BMB & 18F-FDG PET/CT for determining BMI in group of 131 paediatric HL cases.BMB is an invasive process that permits histologic analysis of the bone marrow taken from the posterior iliac crest.The noninvasive method 18F-FDG PET/CT, however, enables viewing of the entire bone marrow and is in contrast to this. 5 According to our findings, PET/CT had a sensitivity, specificity, diagnostic accuracy, PPV and NPV to be 94.1%, 92%, 92%, 64%, and 99% for the identification of bone marrow involvement (BMI).According to a metaanalysis by Wu et al, 18 which comprised of 32 trials, the sensitivity and specificity of PET/CT were 90.3% and 91.6% (95% CI, 85.9, 95.9), respectively.The detection of lymphoma's involvement in the bone marrow by PET/ CT was discovered to be a highly sensitive and specific method.However, the meta-analysis performed by Pakos et al, 19 which involved 587 patients, the results of 18F-FDG PET/CT for diagnosing BMI did not Diagnostic Accuracy of 18F-FDG PET-CT in BMI determination in pediatric HL exhibit outstanding concordance with that of BMB and displayed sensitivity and specificity of 51% (95% CI, 38-64%) and 91% (95% CI, 85-95%) respectively.This metaanalysis solely employed BMB as the gold standard, hence 18F-FDG PET/CT was not advised to take the place of the standard BMB in this meta-analysis.
In the present study, all of the patients with a positive BMB also had a positive PET/CT scan.However, there are published studies in which PET/CT identified BMI in patients that were missed by the BMB.In a study by Cheng et al. 20 PET/CT identified BMI in two additional pediatric HL patients in a sample size of 31 cases.Agarwal et al. reported the BMI detected by FDG PET/CT in three extra patients in a study cohort of 38 pediatric HL patients that were missed by BMB giving the FDG PET/CT a sensitivity, specificity, NPV and PPV of 87.5%, 100%, 100%, and 96%, respectively. 11 study conducted by Purz et al. evaluated the ability to detect the BMI by F-18 FDG PET/CT and BMB in a patient population of 175 pediatric and adolescent HL patients with stage more than IIA, and reported that F-18 FDG PET/CT was able to detect BMI in 22% more cases in comparison to BMB.21 This led them to concluding that F-18 FDG PET may take role of BMB in normal staging procedures and was also found to be in line with other studies that advised against routinely using BMB for staging in these individuals.[22][23][24] In the current study, we discovered that 105/131 (80%) of patients also had negative bone/bone marrow PET/CT scans, indicating to the fact that routine BMB might not always be indicated if 18F-FDG-PET/CT is negative.Our work supports the finding of other authors previously noted that PET/CT has a strong NPV & is an effective tool for evaluating bone and bone marrow in addition to BMB. 22 Our results are consistent with the accumulating data suggesting that BMB may eventually become unnecessary due to normal bone/bone marrow FDG uptake.Further research is necessary due to the importance of multifocal aberrant bone and bone marrow FDG uptake, which is underlined by instances where the two are inconsistent.Future research may use targeted biopsies or correlative imaging to confirm contradictory findings.

Limitation:
The primary limitation of this study is small sample size.Future studies with large sample size are needed to confirm our observations.

CONCLUSION
In a series of 131 paediatric patients with HL, we have presented data on 18F-FDG PET/CT and BMB performance in the detection of BMI.Our findings support the idea that BMB should not be routinely conducted in all patients but rather can be reserved exclusively for patients with dubious 18F-FDG bone marrow findings, as this test has strong diagnostic potential for evaluating BMI involvement in HL.

Fig. 1 :
Fig.1: Mononuclear variant of Hodgkin cell with increased background fibrosis (H and E stained section of bone marrow trephine; 40x objective).
18rief history of demographic information like age, gender, height, weight, BMI, histological distribution of HL and staging was obtained and was recorded on predesigned proforma.All participants underwent both18FFDG-PET/CT & BMB. Rlts were assessed by expert reviewers who were not aware of clinical outcome.Sensitivity, specificity, PPV, NPV & diagnostic precision was calculated as follows: Sensitivity: Sensitivity refers to ability of 18 FFDG: PET/ CT imaging to correctly recognize patients who have BMI and was calculated using formula: 2).Statistical Analysis: The data analyzed through SPSS.26.0.Mean and Standard deviation were calculated for continuous variables such as age, height, weight and BMI while frequency and percentages were calculated for categorical variables such as gender, histological distribution of HL & staging.A 2x2 contingency table was built to evaluate the sensitivity, specificity, PPV, NPV & diagnostic precision of 18 F-FDG PET -CT imaging in determining BMI in pediatric HL by taking BMB as gold standard.

Table - I
: Basic Demographics of patients and details Delta neutrophil index and other laboratory markers (n=131).