Positron Emission Tomography Molecular Imaging for Phenotyping and Management of Lymphoma

Abstract

Positron emission tomography (PET) represents molecular imaging for non-invasive phenotyping of physiological and biochemical processes in various oncological diseases. PET imaging with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) for glucose metabolism evaluation is the standard imaging modality for the clinical management of lymphoma. One of the ¹⁸F-FDG PET applications is the detection and pre-treatment staging of lymphoma, which is highly sensitive. ¹⁸F-FDG PET is also applied during treatment to evaluate the individual chemo-sensitivity and accordingly guide the response-adapted therapy. At the end of the therapy regiment, a negative PET scan is indicative of a good prognosis in patients with advanced Hodgkin’s lymphoma and diffuse large B-cell lymphoma. Thus, adjuvant radiotherapy may be alleviated. Future PET studies using non-¹⁸F-FDG radiotracers, such as ⁶⁸Ga-labeled pentixafor (a cyclic pentapeptide that enables sensitive and high-contrast imaging of C–X–C motif chemokine receptor 4), ⁶⁸Ga-labeled fibroblast activation protein inhibitor (FAPI) that reflects the tumor microenvironment, and ⁸⁹Zr-labeled atezolizumab that targets the programmed cell death-ligand 1 (PD-L1), may complement ¹⁸F-FDG and offer essential tools to decode lymphoma phenotypes further and identify the mechanisms of lymphoma therapy.

Introduction

Positron emission tomography (PET) is a representative technique of molecular imaging that provides non-invasive phenotyping of biochemical processes at the molecular level in living subjects, based on the principle of tracing radioactivity. Since PET enables in vivo quantification of radioisotopes in nanomolar to picomolar level (Jacobs et al. 2003; Phelps 2000), it can provide whole-body phenotypic information and serve as a transpathological approach to precisely assess protein expression, receptor availability, transporter systems, signal transduction, gene mutation and histological profiles (Chen et al. 2017; Jacobs et al. 2003; Tian et al. 2021; Zhu et al. 2017). With the rapid development of equipment and probes, PET molecular imaging can detect the pathophysiological changes of various oncological diseases with high sensitivity, thus playing a vital role in diagnosing, evaluating, and treating many types of cancers (Jones and Price 2012; Rohren et al. 2004).

Lymphoma is a group of hematological malignancies categorized into Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). NHL can be further subclassified into aggressive and indolent NHL, together accounting for more than 30 distinct subtypes with different diagnostic, prognostic, and therapeutic implications (Armitage et al. 2017). The definite diagnosis and molecular analysis of lymphoma rely predominantly on histopathological assessment. However, due to the high degree of clinical and biological heterogeneity of lymphoma, traditional single-biopsy may not provide a comprehensive and global characterization of the disease. PET/computed tomography (PET/CT) with the glucose analog ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) can provide whole-body glucose metabolism evaluation and be used extensively as an indispensable tool for pre-treatment staging, response assessment, and outcome prediction of lymphoma (Barrington and Kludge 2017; Barrington et al. 2014). More recently, with therapeutic advances in lymphoma, such as the advent of targeted therapies, additional novel PET tracers have been developed, which hold promise for visualizing other metabolic and receptor pathways at diagnosis and during treatment.

Although PET/CT has been widely applied in the diagnosis and treatment of lymphoma, the need for repeated examinations in which both PET and CT involve ionizing radiation is a concern for lymphoma patients, especially in younger individuals, and late risks of radiation exposure should be taken into account (Pearce et al. 2012). Recent advance in imaging hardware, such as the hybrid PET/magnetic resonance imaging (PET/MRI), offers the opportunity of gleaning the metabolic activity by PET and anatomic information by MRI while reducing the exposure to ionizing radiation compared to PET/CT (Torigian et al. 2013; Wehrl et al. 2015). Moreover, MRI also offers possibilities to evaluate tissue structure and metabolism not offered by CT, such as diffusion-weighed imaging (DWI) or MR spectroscopy (Mayerhoefer et al. 2015; Punwani et al. 2013).

In this review, we present an overview of the role of ¹⁸F-FDG PET/CT in managing patients with lymphoma, with an emphasis on HL, diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). Furthermore, PET tracers other than ¹⁸F-FDG and their potential alternative applications, including PET image-guided therapy are discussed. We also discuss recent advances regarding the clinical application of ¹⁸F-FDG PET/MRI in lymphoma.

¹⁸F-FDG PET/CT in Pre-treatment Staging of Lymphoma

An accurate disease staging leads to better treatment planning and outcome. Current guidelines from the International Conference on Malignant Lymphoma recommend ¹⁸F-FDG PET/CT for staging in all lymphomas, except some indolent NHL subtypes such as small lymphocytic lymphoma and marginal zone lymphoma (Barrington et al. 2014; Cheson et al. 2014) (Fig. 1 and Table 1). ¹⁸F-FDG PET/CT shows superior staging accuracy than CT in HL and NHL, mainly due to improved detection of lymphoma in small lymph nodes and at extranodal sites. In the Response-Adapted Therapy in Hodgkin’s Lymphoma study (RATHL), ¹⁸F-FDG PET/CT led to upstaging in 14% of the patients and downstaging in 6% of the patients, with the extranodal disease in bone marrow, lung, or multiple sites accounting for the most discrepancies (Barrington et al. 2016). The superior sensitivity of ¹⁸F-FDG PET in lesion detection has made bone marrow biopsy (BMB) unnecessary for risk assessment in Hodgkin’s lymphoma. Importantly, increased sensitivity with FDG PET does not come at the cost of reduced specificity (Hutchings et al. 2006a). The focal FDG uptake in bone marrow could be detected by PET in 20% of newly diagnosed HL, compared to 5% detected by BMB (Barrington et al. 2016; El-Galaly et al. 2012a). Since BMB can rarely add more to diagnostic value to ¹⁸F-FDG PET/CT in staging HL, it is discouraged by the current guidelines (Cheson et al. 2014).

Fig. 1.

Pre-treatment ¹⁸F-FDG PET/CT for staging of lymphoma based on the Ann Arbor staging system. Stage I is defined as lymphomatous involvement confined to a single lymph node region or extranodal site. Stage II refers to lymphomatous involvement of more lymph node regions on one side of the diaphragm with or without limited contiguous extranodal involvement. Stage III is defined as lymph node involvement on both sides of the diaphragm. Stage IV refers to extensive extranodal involvement. White arrows denote bone marrow involvement. SUV indicates standardized uptake value

Table 1.

Evidence-based recommendations for the use of ¹⁸F-FDG PET at different treatment time points

Time point	Indication	HLa	DLBCLa
Pre-treatment PET	Staging	+++	+++
Interim PET	Early response assessment	++	++
End-of-treatment PET	Remission assessment	++	++
PET during follow-up	Disease surveillance	±	±

^a+++: standard of care. ++: standard—depending on therapy regimen. ±: optional—recommended in selected cases, e.g., suspected relapse

FDG fluorodeoxyglucose, PET positron emission tomography, HL Hodgkin’s lymphoma, DLBCL diffuse large B-cell lymphoma

The use of ¹⁸F-FDG PET/CT is needed in staging both HL and DLBCL and can upstage 5–15% of patients, while downstaging is unusual (Elstrom et al. 2008; Fuertes et al. 2007). In patients with newly diagnosed DLBCL, ¹⁸F-FDG PET/CT is an accurate examination and complementary to BMB for the detection of focal bone marrow metastasis (Adams et al. 2014). The frequently observed diffuse increased BM skeletal FDG uptake in newly diagnosed BMB positive DLBCL patients may account for the relatively low PET sensitivity. The international guidelines recommend that positive ¹⁸F-FDG PET/CT findings prevent the need for BMB to detect bone marrow involvement in DLBCL patients. On the other hand, BMB might be the choice since negative ¹⁸F-FDG PET/CT findings cannot rule out bone marrow involvement. In clinical practice, however, BMB is performed whenever the presence or absence of bone marrow involvement affects the choice of therapy regiment, i.e., upstaging or downstaging.

For staging indolent lymphoma, ¹⁸F-FDG PET/CT is more accurate than CT alone, with high sensitivity of 94–98% and specificity of 88–100% (Karam et al. 2006; Wohrer et al. 2006). FDG PET upstages many, as high as 45%, patients with CT stage I/II FL altering their treatment strategy (Luminari et al. 2013; Wirth et al. 2008). The upstaging of patients have a profound impact on treatment planning, since such patients can no longer be considered for definitive radiotherapy (Dreyling et al. 2021). However, PET/CT has relatively low sensitivity and specificity for detecting bone marrow involvement. Because the increased BM FDG activity might be due to inflammation, infection, or stimulation of normal marrow rather than the lymphomatous infiltration (Dubreuil et al. 2017). In such patients, FDG PET/CT could help by navigating an accurate site for BMB selection, especially when the histologic transformation is clinically suspected (Barrington et al. 2014).

Role of Interim-Treatment ¹⁸F-FDG PET/CT

Interim ¹⁸F-FDG PET/CT is a promising approach for guiding response-adapted treatment, which aims to ensure the effectiveness of treatment and prohibit the possibility of progression. ¹⁸F-FDG PET shows metabolic response earlier than anatomic response and has the potential to replace CT. Studies have shown that the interim ¹⁸F-FDG PET is a robust prognostic indicator in HL (Biggi et al. 2013; Cerci et al. 2010a; Gallamini et al. 2007; Zinzani et al. 2012) and aggressive NHL (Mikhaeel et al. 2005; Terasawa et al. 2009; Yang et al. 2011), outperforming the International Prognostic Score (Gallamini et al. 2007) and International Prognostic Index (Mikhaeel et al. 2005) (Table 1). These findings highlight the potential of using interim ¹⁸F-FDG PET to tailor treatment according to individual response. The Deauville criteria (Table 2 and Fig. 2) and Lugano Classification criteria (Table 3) are currently recommended for ¹⁸F-FDG PET/CT based response assessment (Barrington et al. 2014; Cheson et al. 2014).

Table 2.

The Deauville criteria for response assessment of FDG-avid lymphomas

Score	Criteria
1	No FDG uptake
2	FDG uptake ≤ mediastinum
3	FDG uptake > mediastinum but ≤ liver
4	FDG uptake moderately increased compared to the liver
5	FDG uptake markedly increased compared to the liver and/or new sites of disease

FDG fluorodeoxyglucose

Fig. 2.

Coronal slices of pre-treatment and interim ¹⁸F-FDG PET images for response assessment in lymphoma, from left to right corresponding to Deauville score (DS) 1–5 with different FDG uptake (red arrows)

Table 3.

The Lugano classification criteria for response assessment of lymphoma

Response and site	PET/CT-based criteria	CT-based criteria
CR	Complete metabolic response: Deauville score 1, 2, or 3 with or without a residual mass on 5PS	Complete radiologic response: target nodes/nodal masses must regress to ≤ 1.5 cm in LDi
PR	Partial metabolic response: deauville score 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size	Partial remission: ≥ 50% decrease in SPD of up to 6 target measurable nodes and extranodal sites
SD	No metabolic response: deauville score 4 or 5 with no significant change in FDG uptake from baseline at interim or end of treatment	Stable disease: < 50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease are met
PD	Progressive metabolic disease	Progressive disease
Individual target nodal masses	Deauville score 4 or 5 with an increase in intensity of uptake from baseline and/or	An individual node/lesion must be abnormal with: LDi > 1.5 cm and increase by ≥ 50% from PPD nadir and an increase in LDi or SDi from nadir 0.5 cm for lesions ≤ 2 cm 1.0 cm for lesions > 2 cm In the setting of splenomegaly, the splenic length must increase by > 50% of the extent of its prior increase beyond baseline (e.g., a 15-cm spleen must increase to > 16 cm). If no prior splenomegaly, must increase by ≥ 2 cm from baseline New or recurrent splenomegaly
Extranodal lesions	New FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment
Nonmeasured lesions	None	New or clear progression of preexisting nonmeasured lesions
New lesions	New FDG-avid foci consistent with lymphoma rather than another etiology (e.g., infection, inflammation). If uncertain regarding etiology of new lesions, biopsy or interval scan may be considered	Regrowth of previously resolved lesions A new node > 1.5 cm in any axis A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any axis, its presence must be unequivocal and must be attributable to lymphoma Assessable disease of any size unequivocally attributable to lymphoma
Bone marrow	New or recurrent FDG-avid foci	New or recurrent involvement

CR complete response, 5PS 5-point scale, LDi longest transverse diameter of a lesion, PR partial response, SPD sum of the product of the perpendicular diameters for multiple lesions, SD stable disease, FDG fluorodeoxyglucose, PD progression disease, PPD cross product of the LDi and perpendicular diameter, SDi shortest axis perpendicular to the LDi

Hodgkin’s Lymphoma (HL)

Since shrinkage of the tumor size takes a longer time compared to the observed decrease in radiotracer activity (function), conventional imaging with CT, especially in HL, lacked specificity in the setting of early treatment response assessment (Hutchings et al. 2006b). The negative predictive value (NPV) of PET during ongoing treatment depends on the cut-off for interim PET positivity and timing. Very early PET evaluation, such as after one cycle of chemotherapy, identifies fast responders; however, about 50% of patients with positive findings ultimately turn out negative after two cycles of chemotherapy. A meta-analysis involving more than 1300 patients with HL of all stages suggested that the interim treatment PET had a high NPV and moderate sensitivity of 67–71% (Adams et al. 2015). Interim-treatment PET showed consistently high NPV but a low positive predictive value (PPV) in early-stage (stage IA and stage IIA) HL, most likely due to the high performance of radiotherapy after chemotherapy with subsequent excellent prognosis (Radford et al. 2015).

The findings from several large prospective trials encourage interim PET for guiding treatment strategy in early-stage HL (André et al. 2017; Barrington et al. 2019; Fuchs et al. 2019). In the UK RAPID Trial, 571 patients with stage IA or IIA Hodgkin’s lymphoma without mediastinal bulk underwent interim PET after three cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), of whom 426 (75%) patients had negative findings on interim PET (Deauville score 1 or 2) were randomly assigned to either involved-field radiotherapy (IFRT) or no further treatment, radiotherapy (Barrington et al. 2019). This study did not prove non-inferiority of chemotherapy alone, thus generally not recommending to omit consolidative radiotherapy in PET-negative patients after three cycles of ABVD. Radiotherapy omission appeared questionable in the H10 trial, which randomized 1950 patients with limited-stage favorable and unfavorable HL to PET-guided or standard treatment with 3–4 ABVD cycles plus involved-node radiotherapy (André et al. 2017). Furthermore, radiotherapy omission resulted in worse disease control in the HD16 research conducted by the German Hodgkin Study Group (GHSG) (Fuchs et al. 2019). Thus, generally, radiotherapy is recommended in limited-stage favorable HL after treatment with two cycles of ABVD. However, as revealed by the H10 trial, interim PET, after two cycles of chemotherapy, seems able to identify high-risk patients who might benefit from intensified therapy with escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (André et al. 2017).

For advanced-stage HL, there is significant evidence regarding the use of FDG PET for tailoring treatment suggested by multiple trials, such as RATHL (Johnson et al. 2016), Italian HD 0607 (Gallamini et al. 2018), GHSG HD18 (Borchmann et al. 2017), and AHL2011 (Casasnovas et al. 2019). The RATHL trial used interim PET after two cycles of ABVD in 1214 patients, of whom 703 (59%) had the advanced-stage disease (Johnson et al. 2016). Patients with negative interim PET (Deauville score 1–3) were randomized to continue ABVD or therapeutic de-escalation by omitting bleomycin, namely AVD. With an updated follow-up of 52 months, the two groups had comparable 3-year progression-free survival (PFS), 85.4% versus 84.0%. However, patients receiving AVD had fewer infections, neutropenic fever events, and respiratory adverse events. Patients with positive interim PET (Deauville score 4 or 5) were assigned either four additional cycles of escalated BEACOPP or six other cycles of BEACOPP14, resulting in a 5-year PFS of 65.7%, comparing favorably with historic controls in which ABVD continued in interim PET-positive patients. Notably, the Deauville score among patients with negative interim PET was not predictive of outcome, suggesting that the omission of bleomycin in cycles 3–6 for patients with a Deauville score of 3 is safe as with a score of 1–2. The Italian HD 0607 study, including 782 patients with stage IIB–IV HL, showed similarly encouraging results (Gallamini et al. 2018). The 3-year PFS of PET-positive patients who were assigned escalated BEACOPP after initial ABVD was 57%. They also observed that irradiation of large nodal masses (> 5 cm) did not improve outcomes in PET-negative patients after six cycles of ABVD. In the GHSG HD18 study, treatment with four cycles of escalated BEACOPP was as effective as standard six cycles for PET-negative patients in 5-year PFS (90.8% versus 92.2%). Still, it was associated with significantly fewer infections and toxicities (Borchmann et al. 2017). Of note, in contrast to other studies limiting PET-positive to score 4 and 5, Deauville score 3–5 was defined as a positive interim PET in the GHSG HD18 study. Therefore, 12 weeks of escalated BEACOPP could be an attractive alternative to 24 weeks of ABVD treatment, especially for young patients. Importantly, PET-positive patients with a Deauville score of 4 who received continuing escalated BEACOPP still had an impressive 3-year PFS of 87.6%, indicating that the treatment strategy may influence the positive predictive value of interim FDG PET/CT. The AHL2011 study explored de-escalation to ABVD after initial escalated BEACOPP in PET-negative patients (Casasnovas et al. 2019). With a median follow-up of 50.4 months, patients in the full escalated BEACOPP group showed comparable 5-year PFS to those in the PET-driven de-escalation group (86.2% versus 85.7%, p = 0.65). Thus, for advanced-stage HL patients, negative interim PET can serve as an indication for treatment de-escalation. However, the insufficient initial response to ABVD should trigger the escalation to BEACOPP. Combining early response with molecular profiling and tumor burden assessment for prognostication needs to be explored for PET-adapted approaches (Agostinelli et al. 2016; Cottereau et al. 2018).

Diffuse Large B-Cell Lymphoma (DLBCL)

The current standard-of-care chemotherapy for DLBCL combines rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), which is curative for approximately 70% of the patients (Coiffier et al. 2010; Pfreundschuh et al. 2011). Interim-PET is a possible biomarker for evaluating early response to R-CHOP chemotherapy in several studies (Casasnovas et al. 2017; Hertzberg et al. 2017; Mamot et al. 2015; Moskowitz et al. 2010; Pardal et al. 2014; Stewart et al. 2014; Swinnen et al. 2015). The rate of interim PET negativity varies widely, which may be due to variable timing of the interim-PET (reported as after 2, 3, or 4 cycles of chemotherapy), and various interpretation criteria with different definitions of FDG PET/CT positivity including internal visual point systems, International Harmonization Project criteria, Deauville criteria, and Lugano Classification criteria.

The prognostic value of interim-FDG PET/CT in DLBCL has been investigated in several prospective studies, which conducted serial FDG PET at baseline, interim, and end of treatment (Carr et al. 2014; Fan et al. 2017; Mamot et al. 2015; Schöder et al. 2020). Chemotherapy was not modified based on interim FDG PET/CT results unless there was clear disease progression. These studies demonstrated that interim PET negativity was strongly associated with end-of-treatment PET/CT negativity and favorable prognosis. However, in the International Atomic Energy Agency study, 13/205 (6%) patients with negative interim PET/CT developed a positive end-of-treatment PET/CT, of which 11 patients (85%) had the biopsy-proven refractory disease (Carr et al. 2014). The CALGB 50303 trial reported a similar result that 4/87 (5%) patients with negative interim-PET had a positive end-of-treatment PET (Schöder et al. 2020). In the SAKK 38/07, the International Atomic Energy Agency, and CALGB 50303 studies, more than half of the patients with positive interim PET eventually turned negative, with favorable 2-year event-free survival (EFS) and overall survival (OS) (86% and 92%, respectively) for this subgroup in the International Atomic Energy Agency study (Carr et al. 2014; Mamot et al. 2015; Schöder et al. 2020). These findings suggested that despite the very high negative predictive value of an interim-PET, false-positive results could occur in more than half of the cases. Therefore, treatment modification or escalation is likely unnecessary for patients with positive interim PET findings.

Several prospective trials have explored the role of interim FDG PET/CT in guiding treatment escalation for patients with positive interim PET findings (Casasnovas et al. 2017; Dührsen et al. 2018; Hertzberg et al. 2017; Kasamon et al. 2009; Moskowitz et al. 2010; Pardal et al. 2014; Stewart et al. 2014; Swinnen et al. 2015). However, these studies couldn't confirm a uniform relationship between treatment modification and outcome improvement. Furthermore, most of these studies were phase II investigations without a comparison arm, eliminating the ability to identify the actual contribution from the treatment escalation. For these reasons, current guidelines, outside of clinical trials, do not recommend treatment escalation based on a positive interim-FDG PET/CT. Future studies are required to incorporate other biomarkers for early treatment failure or novel regimens to improve outcomes for these individuals.

Follicular Lymphoma (FL)

The interim-PET is predictive of positive treatment response in patients with FL. A prospective study evaluated the prognostic value of interim and end-of-treatment PET in 121 FL patients treated with R-CHOP (Dupuis et al. 2012). Similar to the results reported in DLBCL, the power of interim-PET in discriminating between patients who responded and those who did not respond to the therapy regimen is not as effective as the end-of-treatment PET. However, in FL, the role of interim PET is less relevant to patient management because the assessment of response is a contiguous process throughout initial and maintenance therapy.

Role of End-of-Treatment ¹⁸F-FDG PET/CT

End-of-treatment PET/CT is more accurate than CT alone in remission assessment in patients with HL (Barnes et al. 2011; Cerci et al. 2010b), DLBCL (Micallef et al. 2011), and high-tumor-burden FL (Dupuis et al. 2012; Trotman et al. 2011). Unlike CT, end-of-treatment PET/CT can distinguish between the residual active tumor tissue and post-treatment fibrosis. Immediately after successful treatment regimens, including after immunotherapy, there might be relative increase in FDG activity of the tumor, which may cause a high false-positive rate. To minimize the risk of a high false-positive rate and in an attempt to eliminate the increase in nonspecific ¹⁸F-FDG uptake, the end-of-treatment PET should be performed optimally 4–6 weeks after completion of chemotherapy and at least eight weeks after radiotherapy (NCCN Clinical Practice Guidelines in Oncology 2021).

Hodgkin’s Lymphoma (HL)

Several studies have consistently suggested that achieving a negative end-of-treatment PET is associated with a high NPV and favorable outcomes in HL (De Wit et al. 2001; Engert et al. 2012; Kobe et al. 2008; Markova et al. 2012; Radford et al. 2015; Schaefer et al. 2007). For instance, the HD15 trial study reported that the NPV of FDG PET/CT with a Deauville score of 1–3 was 94% in patients with residual masses measuring ≥ 2.5 cm on CT (Engert et al. 2012). The prognosis of this subgroup is favorable, with a 4-year PFS of 92%. As a result, the current response criteria define a complete remission as a negative end-of-treatment PET regardless of the size of residual masses on CT.

In contrast to its high NPV, the PPV of end-of-treatment PET is generally lower and more variable, as a significant number of PET-positive patients do not develop refractory HL. In the HD15 trial, 191 patients with residual masses measuring ≥ 2.5 cm had a positive end-of-treatment PET with a Deauville score of 4–5 and received radiotherapy to the residual diseases (Engert et al. 2012). Even if their prognosis was worse than the PET-negative patients, the findings from this study demonstrated a high false-positive rate of end-of-treatment PET in a substantial proportion of patients. Furthermore, the study design did not permit an evaluation of the radiotherapy-related benefit (Engert et al. 2012). Based on these results, radiotherapy is limited to end-of-treatment PET-positive residual tissue in advanced-stage HL after escalated BEACOPP therapy. It could be omitted in end-of-treatment PET-negative cases. The findings of the randomized HD0607 trial supported this conclusion (Gallamini et al. 2020).

Diffuse Large B-Cell Lymphoma (DLBCL)

The current guidelines (NCCN Clinical Practice Guidelines in Oncology 2021) recommend the end-of-treatment PET as the standard of care for remission assessment in DLBCL. Importantly, in DLBCL, after R-CHOP therapy, the end-of-treatment PET positivity should be interpreted as a sign of unfavorable prognosis (Carr et al. 2014; Mamot et al. 2015). Several retrospective cohort studies evaluated the role of end-of-treatment PET in guiding consolidative radiotherapy to residual diseases and demonstrated improved outcomes (Dorth et al. 2012; Freeman et al. 2021; Held et al. 2014; Phan et al. 2010; Shi et al. 2013). Current guidelines state that a Deauville score of 4–5 with unchanged or increased intensity from baseline and appearance of new FDG-avid foci that is consistent with lymphoma deemed as treatment failure (Cheson et al. 2014) (Fig. 3). In the presence of remaining metabolically active tissue, one might consider a confirmatory biopsy with a subsequent salvage treatment (Tilly et al. 2015).

Fig. 3.

Serial ¹⁸F-FDG PET images of a 62-year-old woman with diffuse large B-cell lymphoma. a The initial staging PET image reveals lymphomatous involvement of para-aortic and iliac lymph nodes (defined as Stage II disease). b The PET image after six cycles of chemotherapy (R-CHOP) shows PET-positive residual uptake at the iliac lymph nodes (Deauville score 5). c The PET image after involved field radiotherapy indicates complete metabolic response

Follicular Lymphoma (FL)

In FL, PET predicts inferior outcomes in patients with high tumor burden who remain PET positive after first-line treatment (Trotman et al. 2018). In the GALLIUM study, patients with a complete metabolic response with a Deauville score of 1–3 had better 2.5-year PFS than those who did not have a complete metabolic response (87.4% versus 54.9%) (Trotman et al. 2018). The multivariate analysis showed that PET status at the end of induction therapy was the only independent predictor of OS. These findings have set the scene for exploring the need for maintenance therapy in FL patients with complete metabolic response and treatment escalation in patients classified as non-responding (Federico et al. 2019). Furthermore, the GALLIUM study demonstrated that at the end of induction therapy, 5/213 (2%) patients with a complete metabolic response had persistent bone marrow involvement, which implied the additional value of repeat biopsy in these patients (Rutherford et al. 2020).

The FOLL12 study investigated the role of PET at the end of induction therapy in treatment modifications in FL (Federico et al. 2019). Preliminary results from this study showed that even if a patient has a negative-PET at the end of induction therapy, the exclusion of the maintenance rituximab therapy results in an inferior PFS. On the other hand, PFS could be prolonged in PET-negative patients at the end of induction therapy when maintenance rituximab therapy is maintained. The ongoing UK-led PETReA trial (EudraCT number 2016-004010-10) may add further clarity to the effect of PET at the end of induction therapy on response-adapted treatment in FL.

¹⁸F-FDG PET/CT in Post-treatment Surveillance of Lymphomas

Although the initial first-line therapy could cure most aggressive lymphomas, depending on their histologic subtype and other prognostic factors, a subgroup of patients will experience relapse. Most relapses occur within the first two years after completing the primary therapy, which is usually not identifiable on routine CT imaging if at a subclinical stage (Thompson et al. 2014). Several retrospective and prospective studies explored the role of FDG PET/CT in the disease surveillance in such patients (Avivi et al. 2013; Cheah et al. 2013, 2014; Dann et al. 2014; El-Galaly et al. 2012b; Zinzani et al. 2009). For example, a prospective study of 421 patients with various lymphoma subtypes, including HL, aggressive NHL, and FL, who achieved complete remission after the initial therapy demonstrated that the rate of relapse detection by PET was higher among the subset of patients with the greatest a priori risk of recurrence (Zinzani et al. 2009). Another multicenter study of 161 patients with HL reported that PET/CT surveillance could detect 45% of subclinical relapses with a high false-positive rate (El-Galaly et al. 2012b). In a retrospective study of 116 DLBCL patients, PET/CT showed a limited role in disease surveillance for patients achieving complete remission after primary therapy (Cheah et al. 2013). For FL, a retrospective study examined the effect of surveillance imaging on relapse detection and OS and suggested that no OS benefit was associated with imaging-detected relapse (Goldman et al. 2021).

Owing to the lack of sufficient evidence demonstrating an improved outcome for the detection of relapse, the latest NCCN Guidelines do not recommend ¹⁸F-FDG PET as routine surveillance for patients with stage I–II disease who have achieved complete metabolic response after the initial therapy (NCCN Clinical Practice Guidelines in Oncology 2021). For patients with stage III–IV disease who achieve remission after initial treatment, the NCCN Guidelines recommend CT scans no more than every six months for up to two years after completion of the treatment, with no ongoing routine surveillance imaging beyond 2 years ( NCCN Clinical Practice Guidelines in Oncology 2021). In patients with primarily osseous presentations, PET/CT may be the preferable follow-up imaging modality. When the imaging studies reveal suspected recurrence, biopsy confirmation of the diagnosis is necessary before proceeding with a second-line therapy (Table 1). For these patients, response criteria are identical to those of first-line treatment evaluation.

¹⁸F-FDG PET/CT for Pre-transplantation Assessment

Up to 30% of patients with HL and DLBCL relapse after, or do not respond to, first-line treatment. A therapy choice for these patients is salvage chemotherapy followed by consolidation with high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) (NCCN Clinical Practice Guidelines in Oncology 2021). Several studies have investigated the prognostic impact of PET-assessed response to salvage chemotherapy before HDT-ASCT for relapsed or refractory lymphoma (Derenzini et al. 2008; Dickinson et al. 2010; Moskowitz et al. 2015; Sauter et al. 2015). In a phase II study of 129 patients with relapsed or refractory HL, PET-adapted sequential salvage chemotherapy followed by HDT resulted in a significant proportion of patients achieving negative PET results, potentially optimizing the chance of cure after ASCT (Moskowitz et al. 2015). Multiple studies focusing on relapsed or refractory DLBCL reported similar results (Derenzini et al. 2008; Dickinson et al. 2010; Sauter et al. 2015). These findings highlight both the importance of achieving negative PET status before ASCT and the potential benefit of PET-adapted salvage strategies to improve cure rates in relapsed disease.

PET/CT Lymphoma Imaging with Non-¹⁸F-FDG Radiotracers

Although ¹⁸F-FDG is not a malignant tumor-specific PET tracer, in the clinic, ¹⁸F-FDG is frequently used to follow the metabolic changes of the tumor tissue at a molecular level. In ¹⁸F-FDG PET imaging of tumors, myocardium, and inflammation, hypoxia may be one of the fundamental driving forces. The possible mechanism of ¹⁸F-FDG uptake caused by hypoxia may be related to metabolic changes, macrophage activation, and alterations in glycolysis-related enzyme activity. Most of the solid malignant tumors, nearly 95%, have some degree of hypoxia. ¹⁸F-FDG accumulates heavily in anoxic, hypoxic tumor cells with poor proliferation and low blood flow. However, its uptake decreases in well-oxygenated, oxygen-rich tumor cells with intense proliferation and high perfusion. This explanation describes the reason why some treatment-naive malignant lesions may have little or no ¹⁸F-FDG uptake. Furthermore, since well-oxygenated or necrotic cancer cells also have low ¹⁸F-FDG uptake, low ¹⁸F-FDG accumulation after anticancer therapy does not necessarily mean the total elimination of all viable cancer cells (Yao et al. 2021).

Despite the fact that ¹⁸F-FDG PET has accomplished remarkable progress in the diagnosis and treatment of lymphoma, related to the aforementioned issues, in clinical practice, there are a substantial demand for more accurate, non-¹⁸F-FDG radiotracers that can target other metabolic or receptor pathways, with the aim of being more specific in the setting of aggressive, highly FDG-avid lymphomas and more sensitive in low or variably FDG-avid subtypes. Table 4 shows potential targets and PET tracers for phenotyping the biochemical processes in lymphoma.

Table 4.

PET imaging for phenotyping the biochemical processes in lymphoma

Target	Tracer
Substrate metabolism	18F-FDG, 11C-choline, 11C-acetate
Protein synthesis	11C-MET, 11C-tyrosine, 18F-FET
DNA synthesis	11C-thymidine, 18F-FLT
Receptor affinity	68Ga-pentixafor (targeting CXCR4), 89Zr-rituximab (targeting CD20), 68Ga-DOTATOC (targeting somatostatin receptor), 89Zr-atezolizumab (targeting PD-L1)
Tumor microenvironment	68Ga-FAPI (targeting FAP)
Gene mutation	89Zr-transferrin (reflecting myc status)
Angiogenesis	18F-RGD-K5 (targeting integrin αvβ3)

¹⁸F-FDG ¹⁸F-fluorodeoxyglucose, ¹¹C-MET ¹¹C-methionine, ¹⁸F-FET ¹⁸F-fluoroethyltyrosine, ¹⁸F-FLT ¹⁸F-fluorothymidine, CXCR4 C–X–C motif chemokine receptor 4, ⁶⁸Ga-DOTATOC ⁶⁸Ga-labeled dotatate-D-Phe-Tyr-octreotide, PD-L1 programmed cell death-ligand 1, ⁶⁸Ga-FAPI ⁶⁸Ga-labeled fibroblast activation protein inhibitor, FAP fibroblast activation protein, ¹⁸F-RGD-K5 ¹⁸F-labeled arginine-glycine-aspartic

¹⁸F-Fluorothymidine

¹⁸F-Fluorothymidine (¹⁸F-FLT) is a radiolabeled thymidine analog that can reflect in vivo cell proliferation. ¹⁸F-FLT is less affected by post-treatment inflammatory changes caused by macrophages or monocyte infiltration and therefore expected to be more lymphoma-specific than ¹⁸F-FDG. A previous study compared the performance of interim FLT PET and FDG PET in response assessment in 48 patients with DLBCL (Minamimoto et al. 2016). The interim-FLT PET had a significantly higher PPV (91%) in predicting residual disease than interim FDG PET (range, 42–46%), regardless of the criteria used for FDG PET interpretation. The NPV of interim-FLT PET (94%) was higher than or similar to the NPV of interim-FDG PET (range, 82–95%). A recent multicenter study compared the prognostic value of interim-FLT PET and interim-FDG PET in 92 DLBCL patients (Minamimoto et al. 2021). The multivariate analysis showed that only interim-FLT PET status was an independent predictor for 3- and 5-year PFS. These findings suggest that interim-FLT PET may be more accurate than interim-FDG PET for therapy monitoring and prognostication of DLBCL and possibly other aggressive lymphomas.

⁶⁸Ga-Pentixafor

C–X–C motif chemokine receptor 4 (CXCR4) is a widely studied transmembrane chemokine receptor involved in tumor growth, metastasis, and hematopoietic stem cell/progenitor homing and retention in hematopoietic sites (Jacobson and Weiss 2013). Due to overexpression in many solid and hematological malignancies, CXCR4 is an attractive target for cancer diagnosis and treatment. ⁶⁸Ga-pentixafor is a radiolabeled CXCR4-targeted ligand developed for PET imaging. It is capable to non-invasively visualize CXCR4 expression in a variety of lymphomas, including DLBCL (Wester et al. 2015), lymphoplasmacytic lymphoma (Pan et al. 2020), and mantle cell lymphoma (MCL) (Mayerhoefer et al. 2021). Previous literature reported that ⁶⁸Ga-pentixafor bound to CXCR4 with high affinity and selectivity in mouse models and lymphoma patients (Wester et al. 2015). Another study with 27 NHL patients investigated the CXCR4 expression by ⁶⁸Ga-pentixafor PET, and demonstrated that CXCR4 expression varied in different types of non-Hodgkin’s lymphomas, such as lymphoplasmacytic lymphoma, marginal zone lymphoma, DLBCL, FL, and MCL (Pan et al. 2020). In a very recent study including 22 MCL patients, ⁶⁸Ga-pentixafor PET showed higher detection rates and better tumor-to-background contrast ratios than ¹⁸F-FDG PET (Mayerhoefer et al. 2021). These results indicate that ⁶⁸Ga-pentixafor PET holds potential for the non-invasive assessment of CXCR4 expression and may serve as an intriguing candidate for imaging lymphomas.

⁶⁸Ga-FAPI

Cancer-associated fibroblasts (CAFs) that overexpress fibroblast activation protein (FAP) are abundant in many epithelial carcinomas and hematological neoplasms. Several previous lymphoma studies evaluated PET imaging with radiolabeled FAP inhibitor (FAPI) with promising results (Jin et al. 2021; Wang et al. 2021; Yang et al. 2021). A recent study identified FAP expression with ⁶⁸Ga-FAPI PET in 73 patients with different lymphoma subtypes (Jin et al. 2021) (Fig. 4). Significantly elevated FAP uptake was observed in HL lesions, correlating with the intensity of FAP immunostaining. Aggressive NHL lesions exhibited intense to moderate ⁶⁸Ga-FAPI uptake with moderate-to-strong FAP immunostaining, while indolent NHL lesions showed weak FAP staining and mild to moderate ⁶⁸Ga-FAPI uptake. These encouraging data make ⁶⁸Ga-FAPI PET an alternate imaging method for detecting FAP expression in lymphoma lesions and characterizing lymphoma profiles.

Fig. 4.

⁶⁸Ga-FAPI PET/CT images of various extranodal sites in different subtypes of lymphoma patients. a Primary thyroid Burkitt lymphoma (arrow). b Hodgkin lymphoma with lung involvement (arrow). c Primary gastric diffuse large B-cell lymphoma (DLBCL, arrow). d Ileum DLBCL (arrow). e Left breast DLBCL (arrow). f Left testicle DLBCL (arrow). g Left temporal lobe DLBCL lesion (arrow) after left frontal lymphoma resection (thick arrow).

Adapted from Jin et al. (2021). Reprint permission was obtained

⁸⁹Zr-Rituximab

CD20 is a well-studied transmembrane protein, which increases during the maturation of B-lineage lymphocytes and is lost upon differentiation towards plasma cells, making it a good target for treatment of B-cell lymphoma. Rituximab, an anti-CD20 monoclonal antibody, is incorporated in all first-line and subsequent treatment regimens for most B-cell lymphomas. An earlier study investigated the effectiveness of ⁸⁹Zr-labeled rituximab in five patients with indolent lymphomas scheduled to receive ⁹⁰Y-rituximab radioimmunotherapy (Muylle et al. 2015). This study showed that preloading with unlabeled rituximab had a marked effect on tracer biodistribution, with a higher tumor-to-background ratio compared with no preloading with unlabeled rituximab (Fig. 5). A later study investigated the use of ⁸⁹Zr-rituximab in six patients with relapsed or refractory diffuse large B-cell lymphoma, revealing that tracer uptake corresponded with CD20 expression measured by immunohistochemistry in tumor biopsies (Jauw et al. 2017).

Fig. 5.

¹⁸F-FDG PET/CT and ⁸⁹Zr-rituximab immuno-PET/CT images of a 51-year-old man with follicular lymphoma. ⁸⁹Zr-rituximab immuno-PET/CT images obtained 6 days after injection with and without a preload of unlabelled rituximab show lower tracer uptake in involved lymph nodes with the preload (white arrows), but higher uptake in less accessible visceral lesions (esophagus and stomach; blue arrows) resulting in better tumor targeting.

Adapted from Muylle et al. (2015). Reprint permission was obtained

Furthermore, these two studies also observed uptake of anti-CD20 tracers in patients that had previously received rituximab and relapsed after anti-CD20 therapy. These data validated the feasibility of ⁸⁹Zr-rituximab PET imaging in lymphoma. However, before the routine clinical use of ⁸⁹Zr-rituximab PET imaging, several important issues, such as the influence of different treatment regimens, B-cell lymphoma subtypes, and preload doses of unlabeled rituximab on tracer uptake and clearance, should be addressed.

¹⁸F-FDG PET/MRI in Management of Lymphoma

¹⁸F-FDG PET/MRI has been successfully established as an alternative modality in initial staging of lymphoma. A retrospective study with 27 lymphoma patients suggested that ¹⁸F-FDG PET/MRI has high sensitivity and specificity for nodal involvement (Platzek et al. 2014). Similar results were observed in other studies which reported that ¹⁸F-FDG PET/MRI offers an equivalent whole-body staging examination as compared with ¹⁸F-FDG PET/CT (Atkinson et al. 2016; Heacock et al. 2015; Verhagen et al. 2021). A prospective study compared ¹⁸F-FDG PET/MRI with and without DWI to ¹⁸F-FDG PET/CT in lesion detection in 34 lymphoma patients. The authors observed that in indolent NHLs, which included those with a variable FDG avidity, the addition of DWI improved the sensitivity and accuracy of ¹⁸F-FDG PET/MRI and provided results that are superior to those of ¹⁸F-FDG PET/CT (Giraudo et al. 2016). However, another prospective study with 66 lymphoma patients indicated that DWI could not alter diagnostic accuracy (Afaq et al. 2017). Therefore, the added diagnostic value of DWI still requires further investigation.

To date, there are only a limited number of studies investigating the use of ¹⁸F-FDG PET/MRI in response assessment of lymphoma. In an early pilot study, 9 lymphoma patients who underwent pre- and post-treatment ¹⁸F-FDG PET/MRI were enrolled (Platzek et al. 2013). Despite the small number of patients and lack of follow-up data, the study demonstrated that ¹⁸F-FDG PET/MRI is feasible for response assessment in lymphoma. Another prospective study investigated the value of ¹⁸F-FDG PET/MRI for ultra-early response assessment in 58 lymphoma patients, and indicated that ¹⁸F-FDG PET/MRI can capture treatment-induced changes in glucose metabolism and cell density as early as 48–72 h after treatment initiation (Mayerhoefer et al. 2018). However, the above-mentioned two studies were limited by the lack of comparison between ¹⁸F-FDG PET/MRI and ¹⁸F-FDG PET/CT. In a very recent prospective study involving 24 patients with HL, ¹⁸F-FDG PET/MRI showed a comparable accuracy to ¹⁸F-FDG PET/CT for response evaluation (Verhagen et al. 2021) (Fig. 6). Besides, Deauville grading agreement between ¹⁸F-FDG PET/MRI and ¹⁸F-FDG PET/CT was excellent. These data suggested that ¹⁸F-FDG PET/MRI is a promising alternative to ¹⁸F-FDG PET/CT for response assessment in patients with HL. However, larger cohort studies including different subtypes of lymphoma are required to further illuminate the clinical implications of ¹⁸F-FDG PET/MRI.

Fig. 6.

Pre-treatment and interim ¹⁸F-FDG PET/MRI images of a 14-year-old male with Hodgkin’s lymphoma. Coronal a short tau inversion recovery (STIR), b ¹⁸F-FDG PET, and c ¹⁸F-FDG PET/MRI fused images demonstrate lymphomatous involvement of right supraclavicular and right paratracheal lymph nodes, and a right lung nodule (arrows). Early response assessment following 2 cycles of chemotherapy shows d residual right supraclavicular lymph node on coronal STIR, with no uptake on coronal e ¹⁸F-FDG PET and f fused ¹⁸F-FDG PET/MRI (arrows). The other sites of disease have not been detected.

Adapted from Verhagen et al. (2021). Reprint permission was obtained

Conclusion and Future Perspectives

¹⁸F-FDG PET is the established standard modality for both staging and therapy monitoring of FDG-avid lymphomas. ¹⁸F-FDG PET is highly sensitive for detecting lymphoma lesions and therefore plays a crucial role in current treatment strategies. However, it is noteworthy that the positive predictive value of PET is relatively moderate, with numerous non-malignant causes for ¹⁸F-FDG avidity potentially resulting in false-positive interpretations. Notably, undirected bone marrow biopsy can be safely omitted in patients with HL or DLBCL when ¹⁸F-FDG PET documents the disease involvement. The overall predictive value of interim-PET was exceptionally high in HL, and therefore its use was established earlier in this setting than in other lymphoma subtypes. In aggressive NHL, baseline and interim PET imaging provide essential information for disease prognosis as well. It is also necessary for response assessment at therapy completion since a positive end-of-treatment PET most likely demonstrates treatment failure. In contrast, a negative end-of-treatment PET is indicative of a good prognosis that no additional treatment is required, restricting the use of adjuvant radiotherapy in advanced HL and DLBCL and routine use of PET surveillance.

We anticipate precise imaging to improve our understanding of the dynamic tumor microenvironment and enable optimization of checkpoint inhibitor-based therapy strategies in solid tumors and also lymphoma. With therapeutic advances in lymphoma, novel PET tracers other than ¹⁸F-FDG are necessary to meet the growing demand for precision medicine. Currently, several studies in lymphoma are ongoing using non-¹⁸F-FDG PET tracers, including ⁶⁸Ga-pentixafor for diagnosis and pre-therapy evaluation of CXCR4 expression in lymphoma (NCT03436342) and ⁸⁹Zr-atezolizumab for quantification of programmed cell death-ligand 1 (PD-L1) expression in patients with DLBCL (NCT03850028). In the future, PET molecular imaging with novel tracers may serve as a promising approach for precise evaluation of metabolic change, functional alteration, gene mutation, and histological profile of lymphoma, thus providing opportunities for decoding lymphoma phenotypes and identifying treatment-related mechanisms. Recent advances in imaging hardware, such as the introduction of PET/MRI in clinical use, are also expected to improve our ability to achieve the goals of precise imaging, and aid us to better understand and manage lymphoma with much improved diagnostic, therapeutic, and prognostic outcomes (Civelek et al. 2021).

Authors' Contributions

MT, ACC, and HZ conceived and supervised the work. XZ and HJ drafted the paper. SW, JW, RZ, XH, SQ, SZ supported in gathering study data and made critical revisions. MT, ACC, and HZ made critical revisions and approved the final version.

Funding

This study was partially supported by National Natural Science Foundation of China (81761148029, 81725009, 82030049, 32027802), National Key R&D Program of China (2021YFA110004500, 2021YFE0108300) and Fundamental Research Funds for the Central Universities (2021FZZX002-05).

Data Availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

Code Availability

Not applicable.

Declarations

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Ethics Approval

Patients included in this work were from a previous study which has been approved by the Institutional Review Board of The Second Affiliated Hospital of Zhejiang University School of Medicine (Approval No. 2019-350).

Consent to Participate

Informed consent was obtained from individual participant included in this study.

Consent to Publication

Not applicable.