## 4 Discussion  
This systematic review included 41 studies that included a total of 6147 newly diagnosed NHL patients. All patients underwent both [18F]FDG PET/CT and BMB to diagnose the involvement of the bone marrow. Most of the patients were classified as stage IV according to the Ann Arbor staging system. Overall, the included studies were of high quality with few methodological concerns in the outcome measurements. The results of this systematic review showed that [18F]FDG PET/CT achieves a high specificity (90%) but a moderate sensitivity (73%) in detecting bone marrow involvement in newly diagnosed NHL patients. Our results regarding the diagnostic performance of PET/CT are not in full agreement with the previous systematic review by [PERSON] et al., [14], which found lower sensitivity (43%) and similar specificity (88%). However, [PERSON] et al., [14] only included three studies with a mixed population of a total of 239 NHL patients, whereas our investigation includes 41 studies with a total of 6147 NHL patients. The larger sample size of our study also included more patients with various bone marrow involvement, making the generalisations more robust. Another difference between our systematic review and [PERSON] et. al. [14], is that they investigated single PET units, whereas our paper considers studies including only PET/CT. However, previous studies have shown that although PET/CT has higher sensitivity in detecting bone marrow infiltration compared to a single PET unit, their differences are not expected to be statistically significant [56]. When [18F]FDG PET/CT was compared with the BMB, which is the traditional method used for determining the BMI in NHL patients, we found that the [18F]FDG PET/CT achieves a higher sensitivity than BMB. More specifically, BMB achieves a sensitivity of 56%, whereas [18F]FDG PET/CT achieves a sensitivity of 73%. The lower sensitivity of BMB compared to [18F]FDG PET/CT indicates that biopsy in the iliac crest area may miss bone marrow involvement that can be found by the [18F]FDG PET/CT. In addition, if a PET/CT scan is positive, bone marrow involvement can be excluded with high certainty and BMB may be avoided. On the other hand, if a [18F]FDG PET/CT is negative a BMB should be performed as we cannot exclude the presence of BMI. A blind BMB was recommended for all DLBCL patients from the European Society for Medical Oncology (ESMO) until 2015 when new guidelines were published [57] advising that BMB is not required when there is a positive PET/CT for bone marrow involvement. However, a BMB is required in case of negative PET, when its results would change prognosis and treatment, especially if a shortened number of immunochemotherapy cycles is proposed. On the basis of these findings, a blind BMB in all NHL for staging purposes needs to be re-evaluated. The results of our study might impact on the guidelines for the general population of NHL patients since it is still not clear whether biopsy is or not required. The patient population of this systematic review was separated based on the different subtypes of NHL. For the mixed population of indolent NHL the results of this review indicated that BMB is far more sensitive in indolent NHL than [18]FFDG PET/CT and thus it is not recommended to replace the routine BMB with PET/CT for identifying BMI in such patients, as many cases will be missed. For less aggressive or indolent lymphomas 11C-Acetate PET/CT might be a promising approach although it requires further evaluation as it has been found to achieve a higher sensitivity compared to the [18]FFDG PET/CT [58]. The largest percentage (about 70%) of all indolent lymphomas worldwide are FL [59]. FL is also the second most common subtype of NHL. For patient cases with FL disease, across the studies investigated in this review, the sensitivity of BMB compared to [18]FFDG PET/CT in determining BMI was superior. FL is highly variable in terms of presentation of the disease.