(a) The method of MTV evaluation should “join” the clinical context, otherwise, the type of sarcoma and time of evaluation. OST patients, in general, have lesions with less soft-tissue component and consequently less post-treatment volume shrinkage than ESFT patients. Moreover, persistent bone 

(a)

The method of MTV evaluation should “join” the clinical context, otherwise, the type of sarcoma and time of evaluation. OST patients, in general, have lesions with less soft-tissue component and consequently less post-treatment volume shrinkage than ESFT patients. Moreover, persistent bone 

¹⁸F-FDG uptake could be related to the post-treatment bone-healing reaction ^[53]. Thus, MTV-fixed “relative” methods could preferably be avoided to limit post-treatment MTV overestimation in OST patients ^[53].

(b) An early prediction of histopathological response by MTV/TLG and textural features could be most useful after approval of new targeted therapies, which aim to change the standard of care and outcome for pediatric sarcomas. In the current published guide for the practical evaluation of PET response criteria in solid tumors (PERCIST) ^[74], the concomitant estimation of MTV/TLG parameters (usually by liver-based threshold segmentation methods) has been proposed for better consensus in the assignment of stable, partial, or progressive response to induction treatment. However, reproducibility of MTV/TLG evaluation is a prerequisite for treatment response prediction, still interfering with the MTV/TLG prognostic value in clinical practice.

(c) It should be clear that given the histologic type, pediatric sarcomas are different compared to those of adults. The tumor microenvironment is much more important and a possible target for immunotherapy agents, as implicated in the tumor response to treatment. On the contrary, mutational load and relative neoantigens are less expressed by tumor cells of pediatric sarcomas compared to adult sarcomas. Thus, targeted agents, as those implicated in cell differentiation, are probably more effective in pediatric sarcomas, according to experimental data for the “embryonal” RMS histologic subtype, the most common soft-tissue pediatric sarcoma ^{[42][75][76][77]}. Overall, tumor heterogeneity 

F-FDG uptake could be related to the post-treatment bone-healing reaction [92]. Thus, MTV-fixed “relative” methods could preferably be avoided to limit post-treatment MTV overestimation in OST patients [92].

(b)

An early prediction of histopathological response by MTV/TLG and textural features could be most useful after approval of new targeted therapies, which aim to change the standard of care and outcome for pediatric sarcomas. In the current published guide for the practical evaluation of PET response criteria in solid tumors (PERCIST) [105], the concomitant estimation of MTV/TLG parameters (usually by liver-based threshold segmentation methods) has been proposed for better consensus in the assignment of stable, partial, or progressive response to induction treatment. However, reproducibility of MTV/TLG evaluation is a prerequisite for treatment response prediction, still interfering with the MTV/TLG prognostic value in clinical practice.

(c)

It should be clear that given the histologic type, pediatric sarcomas are different compared to those of adults. The tumor microenvironment is much more important and a possible target for immunotherapy agents, as implicated in the tumor response to treatment. On the contrary, mutational load and relative neoantigens are less expressed by tumor cells of pediatric sarcomas compared to adult sarcomas. Thus, targeted agents, as those implicated in cell differentiation, are probably more effective in pediatric sarcomas, according to experimental data for the “embryonal” RMS histologic subtype, the most common soft-tissue pediatric sarcoma [85,106,107,108]. Overall, tumor heterogeneity 

¹⁸F-FDG imaging data reflects the histologic subtype, tumor microenvironment, and tumor molecular and genomic characteristics. Integrating all this information could lead to a more accurate interpretation of PET-based risk stratification and treatment monitoring of the whole tumor lesion of pediatric sarcomas. Interestingly, the first data in “radiogenomics” of adulthood carcinomas revealed an accurate tumor phenotyping and decoding of breast cancer lesions by PET/MR textural features ^[78][79].

F-FDG imaging data reflects the histologic subtype, tumor microenvironment, and tumor molecular and genomic characteristics. Integrating all this information could lead to a more accurate interpretation of PET-based risk stratification and treatment monitoring of the whole tumor lesion of pediatric sarcomas. Interestingly, the first data in “radiogenomics” of adulthood carcinomas revealed an accurate tumor phenotyping and decoding of breast cancer lesions by PET/MR textural features [109,110].

Concerning RMS, adolescents, regardless of the histologic subtype (embryonal or alveolar), have a worse prognosis than preschoolers ^[80][111]. As previously mentioned, dichotomizing the patient population into children and adults is useful but arbitrary. In the context of textural features’ cut-off values and interpretation, such as the shape feature of elongation in pediatric OST ^[57][96], age and other somatometric parameters could contribute to a better understanding of the biological characteristics of pediatric sarcomas.

In conclusion, treatment response evaluation by radiomic analysis should include both primary and metastatic tumor sites if the minimum required volume is guaranteed ^[60][54]. Volume-dependent ^[72][57] radiomic analysis that estimates the dynamic process of tumor heterogeneity could help guide decisions for further local treatment of metastatic sites. Inversely, radiomic analysis could detect recurrence in pediatric sarcomas or even sarcomatous dedifferentiation of neurofibromas in children with neurofibromatosis type I more accurately than the SUV indexes. Finally, PET-directed biopsy and in the case of unresectable sarcomas, PET-based radiation treatment planning ^[81][112], could represent the further application fields of radiomic analysis in heterogeneous pediatric sarcomas. Evidently, multiparameter radiomic analysis, including CT or MR imaging systems, could be integrated into ¹⁸F-FDG PET metabolic and textural parameters and interchanged between the two different PET/CT or PET/MR hybrid systems used in pediatric oncology ^[82][113] for even better risk-stratification, treatment response prediction ^[83][114], and recurrence detection of pediatric sarcomas.

3. Pediatric Lymphomas

Pediatric lymphomas constitute about 12% of pediatric malignancies. HL are less frequent compared to NHL and account for about 40% of pediatric lymphomas ^[3][7][3,7]. HL probably represents the most common indication for ¹⁸F-FDG PET/CT imaging in pediatric oncologic patients (Figure 1), reflecting that the role of PET imaging in HL is mostly standardized and, more significantly, is used to implement a modified therapeutic strategy. Unlike pediatric sarcomas, the treatment response assessment in pediatric lymphomas is PET-based. As mentioned above, as the survival rate achieved by treatment advances in lymphomas, especially in HL, is exceptionally high (>95%), the new challenge is to reduce overtreatment ^[84][115]. Thus, unlike HL treatment management in adults, radiotherapy, particularly toxic in underage patients, should be administered even more selectively. Indeed, the previous multicentric trial for the classical HL, Euro-PHL-C1 ^[85][32], leads to two crucial achievements. The first one was the optimal outcome, despite omitting radiotherapy in good mid-treatment responders or otherwise, in children with the interim PET of Deauville score (DS) 1 and 2 ^[86][116]. The second one was the validation of qPET, although retrospectively in the Euro-PHL-C1 trial population, which was a more reproducible semiquantitative method for treatment response evaluation than the Deauville score ^[87][31]. Based on these two previous achievements, the ongoing multicentric trial, Euronet-PHL-C2 ^[88][117], is currently focused on the achievement of further radiotherapy reduction, avoiding interferences with curability. For that reason, early-stage HL pediatric patients with risk factors, including tumor bulk ≥ 200 mL (calculated as ellipsoidal volume, by the product of the principal axes divided by 2 ^[88][117]), have been upgraded from chemotherapeutic treatment level 1 (TL1) to chemotherapeutic TL2. In contrast, the indications for post-chemotherapeutic irradiation have been reduced. In particular, according to the new protocol ^[88][117], radiotherapy is omitted in a wider pediatric patient population, as good mid-treatment responders are considered children with a qPET score < 1.3, which approximately corresponds to children with a Deauville score of 1, 2, and 3. Moreover, some ¹⁸F-FDG PET avid lesions, as small lymph nodes with the largest diameter < 10 mm, are not included in initial or residual disease burden, which means that these lesions will not be irradiated in the case of inadequate response. In addition, bone marrow involvement is based only on ¹⁸F-FDG PET findings, excluding biopsy and molecular assessment techniques to evaluate minimal disseminated disease (MDD). This is also following the overtreatment reduction strategy of the ongoing trial ^[88][117], as the omission of minimal disseminated disease, similar to that of small lesions, is considered without effect on TL upstaging or the prognosis of pediatric HL patients.

Pediatric NHL is generally considered a diffuse disease regardless of typical staging, based on conventional or ¹⁸F-FDG PET/CT imaging. Thus, MDD assessment in bone marrow or peripheral blood, by FISH (fluorescence in situ hybridization) or PCR (polymerase chain reaction) analysis, is reported as additional information in the revised international pediatric NHL staging system (IPNHLSS) ^[34][77]. Although stage-dependent, MDD is considered an additional tool for the prognosis and evaluation of response to treatment ^[89][118]. Both PET/CT imaging and molecular techniques (FISH and PCR) for the assessment of minimal residual disease (MRD) are included in the international response criteria for pediatric NHL ^[90][119]. As about 40% of lymphomas present residual masses after treatment ^[90][119], ¹⁸F-FDG PET/CT and qPET evaluation is preferred. However, the clinical impact of qPET evaluation or otherwise, of PET-negative or PET-positive residual masses, is still unclear in pediatric NHL, as opposed to HL. According to published data, the negative predictive value of post-treatment PET findings in pediatric NHL is high but the positive predictive value is low ^[91][92][93][120,121,122]. Therefore, metabolically active residual masses, particularly of qPET around 1.3, should be further investigated by biopsy for differential diagnosis between residual disease and post-treatment inflammation ^[34][77]. Moreover, the refinement of the Lugano classification response criteria for adulthood NHL in the era of immunomodulatory agents highlights another issue ^[94][123]. The tumor “flare” phenomenon should be considered to avoid false-positive results during PET-based treatment response assessment. These agents have been already integrated in the management of relapsed/refractory pediatric lymphomas ^[95][124] and are being increasingly integrated in the front-line treatment of advanced pediatric lymphomas, accordingly, in the recently published results of a randomized and international trial ^[96][125]. As an initial or salvage therapy, chemotherapy is the primary treatment in pediatric NHL, unlike pediatric HL, where radiotherapy could be integrated into the therapeutic protocol template ^[88][117]. However, despite the current high-efficiency first-line treatment strategies and the optimal response and outcome achieved in the overwhelming majority of pediatric lymphoma patients, a small amount of about 10% of the cases, concerning mainly NHL patients, will not respond or will relapse, significantly compromising the outcome ^[97][126]. Consequently, treatment optimization and precision medicine in pediatric lymphomas have to deal with primary identification of overtreatment or undertreatment of cases to adequately and timely reduce or intensify a first-line treatment approach. PET metabolic and textural parameters could enhance the accuracy of PET imaging in the management of pediatric lymphomas.

Unlike sarcomas, the pretreatment SUVmax is generally not considered a prognostic factor in lymphomas ^{[98][99][100]}[27,127,128]. SUVmax is generally lower in HL than NHL, probably related to the higher ratio of inflammatory cells in the lymphomatous lesions. Higher SUVmax has been inconsistently related to good and poor prognosis of more proliferative/aggressive lymphomas, due to higher chemosensitivity and a higher propensity to relapse, respectively. It is comprehensible that due to the multifocal/systemic nature of lymphomas, as opposed to sarcomas, SUVmax is less critical than the number of sites and the total volume of lymphomatous disease ^[101][129].

A literature search has been performed on pediatric lymphomas, as in the case of pediatric sarcomas. The most important findings of this search are summarized in Table 2 and the following paragraphs.

Despite some contradictory results, especially regarding indolent forms of lymphomas ^{[102][103][104]}[130,131,132], a recently published meta-analysis, including 24 retrospective and three prospective studies and more than 2700 patients, has revealed the prognostic survival value of baseline MTV/TLG in adulthood HL and NHL ^[105][133] (Table 2). Although the cut-offs were method-dependent, MTV/TLG prognostication value was method-independent in both types of aggressive lymphomas. The parameters that tested the skills of segmentation methods were the multiplicity of nodal and/or extranodal tumor sites and the heterogeneity, in the case of the bulky disease, in particular. Despite the known limitations in low uptake or heterogeneous lesions, the negative and positive predictive values of the 41% threshold method were higher than the other methods in the meta-analysis mentioned above ^[105][133]. According to the authors, however, as qPET treatment response evaluation in lymphomas is based on liver SUVmean, the liver-threshold methods are theoretically more appropriate for baseline and post-treatment MTV/TLG evaluation in lymphomas. This is because they have the advantage of being adapted to each patient without the percentage-based methods’ variability issues, as the same SUV threshold is applied in all VOIs ^[105][133].

Similarly, another most recently published meta-analysis ^[106][134], including 41 studies, confirmed the MTV’s prognostication value and the prognostication value of a few radiomic parameters, evaluated in a minority (7/41) of studies, despite the extreme heterogeneity of cut-off values. In addition, in the SAKK38/07 study cohort ^[107][135], MTV, evaluated using a fixed SUV threshold of 2.5 and associated with the textural parameter of metabolic heterogeneity (MH) and evaluated by the cumulative SUV volume histogram of the lesion with the highest ¹⁸F-FDG uptake, could further stratify the outcome in diffuse large B-cell lymphoma (DLBCL). A shorter progression-free survival (PFS) was revealed in DLBCL patients with high MTV and MH values, independent from their response to therapy. Similarly, a correlation between MTV and survival, independent from response to treatment, has also been recently reported in the REMARC study DLBCL cohort population ^[108][136]. The role of MTV/TLG in risk stratification could be strengthened by the fact that the current staging systems have a weak correlation with metabolic tumor burden: one-third of those recognized as advanced-stage have the low burden, and, vice versa, about half of the intermediate-risk patients have high tumor burden ^[109][137]. Therefore, optimum performance cut-offs are the sine qua non for use in clinical practice, meaning further work is required concerning the methodological and software choices that need to be standardized and simplified. As less variable and mainly less time-consuming, automated segmentation methods are a valuable segmentation option for lymphomas ^[106][110][134,138].

In agreement with previous results ^[111][139], a post hoc analysis from the PETAL trial confirmed that baseline MTV with a cut-off value of 328 mL evaluated by the segmentation threshold method of 41% SUVmax could further stratify prognosis in patients with DLBCL in association with interim PET ^[112][140]. Similarly, another study based on the early-stage HL population of the H10 trial ^[113][141] provided that MTV is critical in the substratification of these patients regardless of the current staging systems. Baseline MTV with a cut-off value of 147 mL evaluated by the 41% SUVmax threshold method improved the predictive value of interim PET treatment response evaluation, classifying patients in those with particularly low, particularly high, intermediate-low, and intermediate-high risk to relapse. High MTV-poor PET interim responders had a 5-year PFS of 25% compared to 95% of low MTV-good PET interim responders ^[113][141].

Baseline metabolic and textural parameters were also investigated recently for assessing interim PET treatment response ^[114][142]. The investigators studied a cohort of patients with bulky HLs and NHLs with high optimal MTV cut-off value (600 mL). Optimal cut-off values for MTV are influenced by the data acquisition protocol and resolution, the segmentation method, and the study population. The investigators opted to focus on bulky lymphomas, as textural analysis is volume-depended, and consequently, the number of processing data and results increases as lesion volume increases ^{[60][70][71][72]}[54,55,56,57]. “Contrast”, “dissimilarity”, “granularity”, and shape parameters (“surface extension” and “2D and 3D fractal dimensions”) were independent predictors of early metabolic response. Although the corresponding value of each of these parameters is only hypothesized (e.g., a higher “surface extension” could be associated with better exposure to the chemotherapeutics) ^[114][142], the textural analysis could be another tool for identifying particularly high-risk patients, when the MTV/TLG metabolic parameters are borderline.

Regardless of the reproducibility problems that prevent specific clinical implementation, MTV/TLG have been demonstrated to be prognostic biomarkers in adulthood lymphomas ^{[105][106][107][108][109][110][111][112][113][114][115]}[133,134,135,136,137,138,139,140,141,142,143] (Table 2). However, the following considerations should be considered in the case of pediatric lymphomas. Firstly, the histologic subtypes are usually different. For example, in classical HL, the more common pediatric form in Europe and the United States is nodular sclerosis instead of mixed cellularity, which is more common in adults. Furthermore, the indolent forms of NHL, as a marginal zone lymphoma, are rare in children, in whom the more common subtype is Burritt lymphoma, an aggressive B-cell lymphoma, as opposed to DLBCL, which is the more common subtype in adults. Secondly, children with NHL, as opposed to adults, typically have an extranodal disease involving mediastinal structures, gastrointestinal system, central nervous system, or bone marrow. Thus, apart from the different implications in staging and prognosis in extranodal disease, MTV evaluation may become more challenging than that of nodal disease. Thirdly, PET-based response criteria could differ. Moreover, unlike adulthood NHL, chemotherapy is the only treatment in childhood NHL, as radiotherapy is only exceptionally used. Finally, additional effort is needed in pediatric lymphomas to organize well-conducted studies, due to more important patient number limitations.

A single-center, recently published, retrospective study ^[116][144] on 46 pediatric patients with B-NHL investigated if MTV could identify those children most at risk of treatment failure and disease progression. In multivariate analysis, MTV and TLG outperformed serum lactate dehydrogenase and bone marrow involvement on biopsy, confirming that they are predictors of survival. Moreover, baseline MTV and TLG were particularly powerful in substratification of high-risk patients, according to the FAB/LMB 96 risk classification criteria ^[117][145], identifying the group of children with particularly high risk for a refractory or relapsed disease ^[116][118][144,146]. Similarly, baseline MTV was the independent prognostic parameter of progression-free and overall survival in pediatric Burkitt ^[119][147], LBL (lymphoblastic) ^[120][148], and ALCL (anaplastic large cell lymphoma) patients ^[121][149]. Results from the AHOD0031 study cohort of pediatric HL patients are also consistent with the fact that the incorporation of baseline MTV into risk-based treatment algorithms may improve outcomes in intermediate-risk (limited stage with risk factors) HL ^[122][150]. Importantly, the investigators compared the accuracy of 15 different segmentation thresholds for the MTV/TLG evaluation to predict outcome. After adjustment for the other risk factors, the MTV evaluated by a blood pool-based threshold was the only independent prognostic parameter in pediatric intermediate-risk HL patients ^[122][123][150,151].

Another recently published study ^[101][129] on 50 pediatric patients with HL treated with EuroNET-PHL-C1 or -C2 protocol investigated the prognostic value of metabolic and textural PET parameters. MTV was delineated by a fixed relative threshold of 41% SUVmax and a fixed absolute threshold of SUV 2.5 and was manually corrected in about half of the patients due to relatively low activity and high heterogeneity lesions. Baseline MTV and TLG were found predictors of EFS and OS. Although cut-off values were different in the different risk-stratification groups (according to the current pediatric HL classification systems ^[88][117]), high MTV best predicted the interim PET inadequate response to induction chemotherapy, in both early and advanced stages (cut-offs of 80 mL vs. 410 mL) as well as in the three (based on stage, tumor bulk, and ESR) treatment levels (cut-offs of 80 mL vs. 160 mL vs. 410 mL). High “asphericity”, a textural parameter reflecting the lesion surface complexity was also correlated with the interim PET inadequate response. In a most recent prospective study in a small population of HL pediatric patients ^[124][152], four textural parameters, from the textural families of the grey-level co-occurrence matrix and neighborhood grey tone difference matrix were also predictors of interim PET treatment response (Table 2).

The aim is to further evolve the PET-based management of pediatric lymphomas by predicting interim PET treatment response from baseline MTV and textural PET imaging parameters. The integration of low dose CT or MR images of the PET hybrid systems in textural analysis could provide complementary information that could be particularly useful during the PET-based treatment response evaluation of pediatric lymphomas ^[125][153]. This is a primary clinical goal, as the appropriate intensification of front-line treatment will reduce cases of radiotherapy consolidation and cases of inadequate end-treatment response with increased risk to relapse and better balancing achieved between toxicity and curability. The recent multicentric and randomized trial in advanced-stage pediatric NHL ^[96][125], concerning the integration of immunotherapy in the front-line treatment, was designed to minimized dismal outcomes and increase the treatment response rate, as the significant predictor of survival. Interestingly, following the concept of “personalized” immunotherapy, MTV could help to adjust administered doses in order to achieve a more effective treatment response ^[126][154].

Table 2. Summary of observational ¹⁸F-FDG PET/CT studies in lymphomas, including eight studies in pediatric lymphomas.

1st Author, [Reference]	Year	Study Design	Type of Lymphomas	Population (Mean/ Median Age)	18F-FDG PET/CT Time-Points	18F-FDG Parameters Correlated with Prognosis	Segmentation Methods (Thresholds)	Prognostic Parameters Predicted
Guo B., [105][133]	2019	Meta-analysis P:3/R:24	HL:3 DLBCL:16 Other NHL:8	2729 *	Baseline	MTV, TLG	Fixed-absolute, liver-based, fixed-relative	PFS, OS
Frood R., [106][134]	2021	Meta-analysis R:41	HL:10 DLBCL:31	>4000 *	Baseline	SUVmax, MTV, TLG MH ** (radiomics)	fixed-absolute, liver-based, fixed-relative	PFS, OS
Ceriani L., [107][135]	2020	P	DLBCL	141 * (59)	Baseline	MTV, MH ** (radiomics) MTVand MH **	Fixed-absolute (SUVmax: 2.5)	PFS, OS
Vercellino L., [108][136]	2020	P	DLBCL	298 * (68)	Baseline	MTV (cut-off: 220 mL), MTV and ECOG PS	Fixed-relative (41% of SUVmax)	PFS, OS
Mikhaeel NG., [111][139]	2016	P	DLBCL	147 * (57)	Baseline Interim	MTV (cut-off: 396 mL), TLG MTV and iPET	Fixed-absolute (SUVmax: 2.5)	PFS, OS
Schmitz C., [112][140]	2020	P	DLBCL	510 * (62)	Baseline, Interim	MTV (cut-off: 328 mL), ΔSUVmax (cut-off: 66%) MTV and iPET	Fixed-relative (41% of SUVmax)	PFS, OS
Albano D., [115][143]	2019	R	Burkitt	65 * (53)	Baseline End-treatment	MTV (cut-off: 230 mL) TLG	Fixed-relative (41% of SUVmax)	PFS, OS
Cottereau AS., [113][141]	2020	P	HL (early stage)	258 * (31)	Baseline Interim	MTV (cut-off: 147 mL) MTV and iPET	Fixed-relative (41% of SUVmax)	PFS, OS
Bouallègue FB., [114][142]	2017	R	Bulky HL and NHL	57 * (52)	Baseline	MTV (cut-off: 600 mL) Shape/texture parameters (radiomics)	Fixed-Relative (30% of SUVmax)	PFS, OS
Zhou Y., [118][146]	2020	R	HL and NHL	47 (14.8)	Baseline	TLG	Fixed-absolute (SUVmax: 2.5)	PFS
Kim J., [116][144]	2019	P	B-NHL	46 (7.5)	Baseline	MTV, TLG	Fixed-Relative (41% of SUVmax)	PFS, OS
Xiao Z., [119][147]	2021	R	Burkitt	68 (7)	Baseline	MTV (cut-off: 550 mL) TLG (cut-off: 2881 g)	Fixed-relative (41% of SUVmax)	PFS, OS
Yang J., [120][148]	2021	R	LBL	30 (6.5)	Baseline	MTV (cut-off: 243 mL)	Fixed-relative (41% of SUVmax)	PFS, OS
Mathew B., [121][149]	2020	R	ALCL	50 (8.5)	Baseline, interim	MTV(cut-off: 180 mL) MTV and iPET	Fixed-relative (40% of SUVmax)	PFS, OS
Milgrom S., [122][150]	2021	P	Intermediate-risk HL	86 (14.5)	Baseline	MTV	Fixed-absolute (SUV blood pool × 2)	PFS
Rogasch J., [101][129]	2018	R	HL	50 (14.8)	Baseline	MTV, TLG asphericity (radiomics)	Fixed-relative (41% of SUVmax)	PFS, OS iPET
Rodriguez-Taroco MG., [124][152]	2021	P	HL	21 (12)	Baseline	GLCM (Entropy, energy) NGTDM (coarseness, busyness)	Fixed-relative (41% of SUVmax)	iPET

* Adult population; ** MH (metabolic heterogeneity) of the target lesion: the lesion with the highest ¹⁸FDG uptake using the area under curve of cumulative SUV-volume histogram method. P (prospective study), R (retrospective study), HL (Hodgkin lymphoma), DLBCL (diffuse large B-cell lymphoma), NHL (non Hodgkin lymphoma), B-NHL (B-cell non Hodgkin lymphoma), ALCL (anaplastic large cell lymphoma), SUVmax (maximum standardized uptake value), MTV (metabolic tumor volume), TLG (tumor lesion glycolysis), iPET (interim PET), ΔSUVmax [differential SUVmax: (baseline SUVmax − iPET SUVmax/baseline SUVmax) × 100%], ECOG PS (eastern cooperative oncology group performance status), GLCM (grey-level co-occurrence matrix), NGTDM (neighborhood grey-tone difference matrix), PFS (progression free survival), OS (overall survival).

4. Other Tumors

Langerhans cell histiocytosis (LCH) is a rare hematologic disorder characterized by the proliferation and accumulation of Langerhans-type clonal cells and accompanying inflammatory infiltrate in various organs and tissues. Although rare (<1% of childhood cancers), the disease is about 10 times more frequent in children compared to adults and more frequently affects bones than soft-tissues. Single-site bone disease is the predominant clinical form of pediatric LCH ^[127][155] According to previous and current guidelines for the diagnosis and management of pediatric LCH ^[127][128][155,156], skeletal radiography remains the gold standard for skeletal staging and exclusion of multisite disease. Whole-body MRI is still not integrated in clinical practice but probably represents a promising imaging modality for the future ^[129][130][157,158]. Nowadays, neither bone scan nor ¹⁸F-FDG PET scan is considered an alternative to skeletal radiography. However, the ¹⁸F-FDG PET scan, instead of a bone scan, which should not be considered for evaluating multisite bone disease, is considered the most accurate tool for detecting bone and soft-tissue lesions (multisystem LCH) and it is strongly recommended during initial staging ^[128][129][156,157]. Most importantly, by evaluating disease metabolic activity, the ¹⁸F-FDG PET scan is the most accurate tool for evaluating front-line response to treatment and further decision making in the case of a multisite/multisystem disease ^[131][132][159,160]. The MTV/TLG metabolic parameters may have a role in better risk stratification of multisystem LCH but, to our knowledge, there is no relevant published data probably because of the disease’s rarity both in children and especially in adults, and the poor prognosis of young children in the case of multisystem disease with risk organ involvement.

¹⁸F-FDG PET/CT also has a complementary role in staging and chemotherapy treatment response assessment of pediatric germ cell tumors, such as yolk sac sacrococcygeal tumors of infants or gonadal tumors of adolescents. The site of disease and the age are significant risk factors in germ cell tumors, with extragonadal thoracic disease and puberty having a worse prognosis ^[133][161]. Although pediatric germ cell tumors are rare, testicular germ cell tumors represent more than 10% of adolescent malignancies and are the most common malignancy in young adult men. A recently published retrospective study ^[134][162] in 51 young adults with testicular germ cell tumors revealed that MTV and TLG metabolic parameters were significant independent predictors of overall survival, suggesting a similar prognostic role even for testicular germ cell tumors in adolescents. However, despite the significant biological overlap, etiopathogenesis of underage germ cell tumors is generally characterized by a more salient role of abnormal developmental pathways and a relative lack of traditional oncogenes, especially in prime childhood ^[135][163]. Although better risk stratification is undoubtedly of clinical impact, the need for more appropriate treatment regimens based on differentiation-induced therapies is more imperative for these non-somatic lineage tumors, to avoid long-term adverse effects in young children and adolescents by the chemotherapeutic cytotoxic drugs used in adults ^[136][164].

Finally, neuroblastoma is the most common of pediatric blastomas and accounts for about 6% of childhood cancers, usually affecting infants and children under 15 years old. It is extremely rare in adulthood and is generally considered a neural crest embryonal malignancy with adrenal or extra-adrenal localization. The prognosis is varying, being optimal in low-risk patients and severely compromised in high-risk patients (children ≥ 18 months of age with metastatic disease or children with unfavorable histology), particularly in the case of inadequate response to first-line induction chemotherapy ^[137][165]. Regardless of risk stratification, the role of ¹⁸F-FDG is limited in pediatric neuroblastoma, as adrenomedullary tumor cells are particularly rich of type I amine uptake mechanism. Consequently, staging and treatment response assessment is based on findings of the ¹²³I- MIBG [Meta-(radioiodinated)-iodobenzylguanidine] scan, while ¹⁸F-FDG PET/CT is only limited to the detection of highly dedifferentiated ¹⁸F-FDG avid/¹²³I-MIBG negative neuroblastoma ^[138][166]. However, growing evidence based on data from the first prospective study ^[139][167] suggests that ¹⁸F-DOPA PET/CT could be implicated in clinical practice in the imminent future by revealing a higher accuracy in neuroblastoma prognosis, staging, and treatment response assessment compared to ¹²³I-MIBG scan. In that case, similarly to ¹⁸F-FDG, ¹⁸F-DOPA metabolic tumor volume and tumor lesion metabolic activity parameters could improve risk stratification of pediatric neuroblastoma.